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Background: Circulating phospholipid species have been shown to predict Alzheimer’s disease (AD) prognosis but the link between phospholipid disturbances and subcortical small vessel cerebrovascular disease (CeVD) common in AD patients is not known. Objective: Mass-spectrometry lipidomics was applied to quantify serum diacyl, alkenyl (ether), alkyl, and lyso phospholipid species in individuals with extensive CeVD (n = 29), AD with minimal CeVD (n = 16), and AD with extensive CeVD (n = 14), and compared them to age-matched controls (n = 27). Memory was assessed using the California Verbal Learning Test. 3.0T MRI was used to assess hippocampal volume, atrophy, and white matter hyperintensity (WMH) volumes as manifestations of CeVD. Results: AD was associated with significantly higher concentrations of choline plasmalogen 18:0_18:1 and alkyl-phosphocholine 18:1. CeVD was associated with significantly lower lysophospholipids containing 16:0. Phospholipids containing arachidonic acid (AA) were associated with poorer memory in controls, whereas docosahexaenoic acid (DHA)-containing phospholipids were associated with better memory in individuals with AD+CeVD. In controls, DHA-containing phospholipids were associated with more atrophy, and phospholipids containing linoleic acid and AA were associated with less atrophy. Lysophospholipids containing 16:0, 18:0, and 18:1 were correlated with less atrophy in controls, and of these, alkyl-phosphocholine 18:1 was correlated with smaller WMH volumes. Conversely, 16:0_18:1 choline plasmalogen was correlated with greater WMH volumes in controls. Conclusion: This study demonstrates discernable differences in circulating phospholipids in individuals with AD and CeVD, as well as new associations between phospholipid species with memory and brain structure that were specific to contexts of commonly comorbid vascular and neurodegenerative pathologies.

The blood–brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer’s disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer’s disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT03739905) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer’s disease pathology (P-tau181, amyloid-β42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.

Background: Metabolic and vascular risk factors (MVRF) are associated with neurodegeneration and poor cognition. There is a need to better understand the impact of these risk factors on brain health in the decades that precede cognitive impairment. Longitudinal assessments can provide new insight regarding changes in MVRFs that are related to brain imaging features. Objective: To investigate whether longitudinal changes in MVRF spanning up to 25 years would be associated with midlife brain volume and cognition. Methods: Participants were from the CARDIA study (N = 467, age at year 25 = 50.6±3.4, female/male = 232/235, black/white = 161/306). Three models were developed, each designed to capture change over time; however, we were primarily interested in the average real variability (ARV) as a means of quantifying MVRF variability across all available assessments. Results: Multivariate partial least squares that used ARV metrics identified two significant latent variables (partial correlations ranged between 0.1 and 0.26, p

The connection between vascular and brain metrics is well-studied in older adults, but neglected in youth and in psychiatric populations at increased cardiovascular risk. We therefore examined the association of retinal vascular caliber with cerebral blood flow (CBF) in adolescents with and without bipolar disorder (BD).Ninety-four adolescents (n = 48 BD, n = 46 controls) completed retinal fundus imaging, yielding estimates of arteriolar and venular diameter. Arterial spin labelling MRI was performed to measure CBF. We tested for associations between retinal vascular caliber and CBF in regions of interest; anterior cingulate cortex (ACC), middle frontal gyrus, and hippocampus in BD and controls separately. Complementary voxel-wise analyses were also performed.In the BD group, higher arteriovenous ratio (AVR) was associated with greater ACC CBF (β = 0.34, pLimited sample size; young, medically healthy sample limits signal detection; cross-sectional design.This study reveals that higher AVR is associated with higher regional CBF in adolescents with BD. Present findings advance understanding of potential neurofunctional mechanisms linking retinal vascular caliber with psychiatric diagnoses. This proof-of-concept study was designed to generate initial insights to guide future studies focusing on the vascular-brain connection in youth and in psychiatry.

OBJECTIVE Type 2 diabetes (T2D) increases dementia risk, but clear evidence to recommend interventions that can mitigate that risk remains lacking. This population-based retrospective cohort study aimed to determine whether new use of sodium–glucose cotransporter 2 (SGLT2) inhibitors compared with dipeptidyl peptidase 4 (DPP-4) inhibitors was associated with lower dementia risk. RESEARCH DESIGN AND METHODS Ontario residents aged ≥66 years who were new users of an SGLT2 inhibitor or a DPP-4 inhibitor from 1 July 2016 to 31 March 2021 entered the cohort. Incident dementia was identified using a validated algorithm for Alzheimer’s disease and related dementias. Propensity score–weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and CIs for time to incident dementia. To address reverse causality and disease latency, the observation window started at 1-year lag time from cohort entry. The primary analysis followed intention-to-treat exposure definition, and a secondary as-treated analysis was performed. RESULTS Among 106,903 individuals, SGLT2 inhibitors compared with DPP-4 inhibitors were associated with lower risk of dementia (14.2/1,000 person-years; aHR 0.80 [95% CI 0.71–0.89]) over a mean follow-up of 2.80 years from cohort entry. When stratified by different SGLT2 inhibitors, dapagliflozin exhibited the lowest risk (aHR 0.67 [95% CI 0.53–0.84]), followed by empagliflozin (aHR 0.78 [95% CI 0.69–0.89]), whereas canagliflozin showed no association (aHR 0.96 [95% CI 0.80–1.16]). The as-treated analysis observed a larger association (aHR 0.66 [95% CI 0.57–0.76]) than the intention-to-treat analysis. CONCLUSIONS SGLT2 inhibitors showed an association with lower dementia risk in older people with T2D. Randomized controlled trials are warranted.

Alterations in tissue microstructure in normal-appearing white matter (NAWM), specifically measured by diffusion tensor imaging (DTI) fractional anisotropy (FA), have been associated with cognitive outcomes following stroke. The purpose of this study was to comprehensively compare conventional DTI measures of tissue microstructure in NAWM to diverse vascular brain lesions in people with cerebrovascular disease (CVD) and to examine associations between FA in NAWM and cerebrovascular risk factors. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured in cerebral tissues and cerebrovascular anomalies from 152 people with CVD participating in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). Ten cerebral tissue types were segmented including NAWM, and vascular lesions including stroke, periventricular and deep white matter hyperintensities, periventricular and deep lacunar infarcts, and perivascular spaces (PVS) using T1-weighted, proton density-weighted, T2-weighted, and fluid attenuated inversion recovery MRI scans. Mean DTI metrics were measured in each tissue region using a previously developed DTI processing pipeline and compared between tissues using multivariate analysis of covariance. Associations between FA in NAWM and several CVD risk factors were also examined. DTI metrics in vascular lesions differed significantly from healthy tissue. Specifically, all tissue types had significantly different MD values, while FA was also found to be different in most tissue types. FA in NAWM was inversely related to hypertension and modified Rankin scale (mRS). This study demonstrated the differences between conventional DTI metrics, FA, MD, AD, and RD, in cerebral vascular lesions and healthy tissue types. Therefore, incorporating DTI to characterize the integrity of the tissue microstructure could help to define the extent and severity of various brain vascular anomalies. The association between FA within NAWM and clinical evaluation of hypertension and disability provides further evidence that white matter microstructural integrity is impacted by cerebrovascular function.

Magnetic resonance imaging (MRI) scanner-specific geometric distortions may contribute to scanner induced variability and decrease volumetric measurement precision for multi-site studies. The purpose of this study was to determine whether geometric distortion correction increases the precision of brain volumetric measurements in a multi-site multi-scanner study. Geometric distortion variation was quantified over a one-year period at 10 sites using the distortion fields estimated from monthly 3D T1-weighted MRI geometrical phantom scans. The variability of volume and distance measurements were quantified using synthetic volumes and a standard quantitative MRI (qMRI) phantom. The effects of geometric distortion corrections on MRI derived volumetric measurements of the human brain were assessed in two subjects scanned on each of the 10 MRI scanners and in 150 subjects with cerebrovascaular disease (CVD) acquired across imaging sites.Geometric distortions were found to vary substantially between different MRI scanners but were relatively stable on each scanner over a one-year interval. Geometric distortions varied spatially, increasing in severity with distance from the magnet isocenter. In measurements made with the qMRI phantom, the geometric distortion correction decreased the standard deviation of volumetric assessments by 35% and distance measurements by 42%. The average coefficient of variance decreased by 16% in gray matter and white matter volume estimates in the two subjects scanned on the 10 MRI scanners. Geometric distortion correction using an up-to-date correction field is recommended to increase precision in volumetric measurements made from MRI images.

Periventricular white matter hyperintensities (pvWMHs) are commonly observed on MRI in older individuals and are associated with cognitive and motor decline. The etiology of pvWMH remains unknown. Venous collagenosis has been implicated, which may also interfere with perivascular fluid flow leading to dilation of perivascular spaces (PVS). Here, we examine relationships between in vivo pvWMH volume and ex vivo morphological quantification of collagenosis and the PVS in veins and arteries.Brain tissue from 25 Oregon Alzheimer's Disease Research Center subjects was selected to cover the full range of WMH burden. Tissue from white matter abutting the ventricle was stained with Masson's trichrome and smooth muscle actin. An automated hue based algorithm identified and segmented vessel into collagenized vessel walls, lumen, and PVS. Multiple linear regressions with pvWMH volume as the dependent variable and either collagen thickness or PVS width were performed with covariates of vessel diameter, age at death, sex, and interval between MRI and death.PVS width and collagen thickness were significantly correlated in both arteries (r = 0.21, p = 0.001) and veins (r = 0.23, p = 0.001). Increased venous collagen (p = 0.017) was a significant predictor of higher pvWMH burden while arterial collagen was not (p = 0.128). Neither PVS width in arteries (p = 0.937) nor veins (p = 0.133) predicted pvWMH burden.These findings are consistent with a model in which venous collagenosis mediates the relationship between vascular risk factors and pvWMH. This study confirms the importance of changes to the venous system in contributing to MRI white matter lesions commonly observed with advanced age. ANN NEUROL 2022;92:992-1000.

INTRODUCTIONIt remains unclear to which extent vascular burden promotes neurodegeneration and cognitive dysfunction in a cohort spanning low-to-severe small vessel disease (SVD) and amyloid-beta pathology.METHODSIn 120 subjects, we investigated 1) whether vascular burden, quantified as total or lobar white matter hyperintensity (WMH) volumes, is associated with different cognitive domains; and 2) whether the total WMH effect on cognition is mediated by amyloid (18F-AV45-PET), glucose metabolism (18F-FDG-PET), and/or cortical atrophy.RESULTSIncreased total WMH volume was associated with poorer performance in all cognitive domains tested, with the strongest effects observed for semantic fluency. These relationships were mediated mainly through cortical atrophy, particularly in the temporal lobe, and to a lesser extent through amyloid and metabolism. WMH volumes differentially impacted cognition depending on lobar location and amyloid status.DISCUSSIONOur study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive impairment through temporal lobe atrophy.

Objectives:To evaluate whether cerebrospinal fluid biomarkers, apolipoprotein e4, neuroimaging abnormalities, and neuropsychological data differentially predict progression from mild cognitive impairment (MCI) to dementia for men and women.Methods:Participants who were diagnosed with MCI at baseline (n = 449) were classified as either progressing to Alzheimer’s dementia at follow-up or as not progressing. Men and women were first compared using bivariate analyses. Sex-stratified Cox proportional hazard regressions were performed examining the relationship between baseline data and the likelihood of progressing to dementia. Sex interactions were subsequently examined.Results:Cox proportional hazard regression controlling for age and education indicated that all variables significantly predicted subsequent progression to dementia for men and women. Sex interactions indicated that only Rey Auditory Verbal Learning Test (RAVLT) delayed recall and Functional Activities Questionnaire (FAQ) were significantly stronger risk factors for women. When all variables were entered into a fully adjusted model, significant risk factors for women were Aβ42, hippocampal volume, RAVLT delayed recall, Boston Naming Test, and FAQ. In contrast, for men, Aβ42, p-tau181, p-tau181/Aβ42, hippocampal volume, category fluency and FAQ were significant risk factors. Interactions with sex were only significant for p-tau181/Aβ42 and RAVLT delayed recall for the fully adjusted model.Conclusions:Men and women with MCI may to differ for which factors predict subsequent dementia although future analyses with greater power are needed to evaluate sex differences. We hypothesize that brain and cognitive reserve theories may partially explain these findings.

BackgroundPick’s disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by theMAPTgene. TheMAPTH2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association betweenMAPTH2 and risk of PiD.MethodsWe established the Pick’s disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped forMAPTH1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variantMAPTH1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521).FindingsOur primary analysis found that theMAPTH2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotypeMAPTH1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65).InterpretationThe PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, theMAPTH2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.FundingSee funding section

BackgroundParkinson’s disease (PD) and dementia with Lewy bodies (DLB) are part of a spectrum of Lewy body disorders, who exhibit a range of cognitive and gait impairments. Cognitive-motor interactions can be examined by performing a cognitive task while walking and quantified by a dual task cost (DTC). White matter hyperintensities (WMH) on magnetic resonance imaging have also been associated with both gait and cognition. Our goal was to examine the relationship between DTC and WMH in the Lewy body spectrum, hypothesizing DTC would be associated with increased WMH volume.MethodsSeventy-eight participants with PD, PD with mild cognitive impairment (PD-MCI), PD with dementia or DLB (PDD/DLB), and 20 cognitively unimpaired participants were examined in a multi-site study. Gait was measured on an electronic walkway during usual gait, counting backward, animal fluency, and subtracting sevens. WMH were quantified from magnetic resonance imaging using an automated pipeline and visual rating. A median split based on DTC was performed. Models included age as well as measures of global cognition and cardiovascular risk.ResultsCompared to cognitively unimpaired participants, usual gait speed was lower and DTC was higher in PD-MCI and PDD/DLB. Low DTC participants had higher usual gait speed. WMH burden was greater in high counting DTC participants. Frontal WMH burden remained significant after adjusting for age, cardiovascular risk and global cognition.ConclusionIncreased DTC was associated with higher frontal WMH burden in Lewy body disorders after adjusting for age, cardiovascular risk, and global cognition. Higher DTC was associated with age.

IntroductionThe long-term impact of COVID-19 on brain function remains poorly understood, despite growing concern surrounding post-acute COVID-19 syndrome (PACS). The goal of this cross-sectional, observational study was to determine whether there are significant alterations in resting brain function among non-hospitalized individuals with PACS, compared to symptomatic individuals with non-COVID infection.MethodsData were collected for 51 individuals who tested positive for COVID-19 (mean age 41±12 yrs., 34 female) and 15 controls who had cold and flu-like symptoms but tested negative for COVID-19 (mean age 41±14 yrs., 9 female), with both groups assessed an average of 4-5 months after COVID testing. None of the participants had prior neurologic, psychiatric, or cardiovascular illness. Resting brain function was assessed via functional magnetic resonance imaging (fMRI), and self-reported symptoms were recorded.ResultsIndividuals with COVID-19 had lower temporal and subcortical functional connectivity relative to controls. A greater number of ongoing post-COVID symptoms was also associated with altered functional connectivity between temporal, parietal, occipital and subcortical regions.DiscussionThese results provide preliminary evidence that patterns of functional connectivity distinguish PACS from non-COVID infection and correlate with the severity of clinical outcome, providing novel insights into this highly prevalent disorder.

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com, Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions., This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.

Using administrative data from Norway, we document that gifts and inheritances are a more important component of total income for women than for men. This is particularly true at the very top of the distributions of total lifetime income and net wealth. These differences are not due to gender differences in the receipt of intergenerational transfers but are driven by gender differences in total income. When we calculate counterfactual distributions of total lifetime income where gifts and inheritances are equalized across all individuals, we find that gifts and inheritances tend to reduce gender gaps across the distribution.

BACKGROUND: Progressive supranuclear palsy (PSP)–pallido‐nigro‐luysian atrophy (PNLA) is a neuropathological entity thought to be a variant of classic PSP. Clinical features and pathologic hallmarks are the same in both conditions; however, age and order of symptom onset, disease duration and prognosis, and distribution and density of pathology differentiate the 2 entities. OBJECTIVES: This study presents a PSP‐PNLA case confirmed pathologically with a clinical presentation of hemichorea/ballism, spasticity, progressive hemiparesis, and a frontal behavioral syndrome with relative cognitive sparing early in the disease course. METHODS: We describe the clinical progression in this unique case supplemented with video and imaging findings in the form of magnetic resonance imaging and brain single photon emission computed tomography. Final diagnosis is via pathological analysis at autopsy. RESULTS: We present an elderly gentleman who manifested a clinical syndrome consisting of subacute onset of chorea that at presentation was distinctly unilateral and a frontal behavioral syndrome in the setting of mild thrombocytopenia and elevated anticardiolipin antibodies. Positive antiphospholipid antibodies resulted in an initial antemortem diagnosis of primary antiphospholipid syndrome as a cause of his chorea. Longitudinal follow‐up over 5 years demonstrated a progression of clinical features with hemi‐motor impersistence/chorea, disinhibition and impulsivity, and eventually corticospinal distribution weakness on the initially affected side. He required nursing home care and falls necessitated wheelchair use. Postmortem neuropathological study revealed a diagnosis of frontotemporal lobar degeneration‐tau, PSP‐PNLA. CONCLUSIONS: This case broadens the phenotype of PSP‐PNLA and to our knowledge is the only case presenting with unilateral chorea.

Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap.This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes.We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation.Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Develop and evaluate a deep learning approach to estimate cerebral blood flow (CBF) and arterial transit time (ATT) from multiple post-labeling delay (PLD) ASL MRI.ASL MRI were acquired with 6 PLDs on a 1.5T or 3T GE system in adults with and without cognitive impairment (N = 99). Voxel-level CBF and ATT maps were quantified by training models with distinct convolutional neural network architectures: (1) convolutional neural network (CNN) and (2) U-Net. Models were trained and compared via 5-fold cross validation. Performance was evaluated using mean absolute error (MAE). Model outputs were trained on and compared against a reference ASL model fitting after data cleaning. Minimally processed ASL data served as another benchmark. Model output uncertainty was estimated using Monte Carlo dropout. The better-performing neural network was subsequently re-trained on inputs with missing PLDs to investigate generalizability to different PLD schedules.Relative to the CNN, the U-Net yielded lower MAE on training data. On test data, the U-Net MAE was 8.4 ± 1.4 mL/100 g/min for CBF and 0.22 ± 0.09 s for ATT. A significant association was observed between MAE and Monte Carlo dropout-based uncertainty estimates. Neural network performance remained stable despite systematically reducing the number of input images (i.e., up to 3 missing PLD images). Mean processing time was 10.77 s for the U-Net neural network compared to 10 min 41 s for the reference pipeline.It is feasible to generate CBF and ATT maps from 1.5T and 3T multi-PLD ASL MRI with a fast deep learning image-generation approach.

Background Cardiovascular risk factors co‐occur with one another, and little is known about the extent of their clustering and risk of Alzheimer disease (AD). We identify groups of cardiovascular risk factors in cognitively normal individuals and investigate between‐group differences in incident AD and death. Methods and Results Cognitively normal individuals were recruited from the National Alzheimer's Coordinator Center. A latent class analysis was conducted with hypertension, hypercholesterolemia, heart condition, stroke, smoking history, diabetes, and high body mass index. Between‐group differences in the incidence of AD, mortality, and mortality‐adjusted AD were investigated. This study included 12 412 cognitively normal individuals (average follow‐up, 65 months). Three groups were identified: (1) low probabilities of cardiovascular risk factors (reference; N=5398 [43%]), (2) hypertension and hypercholesterolemia (vascular‐dominant; N=5721 [46%]), and (3) hypertension, hypercholesterolemia, diabetes, and high body mass index (vascular‐metabolic; N=1293 [10%]). Both vascular groups were significantly older, had more men, were slightly less educated, and were slightly more cognitively impaired than the reference group (all P P P P P =0.02). Mortality‐adjusted AD was greater in the vascular‐dominant (OR, 1.54; P =0.02) and vascular‐metabolic groups (OR, 1.46; P =0.04). Conclusions Three distinct cardiovascular risk factor groups were identified in cognitively normal elderly individuals. Only the vascular‐dominant group was associated with a greater incidence of AD. Selective mortality may contribute to the attenuated association between the vascular‐metabolic group and incident AD.

We use the introduction of the Texas Top Ten Percent rule to estimate the effect of access to a selective college on graduation and earnings outcomes for two groups of students. For highly ranked students at more disadvantaged high schools, who gained access under the policy, college enrollment and graduation increased. Less highly ranked students at more advantaged schools, who tended to lose access, shifted toward less-selective colleges under the policy, but did not see declines in overall college enrollment, graduation, or earnings. The policy thus benefited students targeted for admission without evidence of adverse effects on displaced students. (JEL I21, I23, I24, I26)

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

Growing reliance on student loans and repayment difficulties have raised concerns of a student debt crisis in the United States. However, little is known about the effects of student borrowing on human capital and long-run financial well-being. The authors use variation induced by recent expansions in federal loan limits, together with administrative schooling, earnings, and credit records, to identify the effects of increased student borrowing on credit-constrained students’ educational attainment, earnings, debt, and loan repayment. Increased student loan availability raises student debt and improves degree completion, later-life earnings, and student loan repayment while having no effect on homeownership or other types of debt. Annenberg Institute at Brown University

Alzheimer’s disease is a major cause of morbidity and mortality. Currently, there are no disease-modifying pharmacotherapies for this condition. Aducanumab, an amyloid beta-directed monoclonal antibody that targets aggregated forms of amyloid-beta in the brains of people with Alzheimer’s disease, has raised hopes that such a therapy has been discovered, but its approval by the US Food and Drug Administration has engendered a good deal of controversy. A similar application for approval has been submitted to Health Canada. In response to this, a group of Canadian clinical dementia experts representing a number of organizations, including the Canadian Geriatrics Society, was convened by the Canadian Consortium on Neurodegeneration in Aging (CCNA) to discuss the evidence currently available on this agent and seek consensus on what advice they would offer Health Canada on the application. There was wide-spread agreement that it would be premature for aducanumab to receive approval for the treatment of Alzheimer’s disease. It was also noted that the Canadian health-care system is poorly prepared at this time to deal with a disease-modifying therapeutic with targeting, administration, and monitoring characteristics like aducanumab. In this paper, the consensus reached is presented along with its underlying rationale.

Background Cerebral small vessel disease is associated with higher ratios of soluble‐epoxide hydrolase derived linoleic acid diols (12,13‐dihydroxyoctadecenoic acid [DiHOME] and 9,10‐DiHOME) to their parent epoxides (12(13)‐epoxyoctadecenoic acid [EpOME] and 9(10)‐EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra‐high‐performance liquid chromatography–mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13‐DiHOME/12(13)‐EpOME ratio (β=0.251, P =0.023). The 12,13‐DiHOME/12(13)‐EpOME ratio was associated with more lacunes (β=0.266, P =0.028) but not with large vessel stroke volumes. Ratios of 12,13‐DiHOME/12(13)‐EpOME and 9,10‐DiHOME/9(10)‐EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P P P =0.011; β=0.314, P =0.006). In small vessel stroke, the 12,13‐DiHOME/12(13)‐EpOME ratio was associated with higher white matter free water diffusion (β=0.439, P =0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10‐DiHOME/9(10)‐EpOME ratio was associated with temporal lobe atrophy (β=−0.277, P =0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble‐epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular‐glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.

Quality control of morphometric neuroimaging data is essential to improve reproducibility. Owing to the complexity of neuroimaging data and subsequently the interpretation of their results, visual inspection by trained raters is the most reliable way to perform quality control. Here, we present a protocol for visual quality control of the anatomical accuracy of FreeSurfer parcellations, based on an easy-to-use open-source tool called VisualQC. We comprehensively evaluate its utility in terms of error detection rate and inter-rater reliability on two large multi-site datasets and discuss site differences in error patterns. This evaluation shows that VisualQC is a practically viable protocol for community adoption.

Objective Type 2 diabetes increases dementia risk, but clear evidence to recommend interventions that can mitigate that risk remains lacking. This population-based retrospective cohort study aimed to determine whether new use of sodium-glucose cotransporter-2 (SGLT2) inhibitors compared to dipeptidyl peptidase-4 (DPP4) inhibitors was associated with lower dementia risk. Research Design and Methods Ontario residents aged ≥66 years who were new users of an SGLT2 inhibitor or a DPP4 inhibitor from July 1st, 2016 to March 31st, 2021 entered the cohort. Incident dementia was identified using a validated algorithm for Alzheimer’s disease and related dementias. Propensity-score weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and confidence intervals (CI) for time to incident dementia. To address reverse causality and disease latency, the observation window started at 1-year lag-time from cohort entry. The primary analysis followed intention-to-treat exposure definition, and a secondary as-treated analysis was performed. Results Among 106,903 individuals, SGLT2 inhibitors compared with DPP4 inhibitors were associated with lower risk of dementia (14.2/1000 person-years; aHR [95% CI]=0.80 [0.71-0.89]) over a mean follow-up of 2.80 years from cohort entry. When stratified by different SGLT2 inhibitors, dapagliflozin exhibited the lowest risk (aHR [95% CI]=0.67 [0.53-0.84]), followed by empagliflozin (aHR [95% CI]=0.78 [0.69-0.89]), whereas canagliflozin showed no association (aHR [95% CI]=0.96 [0.80-1.16]). The as-treated analysis observed a larger association (aHR [95% CI]=0.66 [0.57-0.76]) than the intention-to-treat analysis. Conclusions SGLT2 inhibitors showed an association with lower dementia risk in older people with type 2 diabetes. Randomized controlled trials are warranted.

Neurological symptoms associated with coronavirus disease 2019 (COVID-19), such as fatigue and smell/taste changes, persist beyond infection. However, little is known of brain physiology in the post-COVID-19 timeframe.To determine whether adults who experienced flu-like symptoms due to COVID-19 would exhibit cerebral blood flow (CBF) alterations in the weeks/months beyond infection, relative to controls who experienced flu-like symptoms but tested negative for COVID-19.Prospective observational.A total of 39 adults who previously self-isolated at home due to COVID-19 (41.9 ± 12.6 years of age, 59% female, 116.5 ± 62.2 days since positive diagnosis) and 11 controls who experienced flu-like symptoms but had a negative COVID-19 diagnosis (41.5 ± 13.4 years of age, 55% female, 112.1 ± 59.5 since negative diagnosis).A 3.0 T; T1-weighted magnetization-prepared rapid gradient and echo-planar turbo gradient-spin echo arterial spin labeling sequences.Arterial spin labeling was used to estimate CBF. A self-reported questionnaire assessed symptoms, including ongoing fatigue. CBF was compared between COVID-19 and control groups and between those with (n = 11) and without self-reported ongoing fatigue (n = 28) within the COVID-19 group.Between-group and within-group comparisons of CBF were performed in a voxel-wise manner, controlling for age and sex, at a family-wise error rate of 0.05.Relative to controls, the COVID-19 group exhibited significantly decreased CBF in subcortical regions including the thalamus, orbitofrontal cortex, and basal ganglia (maximum cluster size = 6012 voxels and maximum t-statistic = 5.21). Within the COVID-19 group, significant CBF differences in occipital and parietal regions were observed between those with and without self-reported on-going fatigue.These cross-sectional data revealed regional CBF decreases in the COVID-19 group, suggesting the relevance of brain physiology in the post-COVID-19 timeframe. This research may help elucidate the heterogeneous symptoms of the post-COVID-19 condition.2.Stage 3.