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Obstructive sleep apnoea (OSA) is associated with an increased risk for cognitive impairment and dementia, which likely involves Alzheimer's disease pathology. Non-rapid eye movement slow-wave activity (SWA) has been implicated in amyloid clearance, but it has not been studied in the context of longitudinal amyloid accumulation in OSA. This longitudinal retrospective study aims to investigate the relationship between polysomnographic and electrophysiological SWA features and amyloid accumulation. From the Mayo Clinic Study of Aging cohort, we identified 71 participants ≥60 years old with OSA (mean baseline age = 72.9 ± 7.5 years, 60.6% male, 93% cognitively unimpaired) who had at least 2 consecutive Amyloid Pittsburgh Compound B (PiB)-PET scans and a polysomnographic study within 5 years of the baseline scan and before the second scan. Annualized PiB-PET accumulation [global ΔPiB(log)/year] was estimated by the difference between the second and first log-transformed global PiB-PET uptake estimations divided by the interval between scans (years). Sixty-four participants were included in SWA analysis. SWA was characterized by the mean relative spectral power density (%) in slow oscillation (SO: 0.5-0.9 Hz) and delta (1-3.9 Hz) frequency bands and by their downslopes (SO-slope and delta-slope, respectively) during the diagnostic portion of polysomnography. We fit linear regression models to test for associations among global ΔPiB(log)/year, SWA features (mean SO% and delta% or mean SO-slope and delta-slope), and OSA severity markers, after adjusting for age at baseline PiB-PET, APOE ɛ4 and baseline amyloid positivity. For 1 SD increase in SO% and SO-slope, global ΔPiB(log)/year increased by 0.0033 (95% CI: 0.0001; 0.0064, P = 0.042) and 0.0069 (95% CI: 0.0009; 0.0129, P = 0.026), which were comparable to 32% and 59% of the effect size associated with baseline amyloid positivity, respectively. Delta-slope was associated with a reduction in global ΔPiB(log)/year by -0.0082 (95% CI: -0.0143; -0.0021, P = 0.009). Sleep apnoea severity was not associated with amyloid accumulation. Regional associations were stronger in the pre-frontal region. Both slow-wave slopes had more significant and widespread regional associations. Annualized PiB-PET accumulation was positively associated with SO and SO-slope, which may reflect altered sleep homeostasis due to increased homeostatic pressure in the setting of unmet sleep needs, increased synaptic strength, and/or hyper-excitability in OSA. Delta-slope was inversely associated with PiB-PET accumulation, suggesting it may represent residual physiological activity. Further investigation of SWA dynamics in the presence of sleep disorders before and after treatment is necessary for understanding the relationship between amyloid accumulation and SWA physiology., Competing Interests: D.Z.C. is supported by the NIA/NIH. E.K.S. has received research support from the Mayo Clinic CCaTS, NIH, Michael J. Fox Foundation and Sunovion, Inc. M.M.M. is supported by the NIA/NIH. B.F.B. has served as an investigator for clinical trials sponsored by Alector, Biogen, Cognition Therapeutics, EIP Pharma and Transposon and served on the Scientific Advisory Board of the Tau Consortium. R.C.P. has served as a consultant for Roche, Inc., Merck, Inc., Genentech, Inc., Biogen, Inc. and GE Healthcare and received royalties from the Oxford University Press for the publication of Mild Cognitive Impairment. V.J.L. has served as a consultant for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., Eli Lilly, AVID Radiopharmaceuticals and Merck Research and received research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals and the NIH. C.R.J. is supported by the NIA/NIH. J.G.-R. is supported by the NIH. He is on the drug safety medical board for NINDS and is the site PI for a clinical trial funded by Eisai. G.A.W. is supported by the NIH. He has licenced intellectual property to NeuroOne Inc. and Cadence Neuroscience Inc. He has served on the Scientific Advisory Boards for LivaNova Inc., NeuroPace Inc., UNEEG Inc and NeuroOne Inc. He has received royalties from NeuroOne Inc. V.K.S. has served as a consultant for ResMed, Zoll, Bayer, Lilly, Huxley, Apnimed, Jazz Pharmaceuticals and Axsome and is on the Scientific Advisory Board for Sleep Number Corporation. A.W.V. has served as a consultant for Jazz Pharmaceuticals. He is supported by R01 AG066870 and R01 AG080609. P.V. is supported by the NIA/NIH. The remaining authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

There is increasing interest in Alzheimer's disease related plasma biomarkers due to their accessibility and scalability. We hypothesized that integrating plasma biomarkers with other commonly used and available participant data (MRI, cardiovascular factors, lifestyle, genetics) using machine learning (ML) models can improve individual prediction of cognitive outcomes. Further, our goal was to evaluate the heterogeneity of these predictors across different age strata. This longitudinal study included 1185 participants from the Mayo Clinic Study of Aging who had complete plasma analyte work-up at baseline. We used the Quanterix Simoa immunoassay to measure neurofilament light, Aβ 1-42 and Aβ 1-40 (used as Aβ 42 /Aβ 40 ratio), glial fibrillary acidic protein, and phosphorylated tau 181 (p-tau181). Participants' brain health was evaluated through gray and white matter structural MRIs. The study also considered cardiovascular factors (hyperlipidemia, hypertension, stroke, diabetes, chronic kidney disease), lifestyle factors (area deprivation index, body mass index, cognitive and physical activities), and genetic factors ( APOE , single nucleotide polymorphisms, and polygenic risk scores). An ML model was developed to predict cognitive outcomes at baseline and decline (slope). Three models were created: a base model with groups of risk factors as predictors, an enhanced model included socio-demographics, and a final enhanced model by incorporating plasma and socio-demographics into the base models. Models were explained for three age strata: younger than 65 years, 65-80 years, and older than 80 years, and further divided based on amyloid positivity status. Regardless of amyloid status the plasma biomarkers showed comparable performance ( R ² = 0.15) to MRI ( R ² = 0.18) and cardiovascular measures ( R ² = 0.10) when predicting cognitive decline. Inclusion of cardiovascular or MRI measures with plasma in the presence of socio-demographic improved cognitive decline prediction ( R ² = 0.26 and 0.27). For amyloid positive individuals Aβ 42 /Aβ 40 , glial fibrillary acidic protein and p-tau181 were the top predictors of cognitive decline while Aβ 42 /Aβ 40 was prominent for amyloid negative participants across all age groups. Socio-demographics explained a large portion of the variance in the amyloid negative individuals while the plasma biomarkers predominantly explained the variance in amyloid positive individuals (21% to 37% from the younger to the older age group). Plasma biomarkers performed similarly to MRI and cardiovascular measures when predicting cognitive outcomes and combining them with either measure resulted in better performance. Top predictors were heterogeneous between cross-sectional and longitudinal cognition models, across age groups, and amyloid status. Multimodal approaches will enhance the usefulness of plasma biomarkers through careful considerations of a study population's socio-demographics, brain and cardiovascular health., Competing Interests: There are no relevant disclosures relevant to this publication., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Age-related and Alzheimer's disease (AD) dementia-related neurodegeneration impact brain health. While morphometric measures from T1-weighted scans are established biomarkers, they may be less sensitive to earlier changes. Neurite orientation dispersion and density imaging (NODDI), offering biologically meaningful interpretation of tissue microstructure, may be an advanced brain health biomarker., Methods: We contrasted regional gray matter NODDI and morphometric evaluations concerning their correlation with (1) age, (2) clinical diagnosis stage, and (3) tau pathology as assessed by AV1451 positron emission tomography., Results: Our study hypothesizes that NODDI measures are more sensitive to aging and early AD changes than morphometric measures. One NODDI output, free water fraction (FWF), showed higher sensitivity to age-related changes, generally better effect sizes in separating mild cognitively impaired from cognitively unimpaired participants, and stronger associations with regional tau deposition than morphometric measures., Discussion: These findings underscore NODDI's utility in capturing early neurodegenerative changes and enhancing our understanding of aging and AD., Highlights: Neurite orientation dispersion and density imaging can serve as an effective brain health biomarker for aging and early Alzheimer's disease (AD).Free water fraction has higher sensitivity to normal brain aging.Free water fraction has stronger associations with early AD and regional tau deposition., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer's Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer's Disease Neuroimaging Initiative, n = 53) and who had Alzheimer's disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer's Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer's disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer's disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials., Competing Interests: V.J.L. consults for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., Avid Radiopharmaceuticals and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, Avid Radiopharmaceuticals and the NIH (NIA, NCI). D.S.K. serves on a Data Safety Monitoring Board for the DIAN study and for a tau therapeutic for Biogen but receives no personal compensation; is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California; has served as a consultant for Roche, Samus Therapeutics, Third Rock and Alzeca Biosciences but receives no personal compensation; and receives funding from the NIH. B.F.B. receives honorarium for SAB activities for the Tau Consortium, is an investigator in clinical trials sponsored by Alector, Biogen, Cognition Therapeutics, EIP Pharma and Transposon and receives funding from the NIH. C.R.J. has no commercial conflicts and receives research support from the NIH, the GHR Foundation and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. R.C.P. consults for Roche, Inc.; Merck, Inc.; Biogen, Inc.; Genentech, Inc.; Eisai, Inc.; and Nestle, Inc. but does not receive significant fees due to NIH limitations from the U24 AG057437 Co-PI role., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: White matter hyperintensities (WMH) are considered hallmark features of cerebral small vessel disease and have recently been linked to Alzheimer's disease (AD) pathology. Their distinct spatial distributions, namely periventricular versus deep WMH, may differ by underlying age-related and pathobiological processes contributing to cognitive decline. We aimed to identify the spatial patterns of WMH using the 4-scale Fazekas visual assessment and explore their differential association with age, vascular health, AD imaging markers, namely amyloid and tau burden, and cognition. Because our study consisted of scans from GE and Siemens scanners with different resolutions, we also investigated inter-scanner reproducibility and combinability of WMH measurements on imaging., Methods: We identified 1144 participants from the Mayo Clinic Study of Aging consisting of a population-based sample from Olmsted County, Minnesota with available structural magnetic resonance imaging (MRI), amyloid, and tau positron emission tomography (PET). WMH distribution patterns were assessed on FLAIR-MRI, both 2D axial and 3D, using Fazekas ratings of periventricular and deep WMH severity. We compared the association of periventricular and deep WMH scales with vascular risk factors, amyloid-PET, and tau-PET standardized uptake value ratio, automated WMH volume, and cognition using Pearson partial correlation after adjusting for age. We also evaluated vendor compatibility and reproducibility of the Fazekas scales using intraclass correlations (ICC)., Results: Periventricular and deep WMH measurements showed similar correlations with age, cardiometabolic conditions score (vascular risk), and cognition, (p < 0.001). Both periventricular WMH and deep WMH showed weak associations with amyloidosis (R = 0.07, p = < 0.001), and none with tau burden. We found substantial agreement between data from the two scanners for Fazekas measurements (ICC = 0.82 and 0.74). The automated WMH volume had high discriminating power for identifying participants with Fazekas ≥ 2 (area under curve = 0.97) and showed poor correlation with amyloid and tau PET markers similar to the visual grading., Conclusion: Our study investigated risk factors underlying WMH spatial patterns and their impact on global cognition, with no discernible differences between periventricular and deep WMH. We observed minimal impact of amyloidosis on WMH severity. These findings, coupled with enhanced inter-scanner reproducibility of WMH data, suggest the combinability of inter-scanner data assessed by harmonized protocols in the context of vascular contributions to cognitive impairment and dementia biomarker research., (© 2024. The Author(s).)

Importance: Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement., Objectives: To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy., Design, Setting, and Participants: This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses., Main Outcomes and Measures: Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET)., Results: Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02)., Conclusions and Relevance: Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

Background and Objectives: Updated criteria for the clinical-MRI diagnosis of cerebral amyloid angiopathy (CAA) have recently been proposed. However, their performance in individuals without symptomatic intracerebral hemorrhage (ICH) presentations is less defined. We aimed to assess the diagnostic performance of the Boston criteria version 2.0 for CAA diagnosis in a cohort of individuals ranging from cognitively normal to dementia in the community and memory clinic settings., Methods: Fifty-four participants from the Mayo Clinic Study of Aging or Alzheimer's Disease Research Center were included if they had an antemortem MRI with gradient-recall echo sequences and a brain autopsy with CAA evaluation. Performance of the Boston criteria v2.0 was compared with v1.5 using histopathologically verified CAA as the reference standard., Results: The median age at MRI was 75 years (interquartile range 65-80) with 28/54 participants having histopathologically verified CAA (i.e., moderate-to-severe CAA in at least 1 lobar region). The sensitivity and specificity of the Boston criteria v2.0 were 28.6% (95% CI 13.2%-48.7%) and 65.3% (95% CI 44.3%-82.8%) for probable CAA diagnosis (area under the receiver operating characteristic curve [AUC] 0.47) and 75.0% (55.1-89.3) and 38.5% (20.2-59.4) for any CAA diagnosis (possible + probable; AUC 0.57), respectively. The v2.0 Boston criteria were not superior in performance compared with the prior v1.5 criteria for either CAA diagnostic category., Discussion: The Boston criteria v2.0 have low accuracy in patients who are asymptomatic or only have cognitive symptoms. Additional biomarkers need to be explored to optimize CAA diagnosis in this population.

Sex differences permeate many aspects of dementia with Lewy bodies (DLB), yet sex differences in patterns of neurodegeneration in DLB remain largely unexplored. Here, we test whether grey matter networks differ between sexes in DLB and compare these findings to sex differences in healthy controls. In this cross-sectional study, we analysed clinical and neuroimaging data of patients with DLB and cognitively healthy controls matched for age and sex. Grey matter networks were constructed by pairwise correlations between 58 regional volumes after correction for age, intracranial volume, and centre. Network properties were compared between sexes and diagnostic groups. Additional analyses were conducted on w-scored data to identify DLB-specific sex differences. Data from 119 (68.7 ± 8.4 years) men and 45 women (69.9 ± 9.1 years) with DLB, and 164 healthy controls were included in this study. Networks of men had a lower nodal strength compared to women. In comparison to healthy women, the grey matter networks of healthy men showed a higher global efficiency, modularity, and fewer modules. None of the network measures showed significant sex differences in DLB. Comparing DLB patients with healthy controls revealed global differences in women and more local differences in men. Modular analyses showed a more distinct demarcation between cortical and subcortical regions in men compared with women. While topologies of grey matter networks differed between sexes in healthy controls, those sex differences were diluted in DLB patients. These findings suggest a disease-driven convergence of neurodegenerative patterns in women and men with DLB, which may inform precision medicine in DLB., (© 2024. The Author(s).)

Dementia with Lewy bodies (DLB) is a neurodegenerative condition often co-occurring with Alzheimer's disease (AD) pathology. Characterizing white matter tissue microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) may help elucidate the biological underpinnings of white matter injury in individuals with DLB. In this study, diffusion tensor imaging (DTI) and NODDI metrics were compared in 45 patients within the dementia with Lewy bodies spectrum (mild cognitive impairment with Lewy bodies (n = 13) and probable dementia with Lewy bodies (n = 32)) against 45 matched controls using conditional logistic models. We evaluated the associations of tau and amyloid-β with DTI and NODDI parameters and examined the correlations of AD-related white matter injury with Clinical Dementia Rating (CDR). Structural equation models (SEM) explored relationships among age, APOE ε4, amyloid-β, tau, and white matter injury. The DLB spectrum group exhibited widespread white matter abnormalities, including reduced fractional anisotropy, increased mean diffusivity, and decreased neurite density index. Tau was significantly associated with limbic and temporal white matter injury, which was, in turn, associated with worse CDR. SEM revealed that amyloid-β exerted indirect effects on white matter injury through tau. We observed widespread disruptions in white matter tracts in DLB that were not attributed to AD pathologies, likely due to α-synuclein-related injury. However, a fraction of the white matter injury could be attributed to AD pathology. Our findings underscore the impact of AD pathology on white matter integrity in DLB and highlight the utility of NODDI in elucidating the biological basis of white matter injury in DLB., (© 2024. The Author(s).)

Introduction: Patients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease., Methods: The cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI-LB), or DLB, with a concurrent blood draw and PET scans., Results: Abnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI-LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p-tau)-181 and neurofilament light (NfL) were found at the DLB stage. Plasma p-tau-181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB., Discussion: The range of AD co-pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p-tau-181 and GFAP., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The implications of positive tau positron emission tomography (T) with negative beta amyloid positron emission tomography (A) are not well understood. We investigated cognitive performance in participants who were T+ but A-., Methods: We evaluated 98 participants from the Mayo Clinic who were T+ and A-. Participants were matched 2:1 to A- and T- cognitively unimpaired (CU) controls. Cognitive test scores were compared between different groups., Results: The A-T+ group demonstrated lower performance than the A-T- group on the Mini-Mental Status Exam (MMSE) (p < 0.001), Wechsler Memory Scale-Revised Logical Memory I (p < 0.001) and Logical Memory II (p < 0.001), Auditory Verbal Learning Test (AVLT) delayed recall (p = 0.004), category fluency (animals p = 0.005; vegetables p = 0.021), Trail Making Test A and B (p < 0.001), and others. There were no significant differences in demographic features or apolipoprotein E (APOE) e4 genotype between CU A-T+ and CI A-T+., Discussion: A-T+ participants show an association with lower cognitive performance., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: To investigate the association between standard pure tone and speech audiometry with neuroimaging characteristics reflective of aging and dementia in older adults., Study Design: Prospective population-based study., Setting: Single tertiary care referral center., Methods: Participants from the Mayo Clinic Study of aging 60 years old or older with normal cognition or mild cognitive impairment, baseline neuroimaging, and a behavioral audiogram associated with neuroimaging were eligible for study. Imaging modalities included structural MRI (sMRI) and fluid-attenuated inversion recovery MRI (FLAIR-MRI; N = 605), diffusion tensor imaging MRI (DTI-MRI; N = 444), and fluorodeoxyglucose-positron emission tomography (FDG-PET; N = 413). Multivariable logistic and linear regression models were used to evaluate associations with neuroimaging outcomes., Results: Mean (SD) pure tone average (PTA) was 33 (15) dB HL and mean (SD) word recognition score (WRS) was 91% (14). There were no significant associations between audiometric performance and cortical thinning assessed by sMRI. Each 10-dB increase in PTA was associated with increased likelihood of abnormal white-matter hyperintensity (WMH) from FLAIR-MRI (odds ratio 1.26, P = .02). From DTI-MRI, participants with <100% WRSs had significantly lower fractional anisotropy in the genu of the corpus callosum (parameter estimate [PE] -0.012, P = .008) compared to those with perfect WRSs. From FDG-PET, each 10% decrease in WRSs was associated with decreased uptake in the anterior cingulate cortex (PE -0.013, P = .001)., Conclusion: Poorer audiometric performance was not significantly associated with cortical thinning but was associated with white matter damage relevant to cerebrovascular disease (increased abnormal WMH, decreased corpus callosum diffusion). These neuroimaging results suggest a pathophysiologic link between hearing loss and cerebrovascular disease., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Introduction: Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI)., Methods: We included 436 patients from the European-DLB consortium and the Mayo Clinic. Sex differences and sex-by-age interactions were assessed through visual atrophy rating scales (n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n = 165; 69 ± 9 years, 72% males)., Results: We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex-by-age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex., Discussion: We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75., Highlights: Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Cost-effective screening tools for vascular contributions to cognitive impairment and dementia (VCID) has significant implications. We evaluated non-imaging indicators of VCID using magnetic resonance imaging (MRI)-measured white matter (WM) damage and hypothesized that these indicators differ based on age., Methods: In 745 participants from the Mayo Clinic Study of Aging (≥50 years of age) with serial WM assessments from diffusion MRI and fluid-attenuated inversion recovery (FLAIR)-MRI, we examined associations between baseline non-imaging indicators (demographics, vascular risk factors [VRFs], gait, behavioral, plasma glial fibrillary acidic protein [GFAP], and plasma neurofilament light chain [NfL]) and WM damage across three age tertiles., Results: VRFs and gait were associated with diffusion changes even in low age strata. All measures (VRFs, gait, behavioral, plasma GFAP, plasma NfL) were associated with white matter hyperintensities (WMHs) but mainly in intermediate and high age strata., Discussion: Non-imaging indicators of VCID were related to WM damage and may aid in screening participants and assessing outcomes for VCID., Highlights: Non-imaging indicators of VCID can aid in prediction of MRI-measured WM damage but their importance differed by age. Vascular risk and gait measures were associated with early VCID changes measured using diffusion MRI. Plasma markers explained variability in WMH across age strata. Most non-imaging measures explained variability in WMH and vascular WM scores in intermediate and older age groups. The framework developed here can be used to evaluate new non-imaging VCID indicators proposed in the future., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objectives: The objective of this case study is to raise awareness of potential 123 I-FP-CIT SPECT interference by lisdexafetamine dimesylate, a prodrug of d -amphetamine., Methods: A 69-year-old man with Rapid Eye Movement sleep behavior disorder and mild cognitive impairment had been treated with lisdexafetamine dimesylate for attention-deficit/hyperactivity disorder. The patient had annual or biennial 123 I-FP-CIT SPECT evaluations after their baseline visit at 69 years old. Nigrostriatal dopamine transporter uptake was semiquantitatively evaluated with 123 I-FP-CIT SPECT using DaTQUANT 2.0 software. Lisdexafetamine dimesylate was discontinued 3 months before the sixth-year visit (76 years old) by his primary care provider., Results: The patient had 4 123 I-FP-CIT SPECT scans with lisdexafetamine dimesylate and 2 scans after the discontinuation of lisdexafetamine dimesylate. The DaTQUANT z -scores of the putamen declined from -1.36 at the baseline visit to -3.02 at the fifth-year visit. After the discontinuation of lisdexafetamine dimesylate, DaTQUANT z -scores of the putamen increased to -0.63 at the sixth-year visit and remained in the normal range of -0.71 at the seventh-year visit., Conclusions: This case suggests that lisdexafetamine dimesylate may have a strong interference with 123 I-FP-CIT SPECT, decreasing the tracer binding to the dopamine transporter and presenting false positive results., Competing Interests: Conflicts of Interest and Source of Funding: J.A.F. serves as a paid consultant for Medtronic, Inc. K.K. serves as a paid consultant for Biogen and receives research support from Avid Radiopharmaceuticals, Eli Lilly. V.J.L. serves as a consultant for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc, AVID Radiopharmaceuticals, and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH (NIA, NCI). B.F.B. receives honoraria for SAB activities for the Tau Consortium and receives institutional research grant support from Alector, Biogen, Transposon, Cognition Therapeutics, and GE Healthcare. The other authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Genetic mutations causative of frontotemporal lobar degeneration (FTLD) are highly predictive of a specific proteinopathy, but there exists substantial inter-individual variability in their patterns of network degeneration and clinical manifestations. We collected clinical and 18 Fluorodeoxyglucose-positron emission tomography (FDG-PET) data from 39 patients with genetic FTLD, including 11 carrying the C9orf72 hexanucleotide expansion, 16 carrying a MAPT mutation and 12 carrying a GRN mutation. We performed a spectral covariance decomposition analysis between FDG-PET images to yield unbiased latent patterns reflective of whole brain patterns of metabolism ("eigenbrains" or EBs). We then conducted linear discriminant analyses (LDAs) to perform EB-based predictions of genetic mutation and predominant clinical phenotype (i.e., behavior/personality, language, asymptomatic). Five EBs were significant and explained 58.52 % of the covariance between FDG-PET images. EBs indicative of hypometabolism in left frontotemporal and temporo-parietal areas distinguished GRN mutation carriers from other genetic mutations and were associated with predominant language phenotypes. EBs indicative of hypometabolism in prefrontal and temporopolar areas with a right hemispheric predominance were mostly associated with predominant behavioral phenotypes and distinguished MAPT mutation carriers from other genetic mutations. The LDAs yielded accuracies of 79.5 % and 76.9 % in predicting genetic status and predominant clinical phenotype, respectively. A small number of EBs explained a high proportion of covariance in patterns of network degeneration across FTLD-related genetic mutations. These EBs contained biological information relevant to the variability in the pathophysiological and clinical aspects of genetic FTLD, and for offering valuable guidance in complex clinical decision-making, such as decisions related to genetic testing., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: AD and CVD, which frequently co-occur, are leading causes of age-related cognitive decline. We assessed how demographic factors, socioeconomic status (SES) as indicated by education and occupation, vascular risk factors, and a range of biomarkers associated with both CVD (including white matter hyperintensities [WMH], diffusion MRI abnormalities, infarctions, and microbleeds) and AD (comprising amyloid-PET and tau-PET) collectively influence cognitive function., Methods: In this cross-sectional population study, structural equation models were utilized to understand these associations in 449 participants (mean age (SD) = 74.5 (8.4) years; 56% male; 7.5% cognitively impaired)., Results: (1) Higher SES had a protective effect on cognition with mediation through the vascular pathway. (2) The effect of amyloid directly on cognition and through tau was 11-fold larger than the indirect effect of amyloid on cognition through WMH. (3) There is a significant effect of vascular risk on tau deposition., Discussion: The utilized biomarkers captured the impact of CVD and AD on cognition. The overall effect of vascular risk and SES on these biomarkers are complex and need further investigation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.M. Mielke served as a consultant to Brain Protection Company, Biogen, and LabCorp and receives research support from the National Institutes of Health and the Department of Defense. She is a Senior Associate Editor forAlzheimer's and Dementia: The Journal of the Alzheimer's Association. Dr. Knopman serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network Treatment Unit study. He served on a Data Safety monitoring Board for a tau therapeutic for Biogen (until 2021) but received no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California. He has served as a consultant for Roche, Samus Therapeutics, Magellan Health, Biovie and Alzeca Biosciences but receives no personal compensation. He attended an Eisai advisory board meeting for Lecanemab on December 2, 2022 but received no compensation directly or indirectly. He receives funding from the NIH. Maria Vassilaki has received research funding from F. Hoffmann-La Roche Ltd and Biogen in the past and consulted for F. Hoffmann-La Roche Ltd; she currently receives research funding from NIH and have equity ownership in Johnson and Johnson, Merck, Medtronic, and Amgen. P. Vemuri received speaking fees from Miller Medical Communications, LLC, and receives research support from the National Institutes of Health. J. Graff-Radford receives NIH funding and serves on the data and safety monitoring board board for Neurology. He has received payment for speaking at the American Academy of Neurology Annual meeting. C.R. Jack serves on an independent data monitoring board for Roche, but he receives no personal compensation from any commercial entity. He receives research support from the National Institutes of Health, the GHR Foundation and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. R.C. Petersen is a consultant for Roche, Inc., Eli Lilly and Co. Nestle, Inc. and Eisai, Inc. He receives royalties from Oxford University Press and UpToDate and receives research support from the National Institutes of Health. V. J. Lowe consults for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals, Elly Lilly and Company and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals and the NIH (NIA, NCI). D. Shir, T.G. Lesnick, S. Przybelski, A.J. Fought, and M.M. Machulda have no conflicts to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Our objective was to determine whether polysomnographic (PSG) sleep parameters are associated with neuroimaging biomarkers of cerebrovascular disease (CVD) related to white matter (WM) integrity in older adults with obstructive sleep apnea (OSA)., Methods: From the population-based Mayo Clinic Study of Aging, we identified participants without dementia who underwent at least 1 brain MRI and PSG. We quantified 2 CVD biomarkers: WM hyperintensities (WMHs) from fluid-attenuated inversion recovery (FLAIR)-MRI, and fractional anisotropy of the genu of the corpus callosum (genu FA) from diffusion MRI. For this cross-sectional analysis, we fit linear models to assess associations between PSG parameters (NREM stage 1 percentage, NREM stage 3 percentage [slow-wave sleep], mean oxyhemoglobin saturation, and log of apnea-hypopnea index [AHI]) and CVD biomarkers (log of WMH and log of genu FA), respectively, while adjusting for age (at MRI), sex, APOE ε4 status, composite cardiovascular and metabolic conditions (CMC) score, REM stage percentage, sleep duration, and interval between MRI and PSG., Results: We included 140 participants with FLAIR-MRI (of which 103 had additional diffusion MRI). The mean ± SD age was 72.7 ± 9.6 years at MRI with nearly 60% being men. The absolute median (interquartile range [IQR]) interval between MRI and PSG was 1.74 (0.9-3.2) years. 90.7% were cognitively unimpaired (CU) during both assessments. For every 10-point decrease in N3%, there was a 0.058 (95% CI 0.006-0.111, p = 0.030) increase in the log of WMH and 0.006 decrease (95% CI -0.012 to -0.0002, p = 0.042) in the log of genu FA. After matching for age, sex, and N3%, participants with severe OSA had higher WMH (median [IQR] 0.007 [0.005-0.015] vs 0.006 [0.003-0.009], p = 0.042) and lower genu FA (median [IQR] 0.57 [0.55-0.63] vs 0.63 [0.58-0.65], p = 0.007), when compared with those with mild/moderate OSA., Discussion: We found that reduced slow-wave sleep and severe OSA were associated with higher burden of WM abnormalities in predominantly CU older adults, which may contribute to greater risk of cognitive impairment, dementia, and stroke. Our study supports the association between sleep depth/fragmentation and intermittent hypoxia and CVD biomarkers. Longitudinal studies are required to assess causation., (© 2023 American Academy of Neurology.)

Background and Objectives: β-Amyloid (Aβ) plaques can co-occur with Lewy-related pathology in patients with dementia with Lewy bodies (DLB), but Aβ load at prodromal stages of DLB still needs to be elucidated. We investigated Aβ load on PET throughout the DLB continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD) to a stage of mild cognitive impairment with Lewy bodies (MCI-LB), and finally DLB., Methods: We performed a cross-sectional study in patients with a diagnosis of iRBD, MCI-LB, or DLB from the Mayo Clinic Alzheimer Disease Research Center. Aβ levels were measured by Pittsburgh compound B (PiB) PET, and global cortical standardized uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared with each other and with those of cognitively unimpaired (CU) individuals (n = 100) balanced on age and sex using analysis of covariance. We used multiple linear regression testing for interaction to study the influences of sex and APOE ε4 status on PiB SUVR along the DLB continuum., Results: Of the 162 patients, 16 had iRBD, 64 had MCI-LB, and 82 had DLB. Compared with CU individuals, global cortical PiB SUVR was higher in those with DLB ( p < 0.001) and MCI-LB ( p = 0.012). The DLB group included the highest proportion of Aβ-positive patients (60%), followed by MCI-LB (41%), iRBD (25%), and finally CU (19%). Global cortical PiB SUVR was higher in APOE ε4 carriers compared with that in APOE ε4 noncarriers in MCI-LB ( p < 0.001) and DLB groups ( p = 0.049). Women had higher PiB SUVR with older age compared with men across the DLB continuum (β estimate = 0.014, p = 0.02)., Discussion: In this cross-sectional study, levels of Aβ load was higher further along the DLB continuum. Whereas Aβ levels were comparable with those in CU individuals in iRBD, a significant elevation in Aβ levels was observed in the predementia stage of MCI-LB and in DLB. Specifically, APOE ε4 carriers had higher Aβ levels than APOE ε4 noncarriers, and women tended to have higher Aβ levels than men as they got older. These findings have important implications in targeting patients within the DLB continuum for clinical trials of disease-modifying therapies., (© 2023 American Academy of Neurology.)

Background and Objectives: The dynamics of white matter (WM) changes are understudied in Alzheimer disease (AD). Our goal was to study the association between flortaucipir PET and WM health using neurite orientation dispersion and density imaging (NODDI) and evaluate its association with cognitive performance. Specifically, we focused on NODDI's Neurite Density Index (NDI), which aids in capturing axonal degeneration in WM and has greater specificity than single-shell diffusion MRI methods., Method: We estimated regional flortaucipir PET standard uptake value ratios (SUVRs) from 3 regions corresponding to Braak stage I, III/IV, and V/VI to capture the spatial distribution pattern of the 3R/4R tau in AD. Then, we evaluated the associations between these measurements and NDIs in 29 candidate WM tracts using Pearson correlation and multiple regression models., Results: Based on 223 participants who were amyloid positive (mean age of 78 years and 57.0% male, 119 cognitively unimpaired, 56 mild cognitive impairment, and 48 dementia), the results showed that WM tracts NDI decreased with increasing regional Braak tau SUVRs. Of all the significant WM tracts, the uncinate fasciculus ( r = -0.274 for Braak I, -0.311 for Braak III/IV, and -0.292 for Braak V/VI, p < 0.05) and cingulum adjoining hippocampus ( r = -0.274, -0.288, -0.233, p < 0.05), both tracts anatomically connected to areas of early tau deposition, were consistently found to be within the top 5 distinguishing WM tracts associated with flortaucipir SUVRs. The increase in tau deposition measurable outside the medial temporal lobes in Braak III-VI was associated with a decrease in NDI in the middle and inferior temporal WM tracts. For cognitive performance, WM NDI had similar coefficients of determination ( r 2 = 31%) as regional Braak flortaucipir SUVRs (29%), and together WM NDI and regional Braak flortaucipir SUVRs explained 46% of the variance in cognitive performance., Discussion: We found spatially dependent WM degeneration associated with regional flortaucipir SUVRs in Braak stages, suggesting a spatial pattern in WM damage. NDI, a specific marker of axonal density, provides complementary information about disease staging and progression in addition to tau deposition. Measurements of WM changes are important for the mechanistic understanding of multifactorial pathways through which AD causes cognitive dysfunction., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Whether a relationship exists between cerebrovascular disease and Alzheimer's disease has been a source of controversy. Evaluation of the temporal progression of imaging biomarkers of these disease processes may inform mechanistic associations. We investigate the relationship of disease trajectories of cerebrovascular disease (white matter hyperintensity, WMH, and fractional anisotropy, FA) and Alzheimer's disease (amyloid and tau PET) biomarkers in 2406 Mayo Clinic Study of Aging and Mayo Alzheimer's Disease Research Center participants using accelerated failure time models. The model assumes a common pattern of progression for each biomarker that is shifted earlier or later in time for each individual and represented by a per participant age adjustment. An individual's amyloid and tau PET adjustments show very weak temporal association with WMH and FA adjustments (R = -0.07 to 0.07); early/late amyloid or tau timing explains <1% of the variation in WMH and FA adjustment. Earlier onset of amyloid is associated with earlier onset of tau (R = 0.57, R 2  = 32%). These findings support a strong mechanistic relationship between amyloid and tau aggregation, but not between WMH or FA and amyloid or tau PET., (© 2023. The Author(s).)

Background: Hospitalization in older age is associated with accelerated cognitive decline, typically preceded by neuropathologic changes. We assess the association between indication for hospitalization and brain neurodegeneration., Methods: Included were participants from the Mayo Clinic Study of Aging, a population-based longitudinal study, with ≥1 brain imaging available in those older than 60 years of age between 2004 and 2017. Primary analyses used linear mixed-effects models to assess association of hospitalization with changes in longitudinal trajectory of cortical thinning, amyloid accumulation, and white matter hyperintensities (WMH). Additional analyses were performed with imaging outcomes dichotomized (normal vs abnormal) using Cox proportional hazards regression., Results: Of 2 480 participants, 1 966 had no hospitalization and 514 had ≥1 admission. Hospitalization was associated with accelerated cortical thinning (annual slope change -0.003 mm [95% confidence interval (CI) -0.005 to -0.001], p = .002), but not amyloid accumulation (0.003 [95% CI -0.001 to 0.006], p = .107), or WMH increase (0.011 cm3 [95% CI -0.001 to 0.023], p = .062). Interaction analyses assessing whether trajectory changes are dependent on admission type (medical vs surgical) found interactions for all outcomes. While surgical hospitalizations were not, medical hospitalizations were associated with accelerated cortical thinning (-0.004 mm [95% CI -0.008 to -0.001, p = .014); amyloid accumulation (0.010, [95% CI 0.002 to 0.017, p = .011), and WMH increase (0.035 cm3 [95% CI 0.012 to 0.058, p = .006). Hospitalization was not associated with developing abnormal cortical thinning (p = .407), amyloid accumulation (p = .596), or WMH/infarctions score (p = .565)., Conclusions: Medical hospitalizations were associated with accelerated cortical thinning, amyloid accumulation, and WMH increases. These changes were modest and did not translate to increased risk for crossing the abnormality threshold., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Although alpha-synuclein-related pathology is the hallmark of dementia with Lewy bodies (DLB), cerebrovascular and Alzheimer disease pathologies are common in patients with DLB. Little is known about the contribution of these pathologies to neurodegeneration in DLB. We investigated associations of cerebrovascular, β-amyloid, and tau biomarkers with gray matter (GM) volume in patients with probable DLB., Methods: We assessed patients with probable DLB and cognitively unimpaired (CU) controls with 11 C-Pittsburgh compound B (PiB) and 18 F-flortaucipir PET as markers of β-amyloid and tau, respectively. MRI was used to assess white matter hyperintensity (WMH) volume (a marker of cerebrovascular lesion load) and regional GM volume (a marker of neurodegeneration). We used correlations and analysis of covariance (ANCOVA) in the entire cohort and structural equation models (SEMs) in patients with DLB to investigate associations of WMH volume and regional β-amyloid and tau PET standardized uptake value ratios (SUVrs) with regional GM volume., Results: We included 30 patients with DLB (69.3 ± 10.2 years, 87% men) and 100 CU controls balanced on age and sex. Compared with CU controls, patients with DLB showed a lower GM volume across all cortical and subcortical regions except for the cuneus, putamen, and pallidum. A larger WMH volume was associated with a lower volume in the medial and orbital frontal cortices, insula, fusiform cortex, and thalamus in patients with DLB. A higher PiB SUVr was associated with a lower volume in the inferior temporal cortex, while flortaucipir SUVr did not correlate with GM volume. SEMs showed that a higher age and absence of the APOE ε4 allele were significant predictors of higher WMH volume, and WMH volume in turn was a significant predictor of GM volume in medial and orbital frontal cortices, insula, and inferior temporal cortex. By contrast, we observed 2 distinct paths for the fusiform cortex, with age having an effect through PiB and flortaucipir SUVr on one path and through WMH volume on the other path., Discussion: Patients with probable DLB have widespread cortical atrophy, most of which is likely influenced by alpha-synuclein-related pathology. Although cerebrovascular, β-amyloid, and tau pathologies often coexist in probable DLB, their contributions to neurodegeneration seem to be region specific., (© 2022 American Academy of Neurology.)

Alterations of cerebral glucose metabolism can be detected in patients with isolated rapid eye movement sleep behaviour disorder, a prodromal feature of neurodegenerative diseases with α-synuclein pathology. However, metabolic characteristics that determine clinical progression in isolated rapid eye movement sleep behaviour disorder and their association with other biomarkers need to be elucidated. We investigated the pattern of cerebral glucose metabolism on 18 F-fluorodeoxyglucose PET in patients with isolated rapid eye movement sleep behaviour disorder, differentiating between those who clinically progressed and those who remained stable over time. Second, we studied the association between 18 F-fluorodeoxyglucose PET and lower dopamine transporter availability in the putamen, another hallmark of synucleinopathies. Patients with isolated rapid eye movement sleep behaviour disorder from the Mayo Clinic Alzheimer's Disease Research Center and Center for Sleep Medicine ( n = 22) and age-and sex-matched clinically unimpaired controls (clinically unimpaired; n = 44) from the Mayo Clinic Study of Aging were included. All participants underwent 18 F-fluorodeoxyglucose PET and dopamine transporter imaging with iodine 123-radiolabeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane on single-photon emission computerized tomography. A subset of patients with isolated rapid eye movement sleep behaviour disorder with follow-up evaluations ( n = 17) was classified as isolated rapid eye movement sleep behaviour disorder progressors ( n = 7) if they developed mild cognitive impairment or Parkinson's disease; or isolated rapid eye movement sleep behaviour disorder stables ( n = 10) if they remained with a diagnosis of isolated rapid eye movement sleep behaviour disorder with no cognitive impairment. Glucose metabolic abnormalities in isolated rapid eye movement sleep behaviour disorder were determined by comparing atlas-based regional 18 F-fluorodeoxyglucose PET uptake between isolated rapid eye movement sleep behaviour disorder and clinically unimpaired. Associations between 18 F-fluorodeoxyglucose PET and dopamine transporter availability in the putamen were analyzed with Pearson's correlation within the nigrostriatal pathway structures and with voxel-based analysis in the cortex. Patients with isolated rapid eye movement sleep behaviour disorder had lower glucose metabolism in the substantia nigra, retrosplenial cortex, angular cortex, and thalamus, and higher metabolism in the amygdala and entorhinal cortex compared with clinically unimpaired. Patients with isolated rapid eye movement sleep behaviour disorder who clinically progressed over time were characterized by higher glucose metabolism in the amygdala and entorhinal cortex, and lower glucose metabolism in the cerebellum compared with clinically unimpaired. Lower dopamine transporter availability in the putamen was associated with higher glucose metabolism in the pallidum within the nigrostriatal pathway; and with higher 18 F-fluorodeoxyglucose uptake in the amygdala, insula, and temporal pole on a voxel-based analysis, although these associations did not survive after correcting for multiple comparisons. Our findings suggest that cerebral glucose metabolism in isolated rapid eye movement sleep behaviour disorder is characterized by hypometabolism in regions frequently affected during the prodromal stage of synucleinopathies, potentially reflecting synaptic dysfunction. Hypermetabolism is also seen in isolated rapid eye movement sleep behaviour disorder, suggesting that synaptic metabolic disruptions may be leading to a lack of inhibition, compensatory mechanisms, or microglial activation, especially in regions associated with nigrostriatal degeneration., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Dementia with Lewy bodies (DLB) is a neurodegenerative disorder with a wide heterogeneity of symptoms, which suggests the existence of different subtypes. We used data-driven analysis of magnetic resonance imaging (MRI) data to investigate DLB subtypes. We included 165 DLB from the Mayo Clinic and 3 centers from the European DLB consortium and performed a hierarchical cluster analysis to identify subtypes based on gray matter (GM) volumes. To characterize the subtypes, we used demographic and clinical data, as well as β-amyloid, tau, and cerebrovascular biomarkers at baseline, and cognitive decline over three years. We identified 3 subtypes: an older subtype with reduced cortical GM volumes, worse cognition, and faster cognitive decline (n = 49, 30%); a subtype with low GM volumes in fronto-occipital regions (n = 76, 46%); and a subtype of younger patients with the highest cortical GM volumes, proportionally lower GM volumes in basal ganglia and the highest frequency of cognitive fluctuations (n = 40, 24%). This study shows the existence of MRI subtypes in DLB, which may have implications for clinical workout, research, and therapeutic decisions., (© 2023. The Author(s).)

Brain imaging research studies increasingly use "de-facing" software to remove or replace facial imagery before public data sharing. Several works have studied the effects of de-facing software on brain imaging biomarkers by directly comparing automated measurements from unmodified vs de-faced images, but most research brain images are used in analyses of correlations with cognitive measurements or clinical statuses, and the effects of de-facing on these types of imaging-to-cognition correlations has not been measured. In this work, we focused on brain imaging measures of amyloid (A), tau (T), neurodegeneration (N), and vascular (V) measures used in Alzheimer's Disease (AD) research. We created a retrospective sample of participants from three age- and sex-matched clinical groups (cognitively unimpaired, mild cognitive impairment, and AD dementia, and we performed region- and voxel-wise analyses of: hippocampal volume (N), white matter hyperintensity volume (V), amyloid PET (A), and tau PET (T) measures, each from multiple software pipelines, on their ability to separate cognitively defined groups and their degrees of correlation with age and Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB). We performed each of these analyses twice: once with unmodified images and once with images de-faced with leading de-facing software mri&#95;reface, and we directly compared the findings and their statistical strengths between the original vs. the de-faced images. Analyses with original and with de-faced images had very high agreement. There were no significant differences between any voxel-wise comparisons. Among region-wise comparisons, only three out of 55 correlations were significantly different between original and de-faced images, and these were not significant after correction for multiple comparisons. Overall, the statistical power of the imaging data for AD biomarkers was almost identical between unmodified and de-faced images, and their analyses results were extremely consistent., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Summarizing the multiplicity and heterogeneity of cerebrovascular disease (CVD) features into a single measure has been difficult in both neuropathology and imaging studies. The objective of this work was to evaluate the association between neuroimaging surrogates of CVD and two available neuropathologic CVD scales in those with both antemortem imaging CVD measures and postmortem CVD evaluation. Individuals in the Mayo Clinic Study of Aging with MRI scans within 5 years of death (N = 51) were included. Antemortem CVD measures were computed from diffusion MRI (dMRI), FLAIR, and T2* GRE imaging modalities and compared with postmortem neuropathologic findings using Kalaria and Strozyk Scales. Of all the neuroimaging measures, both regional and global dMRI measures were associated with Kalaria and Strozyk Scales (p < 0.05) and modestly correlated with global cognitive performance. The major conclusions from this study were: (i) microstructural white matter injury measurements using dMRI may be meaningful surrogates of neuropathologic CVD scales, because they aid in capturing diffuse (and early) changes to white matter and secondary neurodegeneration due to lesions; (ii) vacuolation in the corpus callosum may be associated with white matter changes measured on antemortem dMRI imaging; (iii) Alzheimer's disease neuropathologic change did not associate with neuropathologic CVD scales; and (iv) future work should be focused on developing better quantitative measures utilizing dMRI to optimally assess CVD-related neuropathologic changes., (© 2022. The Author(s).)

The objective of this study was to determine the differential mapping of plasma biomarkers to postmortem neuropathology measures. We identified 64 participants in a population-based study with antemortem plasma markers (amyloid-β [Aβ] x-42, Aβx-40, neurofilament light [NfL], and total tau [T-tau]) who also had neuropathologic assessments of Alzheimer's and cerebrovascular pathology. We conducted weighted linear-regression models to evaluate relationships between plasma measures and neuropathology. Higher plasma NfL and Aβ42/40 ratio were associated with cerebrovascular neuropathologic scales (p < 0.05) but not with Braak stage, neuritic plaque score, or Thal phase. Plasma Aβ42/40 and NfL explained up to 18% of the variability in cerebrovascular neuropathologic scales. In participants predominantly with modest levels of Alzheimer's pathologic change, biomarkers of amyloid and neurodegeneration were associated with cerebrovascular neuropathology. NfL is a non-specific marker of brain injury, therefore its association with cerebrovascular neuropathology was expected. The association between elevated Aβ42/40 and cerebrovascular disease pathology needs further investigation but could be due to the use of less specific amyloid-β assays (x-40, x-42)., (Copyright © 2022. Published by Elsevier Inc.)

Background: The hippocampus and temporal lobe are atrophic in typical amnestic Alzheimer's disease (tAD) and are used as imaging biomarkers in treatment trials. However, a better understanding of how temporal structures differ across atypical AD phenotypes and relate to cognition is needed., Objective: Our goal was to compare temporal lobe regions between tAD and two atypical AD phenotypes (logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA)), and assess cognitive associations., Methods: We age and gender-matched 77 tAD participants to 50 LPA and 27 PCA participants, all of which were amyloid-positive. We used linear mixed-effects models to compare FreeSurfer-derived hippocampal volumes and cortical thickness of entorhinal, inferior and middle temporal, and fusiform gyri, and to assess relationships between imaging and memory, naming, and visuospatial function across and within AD phenotype., Results: Hippocampal volume and entorhinal thickness were smaller bilaterally in tAD than LPA and PCA. PCA showed greater right inferior temporal and bilateral fusiform thinning and LPA showed greater left middle and inferior temporal and left fusiform thinning. Atypical AD phenotypes differed with greater right hemisphere thinning in PCA and greater left hemisphere thinning in LPA. Verbal and visual memory related most strongly to hippocampal volume; naming related to left temporal thickness; and visuospatial related to bilateral fusiform thickness. Fewer associations remained when examined within AD group., Conclusion: Atypical AD phenotypes are associated with greater thinning of lateral temporal structures, with relative sparing of medial temporal lobe, compared to tAD. These findings may have implications for future clinical trials in AD., Competing Interests: Drs. Machulda, Josephs, Whitwell, and Duffy receive funding from the NIH. Dr. Lowe consults for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals, and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH (NIA, NCI). Dr. Graff-Radford is funded by the NIH and serves on the Neurology editorial board. Dr. Jack serves on an independent data monitoring board for Roche, has served as a speaker for Eisai, and consulted for Biogen, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. Dr. Knopman serves on a Data Safety Monitoring Board for the DIAN study. He serves on a Data Safety monitoring Board for a tau therapeutic for Biogen but receives no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He has served as a consultant for Roche, Samus Therapeutics, Third Rock and Alzeca Biosciences but receives no personal compensation. He receives funding from the NIH. The remaining authors have no conflict of interest to report., (© 2022 – The authors. Published by IOS Press.)

PET imaging with β-amyloid ligands is emerging as a molecular imaging technique targeting white matter integrity and demyelination. β-amyloid PET ligands such as 11 C-Pittsburgh compound B ( 11 C-PiB) have been considered for quantitative measurement of myelin content changes in multiple sclerosis, but 11 C-PiB is not commercially available given its short half-life. A 18 F PET ligand such as flutemetamol with a longer half-life may be an alternative, but its ability to differentiate white matter hyperintensities (WMH) from normal-appearing white matter (NAWM) and its relationship with age remains to be investigated. Methods: Cognitively unimpaired (CU) older and younger adults ( n = 61) were recruited from the community responding to a study advertisement for β-amyloid PET. Participants prospectively underwent MRI, 11 C-PiB, and 18 F-flutemetamol PET scans. MRI fluid-attenuated inversion recovery images were segmented into WMH and NAWM and registered to the T1-weighted MRI. 11 C-PiB and 18 F-flutemetamol PET images were also registered to the T1-weighted MRI. 11 C-PiB and 18 F-flutemetamol SUV ratios (SUVrs) from the WMH and NAWM were calculated using cerebellar crus uptake as a reference for both 11 C-PiB and 18 F-flutemetamol. Results: The median age was 38 y (range, 30-48 y) in younger adults and 67 y (range, 61-83 y) in older adults. WMH and NAWM SUVrs were higher with 18 F-flutemetamol than with 11 C-PiB in both older ( P < 0.001) and younger ( P < 0.001) CU adults. 11 C-PiB and 18 F-flutemetamol SUVrs were higher in older than in younger CU adults in both WMH ( P < 0.001) and NAWM ( P < 0.001). 11 C-PiB and 18 F-flutemetamol SUVrs were higher in NAWM than WMH in both older ( P < 0.001) and younger ( P < 0.001) CU adults. There was no apparent difference between 11 C-PiB and 18 F-flutemetamol SUVrs in differentiating WMH from NAWM in older and in younger adults. Conclusion: 11 C-PiB and 18 F-flutemetamol show a similar topographic pattern of uptake in white matter with a similar association with age in WMH and NAWM. 11 C-PiB and 18 F-flutemetamol can also effectively distinguish between WMH and NAWM. However, given its longer half-life, commercial availability, and higher binding potential, 18 F-flutemetamol can be an alternative to 11 C-PiB in molecular imaging studies specifically targeting multiple sclerosis to evaluate white matter integrity., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: Sleepiness has been associated with cognitive decline and dementia in the elderly. Older adults with excessive daytime sleepiness appear to be more vulnerable to longitudinal amyloid PET accumulation before the onset of the dementia. However, it remains unclear whether sleepiness is similarly associated with other biomarkers of Alzheimer's disease (AD), axonal integrity, and inflammation, which may also contribute to neurodegeneration and cognitive decline., Methods: In this cross-sectional analysis, we identified 260 cognitively unimpaired adults (>60 years) from the Mayo Clinic Study of Aging, a population-based cohort from Olmsted County (MN), who underwent CSF quantification of AD biomarkers (Aβ42, p-tau, p-tau/Aβ42) in addition to at least one of the following biomarkers [neurofilament light chain (NfL) interleukin-6 (IL-6), IL-10, and tumor necrosis factor-α (TNF-α)]. We fit linear regression models to assess associations between sleepiness, as measured by the Epworth Sleepiness Scale (ESS), and CSF biomarkers, controlling for age, sex, APOε4 status, body mass index, hypertension, dyslipidemia, and prior diagnosis of obstructive sleep apnea., Results: Higher ESS scores were associated with higher CSF IL-6 and NfL, but not with the other CSF biomarkers. For every ESS score point increase, there was a 0.009 ([95% CI 0.001-0.016], p = 0.033) increase in the log of IL-6 and 0.01 ([95% CI 0.002-0.018], p = 0.016) increase in the log of NfL. A sensitivity analysis showed an association between ESS scores and log of p-tau/Aβ42 only in participants with an abnormal ratio (>0.023), highly predictive of amyloid positivity. For every ESS score point increase, there was a 0.006 ([95% CI 0.001-0.012], p = 0.021) increase in the log of CSF p-tau/Aβ42., Conclusion: Sleepiness was associated with greater CSF IL-6 and NfL levels, which could contribute to neurodegeneration or alternatively cause sleepiness. Higher NfL levels may result from sleep disruption and/or contribute to sleepiness via disturbed connectivity or damage to wake-promoting centers. Associations between sleepiness and p-tau/Aβ42 in participants with abnormal ratio suggest that amyloid positivity contributes to vulnerability to sleep disturbance, which may further amyloid accumulation in a feed-forward loop process. Prospective studies of these markers are needed to determine cause-effect relationships between these associations., Competing Interests: ES has received research support from Mayo Clinic CCaTS, NIH, the Michael J. Fox Foundation, and Sunovion, Inc. MaM receives research funding from the NIH. BB has served as an investigator for clinical trials sponsored by Alector and Biogen. He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from the NIH the Mangurian Foundation, the Little Family Foundation, and the Ted Turner and Family Foundation. RP consults for Roche, Inc., Merck, Inc., Genentech, Inc., and Biogen, Inc., GE Healthcare and receives royalties from Oxford University Press for the publication of Mild Cognitive Impairment. CJ consults for Lily and serves on an independent data monitoring board for Roche but he receives no personal compensation from any commercial entity. JG-R receives research funding from NIH and serves on the editorial board of Neurology. PV receives research funding from NIH (NIA and NINDS). MiM served as a consultant to Biogen, Brain Protection Company, and LabCorp and receives research support from the NIH and DOD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Carvalho, St. Louis, Przybelski, Morgenthaler, Machulda, Boeve, Petersen, Jack, Graff-Radford, Vemuri and Mielke.)

Background and Objective: Patients with dementia with Lewy bodies (DLB) may have overlapping Alzheimer's disease pathology. We investigated the longitudinal rate of tau accumulation and its association with neurodegeneration and clinical disease progression in DLB., Methods: Consecutive patients with probable DLB (n = 22) from the Mayo Clinic Alzheimer's Disease Research Center and age-matched and sex-matched cognitively unimpaired controls (CU; n = 22) with serial magnetic resonance imaging and flortaucipir positron emission tomography scans within an average of 1.6 years were included. Regional annualized rates of flortaucipir uptake standardized uptake value ratios (SUVr) were calculated. Regional annualized rates of cortical volume change were measured with the Tensor Based Morphometry-Syn algorithm., Results: The annual increase of flortaucipir SUVr was greater in the middle and superior occipital, fusiform, and inferior parietal cortices in DLB (mean: 0.017, 0.019, 0.019, and 0.015, respectively) compared with the CU (mean: -0.006, -0.009, -0.003, and - 0.005, respectively; P < 0.05). In patients with DLB (but not the CU), a longitudinal increase in flortaucipir SUVr was associated with longitudinal cortical atrophy rates in the lateral occipital and inferior temporoparietal cortices, hippocampus, and the temporal pole as well as a concurrent decline on Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes in the lateral occipital and the fusiform cortices., Conclusions: Tau accumulation was faster in DLB compared with the CU, with increased accumulation rates in the lateral occipital and temporoparietal cortices. These increased rates of tau accumulation were associated with neurodegeneration and faster disease progression in DLB. Tau may be a potential treatment target in a subset of patients with DLB. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Specific brain structures (gray matter regions and white matter tracts) play a dominant role in determining cognitive decline and explain the heterogeneity in cognitive aging. Identification of these structures is crucial for screening of older adults at risk of cognitive decline. Using deep learning models augmented with a model-interpretation technique on data from 1432 Mayo Clinic Study of Aging participants, we identified a subset of brain structures that were most predictive of individualized cognitive trajectories and indicative of cognitively resilient vs. vulnerable individuals. Specifically, these structures explained why some participants were resilient to the deleterious effects of elevated brain amyloid and poor vascular health. Of these, medial temporal lobe and fornix, reflective of age and pathology-related degeneration, and corpus callosum, reflective of inter-hemispheric disconnection, accounted for 60% of the heterogeneity explained by the most predictive structures. Our results are valuable for identifying cognitively vulnerable individuals and for developing interventions for cognitive decline., Competing Interests: Declaration of Competing Interest The authors report no competing interests relevant to this manuscript., (Copyright © 2022. Published by Elsevier Inc.)

Tau deposition is one of two hallmark features of biologically defined Alzheimer's disease (AD) and is more closely related to cognitive decline than amyloidosis. Further, not all amyloid-positive individuals develop tauopathy, resulting in wide heterogeneity in clinical outcomes across the population with AD. We hypothesized that a polygenic risk score (PRS) based on tau PET (tau PRS) would capture the aggregate inherited susceptibility/resistance architecture influencing tau accumulation, beyond solely the measurement of amyloid-β burden. Leveraging rich multimodal data from a population-based sample of older adults, we found that this novel tau PRS was a strong surrogate of tau PET deposition and captured a significant proportion of the variance in tau PET levels as compared with amyloid PET burden, APOE (apolipoprotein E) ε4 (the most common risk allele for AD), and a non-APOE PRS of clinical case-control AD risk variants. In independent validation samples, the tau PRS was associated with cerebrospinal fluid phosphorylated tau levels in one cohort and with postmortem Braak neurofibrillary tangle stage in another. We also observed an association of the tau PRS with longitudinal cognitive trajectories, including a statistical interaction of the tau PRS with amyloid burden on cognitive decline. Although additional study is warranted, these findings demonstrate the potential utility of a tau PRS for capturing the collective genetic background influencing tau deposition in the general population. In the future, a tau PRS could be leveraged for cost-effective screening and risk stratification to guide trial enrollment and clinical interventions in AD., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Proton magnetic resonance spectroscopy ( 1 H MRS) may provide information on pathophysiological changes associated with tau deposition in cognitively unimpaired older adults. In this study, the associations of posterior cingulate gyrus tau and amyloid beta (Aβ) deposition on PET with 1 H MRS metabolite ratios acquired from bilateral posterior cingulate gyri were investigated in cognitively unimpaired older adults. Participants (n = 40) from the Mayo Clinic Study of Aging underwent single-voxel sLASER 1 H MRS from the posterior cingulate gyrus at 3 Tesla, 18 F-flortaucipir, and 11 C- Pittsburgh Compound B (PiB) PET. An increase in posterior cingulate gyrus tau deposition, but not elevated Aβ, was associated with lower N-acetylaspartate/total creatine (tCr) and glutamate (Glu)/tCr ratios, and sex by tau interaction was observed in association with Glu/tCr. Higher tau levels in cognitively unimpaired older adults are associated with biomarkers of neural and synaptic injury even in the absence of cognitive impairment and these relationships appear to be stronger in women than in men., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction : Plasma glial fibrillary acidic protein (GFAP) may be associated with amyloid burden, neurodegeneration, and stroke but its specificity for Alzheimer's disease (AD) in the general population is unclear. We examined associations of plasma GFAP with amyloid and tau positron emission tomography (PET), cortical thickness, white matter hyperintensities (WMH), and cerebral microbleeds (CMBs). Methods : The study included 200 individuals from the Mayo Clinic Study of Aging who underwent amyloid and tau PET and magnetic resonance imaging and had plasma GFAP concurrently assayed; multiple linear regression and hurdle model analyses were used to investigate associations controlling for age and sex. Results : GFAP was associated with amyloid and tau PET in multivariable models. After adjusting for amyloid, the association with tau PET was no longer significant. GFAP was associated with cortical thickness, WMH, and lobar CMBs only among those who were amyloid-positive. Discussion : This cross-sectional analysis demonstrates the utility of GFAP as a plasma biomarker for AD-related pathologies., Competing Interests: Michelle M. Mielke served as a consultant to Brain Protection Company, Biogen, and LabCorp and receives research support from the National Institutes of Health and the Department of Defense. She is a senior associate editor for Alzheimer's and Dementia: The Journal of the Alzheimer's Association. David S. Knopman serves on a Data Safety Monitoring Board for Biogen (fee paid to institution), the DIAN‐TU study (receives personal consulting fees), Agenbio (unpaid), and an endovascular carotid reconstruction study (unpaid). He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the Alzheimer's Disease Cooperative Study, and receives research support from the National Institutes of Health and philanthropic funds. Prashanthi Vemuri received speaking fees from Miller Medical Communications, LLC, and receives research support from the National Institutes of Health. Jonathan Graff‐Radford receives NIH funding and serves on the editorial board for Neurology. He has received payment for speaking at the American Academy of Neurology Annual meeting. Clifford R. Jack serves on an independent data monitoring board for Roche, but he receives no personal compensation from any commercial entity. He receives research support from the National Institutes of Health, the GHR Foundation, and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. Ronald C. Petersen is a consultant for Roche, Inc., Merck, Inc., Biogen, Inc., and Eisai, Inc. He has received payment for serving on a Data Safety Monitoring Board for Genentech, receives royalties from Oxford University Press and UpToDate, and receives research support from the National Institutes of Health. Val J. Lowe consults for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals, and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH (NIA, NCI). Nikki H. Stricker served as a consultant to Biogen. She receives research support from the National Institutes of Health and the Kevin Merszei Career Development Award in Neurodegenerative Diseases Research IHO Janet Vittone, MD. Alicia Algeciras‐Schimnich, Michelle R. Campbell, Dror Shir, Timothy G. Lesnick, Scott A. Przybelski, and Ekaterina I. Hofrenning have no conflicts to report., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Mild cognitive impairment with the core clinical features of dementia with Lewy bodies is recognized as a prodromal stage of dementia with Lewy bodies. Although grey matter atrophy has been demonstrated in prodromal dementia with Lewy bodies, longitudinal rates of atrophy during progression to probable dementia with Lewy bodies are unknown. We investigated the regional patterns of cross-sectional and longitudinal rates of grey matter atrophy in prodromal dementia with Lewy bodies, including those who progressed to probable dementia with Lewy bodies. Patients with mild cognitive impairment with at least one core clinical feature of dementia with Lewy bodies (mean age = 70.5; 95% male), who were enrolled in the Mayo Clinic Alzheimer's Disease Research Center and followed for at least two clinical evaluations and MRI examinations, were included ( n  = 56). A cognitively unimpaired control group ( n  = 112) was matched 2:1 to the patients with mild cognitive impairment by age and sex. Patients either remained stable ( n  = 28) or progressed to probable dementia with Lewy bodies ( n  = 28) during a similar follow-up period and pathologic confirmation was available in a subset of cases ( n  = 18). Cross-sectional and longitudinal rates of grey matter atrophy were assessed using voxel-based and atlas-based region of interest analyses. At baseline, prodromal dementia with Lewy bodies was characterized by atrophy in the nucleus basalis of Meynert both in those who remained stable and those who progressed to probable dementia with Lewy bodies ( P  < 0.05 false discovery rate corrected). Increase in longitudinal grey matter atrophy rates were widespread, with greatest rates of atrophy observed in the enthorhinal and parahippocampal cortices, temporoparietal association cortices, thalamus and the basal ganglia, in mild cognitive impairment patients who progressed to probable dementia with Lewy bodies at follow-up ( P  < 0.05 false discovery rate corrected). Rates of inferior temporal atrophy were associated with greater rates of worsening on the clinical dementia rating-sum of boxes. Seventeen of the 18 (94%) autopsied cases had Lewy body disease. Results show that atrophy in the nucleus basalis of Meynert is a feature of prodromal dementia with Lewy bodies regardless of proximity to progression to probable dementia with Lewy bodies. Longitudinally, grey matter atrophy progresses in regions with significant cholinergic innervation, in alignment with clinical disease progression, with widespread and accelerated rates of atrophy in patients who progress to probable dementia with Lewy bodies. Given the prominent neurodegeneration in the cholinergic system, patients with prodromal dementia with Lewy bodies may be candidates for cholinesterase inhibitor treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Multi-compartment modelling of white matter microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) can provide information on white matter health through neurite density index and free water measures. We hypothesized that cerebrovascular disease, Alzheimer's disease, and TDP-43 proteinopathy would be associated with distinct NODDI readouts of white matter damage which would be informative for identifying the substrate for cognitive impairment. We identified two independent cohorts with multi-shell diffusion MRI, amyloid and tau PET, and cognitive assessments: specifically, a population-based cohort of 347 elderly randomly sampled from the Olmsted county, Minnesota, population and a clinical research-based cohort of 61 amyloid positive Alzheimer's dementia participants. We observed an increase in free water and decrease in neurite density using NODDI measures in the genu of the corpus callosum associated with vascular risk factors, which we refer to as the vascular white matter component. Tau PET signal reflective of 3R/4R tau deposition was associated with worsening neurite density index in the temporal white matter where we measured parahippocampal cingulum and inferior temporal white matter bundles. Worsening temporal white matter neurite density was associated with (antemortem confirmed) FDG TDP-43 signature. Post-mortem neuropathologic data on a small subset of this sample lend support to our findings. In the community-dwelling cohort where vascular disease was more prevalent, the NODDI vascular white matter component explained variability in global cognition (partial R 2 of free water and neurite density = 8.3%) and MMSE performance (8.2%) which was comparable to amyloid PET (7.4% for global cognition and 6.6% for memory). In the AD dementia cohort, tau deposition was the greatest contributor to cognitive performance (9.6%), but there was also a non-trivial contribution of the temporal white matter component (8.5%) to cognitive performance. The differences observed between the two cohorts were reflective of their distinct clinical composition. White matter microstructural damage assessed using advanced diffusion models may add significant value for distinguishing the underlying substrate (whether cerebrovascular disease versus neurodegenerative disease caused by tau deposition or TDP-43 pathology) for cognitive impairment in older adults., (© 2022. The Author(s).)

Background: Cerebral microbleeds (CMBs) are a common vascular pathology associated with future intracerebral hemorrhage. Plasma biomarkers of amyloid, tau, and neurodegeneration may provide a screening avenue to identify those with CMBs, but evidence is conflicting., Objective: To determine the association between plasma biomarkers (Aβ40, Aβ42, t-tau, p-tau181, p-tau217, neurofilament light chain (NfL)) and CMBs in a population-based study of aging and whether these biomarkers predict higher signal on Aβ-PET imaging in patients with multiple CMBs., Methods: 712 participants from the Mayo Clinic Study of Aging with T2* GRE MRI and plasma biomarkers were included. Biomarkers were analyzed utilizing Simoa (Aβ40, Aβ42, t-tau, NfL) or Meso Scale Discovery (p-tau181, p-tau217) platforms. Cross-sectional associations between CMBs, plasma biomarkers and Aβ-PET were evaluated using hurdle models and multivariable regression models., Results: Among the 188 (26%) individuals with≥1 CMB, a lower plasma Aβ42/Aβ40 ratio was associated with more CMBs after adjusting for covariables (IRR 568.5 95% CI 2.8-116,127). No other biomarkers were associated with risk or number CMBs. In 81 individuals with≥2 CMBs, higher plasma t-tau, p-tau181, and p-tau217 all were associated with higher Aβ-PET signal, with plasma p-tau217 having the strongest predictive value (r2 0.603, AIC -53.0)., Conclusion: Lower plasma Aβ42/Aβ40 ratio and higher plasma p-tau217 were associated with brain amyloidosis in individuals with CMBs from the general population. Our results suggest that in individuals with multiple CMBs and/or lobar intracranial hemorrhage that a lower plasma Aβ42/Aβ40 ratio or elevated p-tau217 may indicate underlying cerebral amyloid angiopathy.

Background: Brain accumulation of amyloid-β is a hallmark event in Alzheimer's disease (AD) whose underlying mechanisms are incompletely understood. Case-control genome-wide association studies have implicated numerous genetic variants in risk of clinically diagnosed AD dementia., Objective: To test for associations between case-control AD risk variants and amyloid PET burden in older adults, and to assess whether a polygenic measure encompassing these factors would account for a large proportion of the unexplained variance in amyloid PET levels in the wider population., Methods: We analyzed data from the Mayo Clinic Study of Aging (MCSA) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Global cortical amyloid PET burden was the primary outcome. The 38 gene variants from Wightman et al. (2021) were analyzed as predictors, with PRSice-2 used to assess the collective phenotypic variance explained., Results: Known AD risk variants in APOE, PICALM, CR1, and CLU were associated with amyloid PET levels. In aggregate, the AD risk variants were strongly associated with amyloid PET levels in the MCSA (p = 1.51×10-50) and ADNI (p = 3.21×10-64). However, in both cohorts the non-APOE variants uniquely contributed only modestly (MCSA = 2.1%, ADNI = 4.4%) to explaining variation in amyloid PET levels., Conclusion: Additional case-control AD risk variants added only modestly to APOE in accounting for individual variation in amyloid PET burden, results which were consistent across independent cohorts with distinct recruitment strategies and subject characteristics. Our findings suggest that advancing precision medicine for dementia may require integration of strategies complementing case-control approaches, including biomarker-specific genetic associations, gene-by-environment interactions, and markers of disease progression and heterogeneity.

Our goal was to understand the complex relationship between age, sex, midlife risk factors, and early white matter changes measured by diffusion tensor imaging (DTI) and their role in the evolution of longitudinal white matter hyperintensities (WMH). We identified 1564 participants (1396 cognitively unimpaired, 151 mild cognitive impairment and 17 dementia participants) with age ranges of 30-90 years from the population-based sample of Mayo Clinic Study of Aging. We used computational causal structure discovery and regression analyses to evaluate the predictors of WMH and DTI, and to ascertain the mediating effect of DTI on WMH. We further derived causal graphs to understand the complex interrelationships between midlife protective factors, vascular risk factors, diffusion changes, and WMH. Older age, female sex, and hypertension were associated with higher baseline and progression of WMH as well as DTI measures (P ≤ 0.003). The effects of hypertension and sex on WMH were partially mediated by microstructural changes measured on DTI. Higher midlife physical activity was predictive of lower WMH through a direct impact on better white matter tract integrity as well as an indirect effect through reducing the risk of hypertension by lowering BMI. This study identified key risks factors, early brain changes, and pathways that may lead to the evolution of WMH., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α-synuclein aggregates, but many DLB cases show concurrent Alzheimer's disease pathology in the form of amyloid-β plaques and tau neurofibrillary tangles. The first objective of this study was to investigate the effect of Alzheimer's disease co-pathology on functional network changes within the default mode network (DMN) in DLB. Second, we studied how the distribution of tau pathology measured with PET relates to functional connectivity in DLB. Twenty-seven DLB, 26 Alzheimer's disease and 99 cognitively unimpaired participants (balanced on age and sex to the DLB group) underwent tau-PET with AV-1451 (flortaucipir), amyloid-β-PET with Pittsburgh compound-B (PiB) and resting-state functional MRI scans. The resing-state functional MRI data were used to assess functional connectivity within the posterior DMN. This was then correlated with overall cortical flortaucipir PET and PiB PET standardized uptake value ratio (SUVr). The strength of interregional functional connectivity was assessed using the Schaefer atlas. Tau-PET covariance was measured as the correlation in flortaucipir SUVr between any two regions across participants. The association between region-to-region functional connectivity and tau-PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot- and cold spots) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot and cold spots. A reduction in posterior DMN connectivity correlated with overall higher cortical tau- (r = -0.39, P = 0.04) and amyloid-PET uptake (r = -0.41, P = 0.03) in the DLB group, i.e. patients with DLB who have more concurrent Alzheimer's disease pathology showed a more severe loss of DMN connectivity. Higher functional connectivity between regions was associated with higher tau covariance in cognitively unimpaired, Alzheimer's disease and DLB. Furthermore, higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher flortaucipir SUVrs in the target region, whereas higher functional connectivity to the tau cold spot (i.e. sensory-motor cortex) was related to lower flortaucipir SUVr in the target region. Our findings suggest that a higher burden of Alzheimer's disease co-pathology in patients with DLB is associated with more Alzheimer's disease-like changes in functional connectivity. Furthermore, we found an association between the brain's functional network architecture and the distribution of tau pathology that has recently been described in Alzheimer's disease. We show that this relationship also exists in patients with DLB, indicating that similar mechanisms of connectivity-dependent occurrence of tau pathology might be at work in both diseases., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: To determine the contribution of cerebral amyloid angiopathy (CAA) to Pittsburgh compound B (PiB)-PET tracer retention., Methods: Participants from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center with antemortem PiB-PET imaging for β-amyloid (Aβ) who later underwent autopsy were included in this study. Pathologic regional leptomeningeal, parenchymal, capillary CAA, and Aβ plaque burden were calculated from one hemisphere. Regional lobar amyloid standardized uptake value ratio (SUVR) on PET was calculated from the same hemisphere sampled at autopsy. Single- and multiple-predictor linear regression models were used to evaluate the relative contributions of pathologically determined regional CAA and Aβ plaques to antemortem PiB-PET SUVR., Results: Forty-one participants (30 male, 11 female) with a mean (SD) age at death of 75.7 (10.6) years were included. Twenty-seven (66%) had high PiB signal with a mean (SD) of 2.3 (1.2) years from time of PET scan to death; 24 (59%) had a pathologic diagnosis of Alzheimer disease. On multivariate analysis, CAA was not associated with PiB-PET SUVR, while plaques remained associated with PiB-PET SUVR in all regions (all p < 0.05). In patients without frequent amyloid plaques, CAA was not associated with PiB-PET in any region., Discussion: We did not find evidence that pathologically confirmed regional CAA burden contributes significantly to proximal antemortem regional PiB-PET signal, suggesting that amyloid PET imaging for measurement of cortical amyloid burden is unconfounded by CAA on a lobar level. Whether CAA burden contributes to PiB-PET signal in patients with severe CAA phenotypes, such as lobar hemorrhage, requires further investigation., (© 2021 American Academy of Neurology.)