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AimsLewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aβ) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing.MethodsHippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aβ. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing.ResultsLBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P

Kathryn B Holroyd,1 Lisa Fosdick,2 Gwenn S Smith,1 Jeannie-Marie Leoutsakos,1 Cynthia A Munro,1 Esther S Oh,1 Kristen E Drake,2 Paul B Rosenberg,1 William S Anderson,1 Stephen Salloway,3–5 J Cara Pendergrass,6 Anna D Burke,7 David A Wolk,8 David F Tang-Wai,9–11 Francisco A Ponce,12 Wael F Asaad,13,14 Marwan N Sabbagh,15 Michael S Okun,16 Gordon Baltuch,17 Kelly D Foote,18 Steven D Targum,2,6 Andres M Lozano,10,11 Constantine G Lyketsos1 1Johns Hopkins University Memory and Alzheimer's Treatment Center, Baltimore, MD, 2Functional Neuromodulation Ltd, Minneapolis, MN, 3Department of Neurology, Butler Hospital, 4Department of Neurology, Rhode Island Hospital, 5Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, 6Clintara LLC, Boston, MA, 7Banner Alzheimer's Institute, Phoenix, AZ, 8Penn Memory Center, Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA; 9Department of Neurology, 10Department of Neurosurgery, University of Toronto, 11Division of Neurology, University Health Network Memory Clinic, Toronto, ON, Canada; 12Division of Neurological Surgery, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, AZ, 13Department of Neurosurgery, Rhode Island Hospital, 14Department of Neurosurgery, Warren Alpert Medical School of Brown University, Providence, RI, 15Banner Sun Health Research Institute, Sun City, AZ, 16Center for Movement Disorders and Neurorestoration, Department of Neurology, University of Florida – Gainsville, Gainsville, FL, 17Center for Functional and Restorative Neurosurgery, University of Pennsylvania, Philadelphia, PA, 18Department of Neurosurgery, Center for Movement Disorders and Neurorestoration, University of Florida, Gainsville, FL, USA Background: There are currently few available treatments and no cure for Alzheimer disease (AD), a growing public health burden. Animal models and an open-label human trial have indicated that deep brain stimulation (DBS) of memory circuits may improve symptoms and possibly slow disease progression. The ADvance trial was designed to examine DBS of the fornix as a treatment for mild AD. Methods: ADvance is a randomized, double-blind, placebo-controlled, delayed-start, multicenter clinical trial conducted at six sites in the US and one site in Canada. Eighty-five subjects initially consented to be screened for the trial. Of these, 42 subjects who met inclusion and exclusion criteria were implanted with DBS leads anterior to the columns of the fornix bilaterally. They were randomized 1:1 to DBS “off” or DBS “on” groups for the initial 12 months of follow-up. After 1 year, all subjects will have their devices turned “on” for the remainder of the study. Postimplantation, subjects will return for 13 follow-up visits over 48 months for cognitive and psychiatric assessments, brain imaging (up to 12 months), and safety monitoring. The primary outcome measures include Alzheimer's Disease Assessment Scale – cognitive component (ADAS-cog-13), Clinical Dementia Rating sum of boxes (CDR-SB), and cerebral glucose metabolism measured with positron emission tomography. This report details the study methods, baseline subject characteristics of screened and implanted participants, and screen-to-baseline test–retest reliability of the cognitive outcomes. Results: Implanted subjects had a mean age of 68.2 years, were mostly male (55%), and had baseline mean ADAS-cog-13 and CDR-SB scores of 28.9 (SD, 5.2) and 3.9 (SD, 1.6), respectively. There were no significant differences between screened and implanted or nonimplanted subjects on most demographic or clinical assessments. Implanted subjects had significantly lower (better) ADAS-cog-11 (17.5 vs 21.1) scores, but did not differ on CDR-SB. Scores on the major outcome measures for the trial were consistent at screening and baseline. Conclusion: ADvance was successful in enrolling a substantial group of patients for this novel application of DBS, and the study design is strengthened by rigorous subject selection from seven sites, a double-blind placebo-controlled design, and extensive open-label follow-up. Keywords: deep brain stimulation, Alzheimer disease, fornix, methods, clinical trials

Background: Significant heterogeneity in clinical features of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) cases with the pathogenic C9orf72 expansion (C9P) have been described. To clarify this issue, we compared a large C9P cohort with carefully matched non-expansion (C9N) cases with a known or highly-suspected underlying TAR DNA-binding protein 43 (TDP-43) proteinopathy.Methods: A retrospective case-control study was carried out using available cross-sectional and longitudinal clinical and neuropsychological data, MRI voxel-based morphometry (VBM) and neuropathological assessment from 64 C9P cases (ALS=31, FTLD=33) and 79 C9N cases (ALS=36, FTLD=43).Results: C9P cases had an earlier age of onset (p=0.047) and, in the subset of patients who were deceased, an earlier age of death (p=0.014) than C9N. C9P had more rapid progression than C9N: C9P ALS cases had a shortened survival (2.6 ± 0.3 years) compared to C9N ALS (3.8 ± 0.4 years; log-rank λ2=4.183, p=0.041), and C9P FTLD showed a significantly greater annualised rate of decline in letter fluency (4.5 ± 1.3 words/year) than C9N FTLD (1.4 ± 0.8 words/year, p=0.023). VBM revealed greater atrophy in the right frontoinsular, thalamus, cerebellum and bilateral parietal regions for C9P FTLD relative to C9N FTLD, and regression analysis related verbal fluency scores to atrophy in frontal and parietal regions. Neuropathological analysis found greater neuronal loss in the mid-frontal cortex in C9P FTLD, and mid-frontal cortex TDP-43 inclusion severity correlated with poor letter fluency performance.Conclusions: C9P cases may have a shorter survival in ALS and more rapid rate of cognitive decline related to frontal and parietal disease in FTLD. C9orf72 genotyping may provide useful prognostic and diagnostic clinical information for patients with ALS and FTLD. [ABSTRACT FROM AUTHOR]

The frequency and clinical and pathological characteristics associated with the Gly206Ala presenilin 1 (PSEN1) mutation in Puerto Rican and non-Puerto Rican Hispanics were evaluated at the University of Pennsylvania's Alzheimer's Disease Center. DNAs from all cohort subjects were genotyped for the Gly206Ala PSEN1 mutation. Carriers and non-carriers with neurodegenerative disease dementias were compared for demographic, clinical, psychometric, and biomarker variables. Nineteen (12.6%) of 151 unrelated subjects with dementia were discovered to carry the PSEN1 Gly206Ala mutation. Microsatellite marker genotyping determined a common ancestral haplotype for all carriers. Carriers were all of Puerto Rican heritage with significantly younger age of onset, but otherwise were clinically and neuropsychologically comparable to those of non-carriers with AD. Three subjects had extensive topographic and biochemical biomarker assessments that were also typical of non-carriers with AD. Neuropathological examination in one subject revealed severe, widespread plaque and tangle pathology without other meaningful disease lesions. The PSEN1 Gly206Ala mutation is notably frequent in unrelated Puerto Rican immigrants with dementia in Philadelphia. Considered together with the increased prevalence and mortality of AD reported in Puerto Rico, these high rates may reflect hereditary risk concentrated in the island which warrants further study. [ABSTRACT FROM AUTHOR]

There is growing recognition of an interaction between cerebrovascular disease and Alzheimer's disease, but the mechanisms of this interaction remain poorly understood. While macroscopic stroke can clearly produce cognitive deficits and accelerate Alzheimer's disease, the prevalence and implications of microvascular disease in Alzheimer's disease pathogenesis has been harder to define. At present, white matter (WM) lesions, primarily defined as hyperintensities seen on T2-weighted magnetic resonance imaging (MRI), provide the best biomarker of cerebrovascular disease at the microvascular level. However, T2 hyperintensities in WM can also be caused by other mechanisms such as inflammation. Arterial spin labeled (ASL) perfusion MRI provides a noninvasive approach for quantifying cerebral blood flow (CBF). We explored CBF measurements with ASL in AD patients, mild cognitive impairment patients, and an age-matched control group to determine if CBF in gray matter or WM could be correlated with WM lesions, or to stratify patients by microvascular disease severity. In a retrospective sample, we were able to obtain credible measures of WM CBF using ASL MRI and observed trends suggesting that WM CBF may provide a useful biomarker of microvascular disease. Future prospective studies in larger cohorts with optimized ASL MRI protocols will be needed to validate these observations. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether some patients with very mild Alzheimer's disease (AD) demonstrate disproportionate executive dysfunction relative to amnesia and how this relates to functional impairment in daily life, future clinical decline, APOE genotype and regional cortical thickness measured from MRI scan data.Methods: The Alzheimer's Disease Neuroimaging Initiative dataset was interrogated for a primary sample of patients with very mild AD dementia (n=100) and a secondary confirmatory sample of patients with mild cognitive impairment (n=396). An executive predominant subgroup was defined as having executive performance ≥2 SDs worse than memory performance and a memory predominant subgroup was defined conversely. A priori regions of interest from a previous study of an AD patient sample were used to obtain cortical thickness measures.Results: Despite equivalent global measures of impairment (Mini-Mental State Examination, Clinical Dementia Rating (CDR) Sum of Boxes), executive predominant patients (n=88) were more impaired on other executive measures and in the CDR Judgement and Problem Solving box (p<0.005) while memory predominant patients (n=56) were more impaired on other memory measures (p<0.05). The APOE-ε4 allele was much more frequent in the memory predominant subgroup (p<0.0001). Frontoparietal cortical regions were thinner in the executive predominant group than in the memory predominant group (p<0.05).Conclusions: A dysexecutive clinical phenotype of very mild AD is not rare and is associated with more problem solving difficulties and possibly more rapid progression compared with patients with a predominant amnesic phenotype. Executive predominant AD may reflect an alternative underlying pathophysiology related to genetic status, reflected in more prominent pathological alterations in frontoparietal regions subserving executive function. These findings, which deserve further investigation, may have implications for diagnosis, prognostication, monitoring and related issues involved in clinical research and care. [ABSTRACT FROM AUTHOR]

Introduction: The generalizability of neuroimaging and cognitive biomarkers in their sensitivity to detect preclinical Alzheimer's disease (AD) and power to predict progression in large, multisite cohorts remains unclear., Method: Longitudinal demographics, T1-weighted magnetic resonance imaging (MRI), and cognitive scores of 3036 cognitively unimpaired (CU) older adults (amyloid beta [Aβ]-negative/positive [A-/A+]: 1270/1558) were included. Cross-sectional and longitudinal cognition and medial temporal lobe (MTL) structural measures were extracted. Cross-sectional MTL tau burden (T) was computed from tau positron emission tomography (N = 1095)., Results: We found cross-sectional tau and longitudinal structural biomarkers best separated A+ CU from A- CU. A-T+ CU had significantly faster neurodegeneration rate compared to A-T- CU. MTL tau was significantly correlated with MRI and cognitive biomarkers regardless of Aβ status. MTL tau, MRI, and cognition provided complementary information about disease progression., Discussion: This large multisite study replicates prior findings in CU older adults, supporting the utility of neuroimaging and cognitive biomarkers in preclinical AD clinical trials and normal aging studies., Highlights: We investigated neuroimaging and cognitive biomarkers in 3036 cognitively unimpaired (CU) participants. Medial temporal lobe (MTL) tau and longitudinal MTL atrophy best separate amyloid beta positive (A+) CU from amyloid beta negative (A-) CU. A- tau positive (T+) CU had a significantly faster neurodegeneration rate compared to A-T- CU. MTL tau correlated with structural magnetic resonance imaging (MRI) and cognition regardless of amyloid beta status. Combined baseline MTL tau, MRI, and cognition best predict Alzheimer's disease progression., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Tau exhibits change in both spatial extent and density of pathology along the Alzheimer's disease (AD) spectrum with each aspect contributing to the overall burden of pathological tau. Nevertheless, studies using Tau PET have measured either magnitude using standardized uptake value ratios (SUVRs) or extent using number of Tau+ regions. We hypothesized that combining these two dimensions into a single measure of Magnitude and eXtent, Tau-MaX, would provide improved quantification of global tau burden as well as allowing for a region-agnostic measure of global tau burden that does not require a pre-specified region of interest (ROI) or meta-ROI. To test this hypothesis, we analyzed 18 F-flortaucipir PET scans from local and national consortium data (n=1077 participants total) and used Gaussian-mixture models for data from 64 brain regions, to define both tau positivity and magnitude. We examined cross-sectional and longitudinal change in Tau-MaX across the Alzheimer's disease (AD) spectrum and compared the association of Tau-MaX, magnitude, and extent with plasma p-tau 217 and global cognition. We also compared Tau-MaX using a global, region-agnostic approach to temporal lobe or Braak stage meta-ROIs. Whereas separate assessments of extent and magnitude across the disease spectrum found earlier increases in Tau spatial extent and later increases in magnitude, Tau-MaX was able to dynamically capture this shift demonstrating a stronger association with extent in the preclinical stage and a stronger association with magnitude in clinical stages. Global Tau-MaX differed between disease stages cross-sectionally and changed over time in all stages of disease. Further, Tau-MaX significantly improved associations with plasma p-tau 217 and global cognition compared to magnitude or extent alone. Finally, global measures of Tau-MaX performed similarly to meta-ROI measures of Tau-MaX. Together, these findings indicate that combining magnitude and extent provides a robust measure of global tau burden that changes throughout the disease course and is associated with blood-based biomarkers and cognition. This measure may be of particular use for disease staging, as well as serving as an outcome measure to monitor response to therapeutic intervention., Competing Interests: Competing interests CAB, SRD, JAD, PAY, KAQC, and CTM declare no competing interests. Ilya Nasrallah has served on the Scientific Advisory Board for Eisai and done educational speaking for Biogen. Alice Chen-Plotkin has a patent licensed to Prevail Therapeutics for genetic approaches to treating frontotemporal dementia. Leslie Shaw has served on scientific advisory boards and/or as a consultant for Biogen, Roche Diagnostics, Fujirebio, Siemens, and Diadem and has given lectures for Biogen, Roche, and Fujirebio. Edward Lee has served as a paid consultant for Wavebreak Therapeutics and Eli Lilly. David Wolk has served as a paid consultant for Eli Lilly and Beckman Coulter. He has also served on the DSMB for Functional Neuromodulation and GSK. He has received research support paid to his institution by Biogen. Data collection and sharing for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) is funded by the National Institute on Aging (National Institutes of Health Grant U19 AG024904). The grantee organization is the Northern California Institute for Research and Education. In the past, ADNI has also received funding from the National Institute of Biomedical Imaging and Bioengineering, the Canadian Institutes of Health Research, and private sector contributions through the Foundation for the National Institutes of Health (FNIH) including generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research &Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics.

Behavioural variant frontotemporal dementia (bvFTD) is a clinical syndrome caused primarily by either tau (bvFTD-tau) or transactive response DNA-binding protein of 43 kDa (TDP-43) (bvFTD-TDP) proteinopathies. We previously found that lower cortical layers and dorsolateral regions accumulate greater tau than TDP-43 pathology; however, the patterns of laminar neurodegeneration across diverse cytoarchitecture in bvFTD are understudied. We hypothesized that bvFTD-tau and bvFTD-TDP have distinct laminar distributions of pyramidal neurodegeneration along cortical gradients, a topological order of cytoarchitectonic subregions based on increasing pyramidal density and laminar differentiation. Here, we tested this hypothesis in a frontal cortical gradient consisting of five cytoarchitectonic types (i.e. periallocortex, agranular mesocortex, dysgranular mesocortex, eulaminate-I isocortex and eulaminate-II isocortex) spanning the anterior cingulate, paracingulate, orbitofrontal and mid-frontal gyri in bvFTD-tau (n = 27), bvFTD-TDP (n = 47) and healthy controls (n = 32). We immunostained all tissue for total neurons (NeuN; neuronal-nuclear protein) and pyramidal neurons (SMI32; non-phosphorylated neurofilament) and digitally quantified NeuN-immunoreactivity (ir) and SMI32-ir in supragranular II-III, infragranular V-VI and all I-VI layers in each cytoarchitectonic type. We used linear mixed-effects models adjusted for demographic and biological variables to compare SMI32-ir between groups and examine relationships with the cortical gradient, long-range pathways and clinical symptoms. We found regional and laminar distributions of SMI32-ir expected for healthy controls, validating our measures within the cortical gradient framework. The SMI32-ir loss was relatively uniform along the cortical gradient in bvFTD-TDP, whereas SMI32-ir decreased progressively along the cortical gradient of bvFTD-tau and included greater SMI32-ir loss in supragranular eulaminate-II isocortex in bvFTD-tau versus bvFTD-TDP (P = 0.039). Using a ratio of SMI32-ir to model known long-range connectivity between infragranular mesocortex and supragranular isocortex, we found a larger laminar ratio in bvFTD-tau versus bvFTD-TDP (P = 0.019), suggesting that select long-projecting pathways might contribute to isocortical-predominant degeneration in bvFTD-tau. In cytoarchitectonic types with the highest NeuN-ir, we found lower SMI32-ir in bvFTD-tau versus bvFTD-TDP (P = 0.047), suggesting that pyramidal neurodegeneration might occur earlier in bvFTD-tau. Lastly, we found that reduced SMI32-ir was related to behavioural severity and frontal-mediated letter fluency, not temporal-mediated confrontation naming, demonstrating the clinical relevance and specificity of frontal pyramidal neurodegeneration to bvFTD-related symptoms. Our data suggest that loss of neurofilament-rich pyramidal neurons is a clinically relevant feature of bvFTD that worsens selectively along a frontal cortical gradient in bvFTD-tau, not bvFTD-TDP. Therefore, tau-mediated degeneration might preferentially involve pyramidal-rich layers that connect more distant cytoarchitectonic types. Moreover, the hierarchical arrangement of cytoarchitecture along cortical gradients might be an important neuroanatomical framework for identifying which types of cells and pathways are involved differentially between proteinopathies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is highly prevalent in late life and a common co-pathology with Alzheimer's disease neuropathologic change (ADNC). LATE-NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE-NC is associated with a more rapid course. With the emergence of anti-amyloid therapeutics, discrimination of LATE-NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co-pathology with LATE-NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE-NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). HIGHLIGHTS: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE-NC) is a common co-pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease-modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE-NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: We describe the Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core major activities from October 2004 to March 2024, including biobanking ADNI cerebrospinal fluid (CSF), plasma, and serum biofluid samples, biofluid analyses for Alzheimer's disease (AD) biomarkers in the Biomarker Core and various non-ADNI laboratories, and continuous assessments of pre-analytics., Results: Validated immunoassay and mass spectrometry-based assays were performed in CSF with a shift to plasma, a more accessible biofluid, as qualified assays became available. Performance comparisons across different CSF and plasma AD biomarker measurement platforms have enriched substantially the ADNI participant database enabling method performance determinations for AD pathology detection and longitudinal assessments of disease progression., Discussion: Close collaboration with academic and industrial partners in the validation and implementation of AD biomarkers for early detection of disease pathology in treatment trials and ultimately in clinical practice is a key factor for the success of the work done in the Biomarker Core., Highlights: Describe ADNI Biomarker Core biobanking and sample distribution from 2007 to 2024. Discuss validated mass spectrometry and immunoassay methods for ADNI biofluid analyses. Review collaborations with academic and industrial partners to detect AD and progression. Discuss major challenges, and progress to date, for co-pathology detection. Implementation in the ATN scheme: co-pathology and modeling disease progression., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Alzheimer's disease (AD) typically involves both neurodegenerative and vascular pathologies, each associated with reductions in cerebral blood flow (CBF). However, it remains unclear whether vascular and neural contributions to regional CBF can be differentiated., Methods: Using 3D background-suppressed arterial spin labeled perfusion magnetic resonance imaging, we evaluated regional CBF in a cohort of 257 participants across the AD continuum and assessed the impact of risk factors for both AD and small vessel disease (SVD) on regional CBF., Results: Vascular risk factors (VRFs) were associated with reduced CBF in normal-appearing periventricular white matter, while amyloid positivity was associated with reduced CBF in the posterior cingulate cortex and precuneus. Putative SVD-sensitive regions in white matter exhibited diagnosis-related CBF changes comparable to those in typical AD cortical regions., Discussion: Spatial patterns of hypoperfusion may differentiate AD and VRF-related effects on regional CBF. Our findings also support the contribution of SVD in AD pathogenesis., Highlights: We used 3D background-suppressed pCASL MRI to evaluate CBF across the AD continuum. Putative SVD-sensitive regions in white matter exhibited diagnosis-related CBF changes. AD and/or SVD risk correlated with reduced CBF in AD and/or SVD-related regions. VRFs were associated with more widespread CBF reductions than amyloid positivity. Spatial patterns of hypoperfusion may differentiate AD and VRF-related effects., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The presence of multiple pathologies is the largest predictor of dementia. A major gap in the field is the in vivo detection of mixed pathologies and their antecedents. The Alzheimer's Disease Research Centers (ADRCs) are uniquely positioned to address this gap. The ADRCs longitudinally follow ≈ 17,000 participants, ranging from cognitively unimpaired to dementia, arising from Alzheimer's disease (AD) and related dementias (ADRD; e.g., AD, Lewy body disorders, vascular). Motivated by the Alzheimer's Disease Neuroimaging Initiative's (ADNI) impact, the ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) was formed. Leveraging existing ADRC infrastructure, CLARiTI will integrate standardized imaging and plasma collection to characterize mixed pathologies and use community-engaged research methods to ensure that ≥ 25% of the sample is from underrepresented populations (e.g., ethnoculturally minoritized, low education). The resulting ADRD profiles, within a more diverse sample, will provide key resources for ADRCs and an unprecedented, more generalizable publicly available imaging-plasma dataset. HIGHLIGHTS: In vivo detection of mixed pathologies is critical for Alzheimer's disease and related dementias research. The Alzheimer's Disease Research Centers (ADRCs) are uniquely positioned to address gaps related to mixed pathologies. The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will enhance this national program by adding standardized imaging and plasma collection to existing ADRC infrastructure. This effort will provide key resources for ADRCs and an unprecedented publicly available imaging-plasma-neuropath dataset., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) share similar amyloid etiology, but evidence from smaller-scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD., Methods: Z-score cognitive-domain composites for 311 amyloid-positive sporadic EOAD and 314 amyloid-positive LOAD participants were calculated from baseline data from age-appropriate control cohorts. Z-score composites were compared between AD groups for each domain., Results: After controlling for cognitive status, EOAD displayed worse visuospatial, executive functioning, and processing speed/attention skills relative to LOAD, and LOAD displayed worse language, episodic immediate memory, and episodic delayed memory., Discussion: Sporadic EOAD possesses distinct cognitive profiles relative to LOAD. Clinicians should be alert for non-amnestic impairments in younger patients to ensure proper identification and intervention using disease-modifying treatments., Highlights: Both early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) participants displayed widespread cognitive impairments relative to their same-aged peers. Cognitive impairments were more severe for EOAD than for LOAD participants in visuospatial and executive domains. Memory and language impairments were more severe for LOAD than for EOAD participants Results were comparable after removing clinical phenotypes of posterior cortical atrophy (PCA), primary progressive aphasia (lv-PPA), and frontal-variant AD., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Early-onset Alzheimer's disease (EOAD) manifests prior to the age of 65, and affects 4%-8% of patients with Alzheimer's disease (AD). The current analyses sought to examine longitudinal cognitive trajectories of participants with early-onset dementia., Methods: Data from 307 cognitively normal (CN) volunteer participants and those with amyloid-positive EOAD or amyloid-negative cognitive impairment (EOnonAD) were compared. Cognitive trajectories across a comprehensive cognitive battery spanning 42 months were examined using mixed-effects modeling., Results: The EOAD group displayed worse cognition at baseline relative to EOnonAD and CN groups, and more aggressive declines in cognition over time. The largest effects were observed on measures of executive functioning domains, while memory declines were blunted in EOAD., Discussion: EOAD declined 2-4× faster than EOnonAD, and EOAD pathology is not restricted to memory networks. Early identification of deficits is critical to ensure that individuals with sporadic EOAD can be considered for treatment using disease-modifying medications., Highlights: Represents the most comprehensive longitudinal characterization of sporadic EOAD to date. The trajectory of cognitive declines was steep for EOAD participants and worse than for other groups. Executive functioning measures exhibited the greatest declines over time in EOAD., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Primary age-related tauopathy (PART) and Alzheimer's disease (AD) share hippocampal phospho-tau (p-tau) pathology but differ in p-tau extent and ß-amyloid presence. As a result, PART uniquely enables investigation of amyloid-independent p-tau mechanisms during brain aging. We conducted an epigenome-wide association (EWAS) study of PART, nominating 13 new and robust p-tau/methylation associations. We then jointly analyzed PART and AD epigenomes to develop novel epigenetic clocks, "TauAge", that predict p-tau severity in region-specific, age-, and ß-amyloid-independent manners. Integrative transcriptomic analyses revealed that genes involved in synaptic transmission are related to hippocampal p-tau severity in both PART and AD, while neuroinflammatory genes are related to frontal cortex p-tau severity in AD only. Further, a machine learning classifier trained on PART-vs-AD epigenetic differences stratifies an independent cohort of neuropathologically indeterminate cases into pathological subgroups with disparity in cognitive impairment. Together, these findings demonstrate the brain epigenome's substantial role in linking tau pathology to cognitive outcomes in aging and AD.

In neuroimaging research, volumetric data contribute valuable information for understanding brain changes during both healthy aging and pathological processes. Extracting these measures from images requires segmenting the regions of interest (ROIs), and many popular methods accomplish this by fusing labels from multiple expert-segmented images called atlases. However, post-segmentation, current practices typically treat each subject's measurement equally without incorporating any information about variation in their segmentation precision. This naïve approach hinders comparing ROI volumes between different samples to identify associations between tissue volume and disease or phenotype. We propose a novel method that estimates the variance of the measured ROI volume for each subject due to the multi-atlas segmentation procedure. We demonstrate in real data that weighting by these estimates markedly improves the power to detect a mean difference in hippocampal volume between controls and subjects with mild cognitive impairment or Alzheimer's disease., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Lewy body disorders (LBD), encompassing Parkinson disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB), are characterized by alpha-synuclein pathology but often are accompanied by Alzheimer's disease (AD) neuropathological change (ADNC). The medial temporal lobe (MTL) is a primary locus of tau accumulation and associated neurodegeneration in AD. However, it is unclear the extent to which AD copathology in LBD (LBD/AD+) contributes to MTL-specific patterns of degeneration. We employ a MTL subregional segmentation strategy of T1-weighted (T1w) MRI in biomarker-supported or autopsy-confirmed LBD and LBD/AD+ to investigate the anatomic consequences of co-occurring LBD/AD+ pathology on neurodegeneration., Methods: We studied 167 individuals with clinical diagnoses of LBD (PD, n = 124 (74.3 %); PDD, n = 11 (6.6 %); DLB, n = 32 (19.2 %)) with available T1w MRI and AD biomarkers or autopsy evidence of ADNC. Individuals were further biologically classified as LBD/AD+ based on hierarchical evidence of ADNC pathology: 1) AD "intermediate" or "high" by ABC neuropathologic criteria (n = 39 (23.4 %)); 2) positive amyloid PET (n = 2 (1.2 %)); or 3) CSF β-amyloid 1-42  < 185.7 pg/mL n = 126 (75.4 %)). The T1 Automated Segmentation of Hippocampal Subfields (ASHS) pipeline was used to compute volume and thickness measurements of MTL subregions in LBD/AD- and LBD/AD+. Linear regression tested the association of AD copathology and subregion volume/thickness, covarying for age and sex, and intracranial volume for volume measurements. Secondary analyses correlated MTL subregional volume/thickness with cognition and neuropathology., Results: LBD/AD+ had decreased volume/thickness compared to LBD/AD- in all MTL subregions except posterior hippocampus. The greatest effect sizes were seen in Brodmann Area 35 (BA35) (Cohen's d = 0.62, p = 0.002, β = 0.107 ± 0.034), and entorhinal cortex (ERC) (Cohen's d = 0.56, p = 0.006, β = 0.088 ± 0.031). Smaller differences were seen in the parahippocampal cortex (PHC) (Cohen's d = 0.5, p = 0.012, β = 0.082 ± 0.033), BA36 (Cohen's d = 0.47, p = 0.021, β = 0.090 ± 0.039) and anterior hippocampus (Cohen's d = 0.45, p = 0.029, β = 111.790 ± 50.595). Verbal memory scores positively correlated with volume/thickness in anterior and posterior hippocampus, BA35, ERC and PHC, while visuospatial memory positively correlated only in BA35. In the subset of participants with autopsy, lower ERC volume was associated with a higher tau load in ERC (adjusted odds ratio 0.013, 95 % CI [0.0002, 0.841], uncorrected p = 0.041)., Conclusions: Relative to LBD/AD-, LBD/AD+ has greater T1w MRI evidence of atrophy in multiple MTL subregions. Atrophy in MTL subregions associates with memory performance and tau pathological load. The observed pattern of atrophy largely follows expectation from AD Braak stages, except for posterior hippocampus. Longitudinal studies are needed to validate the hypothesized spread of neurodegeneration., Competing Interests: Declaration of competing interest I.M.N. has received payments from Premier, Inc for participating in an advisory board, from Peerview for an educational talk, and from Subtle Medical, Inc for consulting. E.B.L has a consulting agreement with WaveBreak Therapeutics. D.W. has received research funding or support from Michael J. Fox Foundation for Parkinson’s Research, International Parkinson and Movement Disorder Society (IPMDS), National Institute on Health (NIH), The Parkinson’s Foundation and the U.S. Department of Veterans Affairs; honoraria for consultancy from AbbVie, Boehringer Ingelheim, Cerevel Therapeutics, CHDI Foundation, Citrus Health Group, Medscape, Modality.AI, Parkinson Study Group, Roche, Sage Therapeutics, Scion NeuroStim, Signant Health and Vanqua Bio; and license fee payments from the University of Pennsylvania for the QUIP and QUIP-RS.  D.A.W. has served as a paid consultant to Beckman Coulter and Eli Lilly. He also received grants from the NIH and Biogen paid to his institution and received travel support from the Alzheimer's Association.  He has served on the DSMB of studies by Functional Neuromodulation and GSK. The remaining 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 © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Arterial spin labeling (ASL) derived cerebral blood flow (CBF) maps are prone to artifacts and noise that can degrade image quality., Purpose: To develop an automated and objective quality evaluation index (QEI) for ASL CBF maps., Study Type: Retrospective., Population: Data from N = 221 adults, including patients with Alzheimer's disease (AD), Parkinson's disease, and traumatic brain injury., Field Strength/sequence: Pulsed or pseudocontinuous ASL acquired at 3 T using non-background suppressed 2D gradient-echo echoplanar imaging or background suppressed 3D spiral spin-echo readouts., Assessment: The QEI was developed using N = 101 2D CBF maps rated as unacceptable, poor, average, or excellent by two neuroradiologists and validated by 1) leave-one-out cross validation, 2) assessing if CBF reproducibility in N = 53 cognitively normal adults correlates inversely with QEI, 3) if iterative discarding of low QEI data improves the Cohen's d effect size for CBF differences between preclinical AD (N = 27) and controls (N = 53), 4) comparing the QEI with manual ratings for N = 50 3D CBF maps, and 5) comparing the QEI with another automated quality metric., Statistical Tests: Inter-rater reliability and manual vs. automated QEI were quantified using Pearson's correlation. P < 0.05 was considered significant., Results: The correlation between QEI and manual ratings (R = 0.83, CI: 0.76-0.88) was similar (P = 0.56) to inter-rater correlation (R = 0.81, CI: 0.73-0.87) for the 2D data. CBF reproducibility correlated negatively (R = -0.74, CI: -0.84 to -0.59) with QEI. The effect size comparing patients and controls improved (R = 0.72, CI: 0.59-0.82) as low QEI data was discarded iteratively. The correlation between QEI and manual ratings (R = 0.86, CI: 0.77-0.92) of 3D ASL was similar (P = 0.09) to inter-rater correlation (R = 0.78, CI: 0.64-0.87). The QEI correlated (R = 0.87, CI: 0.77-0.92) significantly better with manual ratings than did an existing approach (R = 0.54, CI: 0.30-0.72)., Data Conclusion: Automated QEI performed similarly to manual ratings and can provide scalable ASL quality control., Evidence Level: 2 TECHNICAL EFFICACY: Stage 1., (© 2024 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: The hippocampus plays a crucial role in memory and is one of the first structures affected by Alzheimer's disease. Postmortem MRI offers a way to quantify the alterations by measuring the atrophy of the inner structures of the hippocampus. Unfortunately, the manual segmentation of hippocampal subregions required to carry out these measures is very time-consuming., New Method: In this study, we explore the use of fully automated methods relying on state-of-the-art Deep Learning approaches to produce these annotations. More specifically, we propose a new segmentation framework made of a set of encoder-decoder blocks embedding self-attention mechanisms and atrous spatial pyramidal pooling to produce better maps of the hippocampus and identify four hippocampal regions: the dentate gyrus, the hippocampal head, the hippocampal body, and the hippocampal tail., Results: Trained using slices extracted from 15 postmortem T1-weighted, T2-weighted, and susceptibility-weighted MRI scans, our new approach produces hippocampus parcellations that are better aligned with the manually delineated parcellations provided by neuroradiologists., Comparison With Existing Methods: Four standard deep learning segmentation architectures: UNet, Double UNet, Attention UNet, and Multi-resolution UNet have been utilized for the qualitative and quantitative comparison of the proposed hippocampal region segmentation model., Conclusions: Postmortem MRI serves as a highly valuable neuroimaging technique for examining the effects of neurodegenerative diseases on the intricate structures within the hippocampus. This study opens the way to large sample-size postmortem studies of the hippocampal substructures., 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 © 2024. Published by Elsevier B.V.)

Polypathology is a major driver of heterogeneity in clinical presentation and extent of neurodegeneration (N) in patients with Alzheimer Disease (AD). Beyond amyloid (A) and tau (T) pathologies, over half of patients with AD have concomitant pathology such as α-synuclein (S) in mixed AD with Lewy Body Disease (LBD). Patients with Mixed Etiology Dementia (MED) such as AD+LBD have faster progression and potentially differential responses to targeted treatments, though the diagnosis of AD+LBD can be challenging given overlapping clinical and imaging features. Development and validation of improved in vivo biomarkers are required to study relationships between N and S and identify imaging patterns reflecting mixed AD+LBD pathologies. We hypothesize that individual proteinopathies, such as T and S, are associated with commensurate levels of N. Thus, we assessed biomarkers of A, T, N and S with positron emission tomography (PET), magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) seeding amplification assay (SAA) data to determine molecular presentations of mixed A+S+ vs. A+S- cognitively impaired patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We found A+S+ patients had parieto-occipital 18F-Fluorodeoxyglucose hypometabolism (a measure of N) disproportionate to the degree of regional atrophy or T burden, highlighting worse hypometabolism associated with S+ SAA. Following up on this hypometabolic mismatch with CSF metabolite and proteome analyses, we found that A+S+ patients exhibited lower CSF levels of dopamine metabolites and synaptic markers like neuronal pentraxin-2 (NPTX2), suggesting that altered neurotransmission and neuron integrity contribute to this dissociation between metabolic PET and MRI. Potential confounders exist when studying relations between N, AD and LBD pathologies, including neuroinflammation and other non-Alzheimer pathologies in MED, though our findings imply posterior hypometabolic mismatch is related more to S than vascular or TDP-43 pathology. A+S+ patients had posterior mismatch with excessive 18F-Fluorodeoxyglucose hypometabolism relative to atrophy or T load, possibly reflecting impaired neuron integrity. Further research must disentangle the impact of multiple proteinopathies and clinicopathologic factors on hypometabolism and atrophy. Cumulatively, patients with mixed AD+LBD etiologies harbor a unique metabolic PET mismatch signature., (Published by Oxford University Press on behalf of the Guarantors of Brain 2024.)

Introduction: Anti-amyloid antibody therapies such as lecanemab are increasingly being used to treat Alzheimer's disease (AD). These therapies are associated with a high rate of amyloid-related imaging abnormalities (ARIA)., Methods: We review the case history of a patient who developed ARIA associated with lecanemab treatment., Results: In addition to microhemorrhages and cerebral edema that are recognized features of ARIA, the patient developed several ischemic strokes. The patient also experienced frequent electrographic seizures without overt clinical seizures. The patient demonstrated clinical and radiographic improvement after steroid treatment., Discussion: Our case suggests that ischemic strokes may be a feature of ARIA and highlights the importance of having a high clinical suspicion for seizures in ARIA. As anti-amyloid therapies are likely going to be increasingly used to treat AD, it is important to appreciate the spectrum of clinical and radiographic findings that can result as side effects from this class of therapies., Highlights: We report a patient who developed severe amyloid-related imaging abnormalities (ARIA) after treatment with lecanemab. Our report suggests that ischemic strokes may be a novel imaging feature of ARIA. Our report highlights the need for high clinical suspicion for seizures in ARIA., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

This paper for the 20th anniversary of the Alzheimer's Disease Neuroimaging Initiative (ADNI) provides an overview of magnetic resonance imaging (MRI) of medial temporal lobe (MTL) subregions in ADNI using a dedicated high-resolution T2-weighted sequence. A review of the work that supported the inclusion of this imaging modality into ADNI Phase 3 is followed by a brief description of the ADNI MTL imaging and analysis protocols and a summary of studies that have used these data. This review is supplemented by a new study that uses novel surface-based tools to characterize MTL neurodegeneration across biomarker-defined AD stages. This analysis reveals a pattern of spreading cortical thinning associated with increasing levels of tau pathology in the presence of elevated amyloid beta, with apparent epicenters in the transentorhinal region and inferior hippocampal subfields. The paper concludes with an outlook for high-resolution imaging of the MTL in ADNI Phase 4. HIGHLIGHTS: As of Phase 3, the Alzheimer's Disease Neuroimaging Initiative (ADNI) magnetic resonance imaging (MRI) protocol includes a high-resolution T2-weighted MRI scan optimized for imaging hippocampal subfields and medial temporal lobe (MTL) subregions. These scans are processed by the ADNI core to obtain automatic segmentations of MTL subregions and to derive morphologic measurements. More detailed granular examination of MTL neurodegeneration in response to disease progression is achieved by applying surface-based modeling techniques. Surface-based analysis of gray matter loss in MTL subregions reveals increasing and spatially expanding patterns of neurodegeneration with advancing stages of Alzheimer's disease (AD), as defined based on amyloid and tau positron emission tomography biomarkers in accordance with recently proposed criteria. These patterns closely align with post mortem literature on spread of pathological tau in AD, supporting the role of tau pathology in the presence of elevated levels of amyloid beta as the driver of neurodegeneration., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease (AD) is characterized by a long preclinical stage during which molecular markers of amyloid beta and tau pathology rise, but there is minimal neurodegeneration or cognitive decline. Previous literature suggests that measures of brain function might be more sensitive to neuropathologic burden during the preclinical stage of AD than conventional measures of macrostructure, such as cortical thickness. However, among studies that used resting-state functional Magnetic Resonance Imaging (fMRI) acquisitions with Blood Oxygenation Level Dependent (BOLD) contrast, most employed connectivity-based analytic approaches, which discard information about the amplitude of spontaneous brain activity. Consequently, little is known about the effects of amyloid and tau pathology on BOLD amplitude. To address this knowledge gap, we characterized the effects of preclinical and prodromal AD on the amplitude of low-frequency fluctuations (ALFF) of the BOLD signal both at the whole-brain level and, at a more granular level, focused on subregions of the medial temporal lobe. We observed reduced ALFF in both preclinical and prodromal AD. In preclinical AD, amyloid positivity was associated with a spatially diffuse ALFF reduction in the frontal, medial parietal, and lateral temporal association cortices, while tau pathology was negatively associated with ALFF in the entorhinal cortex. These ALFF effects were observed in the absence of observable macrostructural changes in preclinical AD and remained after adjusting for structural atrophy in prodromal AD, indicating that ALFF offers additional sensitivity to early disease processes beyond what is provided by traditional structural imaging biomarkers of neurodegeneration. We conclude that ALFF may be a promising imaging-based biomarker for assessing the effects of amyloid-clearing immunotherapies in preclinical AD.

Identifying individuals with early-stage Alzheimer's disease (AD) at greater risk of steeper clinical decline would enable better-informed medical, support, and life planning decisions. Despite accumulating evidence on the clinical prognostic value of tau positron emission tomography (PET) in typical late-onset amnestic AD, its utility in predicting clinical decline in individuals with atypical forms of AD remains unclear. Across heterogeneous clinical phenotypes, patients with atypical AD consistently exhibit abnormal tau accumulation in the posterior nodes of the default mode network of the cerebral cortex. This evidence suggests that tau burden in this functional network could be a common imaging biomarker for prognostication across the syndromic spectrum of AD. Here, we examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline in a sample of 48 A+/T+/N+ patients with mild cognitive impairment or mild dementia due to AD with atypical clinical phenotypes: Posterior Cortical Atrophy (n = 16), logopenic variant Primary Progressive Aphasia (n = 15), and amnestic syndrome with multi-domain impairment and young age of onset < 65 years (n = 17). All patients underwent magnetic resonance imaging (MRI), tau PET, and amyloid PET scans at baseline. Each patient's longitudinal clinical decline was assessed by calculating the annualized change in the Clinical Dementia Rating Sum-of-Boxes (CDR-SB) scores from baseline to follow-up (mean time interval = 14.55 ± 3.97 months). Atypical early AD patients showed an increase in CDR-SB by 1.18 ± 1.25 points per year: t(47) = 6.56, p < .001, Cohen's d = 0.95. Across clinical phenotypes, baseline tau in the default mode network was the strongest predictor of clinical decline (R2 = .30), outperforming a simpler model with baseline clinical impairment and demographic variables (R2 = .10), tau in other functional networks (R2 = .11-.26), and the magnitude of cortical atrophy (R2 = .20) and amyloid burden (R2 = .09) in the default mode network. Overall, these findings point to the contribution of default mode network tau to predicting the magnitude of clinical decline in atypical early AD patients one year later. This simple measure could aid the development of a personalized prognostic, monitoring, and treatment plan, which would help clinicians not only predict the natural evolution of the disease but also estimate the effect of disease-modifying therapies on slowing subsequent clinical decline given the patient's tau burden while still early in the disease course., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Regional glucose hypometabolism resulting in glutamate loss has been shown as one of the characteristics of Alzheimer's disease (AD). Because the impact of AD varies between the sexes, we utilized glutamate-weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) for high-resolution spatial mapping of cerebral glutamate and investigated subregional changes in a sex-specific manner., Methods: Eight-month-old male and female AD mice harboring mutant amyloid precursor protein (APP NL-F/NL-F : n = 36) and wild-type (WT: n = 39) mice underwent GluCEST MRI, followed by proton magnetic resonance spectroscopy ( 1 H-MRS) in hippocampus and thalamus/hypothalamus using 9.4T preclinical MR scanner., Results: GluCEST measurements revealed significant (p ≤ 0.02) glutamate loss in the entorhinal cortex (% change ± standard error: 8.73 ± 2.12%), hippocampus (11.29 ± 2.41%), and hippocampal fimbriae (19.15 ± 2.95%) of male AD mice. A similar loss of hippocampal glutamate in male AD mice (11.22 ± 2.33%; p = 0.01) was also observed in 1 H-MRS., Discussions: GluCEST MRI detected glutamate reductions in the fimbria and entorhinal cortex of male AD mice, which was not reported previously. Resilience in female AD mice against these changes indicates an intact status of cerebral energy metabolism., Highlights: Glutamate levels were monitored in different brain regions of early-stage Alzheimer's disease (AD) and wild-type male and female mice using glutamate-weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI). Male AD mice exhibited significant glutamate loss in the hippocampus, entorhinal cortex, and the fimbriae of the hippocampus. Interestingly, female AD mice did not have any glutamate loss in any brain region and should be investigated further to find the probable cause. These findings demonstrate previously unreported sex-specific glutamate changes in hippocampal sub-regions using high-resolution GluCEST MRI., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Brain aging process is influenced by various lifestyle, environmental and genetic factors, as well as by age-related and often coexisting pathologies. Magnetic resonance imaging and artificial intelligence methods have been instrumental in understanding neuroanatomical changes that occur during aging. Large, diverse population studies enable identifying comprehensive and representative brain change patterns resulting from distinct but overlapping pathological and biological factors, revealing intersections and heterogeneity in affected brain regions and clinical phenotypes. Herein, we leverage a state-of-the-art deep-representation learning method, Surreal-GAN, and present methodological advances and extensive experimental results elucidating brain aging heterogeneity in a cohort of 49,482 individuals from 11 studies. Five dominant patterns of brain atrophy were identified and quantified for each individual by respective measures, R-indices. Their associations with biomedical, lifestyle and genetic factors provide insights into the etiology of observed variances, suggesting their potential as brain endophenotypes for genetic and lifestyle risks. Furthermore, baseline R-indices predict disease progression and mortality, capturing early changes as supplementary prognostic markers. These R-indices establish a dimensional approach to measuring aging trajectories and related brain changes. They hold promise for precise diagnostics, especially at preclinical stages, facilitating personalized patient management and targeted clinical trial recruitment based on specific brain endophenotypic expression and prognosis., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Evidence exists for aSyn "strains" - conformations with distinct biological properties. However, biomarkers for PD vs. DLB, including potential aSyn strain differences, are lacking. Here, we used two monoclonal antibodies selective for different in vitro aSyn species - termed Strain A and B - to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma. Surprisingly, levels of Strain A and B aSyn species differed in plasma from individuals with PD vs. DLB in two independent cohorts. Lower plasma aSyn Strain A species also predicted subsequent PD cognitive decline. Strain A and Strain B aSyn species were undetectable in CSF, but plasma aSyn species could template aSyn fibrillization, particularly in PD. Our findings suggest that aSyn strains may impact LBD clinical presentation and originate outside the brain., Competing Interests: Competing interests: Dr Tropea has received consulting fees and honoraria from Sanofi Genzyme, Bial, and the Parkinson Foundation. The following authors declare that they have no competing interests: GTK, SA, RSA JFM, ACP, DJI, RTS, RDR, KD, VL.

The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer's disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies., (© 2024. The Author(s).)

Genetic variants and epigenetic features both contribute to the risk of Alzheimer's disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10 -8 ), the intergenic region between VRTN and SYNDIG1L (Score = - 37.67, P = 2.25 × 10 -9 ), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10 -8 ), PVRL2 (Score = 125.86, P = 1.64 × 10 -9 ), TOMM40 (Score = - 18.58, P = 4.61 × 10 -8 ), and APOE (Score = 75.12, P = 7.26 × 10 -26 ). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P < 0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of SYNDIG1 and TOMM40 were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW., (© 2024. The Author(s).)

Background: Excessive daytime sleepiness (EDS) is a disabling symptom of Lewy body disorders (LBD). The hypothalamus is a key sleep-wake regulator, but its contribution to EDS in LBD remains unclear., Objectives: Use diffusion MRI to evaluate the relationship of hypothalamic microstructure to EDS symptoms in LBD., Methods: We studied 102 patients with clinically-defined LBD (Parkinson's disease, n=93; Parkinson's disease dementia, n=4; and dementia with Lewy bodies, n=5) and Epworth Sleepiness Scale (ESS) within 2 years of MRI. Mean diffusivity (MD) was compared between EDS+ (ESS≥10, n=37) and EDS- (ESS<10, n=65) groups in the whole hypothalamus and three subregions, covarying for age and sex. Secondary analyses tested correlations between subregion MD and continuous ESS, global cognition, and motor scores; and between subregion volume and continuous ESS., Results: MD was increased in EDS+ compared to EDS- only in the inferior tuberal subregion (Cohen's d=0.43, p=0.043, β=0.117±0.057), with trend level differences in the whole hypothalamus (Cohen's d=0.39, p=0.064, β=0.070±0.037) and superior tuberal subregion (Cohen's d=0.38, p=0.073, β=0.063±0.035). No difference was seen in the posterior subregion (Cohen's d=0.1, p=0.628, β=0.019±0.038). Significant correlations with continuous ESS were seen in MD of whole hypothalamus (r 2 =0.074, p=0.0057), superior tuberal (r 2 =0.081, p=0.0038), and inferior tuberal (r 2 =0.073, p=0.0059) subregions. There was no correlation of hypothalamic MD with global cognition or motor scores, and no correlation of whole/subregional hypothalamic volumes with ESS., Conclusions: Daytime sleepiness associates with increased MD in the inferior tuberal hypothalamus in an LBD cohort. This suggests degeneration within this region could contribute to EDS symptoms.

Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with C 2 N Diagnostics' PrecivityAD test for Aβ42 and Aβ40. Compared to white individuals, Black individuals had higher average plasma Aβ42/40 levels at baseline, consistent with a lower average level of amyloid pathology. Interestingly, this difference resulted from lower average levels of plasma Aβ40 in Black participants. Despite the differences, Black and white individuals had similar longitudinal rates of change in Aβ42/40, consistent with a similar rate of amyloid accumulation. Our results agree with multiple recent studies demonstrating a lower prevalence of amyloid pathology in Black individuals, and additionally suggest that amyloid accumulates consistently across both groups., (© 2024. The Author(s).)

The most commonly used neuroimaging biomarkers of brain structure, particularly in neurodegenerative diseases, have traditionally been summary measurements from ROIs derived from structural MRI, such as volume and thickness. Advances in MR acquisition techniques, including high-field imaging, and emergence of learning-based methods have opened up opportunities to interrogate brain structure in finer detail, allowing investigators to move beyond macrostructural measurements. On the one hand, superior signal contrast has the potential to make appearance-based metrics that directly analyze intensity patterns, such as texture analysis and radiomics features, more reliable. Quantitative MRI, particularly at high-field, can also provide a richer set of measures with greater interpretability. On the other hand, use of neural networks-based techniques has the potential to exploit subtle patterns in images that can now be mined with advanced imaging. Finally, there are opportunities for integration of multimodal data at different spatial scales that is enabled by developments in many of the above techniques-for example, by combining digital histopathology with high-resolution ex-vivo and in-vivo MRI. Some of these approaches are at early stages of development and present their own set of challenges. Nonetheless, they hold promise to drive the next generation of validation and biomarker studies. This article will survey recent developments in this area, with a particular focus on Alzheimer's disease and related disorders. However, most of the discussion is equally relevant to imaging of other neurological disorders, and even to other organ systems of interest. It is not meant to be an exhaustive review of the available literature, but rather presented as a summary of recent trends through the discussion of a collection of representative studies with an eye towards what the future may hold.

Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer's Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers., (© 2024. The Author(s).)

Introduction: We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau 181 ), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog)., Methods: Participants were NormCog (n = 132) and ImpCog (n = 461), with confirmed β-amyloid (Aβ+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aβ+ from Aβ-. Survival analyses tested time to clinical dementia rating (global CDR) progression., Results: Multivariable models (p-tau+GFAP+NfL) had the best performance to detect Aβ+ in NormCog (ROCAUC = 0.87) and ImpCog (ROCAUC = 0.87). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aβ+ (hazard ratio [HR] = 2.94; p = 8.1e-06) and Aβ- individuals (HR = 3.11; p = 2.6e-09)., Discussion: Combining plasma biomarkers can optimize detection of Alzheimer's disease (AD) pathology across cognitively normal and clinically diverse neurodegenerative disease., Highlights: Participants were clinically heterogeneous, with autopsy- or biomarker-confirmed Aβ. Combining plasma p-tau 181 , GFAP, and NfL improved diagnostic accuracy for Aβ status. Diagnosis by plasma biomarkers is more accurate in amnestic AD than nonamnestic AD. Plasma analytes show independent associations with tau PET and post mortem Aβ/tau. Plasma NfL predicted longitudinal cognitive decline in both Aβ+ and Aβ- individuals., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Volumetry of subregions in the medial temporal lobe (MTL) computed from automatic segmentation in MRI can track neurodegeneration in Alzheimer's disease. However, image quality may vary in MRI. Poor quality MR images can lead to unreliable segmentation of MTL subregions. Considering that different MRI contrast mechanisms and field strengths (jointly referred to as "modalities" here) offer distinct advantages in imaging different parts of the MTL, we developed a muti-modality segmentation model using both 7 tesla (7T) and 3 tesla (3T) structural MRI to obtain robust segmentation in poor-quality images., Method: MRI modalities including 3T T1-weighted, 3T T2-weighted, 7T T1-weighted and 7T T2-weighted (7T-T2w) of 197 participants were collected from a longitudinal aging study at the Penn Alzheimer's Disease Research Center. Among them, 7T-T2w was used as the primary modality, and all other modalities were rigidly registered to the 7T-T2w. A model derived from nnU-Net took these registered modalities as input and outputted subregion segmentation in 7T-T2w space. 7T-T2w images most of which had high quality from 25 selected training participants were manually segmented to train the multi-modality model. Modality augmentation, which randomly replaced certain modalities with Gaussian noise, was applied during training to guide the model to extract information from all modalities. To compare our proposed model with a baseline single-modality model in the full dataset with mixed high/poor image quality, we evaluated the ability of derived volume/thickness measures to discriminate Amyloid+ mild cognitive impairment (A+MCI) and Amyloid- cognitively unimpaired (A-CU) groups, as well as the stability of these measurements in longitudinal data., Results: The multi-modality model delivered good performance regardless of 7T-T2w quality, while the single-modality model under-segmented subregions in poor-quality images. The multi-modality model generally demonstrated stronger discrimination of A+MCI versus A-CU. Intra-class correlation and Bland-Altman plots demonstrate that the multi-modality model had higher longitudinal segmentation consistency in all subregions while the single-modality model had low consistency in poor-quality images., Conclusion: The multi-modality MRI segmentation model provides an improved biomarker for neurodegeneration in the MTL that is robust to image quality. It also provides a framework for other studies which may benefit from multimodal imaging., Competing Interests: Declaration of Competing Interests D.A.W. has served as a paid consultant to Eli Lilly, GE Healthcare, Merck, Janssen and Qynapse. He serves on a DSMB for Functional Neuromodulation. He received grants from Eli Lilly/Avid Radiopharmaceuticals, Merck and Biogen. He is also now on a DSMB for GSK. S.R.D. received consultation fees from Rancho Biosciences and Nia Therapeutics. L.X. is a paid employee of Siemens Healthineers. He received personal consulting fees from Galileo CDS, Inc. L.E.M.W. was supported by MultiPark, a strategic research area at Lund University.

Postmortem MRI allows brain anatomy to be examined at high resolution and to link pathology measures with morphometric measurements. However, automated segmentation methods for brain mapping in postmortem MRI are not well developed, primarily due to limited availability of labeled datasets, and heterogeneity in scanner hardware and acquisition protocols. In this work, we present a high-resolution dataset of 135 postmortem human brain tissue specimens imaged at 0.3 mm 3 isotropic using a T2w sequence on a 7T whole-body MRI scanner. We developed a deep learning pipeline to segment the cortical mantle by benchmarking the performance of nine deep neural architectures, followed by post-hoc topological correction. We evaluate the reliability of this pipeline via overlap metrics with manual segmentation in 6 specimens, and intra-class correlation between cortical thickness measures extracted from the automatic segmentation and expert-generated reference measures in 36 specimens. We also segment four subcortical structures (caudate, putamen, globus pallidus, and thalamus), white matter hyperintensities, and the normal appearing white matter, providing a limited evaluation of accuracy. We show generalizing capabilities across whole-brain hemispheres in different specimens, and also on unseen images acquired at 0.28 mm 3 and 0.16 mm 3 isotropic T2*w fast low angle shot (FLASH) sequence at 7T. We report associations between localized cortical thickness and volumetric measurements across key regions, and semi-quantitative neuropathological ratings in a subset of 82 individuals with Alzheimer's disease (AD) continuum diagnoses. Our code, Jupyter notebooks, and the containerized executables are publicly available at the project webpage (https://pulkit-khandelwal.github.io/exvivo-brain-upenn/)., Competing Interests: David A. Wolk has received grant support from Merck, Biogen, and Eli Lilly/Avid. David A. Wolk received consultation fees from Neuronix, Eli Lilly, and Qynaps and is on the Data and Safety Monitoring Board for a clinical trial run by Functional Neuromodulation. John Q. Trojanowski received revenue from the sale of Avid to Eli Lilly as co-inventor on imaging-related patents submitted by the University of Pennsylvania. David J. Irwin is member of the science advisory board of Denali Therapeutics. Sandhitsu R. Das received consultation fees from Rancho Biosciences and Nia Therapeutics. The other authors have nothing to disclose., (© 2024 Massachusetts Institute of Technology. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.)