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Introduction: Continuous measures of amyloid burden as measured by positron emission tomography (PET) are being used increasingly to stage Alzheimer's disease (AD). This study examined whether cerebrospinal fluid (CSF) and plasma amyloid beta (Aβ)42/Aβ40 could predict continuous values for amyloid PET., Methods: CSF Aβ42 and Aβ40 were measured with automated immunoassays. Plasma Aβ42 and Aβ40 were measured with an immunoprecipitation-mass spectrometry assay. Amyloid PET was performed with Pittsburgh compound B (PiB). The continuous relationships of CSF and plasma Aβ42/Aβ40 with amyloid PET burden were modeled., Results: Most participants were cognitively normal (427 of 491 [87%]) and the mean age was 69.0 ± 8.8 years. CSF Aβ42/Aβ40 predicted amyloid PET burden until a relatively high level of amyloid accumulation (69.8 Centiloids), whereas plasma Aβ42/Aβ40 predicted amyloid PET burden until a lower level (33.4 Centiloids)., Discussion: CSF Aβ42/Aβ40 predicts the continuous level of amyloid plaque burden over a wider range than plasma Aβ42/Aβ40 and may be useful in AD staging., Highlights: Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/Aβ40 predicts continuous amyloid positron emission tomography (PET) values up to a relatively high burden.Plasma Aβ42/Aβ40 is a comparatively dichotomous measure of brain amyloidosis.Models can predict regional amyloid PET burden based on CSF Aβ42/Aβ40.CSF Aβ42/Aβ40 may be useful in staging AD., Competing Interests: Julie K. Wisch, Anna H. Boerwinkle, Patrick H. Luckett, Yan Li, Rachel L. Henson, and Beau M. Ances report no disclosures. Brian A. Gordon receives research support from Eli Lilly and Avid Radiopharmaceuticals. James G. Bollinger and Vitaliy Ovod have submitted the US provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition” as co‐inventors and may receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. Tim West, Mathew R. Meyer, and Kristopher M. Kirmess are employees of C2N Diagnostics, which offers the plasma Aβ42/Aβ40 assay used in this article. Tammie L.S. Benzinger has consulted on clinical trials with Biogen, Roche, Janssen, and Eli Lilly. She receives research support from Eli Lilly and Avid Radiopharmaceuticals. Neither John C. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Randall J. Bateman co‐founded C2N Diagnostics, which offers the PrecivityAD blood test. Washington University and Randall J. Bateman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. Randall J. Bateman has received research funding from Avid Radiopharmaceuticals, Janssen, Roche/Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb, and Novartis. Randall J. Bateman serves on the Roche Gantenerumab Steering Committee as an unpaid member. Suzanne E. Schindler has analyzed data provided by C2N Diagnostics to Washington University at no cost. She has not received any research funding or personal compensation from C2N Diagnostics or any other for‐profit organization. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background and Purpose: Automated volumetric analysis of structural MR imaging allows quantitative assessment of brain atrophy in neurodegenerative disorders. We compared the brain segmentation performance of the AI-Rad Companion brain MR imaging software against an in-house FreeSurfer 7.1.1/Individual Longitudinal Participant pipeline., Materials and Methods: T1-weighted images of 45 participants with de novo memory symptoms were selected from the OASIS-4 database and analyzed through the AI-Rad Companion brain MR imaging tool and the FreeSurfer 7.1.1/Individual Longitudinal Participant pipeline. Correlation, agreement, and consistency between the 2 tools were compared among the absolute, normalized, and standardized volumes. Final reports generated by each tool were used to compare the rates of detection of abnormality and the compatibility of radiologic impressions made using each tool, compared with the clinical diagnoses., Results: We observed strong correlation, moderate consistency, and poor agreement between absolute volumes of the main cortical lobes and subcortical structures measured by the AI-Rad Companion brain MR imaging tool compared with FreeSurfer. The strength of the correlations increased after normalizing the measurements to the total intracranial volume. Standardized measurements differed significantly between the 2 tools, likely owing to differences in the normative data sets used to calibrate each tool. When considering the FreeSurfer 7.1.1/Individual Longitudinal Participant pipeline as a reference standard, the AI-Rad Companion brain MR imaging tool had a specificity of 90.6%-100% and a sensitivity of 64.3%-100% in detecting volumetric abnormalities. There was no difference between the rate of compatibility of radiologic and clinical impressions when using the 2 tools., Conclusions: The AI-Rad Companion brain MR imaging tool reliably detects atrophy in cortical and subcortical regions implicated in the differential diagnosis of dementia., (© 2023 by American Journal of Neuroradiology.)

The commonalities and differences in cell-type-specific pathways that lead to Alzheimer disease (AD) and Parkinson disease (PD) remain unknown. Here, we performed a single-nucleus transcriptome comparison of control, AD and PD striata. We describe three astrocyte subpopulations shared across different brain regions and evolutionarily conserved between humans and mice. We reveal common features between AD and PD astrocytes and regional differences that contribute toward amyloid pathology and neurodegeneration. In contrast, we found that transcriptomic changes in microglia are largely unique to each disorder. Our analysis identified a population of activated microglia that shared molecular signatures with murine disease-associated microglia (DAM) as well as disease-associated and regional differences in microglia transcriptomic changes linking microglia to disease-specific amyloid pathology, tauopathy and neuronal death. Finally, we delineate undescribed subpopulations of medium spiny neurons (MSNs) in the striatum and provide neuronal transcriptomic profiles suggesting disease-specific changes and selective neuronal vulnerability., Competing Interests: Competing interests The authors declare no competing interests. S.Y. is an employee of Daiichi Sankyo.

A standardized approach to acquiring amyloid PET images increases their value as disease and drug response biomarkers. Most 18 F PET amyloid brain scans often are assessed only visually (per regulatory labels), with a binary decision indicating the presence or absence of Alzheimer disease amyloid pathology. Minimizing technical variance allows precise, quantitative SUV ratios (SUVRs) for early detection of β-amyloid plaques and allows the effectiveness of antiamyloid treatments to be assessed with serial studies. Methods: The Quantitative Imaging Biomarkers Alliance amyloid PET biomarker committee developed and validated a profile to characterize and reduce the variability of SUVRs, increasing statistical power for these assessments. Results: On achieving conformance, sites can justify a claim that brain amyloid burden reflected by the SUVR is measurable to a within-subject coefficient of variation of no more than 1.94% when the same radiopharmaceutical, scanner, acquisition, and analysis protocols are used. Conclusion: This overview explains the claim, requirements, barriers, and potential future developments of the profile to achieve precision in clinical and research amyloid PET imaging., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Off-target binding of [ 18 F]flortaucipir (FTP) can complicate quantitative PET analyses. An underdiscussed off-target region is the skull. Here, we characterize how often FTP skull binding occurs, its influence on estimates of Alzheimer disease pathology, its potential drivers, and whether skull uptake is a stable feature across time and tracers. Methods: In 313 cognitively normal and mildly impaired participants, CT scans were used to define a skull mask. This mask was used to quantify FTP skull uptake. Skull uptake of the amyloid-β PET tracers [ 18 F]florbetapir and [ 11 C]Pittsburgh compound B ( n = 152) was also assessed. Gaussian mixture modeling defined abnormal levels of skull binding for each tracer. We examined the relationship of continuous bone uptake to known off-target binding in the basal ganglia and choroid plexus as well as skull density measured from the CT. Finally, we examined the confounding effect of skull binding on pathologic quantification. Results: We found that 50 of 313 (∼16%) FTP scans had high levels of skull signal. Most were female ( n = 41, 82%), and in women, lower skull density was related to higher FTP skull signal. Visual reads by a neuroradiologist revealed a significant relationship with hyperostosis; however, only 21% of women with high skull binding were diagnosed with hyperostosis. FTP skull signal did not substantially correlate with other known off-target regions. Skull uptake was consistent over longitudinal FTP scans and across tracers. In amyloid-β-negative, but not -positive, individuals, FTP skull binding impacted quantitative estimates in temporal regions. Conclusion: FTP skull binding is a stable, participant-specific phenomenon and is unrelated to known off-target regions. Effects were found primarily in women and were partially related to lower bone density. The presence of [ 11 C]Pittsburgh compound B skull binding suggests that defluorination does not fully explain FTP skull signal. As signal in skull bone can impact quantitative analyses and differs across sex, it should be explicitly addressed in studies of aging and Alzheimer disease., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Estimates of 'brain-predicted age' quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD) but has not been well explored in presymptomatic AD. Prior studies have typically modeled BAG with structural MRI, but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored., Methods: We trained three models to predict age from FC, structural (S), or multimodal MRI (S+FC) in 390 amyloid-negative cognitively normal (CN/A-) participants (18-89 years old). In independent samples of 144 CN/A-, 154 CN/A+, and 154 cognitively impaired (CI; CDR > 0) participants, we tested relationships between BAG and AD biomarkers of amyloid and tau, as well as a global cognitive composite., Results: All models predicted age in the control training set, with the multimodal model outperforming the unimodal models. All three BAG estimates were significantly elevated in CI compared to controls. FC-BAG was significantly reduced in CN/A+ participants compared to CN/A-. In CI participants only, elevated S-BAG and S+FC BAG were associated with more advanced AD pathology and lower cognitive performance., Conclusions: Both FC-BAG and S-BAG are elevated in CI participants. However, FC and structural MRI also capture complementary signals. Specifically, FC-BAG may capture a unique biphasic response to presymptomatic AD pathology, while S-BAG may capture pathological progression and cognitive decline in the symptomatic stage. A multimodal age-prediction model improves sensitivity to healthy age differences., Funding: This work was supported by the National Institutes of Health (P01-AG026276, P01- AG03991, P30-AG066444, 5-R01-AG052550, 5-R01-AG057680, 1-R01-AG067505, 1S10RR022984-01A1, and U19-AG032438), the BrightFocus Foundation (A2022014F), and the Alzheimer's Association (SG-20-690363-DIAN)., Competing Interests: PM, BG, PL, RP, RA, HM, GN, JM, BA No competing interests declared, TB received doses (AV45, AV1451) and partial support for PET scanning through an investigator-initiated research grant awarded to Washington University from Avid Radiopharmaceuticals (a wholly-owned subsidiary of Eli Lilly and Company). The author received consulting fees from Eisai, Siemens, and received payment for Biogen speaker's bureau. Tammie Benzinger acts as site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Jaansen and Roche. The author has no other competing interests to declare, CC has received research support from Biogen, EISAI, Alector and Parabon. Carlos Cruchaga is a member of the advisory board of Vivid Genetics, Circular Genomics and Alector. The author has no other competing interests to declare, AF has received consulting fees from DiamiR and Siemens Healthcare Diagnostics Inc and has received consulting fees for participation on Scientific advisory boards for Roche Diagnostics, Genentech and Diadem. The author has received travel support for in-person attendance at ABC-DS Meeting/Retreat and travel support/honorarium for in-person attendance at Scientific Advisory Board meeting for South Texas Alzheimer's Disease Research Center (ADRC). The author has no other competing interests to declare, JH has received consulting fees from Roche and Parabon Nanolabs. The author has no other competing interests to declare, SS received personal honoraria for presenting lectures from the University of Wisconsin, St. Luke's Hospital, Houston Methodist Medical Center, personal Honoraria for serving on the Alzheimer Disease Center Clinical Task Force from University of Washington and personal honoraria for serving on the National Centralized Repository for Alzheimer's Disease biospecimen review committee from University of Indiana. The author received travel support from National Institute on Aging grant R01AG070941, and is a board member of the Greater Missouri Alzheimer's Association. The author received plasma Ab42/Ab40 data provided by C2N Diagnostics at no cost. No payments/research funding was provided by C2N Diagnostics. No gifts/financial incentives of any kind have been provided to Dr. Schindler by C2N Diagnostics. The author has no other competing interests to declare, GD received fees for consulting and for acting as Dementia Topic Editor from DynaMed (EBSCO Health) and received fees for consulting, grant writing / implementation Parabon Nanonlabs. The author received payment for CME Content development from PeerView Media and Continuing Education Inc, payment for educational content development and focus group participation from Eli Lilly Co, and payment for continuum manuscript authorship from the American Academy of Neurology. The author received payment for expert testimony in the case of Wernicke encephalopathy from Barrow Law. Gregory S Day acts as Clinical Director for Anti-NMDA Receptor Encephalitis Foundation, Inc. The author has stock holdings at ANI Pharmaceuticals, Inc and stock options at Parabon Nanolabs. The author has no other competing interests to declare, MF received grants from AbbVie, Eisai, Novartis, ADCS Posiphen, Genentech and Suven Life Sciences (no grant numbers available). The author has received consulting fees from Artery Therapeutics, Avanir, Biogen, Cyclo Therapeutics, Green Valley, Lexeo, McClena, Nervive, Oligomerix, Pinteon, Prothena, Vaxinity, Athira, AZTherapies, Cognition Therapeutics, Gemvax, Ionis, Longeveron, Merck, Neurotrope Biosciences, Otsuka, Proclara and SToP-AD. The author has no other competing interests to declare, received funding and non-financial support for the DIAN-TU-001 trial from Avid Radiopharmaceuticals, and funding for the DIAN-TU-001 trial from Janssen, Hoffman La-Roche/Genentech, Eli Lilly & Co., Eisai, Biogen, AbbVie and Bristol Meyer Squibb. The author has equity ownership interest in C2N Diagnostics and receives royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. The author received International Conference Lecture Honoraria from Korean Dementia Association and Conference Lecture Honoraria from Weill Cornell Medical College. The author received support for travel expenses from Alzheimer's Association Roundtable and Duke Margolis Alzheimer's Roundtable. The author participates on an unpaid Advisory Board for Roche Gantenerumab Steering Committee and Biogen - Combination Therapy for Alzheimer's Disease, and participates on an unpaid Scientific Advisory Board for UK Dementia Research Institute at University College London and Stanford University, Next Generation Translational Proteomics for Alzheimer's and Related Dementias. The author receives an income from C2N Diagnostics for serving on the scientific advisory board. The author has received equipment and materials from Avid Radiopharmaceuticals, Eli Lilly & Co, Hoffman La-Roche, Eisai and Janssen. Unrelated to this article, Randall Bateman serves as principal investigator of the DIAN-TU, which is supported by the Alzheimer's Association, GHR Foundation, an anonymous organization and the DIAN-TU Pharma Consortium (Active: Eli Lilly and Company/Avid Radiopharmaceuticals, F. Hoffman-La Roche/Genentech, Biogen, Eisai, and Janssen. Previous: Abbvie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, and United Neuroscience). In addition, in-kind support has been received from CogState and Signant Health. Unrelated to this article Randall Bateman has submitted the US nonprovisional patent application "Methods for Measuring the Metabolism of CNS Derived Biomolecules In Vivo" and provisional patent application "Plasma Based Methods for Detecting CNS Amyloid Deposition". The author has no other competing interests to declare, RB has received consulting fees from Barcelona Brain Research Center BBRC and Native Alzheimer Disease-Related Resource Center in Minority Aging Research, Ext Adv Board. The author has received payment or honoraria for lectures from Montefiore Grand Rounds, NY and Tetra-Inst ADRC seminar series, Grand Rds, NY. The author has participated on the Research Strategy Council for the Cure Alzheimer's Fund, the Diverse VCID Observational Study Monitoring Board and the LEADS Advisory Board, Indiana University. The author has no other competing interests to declare, (© 2023, Millar et al.)

Background: 18F-flortaucipir PET received FDA approval to visualize aggregated neurofibrillary tangles (NFTs) in brains of adult patients with cognitive impairment being evaluated for Alzheimer's disease (AD). However, manufacturer's guidelines for visual interpretation of 18F-flortaucipir PET differ from how 18F-flortaucipir PET has been measured in research settings using standardized uptake value ratios (SUVRs). How visual interpretation relates to 18F-flortaucipir PET SUVR, cerebrospinal fluid (CSF) biomarkers, or longitudinal clinical assessment is not well understood., Objective: We compare various diagnostic methods in participants enrolled in longitudinal observational studies of aging and memory (n = 189, 23 were cognitively impaired)., Methods: Participants had tau PET, Aβ PET, MRI, and clinical and cognitive evaluation within 18 months (n = 189); the majority (n = 144) also underwent lumbar puncture. Two radiologists followed manufacturer's guidelines for 18F-flortaucipir PET visual interpretation., Results: Visual interpretation had high agreement with SUVR (98.4%)and moderate agreement with CSF p-tau181 (86.1%). Two participants demonstrated 18F-flortaucipir uptake from meningiomas. Visual interpretation could not predict follow-up clinical assessment in 9.52% of cases., Conclusion: Visual interpretation was highly consistent with SUVR (discordant participants had hemorrhagic infarcts or occipital-predominant AD NFT deposition) and moderately consistent with CSF p-tau181 (discordant participants had AD pathophysiology not detectable on tau PET). However, close association between AD NFT deposition and clinical onset in group-level studies does not necessarily hold at the individual level, with discrepancies arising from atypical AD, vascular dementia, or frontotemporal dementia. A better understanding of relationships across imaging, CSF biomarkers, and clinical assessment is needed to provide appropriate diagnoses for these individuals.

Introduction: As the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others., Methods: We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation., Results: Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors., Discussion: These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression., (© 2022 the Alzheimer's Association.)

Background: Multiple sclerosis (MS) is a prototype neuroinflammatory disorder with increasingly recognized role for neurodegeneration. Most first-line treatments cannot prevent the progression of neurodegeneration and the resultant disability. Interventions can improve symptoms of MS and might provide insights into the underlying pathology., Objective: To investigate the effect of intermittent caloric restriction on neuroimaging markers of MS., Methods: We randomized ten participants with relapsing remitting MS to either a 12-week intermittent calorie restriction (iCR) diet (n = 5) or control (n = 5). Cortical thickness and volumes were measured through FreeSurfer, cortical perfusion was measured by arterial spin labeling and neuroinflammation through diffusion basis spectrum imaging., Results: After 12 weeks of iCR, brain volume increased in the left superior and inferior parietal gyri (p: 0.050 and 0.049, respectively) and the banks of the superior temporal sulcus (p: 0.01). Similarly in the iCR group, cortical thickness improved in the bilateral medial orbitofrontal gyri (p: 0.04 and 0.05 in right and left, respectively), the left superior temporal gyrus (p: 0.03), and the frontal pole (p: 0.008) among others. Cerebral perfusion decreased in the bilateral fusiform gyri (p: 0.047 and 0.02 in right and left, respectively) and increased in the bilateral deep anterior white matter (p: 0.03 and 0.013 in right and left, respectively). Neuroinflammation, demonstrated through hindered and restricted water fractions (HF and RF), decreased in the left optic tract (HF p: 0.02), and the right extreme capsule (RF p: 0.007 and HF p: 0.003)., Conclusion: These pilot data suggest therapeutic effects of iCR in improving cortical volume and thickness and mitigating neuroinflammation in midlife adults with MS.

Background: Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people., Methods: In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated., Findings: 192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p<0·0001) and in people with Down syndrome (n=32; r=-0·801; p<0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). APOE ɛ4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset -23·0 vs -17·5; p=0·0002). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome., Interpretation: Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer's disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome., Funding: The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development., Competing Interests: Declaration of interests TLSB has received funding from the National Institutes of Health and Siemens; has a licensing agreement from Sora Neuroscience but receives no financial compensation; has received honoraria for lectures, presentations, speakers bureaus, or educational events from Biogen and Eisai Genetech; has served on a scientific advisory board for Biogen; holds a leadership role in other board, society, committee, or advocacy groups for the American Society for Neuroradiology (unpaid) and Quantitative Imaging Biomarkers Alliance (unpaid); and has participated in radiopharmaceuticals and technology transfers with Avid Radiopharmaceuticals, Cerveau, and LMI. EMD received support from the National Institute on Aging, an anonymous organisation, the GHR Foundation, the DIAN-TU Pharma Consortium, Eli Lilly, and F Hoffmann La-Roche; has received speaking fees from Eisai and Eli Lilly; and is on the data safety and monitoring board and advisory boards of Eli Lilly, Alector, and Alzamend. WS has received research funding from the National Institute on Aging and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. JPC serves as the chair of the American Neurological Association Dementia and Aging Special Interest Group and is on the medical advisory board of Humana Healthcare. CC has received consulting fees from GSK and Alector. AMF reports personal fees from Roche Diagnostics, Araclon/Grifols, and Diadem Research and grants from Biogen, outside the submitted work. BLH has received research funding from Roche and Autism Speaks; receives royalties from Oxford University Press for book publications; and is the chair of the data safety and monitoring board for the Department of Defense-funded study, “Comparative Effectiveness of EIBI and MABA”. BTC receives research funding from the National Institutes of Health. EH receives research funding from the National Institutes of Health and the BrightFocus Foundation. FL is supported by grants from the National Institute on Aging. HDR has received funding from the National Institutes of Health and is on the scientific advisory committee for the Hereditary Disease Foundation. JHL has received research funding from the National Institutes of Health and the National Institute on Aging. RJP receives research funding from the National Institutes of Health and the National Institute on Aging. RJB is Director of DIAN-TU and Principal Investigator of DIAN-TU001; receives research support from the National Institute on Aging of the National Institutes of Health, DIAN-TU trial pharmaceutical partners (Eli Lilly, F Hoffmann-La Roche, Janssen, Eisai, Biogen, and Avid Radiopharmaceuticals), the Alzheimer's Association, the GHR Foundation, an anonymous organisation, the DIAN-TU Pharma Consortium (active members Biogen, Eisai, Eli Lilly, Janssen, and F Hoffmann-La Roche/Genentech; previous members AbbVie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, and United Neuroscience), the NfL Consortium (F Hoffmann-La Roche, Biogen, AbbVie, and Bristol Myers Squibb), and the Tau SILK Consortium (Eli Lilly, Biogen, and AbbVie); has been an invited speaker and consultant for AC Immune, F Hoffmann-La Roche, the Korean Dementia Association, the American Neurological Association, and Janssen; has been a consultant for Amgen, F Hoffmann-La Roche, and Eisai; and has submitted the US non-provisional patent application named “Methods for Measuring the Metabolism of CNS Derived Biomolecules In Vivo” and a provisional patent application named “Plasma Based Methods for Detecting CNS Amyloid Deposition”. BMA receives research funding from the National Institutes of Health and has a patent pending (“Markers of Neurotoxicity in CAR T patients”). MSR has received consulting fees from AC Immune, Embic, and Keystone Bio and has received research support from the National Institutes of Health, Avid, Baxter, Eisai, Elan, Genentech, Janssen, Lilly, Merck, and Roche. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Alzheimer's disease (AD) and vascular contributions to cognitive impairment and dementia (VCID) pathologies coexist in patients with cognitive impairment. Abnormal amyloid beta (Aβ) deposition is the hallmark pathologic biomarker for AD. Neuroinflammation may be a pathophysiological mechanism in both AD and VCID. In this study, we aimed to understand the role of neuroinflammation and Aβ deposition in white matter hyperintensities (WMH) progression and cognitive decline over a decade in patients with mixed AD and VCID pathologies., Methods: Twenty-four elderly participants (median [interquartile range] age 78 [64.8, 83] years old, 14 female) were recruited from the Knight Alzheimer Disease Research Center. 11 C-PK11195 standard uptake value ratio (SUVR) and 11 C-PiB mean cortical binding potential (MCBP) were used to evaluate neuroinflammation and Aβ deposition in-vivo, respectively. Fluid-attenuated inversion recovery MR images were acquired to obtain baseline WMH volume and its progression over 11.5 years. Composite cognitive scores (global, processing speed and memory) were computed at baseline and follow-up over 7.5 years. Multiple linear regression models evaluated the association between PET biomarkers ( 11 C-PK11195 SUVR and 11 C-PiB MCBP) and baseline WMH volume and cognitive function. Moreover, linear mixed-effects models evaluated whether PET biomarkers predicted greater WMH progression or cognitive decline over a decade., Results: Fifteen participants (62.5%) had mixed AD (positive PiB) and VCID (at least one vascular risk factor) pathologies. Elevated 11 C-PK11195 SUVR, but not 11 C-PiB MCBP, was associated with greater baseline WMH volume and predicted greater WMH progression. Elevated 11 C-PiB MCBP was associated with baseline memory and global cognition. Elevated 11 C-PK11195 SUVR and elevated 11 C-PiB MCBP independently predicted greater global cognition and processing speed declines. No association was found between 11 C-PK11195 SUVR and 11 C-PiB MCBP., Conclusions: Neuroinflammation and Aβ deposition may represent two distinct pathophysiological pathways, and both independently contributed to the progression of cognitive impairment in mixed AD and VCID pathologies. Neuroinflammation, but not Aβ deposition, contributed to WMH volume and progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Alzheimer's disease biomarkers are widely accepted as surrogate markers of underlying neuropathological changes. However, few studies have evaluated whether preclinical Alzheimer's disease biomarkers predict Alzheimer's neuropathology at autopsy. We sought to determine whether amyloid PET imaging or CSF biomarkers accurately predict cognitive outcomes and Alzheimer's disease neuropathological findings. This study included 720 participants, 42-91 years of age, who were enrolled in longitudinal studies of memory and aging in the Washington University Knight Alzheimer Disease Research Center and were cognitively normal at baseline, underwent amyloid PET imaging and/or CSF collection within 1 year of baseline clinical assessment, and had subsequent clinical follow-up. Cognitive status was assessed longitudinally by Clinical Dementia Rating®. Biomarker status was assessed using predefined cut-offs for amyloid PET imaging or CSF p-tau181/amyloid-β42. Subsequently, 57 participants died and underwent neuropathologic examination. Alzheimer's disease neuropathological changes were assessed using standard criteria. We assessed the predictive value of Alzheimer's disease biomarker status on progression to cognitive impairment and for presence of Alzheimer's disease neuropathological changes. Among cognitively normal participants with positive biomarkers, 34.4% developed cognitive impairment (Clinical Dementia Rating > 0) as compared to 8.4% of those with negative biomarkers. Cox proportional hazards modelling indicated that preclinical Alzheimer's disease biomarker status, APOE ɛ4 carrier status, polygenic risk score and centred age influenced risk of developing cognitive impairment. Among autopsied participants, 90.9% of biomarker-positive participants and 8.6% of biomarker-negative participants had Alzheimer's disease neuropathological changes. Sensitivity was 87.0%, specificity 94.1%, positive predictive value 90.9% and negative predictive value 91.4% for detection of Alzheimer's disease neuropathological changes by preclinical biomarkers. Single CSF and amyloid PET baseline biomarkers were also predictive of Alzheimer's disease neuropathological changes, as well as Thal phase and Braak stage of pathology at autopsy. Biomarker-negative participants who developed cognitive impairment were more likely to exhibit non-Alzheimer's disease pathology at autopsy. The detection of preclinical Alzheimer's disease biomarkers is strongly predictive of future cognitive impairment and accurately predicts presence of Alzheimer's disease neuropathology at autopsy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The temporal evolutions and relative orderings of Alzheimer disease biomarkers, including CSF amyloid-β42 (Aβ42), Aβ40, total tau (Tau) and phosphorylated tau181 (pTau181), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar amyloid-β with PET using the 11C-Pittsburgh Compound-B (PiB), MRI-based hippocampal volume and cortical thickness and cognition have been hypothesized but not yet fully tested with longitudinal data for all major biomarker modalities among cognitively normal individuals across the adult lifespan starting from 18 years. By leveraging a large harmonized database from 8 biomarker studies with longitudinal data from 2609 participants in cognition, 873 in MRI biomarkers, 519 in PET PiB imaging and 475 in CSF biomarkers for a median follow-up of 5-6 years, we estimated the longitudinal trajectories of all major Alzheimer disease biomarkers as functions of baseline age that spanned from 18 to 103 years, located the baseline age window at which the longitudinal rates of change accelerated and further examined possible modifying effects of apolipoprotein E (APOE) genotype. We observed that participants 18-45 years at baseline exhibited learning effects on cognition and unexpected directions of change on CSF and PiB biomarkers. The earliest acceleration of longitudinal change occurred for CSF Aβ42 and Aβ42/Aβ40 ratio (with an increase) and for Tau, and pTau181 (with a decrease) at the next baseline age interval of 45-50 years, followed by an accelerated increase for PiB SUVR at the baseline age of 50-55 years and an accelerated decrease for hippocampal volume at the baseline age of 55-60 years and finally by an accelerated decline for cortical thickness and cognition at the baseline age of 65-70 years. Another acceleration in the rate of change occurred at the baseline age of 65-70 years for Aβ42/Aβ40 ratio, Tau, pTau181, PiB SUVR and hippocampal volume. Accelerated declines in hippocampal volume and cognition continued after 70 years. For participants 18-45 years at baseline, significant increases in Aβ42 and Aβ42/Aβ40 ratio and decreases in PiB SUVR occurred in APOE ɛ4 non-carriers but not carriers. After age 45 years, APOE ɛ4 carriers had greater magnitudes than non-carriers in the rates of change for all CSF biomarkers, PiB SUVR and cognition. Our results characterize the temporal evolutions and relative orderings of Alzheimer disease biomarkers across the adult lifespan and the modification effect of APOE ɛ4. These findings may better inform the design of prevention trials on Alzheimer disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Multiple positron emission tomography (PET) tracers are available for amyloid imaging, posing a significant challenge to consensus interpretation and quantitative analysis. We accordingly developed and validated a deep learning model as a harmonization strategy., Method: A Residual Inception Encoder-Decoder Neural Network was developed to harmonize images between amyloid PET image pairs made with Pittsburgh Compound-B and florbetapir tracers. The model was trained using a dataset with 92 subjects with 10-fold cross validation and its generalizability was further examined using an independent external dataset of 46 subjects., Results: Significantly stronger between-tracer correlations (P < .001) were observed after harmonization for both global amyloid burden indices and voxel-wise measurements in the training cohort and the external testing cohort., Discussion: We proposed and validated a novel encoder-decoder based deep model to harmonize amyloid PET imaging data from different tracers. Further investigation is ongoing to improve the model and apply to additional tracers., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The apolipoprotein E ( APOE ) ε4 allele is strongly linked with cerebral β-amyloidosis, but its relationship with tauopathy is less established. We investigated the relationship between APOE ε4 carrier status, regional amyloid-β (Aβ), magnetic resonance imaging (MRI) volumetrics, tau positron emission tomography (PET), APOE messenger RNA (mRNA) expression maps, and cerebrospinal fluid phosphorylated tau (CSF ptau 181 ). Three hundred fifty participants underwent imaging, and 270 had ptau 181 . We used computational models to evaluate the main effect of APOE ε4 carrier status on regional neuroimaging values and then the interaction of ε4 status and global Aβ on regional tau PET and brain volumes as well as CSF ptau 181 . Separately, we also examined the additional interactive influence of sex. We found that, for the same degree of Aβ burden, APOE ε4 carriers showed greater tau PET signal relative to noncarriers in temporal regions, but no interaction was present for MRI volumes or CSF ptau 181 . This potentiation of tau aggregation irrespective of sex occurred in brain regions with high APOE mRNA expression, suggesting local vulnerabilities to tauopathy. There were greater effects of APOE genotype in females, although the interactive sex effects did not strongly mirror mRNA expression. Pathology is not homogeneously expressed throughout the brain but mirrors underlying biological patterns such as gene expression.

Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5-fold, and solanezumab was increased 4-fold. We evaluated to what extent mid-trial dose increases produced a dose-dependent treatment effect., Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low- and high-dose treatment effects in clinical, cognitive, and biomarker outcomes., Results: Both gantenerumab and solanezumab demonstrated dose-dependent treatment effects (significant for gantenerumab, non-significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose-dependent treatment effects were observed in clinical or cognitive outcomes., Conclusions: Mid-trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases., Highlights: We evaluated the dose-dependent treatment effect of two different amyloid-specific immunotherapies.Dose-dependent treatment effects were observed in some biomarkers.No dose-dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations., Competing Interests: Guoqiao Wang, PhD, is the biostatistics core co‐leader for the DIAN‐TU. He reports serving on a Data Safety Committee for Eli Lilly and Company and as a statistical consultant for Alector. Eric McDade, DO, is the Associate Director of the DIAN‐TU. He reports serving on a Data Safety Committee for Eli Lilly and Company and Alector; as a scientific consultant for Eisai and Eli Lilly and Company; receiving institutional grant support from Eli Lilly and Company, F. Hoffmann‐La Roche, Ltd., and Janssen. Anne M. Fagan, PhD, is the Biomarker Core Leader of the DIAN‐TU. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and DiademRes and also consults for DiamiR and Siemens Healthcare Diagnostics, Inc. Tammie L.S. Benzinger, MD, PhD, has investigator‐initiated research funding from the NIH, the Alzheimer's Association, the Barnes‐Jewish Hospital Foundation, and Avid Radiopharmaceuticals. Dr. Benzinger participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Jaansen, and F. Hoffmann‐La Roche, Ltd. She serves as an unpaid consultant to Eisai and Siemens. She is on the Speaker's Bureau for Biogen. David B. Clifford, MD, is Medical Director of the DIAN‐TU and serves as scientific consultant to Biogen, Takeda, Millennium, Genzyme, Amgen, F. Hoffmann‐La Roche, Ltd./Genentech, Glaxo Smith Kline, Serono, Inhibikase, Dr Reddy's Lab, Bristol Myers Squibb, Atara, Mitsubishi Tanabe, Excision BioTherapeutics, Up to Date, and Wolters Kluwer; on DSMB/Data Monitoring Committees for Genentech/ F. Hoffmann‐La Roche, Ltd., Wave, EMD Serono, Shire, Pfizer, Sanofi; does legal consulting: Cook County, State Farm, Wilke & Wilke PC, Shevlin Smith, Sal Indomenico PC. He receives research support from NIH NINDS, NIMH, NIAID, NCATS, and NIA. Andrew J. Aschenbrenner, PhD, has served as a consultant for Biogen Inc, and H. Lundbeck HS. Jason Hassenstab, PhD, is a paid consultant for F. Hoffmann‐La Roche, Ltd., Takeda, and Lundbeck, and is on the Data Safety and Monitoring Board for Eisai. Catherine Mummery, MD, is a consultant for Biogen. Mario Masellis, MD, is a consultant to Arkuda Therapeutics, Ionis, and Alector and receives research funding from F. Hoffmann‐La Roche, Ltd., Novartis, and Alector. Serge Gauthier, MD, FRCPC, is a member of the Scientific Advisory Board for Alzheon, Biogen, Eli Lilly and Company, and TauRx and a member of the Data Safety Monitoring Board for ADCS, ATRI, and Banner Health. Scott Andersen, MS; Karen C. Holdridge, MPH; Saptarshi Chatterjee, PhD; John R. Sims, MD; and Roy Yaari, MD are employees and shareholders of Eli Lilly and Company. Randall J. Bateman, MD, is the Director of the DIAN‐TU and Principal Investigator of the DIAN‐TU‐001. He receives research support from the National Institute on Aging of the National Institutes of Health, DIAN‐TU Trial Pharmaceutical Partners (Eli Lilly and Company, F. Hoffman‐La Roche, Ltd., and Avid Radiopharmaceuticals), Alzheimer's Association, GHR Foundation, Anonymous Organization, DIAN‐TU Pharma Consortium (Active: Biogen, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann‐La Roche, Ltd./Genentech. Previous: AbbVie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, United Neuroscience). He has been an invited speaker for Novartis and serves on the Advisory Board for F. Hoffman La Roche, Ltd. Barbara A. Wendelberger, PhD; Susan L. Mills BS; Anna M. Santacruz BS; Kelley A. Coalier, MS; Brian A. Gordon, PhD; Jorge J. Libre‐Guerra, MD; Austin McCullough; Nelly Joseph‐Mathurin, PhD; Charlie Chen; Yan Li, PhD; Chengji Xiong, PhD, have no conflicts of interest to disclose. Paul Delmar, Geoffrey A. Kerchner, Tobias Bittner, and Carsten Hofmann are full‐time employees of F. Hoffmann‐La Roche, Ltd. and own stock in F. Hoffmann‐La Roche, Ltd. David Holtzman, MD, the prior Department Head of Neurology where the research was conducted, is an inventor on patents for solanezumab, which was tested in the DIAN‐TU‐001 clinical trial. If solanezumab is approved as a treatment for AD or dominantly inherited AD, Washington University and Dr. Holtzman will receive part of the net sales of solanezumab from Eli Lilly and Company, which has licensed patents related to solanezumab from Washington University. All the other authors reported no conflicts of interest. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Purpose: Deep learning-based algorithms have been shown to be able to automatically detect and segment brain metastases (BMs) in magnetic resonance imaging, mostly based on single-institutional data sets. This work aimed to investigate the use of deep convolutional neural networks (DCNN) for BM detection and segmentation on a highly heterogeneous multi-institutional data set., Methods and Materials: A total of 407 patients from 98 institutions were randomly split into 326 patients from 78 institutions for training/validation and 81 patients from 20 institutions for unbiased testing. The data set contained T1-weighted gadolinium and T2-weighted fluid-attenuated inversion recovery magnetic resonance imaging acquired on diverse scanners using different pulse sequences and various acquisition parameters. Several variants of 3-dimensional U-Net based DCNN models were trained and tuned using 5-fold cross validation on the training set. Performances of different models were compared based on Dice similarity coefficient for segmentation and sensitivity and false positive rate (FPR) for detection. The best performing model was evaluated on the test set., Results: A DCNN with an input size of 64 × 64 × 64 and an equal number of 128 kernels for all convolutional layers using instance normalization was identified as the best performing model (Dice similarity coefficient 0.73, sensitivity 0.86, and FPR 1.9) in the 5-fold cross validation experiments. The best performing model demonstrated consistent behavior on the test set (Dice similarity coefficient 0.73, sensitivity 0.91, and FPR 1.7) and successfully detected 7 BMs (out of 327) that were missed during manual delineation. For large BMs with diameters greater than 12 mm, the sensitivity and FPR improved to 0.98 and 0.3, respectively., Conclusions: The DCNN model developed can automatically detect and segment brain metastases with reasonable accuracy, high sensitivity, and low FPR on a multi-institutional data set with nonprespecified and highly variable magnetic resonance imaging sequences. For large BMs, the model achieved clinically relevant results. The model is robust and may be potentially used in real-world situations., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Prior studies of aging and Alzheimer disease have evaluated resting state functional connectivity (FC) using either seed-based correlation (SBC) or independent component analysis (ICA), with a focus on particular functional systems. SBC and ICA both are insensitive to differences in signal amplitude. At the same time, accumulating evidence indicates that the amplitude of spontaneous BOLD signal fluctuations is physiologically meaningful. We systematically compared covariance-based FC, which is sensitive to amplitude, vs. correlation-based FC, which is not, in affected individuals and controls drawn from two cohorts of participants including autosomal dominant Alzheimer disease (ADAD), late onset Alzheimer disease (LOAD), and age-matched controls. Functional connectivity was computed over 222 regions of interest and group differences were evaluated in terms of components projected onto a space of lower dimension. Our principal observations are: (1) Aging is associated with global loss of resting state fMRI signal amplitude that is approximately uniform across resting state networks. (2) Thus, covariance FC measures decrease with age whereas correlation FC is relatively preserved in healthy aging. (3) In contrast, symptomatic ADAD and LOAD both lead to loss of spontaneous activity amplitude as well as severely degraded correlation structure. These results demonstrate a double dissociation between age vs. Alzheimer disease and the amplitude vs. correlation structure of resting state BOLD signals. Modeling results suggest that the AD-associated loss of correlation structure is attributable to a relative increase in the fraction of locally restricted as opposed to widely shared variance., Competing Interests: Declaration of Competing Interest Randall J. Bateman Randall Bateman (RJB), Professor of Neurology at Washington University's School of Medicine (WUSM) receives lab research funding from the National Institutes of Health, Alzheimer's Association, BrightFocus Foundation, Rainwater Foundation Tau Consortium, Association for Frontotemporal Degeneration, the Cure Alzheimer's Fund, Centene Corporation, Tau SILK Consortium (AbbVie, Biogen, and Eli Lilly and Company), and an anonymous organization. RJB has received honoraria as a speaker/consultant/advisory board member from Amgen, AC Immune, Eisai, F. Hoffman-LaRoche, and Janssen; and reimbursement of travel expenses from AC Immune, F. Hoffman-La Roche and Janssen. Unrelated to this article, RJB serves as principal investigator of the DIAN-TU, which is supported by the Alzheimer's Association, GHR Foundation, an anonymous organization and the DIAN-TU Pharma Consortium (Active: Eli Lilly and Company/Avid Radiopharmaceuticals, F. Hoffman-La Roche/Genentech, Biogen, Eisai, Janssen, and United Neuroscience. Previous: Abbvie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi). The DIAN-TU-001 Clinical Trial is supported by Pharmaceutical Partners Eli Lilly and Company, F. Hoffman-La Roche and Janssen, the Alzheimer's Association, NIH U01AG042791, NIH U01AG42791-S1 (FNIH and Accelerating Medicines Partnership), NIH R01AG046179, NIH R56AG053267, NIH R01AG053267, NIH U01AG059798, NIH R01AG068319, Avid Radiopharmaceuticals, GHR Foundation, and an anonymous organization. In-kind support has been received from CogState and Bracket. Washington University, Randall Bateman, and David Holtzman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. RJB receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co-inventor, has submitted the US nonprovisional patent application “Methods for Measuring the Metabolism of CNS Derived Biomolecules In Vivo” and provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition”. Tammie L.S. Benzinger Dr. Benzinger reports grants and non-financial support from Avid Radiopharmaceuticals/ Eli Lilly, during the conduct of the study; grants and non-financial support from Avid Radiopharmaceuticals/ Eli Lilly, other from Eli Lilly, Biogen, Eisai, Jaansen, personal fees from Biogen, non-financial support from Eisai, non-financial support from Siemens, outside the submitted work. Matthew R. Brier Dr. Brier reports grants from NIH, during the conduct of the study. Gregory S. Day Dr. Day reports grants from NIH, during the conduct of the study; personal fees from Parabon Nanolabs, Inc, personal fees from DynaMed (EBSCO Health), outside the submitted work. Brian A. Gordon Dr. Gordon reports participation in clinical trials of therapies to alter the course of Alzheimer Disease. Neill Graff-Radford Dr. Graff-Radford reports grants from NIH, during the conduct of the study; grants from Biogen, grants from AbbVie, grants from Lilly, outside the submitted work. Taleshi Ikeuchi Dr. Ikeuchi reports grants from AMED (Japan Agency for Medical Research and Development), during the conduct of the study. Daniel S. Marcus Dr. Marcus reports other from Radiologics, Inc, outside the submitted work. John C. Morris Dr. Morris reports grants from NIH grant P30 AG066444, grants from NIH grant P01AG003991, grants from NIH grant P01AG026276, grants from NIH grant UF1AG032438, during the conduct of the study. Richard J. Perrin Dr. Perrin reports grants from NIH during the conduct of the study. Stephen Salloway Dr. Salloway reports grants and personal fees from Biogen, grants and personal fees from Eisai, grants and personal fees from Avid, grants and personal fees from Lilly, personal fees from Genentech, personal fees from Novartis, grants and personal fees from Roche, outside the submitted work. Peter Schofield Dr. Schofield reports grants from NIH, grants from Anonymous Foundation, grants from Roth Charitable Foundation, during the conduct of the study. Abraham Z. Snyder Dr. Snyder is a consultant for Sora Neuroimaging, LLC., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study evaluated the safety, dosimetry, and characteristics of 3-((2-fluoro-4-(5-(2'-methyl-2-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)(methyl- 11 C)amino)propanoic acid ( 11 C-CS1P1), a radiotracer targeting sphingosine-1-phosphate receptor (S1PR) 1 (S1PR1). S1PR1 is of clinical interest because of its role in multiple sclerosis (and other conditions), with an expanding class of S1PR modulators approved for relapsing multiple sclerosis. 11 C-CS1P1 binds S1PR1 with high specificity and has shown promise in animal models of inflammatory diseases. Methods: 11 C-CS1P1 was injected into 5 male and 6 female healthy participants. Ten participants were imaged with PET using a multipass whole-body continuous-bed-motion acquisition, and one had dedicated head and neck PET and MRI. Participants were continuously monitored for safety events. Organ time-activity curve data were collected, integrated, and normalized to the injected activity. Organ radiation doses and effective dose were computed using the adult male and female models in OLINDA, version 2.2. SUV images were evaluated for qualitative biodistribution. Results: No adverse events were observed after the dose, including no bradycardia. The liver was the critical organ from dosimetry analysis (mean ± SD: female, 23.12 ± 5.19 μSv/MBq; male, 21.06 ± 1.63 μSv/MBq). The whole-body effective dose (as defined by International Commission on Radiological Protection publication 103) was 4.18 ± 0.30 μSv/MBq in women and 3.54 ± 0.14 μSv/MBq in men. Using a maximum delivered dose of 740 MBq (20 mCi), the effective dose for women would be 3.1 mSv (0.31 rem), with a liver dose of 17.1 mSv (1.7 rem); the effective dose for men would be 2.6 mSv (0.26 rem), with a liver dose of 15.6 mSv (1.56 rem). Brain uptake was seen predominantly in gray matter and correlated with regional S1PR1 RNA expression ( r = 0.84). Conclusion: These results support the safety of 11 C-CS1P1 for evaluation of inflammation in human clinical populations. Dosimetry permits repeated measures in the same participants. Brain uptake correlates well with known target topography., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

White matter lesions in cerebral small vessel disease are related to ischemic injury and increase the risk of stroke and cognitive decline. Pathological changes due to cerebral small vessel disease are increasingly recognized outside of discrete lesions, but the metabolic alterations in nonlesional tissue has not been described. Aerobic glycolysis is critical to white matter myelin homeostasis and repair. In this study, we examined cerebral metabolism of glucose and oxygen as well as blood flow in individuals with and without cerebral small vessel disease using multitracer positron emission tomography. We show that glycolysis is relatively elevated in nonlesional white matter in individuals with small vessel disease relative to healthy, age-matched controls. On the other hand, in young healthy individuals, glycolysis is relatively low in areas of white matter susceptible to lesion formation. These results suggest that increased white matter glycolysis is a marker of pathology associated with small vessel disease., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD)., Methods: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors., Results: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E., Interpretation: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: National Institute on Aging-Alzheimer's Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD)., Objective: To assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-term risk of developing symptomatic AD., Design, Setting, and Participants: This longitudinal cohort study used data from 4 independent population-based cohorts (PREVENT-AD, HABS, AIBL, and Knight ADRC) collected between 2003 and 2021. Participants were older adults without cognitive impairment with 1 year or more of clinical observation after amyloid β and tau positron emission tomography (PET). Median clinical follow-up after PET ranged from 1.94 to 3.66 years., Exposures: Based on binary assessment of global amyloid burden (A) and a composite temporal region of tau PET uptake (T), participants were stratified into 4 groups (A+T+, A+T-, A-T+, A-T-). Presence (+) or absence (-) of neurodegeneration (N) was assessed using temporal cortical thickness., Main Outcomes and Measures: Each cohort was analyzed separately. Primary outcome was clinical progression to mild cognitive impairment (MCI), identified by a Clinical Dementia Rating score of 0.5 or greater in Knight ADRC and by consensus committee review in the other cohorts. Clinical raters were blind to imaging, genetic, and fluid biomarker data. A secondary outcome was cognitive decline, based on a slope greater than 1.5 SD below the mean of an independent subsample of individuals without cognitive impairment. Outcomes were compared across the biomarker groups., Results: Among 580 participants (PREVENT-AD, 128; HABS, 153; AIBL, 48; Knight ADRC, 251), mean (SD) age ranged from 67 (5) to 76 (6) years across cohorts, with between 55% (137/251) and 74% (95/128) female participants. Across cohorts, 33% to 83% of A+T+ participants progressed to MCI during follow-up (mean progression time, 2-2.72 years), compared with less than 20% of participants in other biomarker groups. Progression further increased to 43% to 100% when restricted to A+T+(N+) individuals. Cox proportional hazard ratios for progression to MCI in the A+T+ group vs other biomarker groups were all 5 or greater. Many A+T+ nonprogressors also showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable., Conclusions and Relevance: The clinical prognostic value of NIA-AA research criteria was confirmed in 4 independent cohorts, with most A+T+(N+) older individuals without cognitive impairment developing AD symptoms within 2 to 3 years.

"Brain-predicted age" quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18-89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and significantly younger in preclinical AD compared to controls. There was minimal correspondence between networks predictive of age and AD. Elevated FC-BAG may reflect network disruption during symptomatic AD. Reduced FC-BAG in preclinical AD was opposite to the expected direction, and may reflect a biphasic response to preclinical AD pathology or may be driven by inconsistency between age-related vs. AD-related networks. Overall, FC-predicted brain age may be a sensitive AD biomarker., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interests. JC Morris is funded by NIH grants # P30 AG066444; P01AG003991; P01AG026276; U19 AG032438; and U19 AG024904. Neither Dr. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Dr. Salloway reports personal fees from EISAI, NOVARTIS, GENENTECH, ROCHE, GEMVAX, AVID, and LILLY. Dr. Bateman is on the scientific advisory board of C2N Diagnostics and reports research support from Abbvie, Avid Radiopharmaceuticals, Biogen, Centene, Eisai, Eli Lilly and Company, Genentech, Hoffman-LaRoche, Janssen, and United Neuroscience., (Copyright © 2022. Published by Elsevier Inc.)

Background and Objectives: To evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups., Methods: Individuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age, APOE ε4 carrier status, and cognitive status. Each participant underwent blood and CSF collection, and amyloid PET was performed in 103 participants (68%). Plasma Aβ42/Aβ40 was measured by a high-performance immunoprecipitation-mass spectrometry assay. Plasma p-tau181, p-tau231, and NfL were measured by Simoa immunoassays. CSF Aβ42/Aβ40 and amyloid PET status were used as primary and secondary reference standards of brain amyloidosis, respectively., Results: There were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were APOE ε4 carriers, and 91% were cognitively normal. AA were less likely than NHW participants to have brain amyloidosis by CSF Aβ42/Aβ40 (22% vs 43% positive; p = 0.003). The receiver operating characteristic area under the curve of CSF Aβ42/Aβ40 status with the plasma biomarkers was as follows: Aβ42/Aβ40, 0.86 (95% CI 0.79-0.92); p-tau181, 0.76 (0.68-0.84); p-tau231, 0.69 (0.60-0.78); and NfL, 0.64 (0.55-0.73). In models predicting CSF Aβ42/Aβ40 status with plasma Aβ42/Aβ40 that included covariates (age, sex, APOE ε4 carrier status, race, and cognitive status), race did not affect the probability of CSF Aβ42/Aβ40 positivity. In similar models based on plasma p-tau181, p-tau231, or NfL, AA participants had a lower probability of CSF Aβ42/Aβ40 positivity (odds ratio 0.31 [95% CI 0.13-0.73], 0.30 [0.13-0.71], and 0.27 [0.12-0.64], respectively). Models of amyloid PET status yielded similar findings., Discussion: Models predicting brain amyloidosis using a high-performance plasma Aβ42/Aβ40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-tau181, p-tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA individuals., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Hyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer's disease (AD). However, it remains unknown whether white matter (WM) decline due to AD is associated with specific Tau phosphorylation site(s)., Methods: In autosomal dominant AD (ADAD) mutation carriers (MC) and non-carriers (NC) we compared cerebrospinal fluid (CSF) phosphorylation at tau sites (pT217, pT181, pS202, and pT205) and total tau with WM measures, as derived from diffusion tensor imaging (DTI), and cognition. A WM composite metric, derived from a principal component analysis, was used to identify spatial decline seen in ADAD., Results: The WM composite explained over 70% of the variance in MC. WM regions that strongly contributed to the spatial topography were located in callosal and cingulate regions. Loss of integrity within the WM composite was strongly associated with AD progression in MC as defined by the estimated years to onset (EYO) and cognitive decline. A linear regression demonstrated that amyloid, gray matter atrophy and phosphorylation at CSF tau site pT205 each uniquely explained a reduction in the WM composite within MC that was independent of vascular changes (white matter hyperintensities), and age. Hyperphosphorylation of CSF tau at other sites and total tau did not significantly predict WM composite loss., Conclusions: We identified a site-specific relationship between CSF phosphorylated tau and WM decline within MC. The presence of both amyloid deposition and Tau phosphorylation at pT205 were associated with WM composite loss. These findings highlight a primary AD-specific mechanism for WM dysfunction that is tightly coupled to symptom manifestation and cognitive decline., (Copyright © 2022. Published by Elsevier Inc.)

Purpose of Review: This article discusses neuroimaging in dementia diagnosis, with a focus on new applications of MRI and positron emission tomography (PET)., Recent Findings: Although the historical use of MRI in dementia diagnosis has been supportive to exclude structural etiologies, recent innovations allow for quantification of atrophy patterns that improve sensitivity for supporting the diagnosis of dementia causes. Neuronuclear approaches allow for localization of specific amyloid and tau neuropathology on PET and are available for clinical use, in addition to dopamine transporter scans in dementia with Lewy bodies and metabolic studies with fludeoxyglucose PET (FDG-PET)., Summary: Using computerized software programs for MRI analysis and cross-sectional and longitudinal evaluations of hippocampal, ventricular, and lobar volumes improves sensitivity in support of the diagnosis of Alzheimer disease and frontotemporal dementia. MRI protocol requirements for such quantification are three-dimensional T1-weighted volumetric imaging protocols, which may need to be specifically requested. Fluid-attenuated inversion recovery (FLAIR) and 3.0T susceptibility-weighted imaging (SWI) sequences are useful for the detection of white matter hyperintensities as well as microhemorrhages in vascular dementia and cerebral amyloid angiopathy. PET studies for amyloid and/or tau pathology can add additional specificity to the diagnosis but currently remain largely inaccessible outside of research settings because of prohibitive cost constraints in most of the world. Dopamine transporter PET scans can help identify Lewy body dementia and are thus of potential clinical value., (Copyright © 2022 American Academy of Neurology.)

Background: Cerebrospinal fluid (CSF) neurofilament light chain (NfL) reflects neuro-axonal damage and is increasingly used to evaluate disease progression across neurological conditions including Alzheimer disease (AD). However, it is unknown how NfL relates to specific types of brain tissue. We sought to determine whether CSF NfL is more strongly associated with total gray matter, white matter, or white matter hyperintensity (WMH) volume, and to quantify the relative importance of brain tissue volume, age, and AD marker status (i.e., APOE genotype, brain amyloidosis, tauopathy, and cognitive status) in predicting CSF NfL., Methods: 419 participants (Clinical Dementia Rating [CDR] Scale > 0, N = 71) had CSF, magnetic resonance imaging (MRI), and neuropsychological data. A subset had amyloid positron emission tomography (PET) and tau PET. Pearson correlation analysis was used to determine the association between CSF NfL and age. Multiple regression was used to determine which brain volume (i.e., gray, white, or WMH volume) most strongly associated with CSF NfL. Stepwise regression and dominance analyses were used to determine the individual contributions and relative importance of brain volume, age, and AD marker status in predicting CSF NfL., Results: CSF NfL increased with age (r = 0.59, p < 0.001). Elevated CSF NfL was associated with greater total WMH volume (p < 0.001), but not gray or white matter volume (p's > 0.05) when considered simultaneously. Age and WMH volume were consistently more important (i.e., have greater R 2 values) than AD markers when predicting CSF NfL., Conclusions: CSF NfL is a non-specific marker of aging and white matter integrity with limited sensitivity to specific markers of AD. CSF NfL likely reflects processes associated with cerebrovascular disease., (Copyright © 2022. Published by Elsevier Inc.)

Although often unmeasured in studies of cognition, many older adults possess Alzheimer disease (AD) pathologies such as beta-amyloid (Aβ) deposition, despite being asymptomatic. We were interested in examining whether the behavior-structure relationship observed in later life was altered by the presence of preclinical AD pathology. A total of 511 cognitively unimpaired adults completed magnetic resonance imaging and three attentional control tasks; a subset (n = 396) also underwent Aβ-positron emissions tomography. A vertex-wise model was conducted to spatially represent the relationship between cortical thickness and average attentional control accuracy, while moderation analysis examined whether Aβ deposition impacted this relationship. First, we found that reduced cortical thickness in temporal, medial- and lateral-parietal, and dorsolateral prefrontal cortex, predicted worse performance on the attention task composite. Subsequent moderation analyses observed that levels of Aβ significantly influence the relationship between cortical thickness and attentional control. Our results support the hypothesis that preclinical AD, as measured by Aβ deposition, is partially driving what would otherwise be considered general aging in a cognitively normal adult population., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease., Methods: We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer's disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models., Findings: In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=-4·28 × 10 -2 [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=-5·51 × 10 -3 [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=-0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020)., Interpretation: Our findings in autosomal dominant Alzheimer's disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing., Funding: German Research Foundation, US National Institutes of Health., Competing Interests: Declaration of interests HZ has served at scientific advisory boards for Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, and CogRx, and has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen. MS-C has served as a consultant and at advisory boards for Roche Diagnostics International and has given lectures in symposia sponsored by Roche Diagnostics, Sociedad Limitada Unipersonal, and Roche Farma, Sociedad Anónima. AMF participates in the scientific advisory boards for Roche Diagnostics, Genentech, and DiamiR, and collaborates as a consultant for DiamiR and Siemens Healthcare Diagnostics. TLSB collaborates with Biogen and Siemens as a consultant and participates in the Advisory board of Eisai and Biogen. JH collaborates as a consultant for Roche and Parabon Nanolabs, and participates in the Advisory board of Eisai, CaringBridge, and WallE. EM collaborates as a consultant for Eli Lilly, has received funding for attending meetings from the Alzheimer Association and Foundation Alzheimer, and participates in the Data Safety Monitoring Board of Eli Lilly, Alector, and in the Advisory Board of Fondation Alzheimer, and Alzmend. KS received royalties for co-developing the therapeutic anti-TREM2 mouse antibody 4D9. JCM has served as consultant for Barcelona Beta Brain Research Center, TS Srinivasan Advisory Board (Chennai, India), has received honoraria for lectures given at Montefiori Grand Rounds (NY, USA) and Tetra-Institute Alzheimer Disease Research Center Seminar Series, and participates in the Advisory Boards of Cure Alzheimer's Fund Research Strategy Council and Leads Advisory Board (IN, USA). KB collaborates as a consultant for Abcam, Axon, BioArctic, Biogen, Japanese Organization for Medical Device Development and Shimadzu, Lilly, MagQu, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, has received honoraria for lectures from Grupo de Estudos de Envelhecimento Cerebral e Demência and Roche Diagnostics, and IFCC and SNIBE, has served at data monitoring committees for Julius Clinical and Novartis, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of Gothenburg University Ventures Incubator programme. JL participates as a consultant in Axon Neuroscience and Biogen, has received honoraria for lectures given by Bayer Vital and Roche, support for attending meetings by AbbVie and Biogen, and has participated in the Advisory board of Axon Neuroscience. JL has also received author fees from Thieme medical publishers, W Kohlhammer GmbH medical publishers, and a compensation for duty as part-time chief marketing officer by MODAG GmbH. RJB collaborates as a consultant with Eisai, Amgen, and Hoffman La-Roche, has received travel support from Hoffman La-Roche, and participates in the C2N Diagnostics Scientific Advisory board. RJB also serves as principal investigator of the Dominantly Inherited Alzheimer's Network-Treatment Unit (DIAN-TU), which is supported by the Alzheimer's Association, GHR Foundation, an anonymous organisation, and the DIAN-TU Pharma Consortium (active members include Eli Lilly and Company, Avid Radiopharmaceuticals, F Hoffman-La Roche, Genentech, Biogen, Eisai, and Janssen. Previous members include Abbvie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, and United Neuroscience). In addition, in-kind support has been received from CogState and Signant Health. CH collaborates with Denali Therapeutics, and has participated on one advisory board meeting of Biogen. CH is also chief advisor of ISAR Bioscience and a member of the scientific advisory board of AviadoBio. CH has received honoraria for lectures at Weill Cornell Medicine, Sheikh Hamdan Webinar Series, Washington University, Eisai, and UT Southwestern Medical Center, and participates in the US Patent Application (number 16/319,373)., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Objectives: This study aims to quantify microglial activation in individuals with Alzheimer disease (AD) using the 18-kDa translocator protein (TSPO) PET imaging in the hippocampus and precuneus, the 2 AD-vulnerable regions, and to evaluate the association of baseline neuroinflammation with amyloidosis, tau, and longitudinal cognitive decline., Methods: Twenty-four participants from the Knight Alzheimer Disease Research Center (Knight ADRC) were enrolled and classified into stable cognitively normal, progressor, and symptomatic AD groups based on clinical dementia rating (CDR) at 2 or more clinical assessments. The baseline TSPO radiotracer [11C]PK11195 was used to image microglial activation. Baseline CSF concentrations of Aβ42, Aβ42/Aβ40 ratio, tau phosphorylated at position 181 (p-tau181), and total tau (t-tau) were measured. Clinical and cognitive decline were examined with longitudinal CDR and cognitive composite scores (Global and Knight ADRC-Preclinical Alzheimer Cognitive Composite [Knight ADRC-PACC] Score)., Results: Participants in the progressor and symptomatic AD groups had significantly elevated [11C]PK11195 standard uptake value ratios (SUVRs) in the hippocampus but not in the precuneus region. In the subcohort with CSF biomarkers (16 of the 24), significant negative correlations between CSF Aβ42 or Aβ42/Aβ40 and [11C]PK11195 SUVR were observed in the hippocampus and precuneus. No correlations were observed between [11C]PK11195 SUVR and CSF p-tau181 or t-tau at baseline in those regions. Higher baseline [11C]PK11195 SUVR averaged in the whole cortical regions predicted longitudinal decline on cognitive tests., Discussion: Microglial activation is increased in individuals with brain amyloidosis and predicts worsening cognition in AD., Classification of Evidence: This study provides Class II evidence that in patients with AD, higher baseline [11C]PK11195 SUVR averaged in the whole cortical regions was associated with longitudinal decline on cognitive tests., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Importance: Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism moderates increases in cerebrospinal fluid (CSF) levels of tau and phosphorylated tau 181 (p-tau181), measured using immunoassay, and cognitive decline in presymptomatic dominantly inherited Alzheimer disease (DIAD). Advances in mass spectrometry show that CSF tau phosphorylation occupancy at threonine 181 and 217 (p-tau181/tau181, p-tau217/tau217) increases with initial β-amyloid (Aβ) aggregation, while phosphorylation occupancy at threonine 205 (p-tau205/tau205) and level of total tau increase when brain atrophy and clinical symptoms become evident., Objective: To determine whether site-specific tau phosphorylation occupancy (ratio of phosphorylated to unphosphorylated tau) is associated with BDNF Val66Met in presymptomatic and symptomatic DIAD., Design, Setting, and Participants: This cross-sectional cohort study included participants from the Dominantly Inherited Alzheimer Network (DIAN) and Aβ-positive cognitively normal older adults in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Data were collected from 2009 through 2018 at multicenter clinical sites in the United States, United Kingdom, and Australia, with no follow-up. DIAN participants provided a CSF sample and completed clinical and cognitive assessments. Data analysis was conducted between March 2020 and March 2021., Main Outcomes and Measures: Mass spectrometry analysis was used to determine site-specific tau phosphorylation level; tau levels were also measured using immunoassay. Episodic memory and global cognitive composites were computed., Results: Of 374 study participants, 144 were mutation noncarriers, 156 were presymptomatic mutation carriers, and 74 were symptomatic carriers. Of the 527 participants in the network, 153 were excluded because their CSF sample, BDNF status, or both were unavailable. Also included were 125 Aβ-positive cognitively normal older adults in the ADNI. The mean (SD) age of DIAD participants was 38.7 (10.9) years; 43% were women. The mean (SD) age of participants with preclinical sporadic AD was 74.8 (5.6) years; 52% were women. In presymptomatic mutation carriers, compared with Val66 homozygotes, Met66 carriers showed significantly poorer episodic memory (d = 0.62; 95% CI, 0.28-0.95), lower hippocampal volume (d = 0.40; 95% CI, 0.09-0.71), and higher p-tau217/tau217 (d = 0.64; 95% CI, 0.30-0.97), p-tau181/tau181 (d = 0.65; 95% CI, 0.32-0.99), and mass spectrometry total tau (d = 0.43; 95% CI, 0.10-0.76). In symptomatic mutation carriers, Met66 carriers showed significantly poorer global cognition (d = 1.17; 95% CI, 0.65-1.66) and higher p-tau217/tau217 (d = 0.53; 95% CI, 0.05-1.01), mass spectrometry total tau (d = 0.78; 95% CI, 0.28-1.25), and p-tau205/tau205 (d = 0.97; 95% CI, 0.46-1.45), when compared with Val66 homozygotes. In preclinical sporadic AD, Met66 carriers showed poorer episodic memory (d = 0.39; 95% CI, 0.00-0.77) and higher total tau (d = 0.45; 95% CI, 0.07-0.84) and p-tau181 (d = 0.46; 95% CI, 0.07-0.85)., Conclusions and Relevance: In DIAD, clinical disease stage and BDNF Met66 were associated with cognitive impairment and levels of site-specific tau phosphorylation. This suggests that pharmacological strategies designed to increase neurotrophic support in the presymptomatic stages of AD may be beneficial.

Background: Intracranial internal carotid artery (ICA) calcification is a common incidental finding in non-contrast head CT. We evaluated the predictive value of ICAC (ICAC) for future risk of cognitive decline and compared the results with conventional imaging biomarkers of dementia., Methods: In a retrospective observational cohort, we included 230 participants with a PET-CT scan within 18 months of a baseline clinical assessment and longitudinal imaging assessments. Intracranial ICAC was quantified on baseline CT scans using the Agatson calcium score, and the association between baseline ICA calcium scores and the risk of conversion from a CDR of zero in baseline to a persistent CDR > 0 at any follow-up visit, as well as longitudinal changes in cognitive scores, were evaluated through linear and mixed regression models. We also evaluated the association of conventional imaging biomarkers of dementia with longitudinal changes in cognitive scores and a potential indirect effect of ICAC on cognition through these biomarkers., Results: Baseline ICA calcium score could not distinguish participants who converted to CDR > 0. ICA calcium score was also unable to predict longitudinal changes in cognitive scores, imaging biomarkers of small vessel disease such as white matter hyperintensities (WMH) volume, or AD such as hippocampal volume, AD cortical signature thickness, and amyloid burden. Severity of intracranial ICAC increased with age and in men. Higher WMH volume and amyloid burden as well as lower hippocampal volume and AD cortical signature thickness at baseline predicted lower Mini-Mental State Exam scores at longitudinal follow-up. Baseline ICAC was indirectly associated with longitudinal cognitive decline, fully mediated through WMH volume., Conclusions: In elderly and preclinical AD populations, atherosclerosis of large intracranial vessels as demonstrated through ICAC is not directly associated with a future risk of cognitive impairment, or progression of imaging biomarkers of AD or small vessel disease., (© 2022. The Author(s).)

Background: Insights gained from studying individuals with autosomal dominant Alzheimer's disease have broadly influenced mechanistic hypotheses, biomarker development, and clinical trials in both sporadic and dominantly inherited Alzheimer's disease. Although pathogenic variants causing autosomal dominant Alzheimer's disease are highly penetrant, there is substantial heterogeneity in levels of amyloid β (Aβ) between individuals. We aimed to examine whether this heterogeneity is related to disease progression and to investigate the association with mutation location within PSEN1, PSEN2, or APP., Methods: We did cross-sectional and longitudinal analyses of data from the Dominantly Inherited Alzheimer's Network (DIAN) observational study, which enrols individuals from families affected by autosomal dominant Alzheimer's disease. 340 participants in the DIAN study who were aged 18 years or older, had a history of autosomal dominant Alzheimer's disease in their family, and who were enrolled between September, 2008, and June, 2019, were included in our analysis. 206 participants were carriers of pathogenic mutations in PSEN1, PSEN2, or APP, and 134 were non-carriers. 62 unique pathogenic variants were identified in the cohort and were grouped in two ways. First, we sorted variants in PSEN1, PSEN2, or APP by the affected protein domain. Second, we divided PSEN1 variants according to position before or after codon 200. We examined variant-dependent variability in Aβ biomarkers, specifically Pittsburgh-Compound-B PET (PiB-PET) signal, levels of CSF Aβ1-42 (Aβ42), and levels of Aβ1-40 (Aβ40)., Findings: Cortical and striatal PiB-PET signal showed striking variant-dependent variability using both grouping approaches (p<0·0001), despite similar progression on the clinical dementia rating (p>0·7), and CSF Aβ42 levels (codon-based grouping: p=0·49; domain-based grouping: p=0·095). Longitudinal PiB-PET signal also varied across codon-based groups, mirroring cross-sectional analyses., Interpretation: Autosomal dominant Alzheimer's disease pathogenic variants showed highly differential temporal and regional patterns of PiB-PET signal, despite similar functional progression. These findings suggest that although increased PiB-PET signal is generally seen in autosomal dominant Alzheimer's disease, higher levels of PiB-PET signal at an individual level might not reflect more severe or more advanced disease. Our results have high relevance for ongoing clinical trials in autosomal dominant Alzheimer's disease, including those using Aβ PET as a surrogate marker of disease progression. Additionally, and pertinent to both sporadic and autosomal dominant Alzheimer's disease, our results suggest that CSF and PET measures of Aβ levels are not interchangeable and might reflect different Aβ-driven pathobiological processes., Funding: National Institute on Aging, Doris Duke Charitable Foundation, German Center for Neurodegenerative Diseases, Japanese Agency for Medical Research and Development., Competing Interests: Declaration of interests JPC has served on medical advisory boards for Otsuka Pharmaceuticals and Humana Healthcare, outside of the submitted work. APS has served on medical advisory boards for Janssen Pharmaceuticals and Biogen, outside of the submitted work. SMS reports consulting to Eisai, Novartis, Genentech, F Hoffmann-La Roche, Gemvax, Avid Radiopharmaceuticals, and Eli Lilly, outside of the submitted work. SMS also serves on steering committees for major biomarker and clinical trials and consortia such as the Alzheimer's Disease Neuroimaging Initiative, the Dominantly Inherited Alzheimer Network (DIAN), Alzheimer's Clinical Trial Consortium, Global Alzheimer's Platform- Network, and Longitudinal Early-onset Alzheimer's disease study, and is a project arm leader for the Dominantly Inherited Alzheimer's Network-Treatment Unit (DIAN-TU) study, outside of the submitted work. WEK is a co-inventor of Pittsburgh-Compound-B (PiB) and, as such, has a financial interest in a license agreement held by GE Healthcare and the University of Pittsburgh (PA, USA) based on the PiB-PET technology used in this manuscript. GE Healthcare provided no grant support for this study and had no role in the design or interpretation of results or preparation of this manuscript. AMF has received research funding from the National Institutes of Health and National Institute on Aging, Biogen, Centene, Fujirebio, and Roche Diagnostics, outside of the submitted work. AMF is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and AbbVie, and also consults for Araclon and Grifols, DiademRes, DiamiR, and Otsuka Pharmaceuticals, outside of the submitted work. RJB has equity ownership interest in C2N Diagnostics and receives royalty income based on technology (ie, stable isotope labelling kinetics and a blood plasma assay) licensed by Washington University (WA, USA) to C2N Diagnostics. RJB receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co-inventor, has submitted the US non-provisional patent application “Cerebrospinal fluid (CSF) tau rate of phosphorylation measurement to define stages of Alzheimer's disease and monitor brain kinases/phosphatases activity.” RJB has received honoraria from Janssen and Pfizer as a speaker, and from Merck and Pfizer as an advisory board member. RJB has been an invited speaker, advisory board member, and consultant for F Hoffman La Roche, an invited speaker and consultant for AC Immune and Janssen, and a consultant for Amgen and Eisai, outside of the submitted work. AMG has consulted for Eisai, Biogen, Pfizer, AbbVie, Cognition Therapeutics, and GSK, outside of the submitted work. AMG also served on the Scientific Advisory Board of Denali Therapeutics (from 2015 to 2018), outside of the submitted work. RAS and KAJ are involved in public-private partnership clinical trials sponsored by the National Institutes of Health and Eli Lilly, which owns the distribution rights to flortaucipir, but they do not have any personal financial relationship with Eli Lilly. NG-R reports grants from Biogen, Abbvie, and Lilly, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The kinetics of amyloid beta turnover within human brain is still poorly understood. We previously found a dramatic decline in the turnover of Aβ peptides in normal aging. It was not known if brain interstitial fluid/cerebrospinal fluid (ISF/CSF) fluid exchange, CSF turnover, blood-brain barrier function or proteolysis were affected by aging or the presence of β amyloid plaques. Here, we describe a non-steady state physiological model developed to decouple CSF fluid transport from other processes. Kinetic parameters were estimated using: (1) MRI-derived brain volumes, (2) stable isotope labeling kinetics (SILK) of amyloid-β peptide (Aβ), and (3) lumbar CSF Aβ concentration during SILK. Here we show that changes in blood-brain barrier transport and/or proteolysis were largely responsible for the age-related decline in Aβ turnover rates. CSF-based clearance declined modestly in normal aging but became increasingly important due to the slowing of other processes. The magnitude of CSF-based clearance was also lower than that due to blood-brain barrier function plus proteolysis. These results suggest important roles for blood-brain barrier transport and proteolytic degradation of Aβ in the development Alzheimer's Disease in humans., (© 2022. The Author(s).)

Brain atrophy occurs in aging even in the absence of dementia, but it is unclear to what extent this is due to undetected preclinical Alzheimer disease. Here we examine a cross-sectional cohort (ages 18-88) free from confounding influence of preclinical Alzheimer disease, as determined by amyloid PET scans and three years of clinical evaluation post-imaging. We determine the regional strength of age-related atrophy using linear modeling of brain volumes and cortical thicknesses with age. Age-related atrophy was seen in nearly all regions, with greatest effects in the temporal lobe and subcortical regions. When modeling age with the estimated derivative of smoothed aging curves, we found that the temporal lobe declined linearly with age, subcortical regions declined faster at later ages, and frontal regions declined slower at later ages than during midlife. This age-derivative pattern was distinct from the linear measure of age-related atrophy and significantly associated with a measure of myelin. Atrophy did not detectably differ from a preclinical Alzheimer disease cohort when age ranges were matched., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Apolipoprotein E (APOE) ε4 allele status is associated with amyloid and tau-related pathological changes related to Alzheimer's disease (AD). However, it is unknown whether brain network changes are related to amyloid beta (Aβ) and/or tau-related pathology in cognitively normal APOE ε4 carriers with subthreshold Aβ accumulation., Methods: Resting state functional connectivity measures of network integrity were evaluated in cognitively normal individuals (n = 121, mean age 76.6 ± 7.8 years, 15% APOE ε4 carriers, 65% female) with minimal Aβ per cerebrospinal fluid (CSF) or amyloid positron emission tomography., Results: APOE ε4 carriers had increased lateralized connections relative to callosal connections within the default-mode, memory, and salience networks (P = .02), with significant weighting on linear regression toward CSF total tau (P = .03) and CSF phosphorylated tau at codon 181 (P = .03), but not CSF Aβ 42 ., Discussion: Cognitively normal APOE ε4 carriers with subthreshold amyloid accumulation may have network reorganization associated with tau., (© 2021 the Alzheimer's Association.)

Background: Obesity is an increasingly recognized modifiable risk factor for Alzheimer's disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity., Objective: We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity., Methods: A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm., Results: We identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status., Conclusion: BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD.

Recent studies in cognitively unimpaired elderly individuals suggest that the APOE ε4 allele exerts a dosage-dependent effect on brain tau deposition. The aim of this study was to investigate sex differences in APOE ε4 gene dosage effects on brain tau deposition in cognitively impaired individuals using quantitative 18F-flortaucipir PET. Preprocessed 18F-flortaucipir tau PET images, T1-weighted structural MRI, demographic information, global cortical amyloid-β burden measured by 18F-florbetapir PET, CSF total tau and phosphorylated tau measurements were obtained from the Alzheimer's Disease Neuroimaging Initiative database. Two hundred and sixty-eight cognitively impaired individuals with 146 APOE ε4 non-carriers and 122 carriers (85 heterozygotes and 37 homozygotes) were included in the study. An iterative reblurred Van Cittert iteration partial volume correction method was applied to all downloaded PET images. Magnetic resonance images were used for PET spatial normalization. Twelve regional standardized uptake value ratios relative to the cerebellum were computed in standard space. APOE ε4 dosage × sex interaction effect on 18F-flortaucipir standardized uptake value ratios was assessed using generalized linear models and sex-stratified analysis. We observed a significant APOE ε4 dosage × sex interaction effect on tau deposition in the lateral temporal, posterior cingulate, medial temporal, inferior temporal, entorhinal cortex, amygdala, parahippocampal gyrus regions after adjusting for age and education level (P < 0.05). The medial temporal, entorhinal cortex, amygdala and parahippocampal gyrus regions retained a significant APOE ε4 dosage × sex interaction effect on tau deposition after adjusting for global cortical amyloid-β (P < 0.05). In sex-stratified analysis, there was no significant difference in tau deposition between female homozygotes and heterozygotes (P > 0.05). In contrast, male homozygotes standardized uptake value ratios were significantly greater than heterozygotes or non-carriers throughout all 12 regions of interest (P < 0.05). Female heterozygotes exhibited significantly increased tau deposition compared to male heterozygotes in the orbitofrontal, posterior cingulate, lateral temporal, inferior temporal, entorhinal cortex, amygdala and parahippocampal gyrus (P < 0.05). Results from voxel-wise analysis were similar to the ones obtained from regions of interest analysis. Our findings indicate that an APOE ε4 dosage effect on brain region-specific tau deposition exists in males, but not females. These results have important clinical implications towards developing sex and genotype-guided therapeutics in Alzheimer's disease and uncovers a potential explanation underlying differential APOE ε4-associated Alzheimer's risk in males and females., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Vesicular acetylcholine transporter plays a crucial role in the cholinergic system, and its alterations is implicated in several neurodegenerative disorders. We recently developed a PET imaging tracer [ 18 F]VAT to target VAChT in vivo with high affinity and selectivity. Here we report in vitro characterization of [ 3 H]VAT, a tritiated counterpart of [ 18 F]VAT. Using human VAChT-rich cell membrane extracts, a saturated binding curve was obtained for [ 3 H]VAT with K d  = 6.5 nM and B max  = 22.89 pmol/mg protein. In the [ 3 H]VAT competition-binding assay with a panel of CNS ligands, binding inhibition of [ 3 H]VAT was observed using VAChT ligands, the K i values ranged from 5.41 to 33.3 nM. No inhibition was detected using a panel of other CNS ligands. In vitro [ 3 H]VAT autoradiography of rat brain sections showed strong signals in the striatum, moderate to high signals in vermis, thalamus, cortex, and hippocampus, and weak signals in cerebellum. Strong [ 3 H]VAT ARG signals were also observed from striatal sections of normal nonhuman primates and human brains. Competitive ARG study with human striatal sections demonstrated strong ARG signals of [ 3 H]VAT in caudate and putamen were blocked significantly by either VAChT ligand TZ659 or (-)-vesamicol, but not by the σ 1 receptor ligand Yun-122. ARG study also indicated that signal in the striatal sections from PSP human brains was lower than normal human brains. These data provide solid evidence supporting [ 18 F]VAT as a suitable PET radiotracer for quantitative assessment of VAChT levels in vivo., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Objectives: To predict when cognitively normal individuals with brain amyloidosis will develop symptoms of Alzheimer disease (AD)., Methods: Brain amyloid burden was measured by amyloid PET with Pittsburgh compound B. The mean cortical standardized uptake value ratio (SUVR) was transformed into a timescale with the use of longitudinal data., Results: Amyloid accumulation was evaluated in 236 individuals who underwent >1 amyloid PET scan. The average age was 66.5 ± 9.2 years, and 12 individuals (5%) had cognitive impairment at their baseline amyloid PET scan. A tipping point in amyloid accumulation was identified at a low level of amyloid burden (SUVR 1.2), after which nearly all individuals accumulated amyloid at a relatively consistent rate until reaching a high level of amyloid burden (SUVR 3.0). The average time between levels of amyloid burden was used to estimate the age at which an individual reached SUVR 1.2. Longitudinal clinical diagnoses for 180 individuals were aligned by the estimated age at SUVR 1.2. In the 22 individuals who progressed from cognitively normal to a typical AD dementia syndrome, the estimated age at which an individual reached SUVR 1.2 predicted the age at symptom onset ( R 2 = 0.54, p < 0.0001, root mean square error [RMSE] 4.5 years); the model was more accurate after exclusion of 3 likely misdiagnoses ( R 2 = 0.84, p < 0.0001, RMSE 2.8 years)., Conclusion: The age at symptom onset in sporadic AD is strongly correlated with the age at which an individual reaches a tipping point in amyloid accumulation., (© 2021 American Academy of Neurology.)

Sphingosine-1-phosphate receptor 1 (S1PR1) is ubiquitously expressed among all tissues and plays key roles in many physiological and cellular processes. In the central nervous system (CNS), S1PR1 is expressed in different types of cells including neurons, astrocytes, and oligodendrocyte precursor cells. S1PR1 has been recognized as a novel therapeutic target in multiple sclerosis and other diseases. We previously reported a promising S1PR1-specific radioligand, [ 11 C]CS1P1 (previously named [ 11 C]TZ3321), which is under clinical investigation for human use. In the current study, we performed a detailed characterization of [ 3 H]CS1P1 for its binding specificity to S1PR1 in CNS using autoradiography and immunohistochemistry in human and rat CNS tissues. Our data indicate that [ 3 H]CS1P1 binds to S1PR1 in human frontal cortex tissue with a K d of 3.98 nM and a B max of 172.5 nM. The distribution of [ 3 H]CS1P1 in human and rat CNS tissues is consistent with the distribution of S1PR1 detected by immunohistochemistry studies. Our microPET studies of [ 11 C]CS1P1 in a nonhuman primate (NHP) show a standardized uptake value of 2.4 in the NHP brain, with test-retest variability of 0.23% among six different NHPs. Radiometabolite analysis in the plasma samples of NHP and rat, as well as in rat brain samples, showed that [ 11 C]CS1P1 was stable in vivo . Kinetic modeling studies using a two-compartment tissue model showed that the positron emission tomography (PET) data fit the model well. Overall, our study provides a detailed characterization of [ 3 H]CS1P1 binding to S1PR1 in the CNS. Combined with our microPET studies in the NHP brain, our data suggest that [ 11 C]CS1P1 is a promising radioligand for PET imaging of S1PR1 in the CNS.

Sphingosine-1-phosphate receptor 1 (S1PR1) plays a crucial role in infectious diseases. Targeting S1PR1 provides protection against pathogens, such as influenza viruses. This study is aimed at investigating S1PR1 in response to bacterial infection by assessing S1PR1 expression in S. aureus -infected mice. A rodent local muscle bacterial infection model was developed by injecting S. aureus to the lower hind limb of Balb/c mice. The changes of S1PR1 expression in response to bacterial infection and blocking treatment were assessed using ex vivo biodistribution and in vivo positron emission tomography (PET) after intravenous injection of an S1PR1-specific radiotracer [ 18 F]TZ4877. The specificity of [ 18 F]TZ4877 was assessed using S1PR1-specific antagonist, NIBR-0213, and S1PR1-specific DsiRNA pretreated the animals. Immunohistochemical studies were performed to confirm the increase of S1PR1 expression in response to infection. Ex vivo biodistribution data showed that the uptake of [ 18 F]TZ4877 was increased 30.6%, 54.3%, 74.3%, and 115.3% in the liver, kidney, pancreas, and thymus of the infected mice, respectively, compared to that in normal control mice, indicating that S1PR1 is involved in the early immune response to bacterial infection. NIBR-0213 or S1PR1-specific DsiRNA pretreatment reduced the tissue uptake of [ 18 F]TZ4877, suggesting that uptake of [ 18 F]TZ4877 is specific. Our PET/CT study data also confirmed that infected mice have increased [ 18 F]TZ4877 uptake in several organs comparing to that in normal control mice. Particularly, compared to control mice, a 39% increase of [ 18 F]TZ4877 uptake was observed in the infected muscle of S. aureus mice, indicating that S1PR1 expression was directly involved in the inflammatory response to infection. Overall, our study suggested that S1PR1 plays an important role in the early immune response to bacterial infection. The uptake of [ 18 F]TZ4877 is tightly correlated with the S1R1 expression in response to S. aureus infection. PET with S1PR1-specific radiotracer [ 18 F]TZ4877 could provide a noninvasive tool for detecting the early S1PR1 immune response to infectious diseases., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2021 Hao Jiang et al.)

Pittsburgh compound B (PiB) radiotracer for positron emission tomography (PET) imaging can bind to different types of amyloid-β plaques and blood vessels (cerebral amyloid angiopathy). However, the relative contributions of different plaque subtypes (diffuse versus cored/compact) to in vivo PiB PET signal on a region-by-region basis are incompletely understood. Of particular interest is whether the same staging schemes for summarizing amyloid-β burden are appropriate for both late-onset and autosomal dominant forms of Alzheimer disease (LOAD and ADAD). Here, we compared antemortem PiB PET with follow-up postmortem estimation of amyloid-β burden using stereologic methods to estimate the relative area fraction of diffuse and cored/compact amyloid-β plaques across 16 brain regions in 15 individuals with ADAD and 14 individuals with LOAD. In ADAD, we found that PiB PET correlated with diffuse plaques in the frontal, parietal, temporal, and striatal regions commonly used to summarize amyloid-β burden in PiB PET, and correlated with both diffuse and cored/compact plaques in the occipital lobe and parahippocampal gyrus. In LOAD, we found that PiB PET correlated with both diffuse and cored/compact plaques in the anterior cingulate, frontal lobe (middle frontal gyrus), and parietal lobe, and showed additional correlations with diffuse plaque in the amygdala and occipital lobe, and with cored/compact plaque in the temporal lobe. Thus, commonly used PiB PET summary regions predominantly reflect diffuse plaque burden in ADAD and a mixture of diffuse and cored/compact plaque burden in LOAD. In direct comparisons of ADAD and LOAD, postmortem stereology identified much greater mean amyloid-β plaque burdens in ADAD versus LOAD across almost all brain regions studied. However, standard PiB PET did not recapitulate these stereologic findings, likely due to non-trivial amyloid-β plaque burdens in ADAD within the cerebellum and brainstem-commonly used reference regions in PiB PET. Our findings suggest that PiB PET summary regions correlate with amyloid-β plaque burden in both ADAD and LOAD; however, they might not be reliable in direct comparisons of regional amyloid-β plaque burden between the two forms of AD., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Decades of research has established a shift from an "eveningness" preference to a "morningness" preference with increasing age. Accordingly, older adults typically have better cognition in morning hours compared to evening hours. We present the first known attempt to capture circadian fluctuations in cognition in individuals at risk for Alzheimer disease (AD) using a remotely administered smartphone assessment that samples cognition rapidly and repeatedly over several days. Older adults (N = 169, aged 61-94 years; 93% cognitively normal) completed four brief smartphone-based testing sessions per day for 7 consecutive days at quasi-random time intervals, assessing associate memory, processing speed, and visual working memory. Scores completed during early hours were averaged for comparison with averaged scores completed during later hours. Mixed effects models evaluated time of day effects on cognition. Additional models included clinical status and cerebrospinal fluid (CSF) biomarkers for beta amyloid (Aβ42) and phosphorylated tau181 (pTau). Models with terms for age, gender, education, APOE ε4 status, and clinical status revealed significantly worse performance on associate memory in evening hours compared to morning hours. Contemporaneously reported mood and fatigue levels did not moderate relationships. Using CSF data to classify individuals with and without significant AD pathology, there were no group differences in performance in morning hours, but subtle impairment emerged in associate memory in evening hours in those with CSF-confirmed AD pathology. These findings indicate that memory is worse in evening hours in older adults, that this pattern is consistent across several days, and is independent of measures of mood and fatigue. Further, they provide preliminary evidence of a "cognitive sundowning" in the very earliest stages of AD. Time of day may be an important consideration for assessments in observational studies and clinical trials in AD populations.

Background: Comprehensive testing of cognitive functioning is standard practice in studies of Alzheimer disease (AD). Short-form tests like the Montreal Cognitive Assessment (MoCA) use a "sampling" of measures, administering key items in a shortened format to efficiently assess cognition while reducing time requirements, participant burden, and administrative costs. We compared the MoCA to a commonly used long-form cognitive battery in predicting AD symptom onset and sensitivity to AD neuroimaging biomarkers., Methods: Survival, area under the receiver operating characteristic (ROC) curve (AUC), and multiple regression analyses compared the MoCA and long-form measures in predicting time to symptom onset in cognitively normal older adults (n = 6230) from the National Alzheimer's Coordinating Center (NACC) cohort who had, on average, 2.3 ± 1.2 annual assessments. Multiple regression models in a separate sample (n = 416) from the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) compared the sensitivity of the MoCA and long-form measures to neuroimaging biomarkers including amyloid PET, tau PET, and cortical thickness., Results: Hazard ratios suggested that both the MoCA and the long-form measures are similarly and modestly efficacious in predicting symptomatic conversion, although model comparison analyses indicated that the long-form measures slightly outperformed the MoCA (HRs > 1.57). AUC analyses indicated no difference between the measures in predicting conversion (DeLong's test, Z = 1.48, p = 0.13). Sensitivity to AD neuroimaging biomarkers was similar for the two measures though there were only modest associations with tau PET (rs = - 0.13, ps < 0.02) and cortical thickness in cognitively normal participants (rs = 0.15-0.16, ps < 0.007)., Conclusions: Both test formats showed weak associations with symptom onset, AUC analyses indicated low diagnostic accuracy, and biomarker correlations were modest in cognitively normal participants. Alternative assessment approaches are needed to improve how clinicians and researchers monitor cognitive changes and disease progression prior to symptom onset., (© 2021. The Author(s).)

Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer's disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18-94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology., (© 2021. The Author(s).)

Purpose: Recent studies have shown that standard compartmental models using plasma input or the cerebellum reference tissue input are generally not reliable for quantifying tau burden in dynamic 18 F-flortaucipir PET studies of Alzheimer disease. So far, the optimal reference region for estimating 18 F-flortaucipir delivery and specific tau binding has yet to be determined. The objective of the study is to improve 18 F-flortaucipir brain tau PET quantification using a spatially constrained kinetic model with dual reference tissues., Methods: Participants were classified as either cognitively normal (CN) or cognitively impaired (CI) based on clinical assessment. T1-weighted structural MRI and 105-min dynamic 18 F-flortaucipir PET scans were acquired for each participant. Using both a simplified reference tissue model (SRTM2) and Logan plot with either cerebellum gray matter or centrum semiovale (CS) white matter as the reference tissue, we estimated distribution volume ratios (DVRs) and the relative transport rate constant R 1 for region of interest-based (ROI) and voxelwise-based analyses. Conventional linear regression (LR) and LR with spatially constrained (LRSC) parametric imaging algorithms were then evaluated. Noise-induced bias in the parametric images was compared to estimates from ROI time activity curve-based kinetic modeling. We finally evaluated standardized uptake value ratios at early phase (SUVR EP , 0.7-2.9 min) and late phase (SUVR LP , 80-105 min) to approximate R 1 and DVR, respectively., Results: The percent coefficients of variation of R 1 and DVR estimates from SRTM2 with spatially constrained modeling were comparable to those from the Logan plot and SUVRs. The SRTM2 using CS reference tissue with LRSC reduced noise-induced underestimation in the LR generated DVR images to negligible levels (< 1%). Inconsistent overestimation of DVR in the SUVR LP only occurred using the cerebellum reference tissue-based measurements. The CS reference tissue-based DVR and SUVR LP , and cerebellum-based SUVR EP and R 1 provided higher Cohen's effect size d to detect increased tau deposition and reduced relative tracer transport rate in CI individuals., Conclusion: Using a spatially constrained kinetic model with dual reference tissues significantly improved quantification of relative perfusion and tau binding. Cerebellum and CS are the suggested reference tissues to estimate R 1 and DVR, respectively, for dynamic 18 F-flortaucipir PET studies. Cerebellum-based SUVR EP and CS-based SUVR LP may be used to simplify 18 F-flortaucipir PET study., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)