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Abstract Digital quantification of gait can be used to measure aging- and disease-related decline in mobility. Gait performance also predicts prognosis, disease progression, and response to therapies. Most gait analysis systems require large amounts of space, resources, and expertise to implement and are not widely accessible. Thus, there is a need for a portable system that accurately characterizes gait. Here, depth video from two portable cameras accurately reconstructed gait metrics comparable to those reported by a pressure-sensitive walkway. 392 research participants walked across a four-meter pressure-sensitive walkway while depth video was recorded. Gait speed, cadence, and step and stride durations and lengths strongly correlated (r > 0.9) between modalities, with root-mean-squared-errors (RMSE) of 0.04 m/s, 2.3 steps/min, 0.03 s, and 0.05–0.08 m for speed, cadence, step/stride duration, and step/stride length, respectively. Step, stance, and double support durations (gait cycle percentage) significantly correlated (r > 0.6) between modalities, with 5% RMSE for step and stance and 10% RMSE for double support. In an exploratory analysis, gait speed from both modalities significantly related to healthy, mild, moderate, or severe categorizations of Charleson Comorbidity Indices (ANOVA, Tukey’s HSD, p

Abstract 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

Abstract To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer’s disease, we performed single nucleus RNA sequencing in 24 Alzheimer’s disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3, upregulated in Alzheimer’s disease pericytes, has the highest number of ligands including VEGFA, downregulated in Alzheimer’s disease astrocytes. We validated these findings with external datasets comprising 4,730 pericyte and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with Alzheimer’s disease-related neuroimaging outcomes. We determined inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human iPSC and zebrafish models. Here, we detect vast transcriptome changes in Alzheimer’s disease at the gliovascular-unit, prioritize perturbed pericytic SMAD3-astrocytic VEGFA interactions, and validate these in cross-species models to provide a molecular mechanism of blood-brain-barrier disintegrity in Alzheimer’s disease.

Abstract 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.

Abstract 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.

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show distinct atrophy and overlapping hypometabolism profiles, but it is unknown how disruptions in structural and functional connectivity compare between these disorders and whether breakdowns in connectivity relate to either atrophy or hypometabolism.Thirty amyloid-positive PCA patients, 24 amyloid-negative DLB patients and 30 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN, and underwent a 3T head MRI, including structural MRI, resting state functional MRI (rsfMRI) and diffusion tensor imaging (DTI) sequences, as well as [18F] fluorodeoxyglucose (FDG) PET. We assessed functional connectivity within and between 12 brain networks using rsfMRI and the CONN functional connectivity toolbox and calculated regional DTI metrics using the Johns Hopkins atlas. Multivariate linear-regression models corrected for multiple comparisons and adjusted for age and sex compared DTI metrics and within-network and between-network functional connectivity across groups. Regional gray-matter volumes and FDG-PET standard uptake value ratios (SUVRs) were calculated and analyzed at the voxel-level using SPM12. We used univariate linear-regression models to investigate the relationship between connectivity measures, gray-matter volume, and FDG-PET SUVR.On DTI, PCA showed degeneration in occipito-parietal white matter, posterior thalamic radiations, splenium of the corpus collosum and sagittal stratum compared to DLB and CU, with greater degeneration in the temporal white matter and the fornix compared to CU. We observed no white-matter degeneration in DLB compared to CU. On rsfMRI, reduced within-network connectivity was present in dorsal and ventral default mode networks (DMN) and the dorsal-attention network in PCA compared to DLB and CU, with reduced within-network connectivity in the visual and sensorimotor networks compared to CU. DLB showed reduced connectivity in the cerebellar network compared to CU. Between-network analysis showed increased connectivity in both cerebellar-to-sensorimotor and cerebellar-to-dorsal attention network connectivity in PCA and DLB. PCA showed reduced anterior DMN-to-cerebellar and dorsal attention-to-sensorimotor connectivity, while DLB showed reduced posterior DMN-to-sensorimotor connectivity compared to CU. PCA showed reduced dorsal DMN-to-visual connectivity compared to DLB. The multimodal analysis revealed weak associations between functional connectivity and volume in PCA, and between functional connectivity and metabolism in DLB.These findings suggest that PCA and DLB have unique connectivity alterations, with PCA showing more widespread disruptions in both structural and functional connectivity; yet some overlap was observed with both disorders showing increased connectivity from the cerebellum.

Objective: To assess the effect of atrial fibrillation (AF) on outcomes in hospitalizations for non-traumatic intracerebral hemorrhage (ICH). Patients and Methods: We queried the National Inpatient Sample database between January 1, 2016, and December 31, 2019, to identify hospitalizations with an index diagnosis of non-traumatic ICH using ICD-10 code I61. The cohort was divided into patients with and without AF. Propensity score matching was used to balance the covariates between AF and non-AF groups. Logistic regression was used to analyze the association. All statistical analyses were performed using weighted values. Results: Our cohort included 292,725 hospitalizations with a primary discharge diagnosis of non-traumatic ICH. From this group, 59,005 (20%) recorded a concurrent diagnosis of AF, and 46% of these patients with AF were taking anticoagulants. Patients with AF reported a higher Elixhauser comorbidity index (19.8±6.0 vs 16.6±6.4; P

Abstract 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

Primary progressive aphasia (PPA) variants present with distinct disruptions in speech-language functions with little known about the interplay between affected and spared regions within the speech-language network and their interaction with other functional networks.The Neurodegenerative Research Group, Mayo Clinic, recruited 123 patients with PPA (55 logopenic (lvPPA), 44 non-fluent (nfvPPA) and 24 semantic (svPPA)) who were matched to 60 healthy controls. We investigated functional connectivity disruptions between regions within the left-speech-language network (Broca, Wernicke, anterior middle temporal gyrus (aMTG), supplementary motor area (SMA), planum temporale (PT) and parietal operculum (PO)), and disruptions to other networks (visual association, dorsal-attention, frontoparietal and default mode networks (DMN)).Within the speech-language network, multivariate linear regression models showed reduced aMTG-Broca connectivity in all variants, with lvPPA and nfvPPA findings remaining significant after Bonferroni correction. Additional loss in Wernicke-Broca connectivity in nfvPPA, Wernicke-PT connectivity in lvPPA and greater aMTG-PT connectivity in svPPA were also noted. Between-network connectivity findings in all variants showed reduced aMTG-DMN and increased aMTG-dorsal-attention connectivity, with additional disruptions between aMTG-visual association in both lvPPA and svPPA, aMTG-frontoparietal in lvPPA, and Wernicke-DMN breakdown in svPPA.These findings suggest that aMTG connectivity breakdown is a shared feature in all PPA variants, with lvPPA showing more extensive connectivity disruptions with other networks.

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.

Abstract INTRODUCTION This study evaluated the performance of the Lumipulse plasma beta‐amyloid (Aβ) 42/40 and pTau181 compared to other assays to detect an abnormal amyloid‐positron emission tomography (PET). METHODS Plasma samples from cognitively unimpaired (N = 179) and MCI/AD dementia (N = 36) individuals were retrospectively evaluated. Plasma Aβ42/40 and pTau181 were measured using the Lumipulse and Simoa immunoassays. An immunoprecipitation mass spectrometry (IP‐MS) assay for plasma Aβ42/40 was also evaluated. Amyloid‐PET status was the outcome measure. RESULTS Lumipulse and IP‐MS Aβ42/40 exhibited the highest diagnostic accuracy for detecting an abnormal amyloid‐PET (areas under the curve [AUCs] of 0.81 and 0.84, respectively). The Lumipulse and Simoa pTau181 assays exhibited lower performance (AUCs of 0.74 and 0.72, respectively). The Simoa Aβ42/40 assay demonstrated the lowest diagnostic accuracy (AUC 0.57). Combining Aβ42/40 and pTau181 did not significantly improve performance over Aβ42/40 alone for Lumipulse (AUC 0.83) or over pTau181 alone for Simoa (AUC 0.71) DISCUSSION The Lumipulse Aβ42/40 assay showed similar performance to the IP‐MS Aβ42/40 assay for detection of an abnormal amyloid‐PET; and both assays performed better than the two p‐tau181 immunoassays. The Simoa Aβ42/Aβ40 assay was the least accurate at predicting an abnormal amyloid‐PET status. Highlights Lumipulse plasma Aβ42/Aβ40 AUC for abnormal amyloid‐PET detection was 0.81. This performance was comparable to previously reported IP‐MS and higher than Simoa. Performance of Alzheimer's disease blood biomarkers varies between assays.

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 18Fluorodeoxyglucose-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.

Abstract Background Advances in ultrasensitive detection of phosphorylated tau (p-tau) in plasma has enabled the use of blood tests to measure Alzheimer’s disease (AD) biomarker changes. Examination of postmortem brains of participants with antemortem plasma p-tau levels remains critical to understanding comorbid and AD-specific contribution to these biomarker changes. Methods We analyzed 35 population-based Mayo Clinic Study of Aging participants with plasma p-tau at threonine 181 and threonine 217 (p-tau181, p-tau217) available within 3 years of death. Autopsied participants included cognitively unimpaired, mild cognitive impairment, AD dementia, and non-AD neurodegenerative disorders. Global neuropathologic scales of tau, amyloid-β, TDP-43, and cerebrovascular disease were examined. Regional digital pathology measures of tau (phosphorylated threonine 181 and 217 [pT181, pT217]) and amyloid-β (6F/3D) were quantified in hippocampus and parietal cortex. Neurotransmitter hubs reported to influence development of tangles (nucleus basalis of Meynert) and amyloid-β plaques (locus coeruleus) were evaluated. Results The strongest regional associations were with parietal cortex for tau burden (p-tau181 R = 0.55, p = 0.003; p-tau217 R = 0.66, p

Abstract INTRODUCTION Delay in diagnosis of posterior cortical atrophy (PCA) syndrome is common, and the lack of familiarity with assessment tools for identifying visual cortical dysfunction is a contributing factor. We propose recommendations for the approach to the evaluation of PCA clinical features during the office visit, the neuropsychological evaluation, and the research setting. A recommended screening battery for eye clinics is also proposed. METHODS Recommendations were developed using results from a web‐based survey of members of Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Atypical Alzheimer's Disease Professional Interest Area (PIA), literature review, and consensus by the PCA assessment working party of the Atypical Alzheimer's Disease PIA. RESULTS Survey results revealed robust agreement for assessment tool preferences for PCA features, and many respondents indicated that they reserve assessment tools for use only when PCA is suspected. For some PCA features, curated tools were preferred over validated battery tools, particularly for the office visit. Consensus recommendations superseded survey preferences for two core cognitive features within the 2017 PCA diagnostic criteria. DISCUSSION These consensus recommendations provide an evaluation framework for PCA clinical features and can facilitate timely and accurate recognition and diagnosis of PCA. Broader use of these tools should be sought, and development and validation of novel PCA clinical outcome assessments are needed to improve our understanding of atypical AD and other dementias and support the inclusion of those with PCA in treatment trials.

There is a need to reassess contemporary oral anticoagulation (OAC) trends and barriers against guideline directed therapy in the United States. Most previous studies were performed before major guideline changes recommended direct oral anticoagulant (DOAC) use over warfarin or have otherwise lacked patient level data. Data on overuse of OAC in low-risk group is also limited. To address these knowledge gaps, we performed a nationwide analysis to analyze current trends. This is a retrospective cohort study assessing non-valvular AF identified using a large United States de-identified administrative claims database, including commercial and Medicare Advantage enrollees. Prescription fills were assessed within a 90-day follow-up from the patient’s index AF encounter between January 1, 2016, and December 31, 2020. Among the 339,197 AF patients, 4.4%, 8.0%, and 87.6% were in the low-, moderate-, and high-risk groups (according to CHA2DS2-VASc score). An over (29.6%) and under (52.2%) utilization of OAC was reported in low- and high-risk AF patients. A considerably high frequency for warfarin use was also noted among high-risk group patients taking OAC (33.1%). The results suggest that anticoagulation use for stroke prevention in the United States is still comparable to the pre-DOAC era studies. About half of newly diagnosed high-risk non-valvular AF patients remain unprotected against stroke risk. Several predictors of OAC and DOAC use were also identified. Our findings may identify a population at risk of complications due to under- or over-treatment and highlight the need for future quality improvement efforts.

Abstract Dementia with Lewy bodies (DLB) is clinically diagnosed when patients develop dementia less than a year after parkinsonism onset. Age is the primary risk factor for DLB and mitochondrial health influences ageing through effective oxidative phosphorylation (OXPHOS). Patterns of stable polymorphisms in the mitochondrial genome (mtDNA) alter OXPHOS efficiency and define individuals to specific mtDNA haplogroups. This study investigates if mtDNA haplogroup background affects clinical DLB risk and neuropathological disease severity. 360 clinical DLB cases, 446 neuropathologically confirmed Lewy body disease (LBD) cases with a high likelihood of having DLB (LBD-hDLB), and 910 neurologically normal controls had European mtDNA haplogroups defined using Agena Biosciences MassARRAY iPlex technology. 39 unique mtDNA variants were genotyped and mtDNA haplogroups were assigned to mitochondrial phylogeny. Striatal dopaminergic degeneration, neuronal loss, and Lewy body counts were also assessed in different brain regions in LBD-hDLB cases. Logistic regression models adjusted for age and sex were used to assess associations between mtDNA haplogroups and risk of DLB or LBD-hDLB versus controls in a case-control analysis. Additional appropriate regression models, adjusted for age at death and sex, assessed associations of haplogroups with each different neuropathological outcome measure. No mtDNA haplogroups were significantly associated with DLB or LBD-hDLB risk after Bonferroni correction.Haplogroup H suggests a nominally significant reduced risk of DLB (OR=0.61, P=0.006) but no association of LBD-hDLB (OR=0.87, P=0.34). The haplogroup H observation in DLB was consistent after additionally adjusting for the number of APOE ε4 alleles (OR=0.59, P=0.004). Haplogroup H also showed a suggestive association with reduced ventrolateral substantia nigra neuronal loss (OR=0.44, P=0.033). Mitochondrial haplogroup H may be protective against DLB risk and neuronal loss in substantia nigra regions in LBD-hDLB cases but further validation is warranted.

The clinical usefulness MRI biomarkers for aging and dementia studies relies on precise brain morphological measurements; however, scanner and/or protocol variations may introduce noise or bias. One approach to address this is post-acquisition scan harmonization. In this work, we evaluate deep learning (neural style transfer, CycleGAN and CGAN), histogram matching, and statistical (ComBat and LongComBat) methods. Participants who had been scanned on both GE and Siemens scanners (cross-sectional participants, known as Crossover (n = 113), and longitudinally scanned participants on both scanners (n = 454)) were used. The goal was to match GE MPRAGE (T1-weighted) scans to Siemens improved resolution MPRAGE scans. Harmonization was performed on raw native and preprocessed (resampled, affine transformed to template space) scans. Cortical thicknesses were measured using FreeSurfer (v.7.1.1). Distributions were checked using Kolmogorov-Smirnov tests. Intra-class correlation (ICC) was used to assess the degree of agreement in the Crossover datasets and annualized percent change in cortical thickness was calculated to evaluate the Longitudinal datasets. Prior to harmonization, the least agreement was found at the frontal pole (ICC = 0.72) for the raw native scans, and at caudal anterior cingulate (0.76) and frontal pole (0.54) for the preprocessed scans. Harmonization with NST, CycleGAN, and HM improved the ICCs of the preprocessed scans at the caudal anterior cingulate (>0.81) and frontal poles (>0.67). In the Longitudinal raw native scans, over- and under-estimations of cortical thickness were observed due to the changing of the scanners. ComBat matched the cortical thickness distributions throughout but was not able to increase the ICCs or remove the effects of scanner changeover in the Longitudinal datasets. CycleGAN and NST performed slightly better to address the cortical thickness variations between scanner change. However, none of the methods succeeded in harmonizing the Longitudinal dataset. CGAN was the worst performer for both datasets. In conclusion, the performance of the methods was overall similar and region dependent. Future research is needed to improve the existing approaches since none of them outperformed each other in terms of harmonizing the datasets at all ROIs. The findings of this study establish framework for future research into the scan harmonization problem.

Abstract 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 R2 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. Graphical abstract

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_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.

Abstract Background Total tau protein (T-Tau) and neurofilament light chain (NfL) have emerged as candidate plasma biomarkers of neurodegeneration, but studies have not compared how these biomarkers cross-sectionally or longitudinally associate with cognitive and neuroimaging measures. We therefore compared plasma T-Tau and NfL as cross-sectional and longitudinal markers of (1) global and domain-specific cognitive decline and (2) neuroimaging markers of cortical thickness, hippocampal volume, white matter integrity, and white matter hyperintensity volume. Methods We included 995 participants without dementia who were enrolled in the Mayo Clinic Study of Aging cohort. All had concurrent plasma NfL and T-tau, cognitive status, and neuroimaging data. Follow-up was repeated approximately every 15 months for a median of 6.2 years. Plasma NfL and T-tau were measured on the Simoa-HD1 Platform. Linear mixed effects models adjusted for age, sex, and education examined associations between baseline z-scored plasma NfL or T-tau and cognitive or neuroimaging outcomes. Analyses were replicated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) among 387 participants without dementia followed for a median of 3.0 years. Results At baseline, plasma NfL was more strongly associated with all cognitive and neuroimaging outcomes. The combination of having both elevated NfL and T-tau at baseline, compared to elevated levels of either alone, was more strongly associated at cross-section with worse global cognition and memory, and with neuroimaging measures including temporal cortex thickness and increased number of infarcts. In longitudinal analyses, baseline plasma T-tau did not add to the prognostic value of baseline plasma NfL. Results using ADNI data were similar. Conclusions Our results indicate plasma NfL had better utility as a prognostic marker of cognitive decline and neuroimaging changes. Plasma T-tau added cross-sectional value to NfL in specific contexts. Trial registration Not applicable

Background This study aimed to compare percutaneous left atrial appendage occlusion (LAAO) with non‐vitamin K antagonist oral anticoagulants among patients with atrial fibrillation. Methods and Results Using a US administrative database, 562 850 patients with atrial fibrillation were identified, among whom 8397 were treated with LAAO and 554 453 were treated with non‐vitamin K antagonist oral anticoagulants between March 13, 2015 and December 31, 2018. Propensity score overlap weighting was used to balance baseline characteristics. The primary outcome was a composite end point of ischemic stroke or systemic embolism, major bleeding, and all‐cause mortality. The mean age was 76.4±7.6 years; 280 097 (49.8%) were female. Mean follow‐up was 1.5±1.0 years. LAAO was associated with no significant difference in the risk of the primary composite end point (hazard ratio [HR], 0.93 [0.84–1.03]), or the secondary outcomes including ischemic stroke/systemic embolism (HR, 1.07 [0.81–1.41]), and intracranial bleeding (HR, 1.08 [0.72–1.61]). LAAO was associated with a higher risk of major bleeding (HR, 1.22 [1.05–1.42], P=0.01) and a lower risk of mortality (HR, 0.73 [0.64–0.84], P

IntroductionSleepiness 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.MethodsIn 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.ResultsHigher 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.ConclusionSleepiness 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.

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.

Abstract Although abnormal accumulation of amyloid in the brain is an early biomarker of Alzheimer’s disease (AD), wide variation in cognitive trajectories during life can be seen in the setting of brain amyloidosis, ranging from maintenance of normal function to progression to dementia. It is widely presumed that cognitive resilience (i.e., coping) to amyloidosis may be influenced by environmental, lifestyle, and inherited factors, but relatively little in specifics is known about this architecture. Here, we leveraged multimodal longitudinal data from a large, population-based sample of older adults to discover genetic factors associated with differential cognitive resilience to brain amyloidosis determined by positron emission tomography (PET). Among amyloid-PET positive older adults, the AD risk allele APOE ɛ4 was associated with worse longitudinal memory trajectories as expected, and was thus covaried in the main analyses. Through a genome-wide association study (GWAS), we uncovered a novel association with cognitive resilience on chromosome 8 at the MTMR7/CNOT7/ZDHHC2/VPS37A locus (p = 4.66 × 10–8, β = 0.23), and demonstrated replication in an independent cohort. Post-hoc analyses confirmed this association as specific to the setting of elevated amyloid burden and not explained by differences in tau deposition or cerebrovascular disease. Complementary gene-based analyses and publically available functional data suggested that the causative variant at this locus may tag CNOT7 (CCR4-NOT Transcription Complex Subunit 7), a gene linked to synaptic plasticity and hippocampal-dependent learning and memory. Pathways related to cell adhesion and immune system activation displayed enrichment of association in the GWAS. Our findings, resulting from a unique study design, support the hypothesis that genetic heterogeneity is one of the factors that explains differential cognitive resilience to brain amyloidosis. Further characterization of the underlying biological mechanisms influencing cognitive resilience may facilitate improved prognostic counseling, therapeutic application, and trial enrollment in AD.

Abstract Objective To assess the relationships between MRI volumetry and [18F]flortaucipir PET of typical and atypical clinical phenotypes of Alzheimer’s disease, by genarian (age by decade). Methods Five‐hundred and sixty‐four participants including those with typical (n = 86) or atypical (n = 80) Alzheimer’s dementia and normal controls (n = 398) underwent apolipoprotein E genotyping, MRI, flortaucipir, and 11C‐PiB; all 166 Alzheimer’s participants were beta‐amyloid positive and all controls were beta‐amyloid negative. Grey matter volume and flortaucipir standard uptake value ratios were calculated for hippocampus, entorhinal cortex, and neocortex. Ratios of hippocampal‐to‐neocortical and entorhinal‐to‐neocortical volume and flortaucipir uptake were also calculated. Linear regression models assessed relationships among regional volume, flortaucipir uptake, and ratios and phenotypes, within three genarians (50–59, 60–69, and 70+). Voxel‐level analyses were also performed. Results For 50–59 greater medial temporal atrophy and flortaucipir uptake was observed in the typical compared with atypical phenotype. The typical phenotype also showed greater frontal neocortex uptake with the voxel‐level analysis. For 60–69 and 70+ there was greater hippocampal volume loss in the typical compared with atypical phenotype while only the 60–69, but not the 70+ group, showed a difference in hippocampal flortaucipir uptake. We also observed a pattern for higher neocortical flortaucipir uptake to correlate with younger age decade for both phenotypes. Interpretation MRI volumetry versus flortaucipir PET relationships differ across Alzheimer’s clinical phenotypes, and also within phenotype across age decades. This suggests that there is potential risk of masked effects by not accounting for genarian in participants with beta‐amyloid and tau‐positive biomarker defined Alzheimer’s disease.

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.

Quantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating local tissue magnetic susceptibility properties at every voxel. Iron deposition patterns are well studied in typical Alzheimer’s disease (tAD), but little is known about these patterns in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA). Seventeen PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five-echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions-of-interest across the brain using the Mayo Clinic Adult Lifespan Template. Bayesian hierarchical models were fit per-region and per-hemisphere to compare PCA, LPA, 63 healthy controls, and 20 tAD patients. Strong evidence (posterior probability > 0.99) was observed for greater susceptibility in the middle occipital gyrus and amygdala in both LPA and PCA, and in the right inferior parietal, inferior temporal, and angular gyri in PCA and the caudate and substantia nigra in LPA compared to controls. Moderate evidence for greater susceptibility (posterior probability > 0.90) was also observed in the inferior occipital gyrus, precuneus, putamen and entorhinal cortex in both LPA and PCA, along with superior frontal gyrus in PCA and inferior temporal gyri, insula and basal ganglia in LPA, when compared to controls. Between phenotypic comparisons, LPA had greater susceptibility in the caudate, hippocampus, and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right superior frontal and middle temporal gyri compared to LPA. Both LPA and PCA showed moderate and strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions, while tAD showed greater susceptibility in the hippocampus and basal ganglia. This study proposes the possibility of unique iron profiles existing between LPA and PCA within cortical and subcortical structures. These changes match well with the disease-related changes of the clinical phenotypes, suggesting that QSM could be an informative candidate marker to study iron deposition in these patients.

Abstract Introduction Conventional Z‐scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these “adjusted” Z‐scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z‐scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency. Methods In this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance). Results Corrected Z‐scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted‐R2. Discussion Nonlinearly corrected Z‐scores with respect to age, sex, and education with age‐varying residual standard deviation allow for improved detection of non‐normative extreme cognitive scores.

Using positron emission tomography (PET)-derived amyloid and tau measurements from 1,495 participants, we explore the evolution of these values over time via an accelerated failure time (AFT) model. The AFT model assumes a shared pattern of progression, but one which is shifted earlier or later in time for each individual; an individual's time shift for amyloid and for tau are assumed to be linked. The resulting pattern for each outcome consists of an earlier indolent phase followed by sharp progression of the accumulation rate. APOE ε4 shifts the amyloid curve leftward (earlier) by 6.1 years, and the tau curve leftward by 2.6 years. Female sex shifts the amyloid curve leftward by 2.4 years and the tau curve leftward by 2.6 years. Per-person shifts (i.e., the individual's deviation from the population mean) for the onset of amyloid accumulation ranged from 13 years earlier to 13 years later (10th to 90th percentile) than average and 11 years earlier to 14 years later for tau, with an estimated correlation of 0.49. The average delay between amyloid increase and tau increase was 13.3 years.

Disproportionately enlarged subarachnoid-space hydrocephalus (DESH), characterized by tight high convexity CSF spaces, ventriculomegaly, and enlarged Sylvian fissures, is thought to be an indirect marker of a CSF dynamics disorder. The clinical significance of DESH with regard to cognitive decline in a community setting is not yet well defined. The goal of this work is to determine if DESH is associated with cognitive decline. Participants in the population-based Mayo Clinic Study of Aging (MCSA) who met the following criteria were included: age ≥ 65 years, 3T MRI, and diagnosis of cognitively unimpaired or mild cognitive impairment at enrollment as well as at least one follow-up visit with cognitive testing. A support vector machine based method to detect the DESH imaging features on T1-weighted MRI was used to calculate a “DESH score”, with positive scores indicating a more DESH-like imaging pattern. For the participants who were cognitively unimpaired at enrollment, a Cox proportional hazards model was fit with time defined as years from enrollment to first diagnosis of mild cognitive impairment or dementia, or as years to last known cognitively unimpaired diagnosis for those who did not progress. Linear mixed effects models were fit among all participants to estimate annual change in cognitive z scores for each domain (memory, attention, language, and visuospatial) and a global z score. For all models, covariates included age, sex, education, APOE genotype, cortical thickness, white matter hyperintensity volume, and total intracranial volume. The hazard of progression to cognitive impairment was an estimated 12% greater for a DESH score of +1 versus −1 (HR 1.12, 95% CI 0.97–1.31, p = 0.11). Global and attention cognition declined 0.015 (95% CI 0.005–0.025) and 0.016 (95% CI 0.005–0.028) z/year more, respectively, for a DESH score of +1 vs −1 (p = 0.01 and p = 0.02), with similar, though not statistically significant DESH effects in the other cognitive domains. Imaging features of disordered CSF dynamics are an independent predictor of subsequent cognitive decline in the MCSA, among other well-known factors including age, cortical thickness, and APOE status. Therefore, since DESH contributes to cognitive decline and is present in the general population, identifying individuals with DESH features may be important clinically as well as for selection in clinical trials.

Brain infarctions are closely associated with future risk of stroke and dementia. Our goal was to report (i) frequency and characteristics that differentiate symptomatic vs. silent brain infarctions (SBI) on MRI and (ii) frequency and location by vascular distribution (location of stroke by major vascular territories) in a population based sample. From Mayo Clinic Study of Aging, 347 participants (≥50 years) with infarcts detected on their first MRI were included. Infarct information was identified visually on a FLAIR MRI image and a vascular territory atlas was registered to the FLAIR image data in order to identify the arterial territory of infarction. We identified the subset with a clinical history of stroke based on medical chart review and used a logistic regression to evaluate the risk factors associated with greater probability of a symptomatic stroke vs. SBI. We found that 14% of all individuals with infarctions had a history of symptomatic stroke (Silent: n = 300, symptomatic: n = 47). Factors associated with a symptomatic vs. SBI were size which had an odds ratio of 3.07 (p < 0.001), greater frequency of hypertension (odds ratio of 4.12, p = 0.025) and alcohol history (odds ratio of 4.58, p = 0.012). The frequency of infarcts was greater in right hemisphere compared to the left for SBI. This was primarily driven by middle cerebral artery (MCA) infarcts (right = 60%, left = 40%, p = 0.005). While left hemisphere strokes are more common for symptomatic carotid disease and in clinical trials, right hemispheric infarcts may be more frequent in the SBI group.

Altered iron metabolism has been hypothesized to be associated with Alzheimer's disease pathology, and prior work has shown associations between iron load and beta amyloid plaques. Quantitative susceptibility mapping (QSM) is a recently popularized MR technique to infer local tissue susceptibility secondary to the presence of iron as well as other minerals. Greater QSM values imply greater iron concentration in tissue. QSM has been used to study relationships between cerebral iron load and established markers of Alzheimer's disease, however relationships remain unclear. In this work we study QSM signal characteristics and associations between susceptibility measured on QSM and established clinical and imaging markers of Alzheimer's disease. The study included 421 participants (234 male, median age 70 years, range 34–97 years) from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center; 296 (70%) had a diagnosis of cognitively unimpaired, 69 (16%) mild cognitive impairment, and 56 (13%) amnestic dementia. All participants had multi-echo gradient recalled echo imaging, PiB amyloid PET, and Tauvid tau PET. Variance components analysis showed that variation in cortical susceptibility across participants was low. Linear regression models were fit to assess associations with regional susceptibility. Expected increases in susceptibility were found with older age and cognitive impairment in the deep and inferior gray nuclei (pallidum, putamen, substantia nigra, subthalamic nucleus) (betas: 0.0017 to 0.0053 ppm for a 10 year increase in age, p = 0.03 to

Background and Purpose: Patients with dementia with Lewy bodies (DLB) are characterized by hypometabolism in the parieto–occipital cortex and the cingulate island sign (CIS) on 18F-fluorodeoxyglucose (FDG) PET. Whether this pattern of hypometabolism is present as early as the prodromal stage of DLB is unknown. We investigated the pattern of hypometabolism in patients with mild cognitive impairment (MCI) who progressed to probable DLB compared to MCI patients who progressed to Alzheimer’s disease (AD) dementia and clinically unimpaired (CU) controls. Methods: Patients with MCI from the Mayo Clinic Alzheimer’s Disease Research Center who underwent FDG PET at baseline and progressed to either probable DLB (MCI-DLB; n = 17) or AD dementia (MCI-AD; n = 41) during follow-up, and a comparison cohort of CU controls (n = 100) were included. Results: Patients with MCI-DLB had hypometabolism in the parieto-occipital cortex extending into temporal lobes, substantia nigra and thalamus. When compared to MCI-AD, medial temporal and posterior cingulate metabolism were preserved in patients with MCI-DLB, accompanied by greater hypometabolism in the substantia nigra in MCI-DLB compared to MCI-AD. In distinguishing MCI-DLB from MCI-AD at the maximum value of Youden’s index, CIS ratio was highly specific (90%) but not sensitive (59%), but a higher medial temporal to substantia nigra ratio was both sensitive (94%) and specific (83%). Conclusion: FDG PET is a potential biomarker for the prodromal stage of DLB. A higher medial temporal metabolism and CIS ratio, and lower substantia nigra metabolism have additive value in distinguishing prodromal DLB and AD.

Abstract Introduction The aim of this study was to examine white matter hyperintensities (WMH) and fractional anisotropy (FA) in empirically derived incident mild cognitive impairment (MCI) subtypes. Methods We evaluated 188 participants with incident MCI in the Mayo Clinic Study of Aging (MCSA) identified as having one of four cluster‐derived subtypes: subtle cognitive impairment, amnestic, dysnomic, and dysexecutive. We used linear regression models to evaluate whole brain and regional WMH volumes. We examined fractional anisotropy (FA) on a subset of 63 participants with diffusion tensor imaging. Results Amnestic and dysexecutive subtypes had higher WMH volumes in differing patterns than cognitively unimpaired; the dysexecutive subtype had higher WMH than subtle cognitive impairment. There was widespread WM degeneration in long association and commissural fibers in the amnestic, dysnomic, and dysexecutive subtypes, and corpus callosum FA accounted for significant variability in global cognition. Discussion White matter changes likely contribute to cognitive symptoms in incident MCI.

Background Intracerebral hemorrhage (ICH) risk is higher in elderly patients with atrial fibrillation on antithrombotic therapy as well as those with cerebral amyloid angiopathy (CAA). We investigated if mortality among patients with atrial fibrillation on antithrombotic therapy presenting with non‐traumatic ICH was influenced by underlying CAA. Methods and Results We used the Rochester Epidemiology Project to identify 6045 patients with atrial fibrillation aged >55 years on anticoagulation or antiplatelet therapy from 1995 to 2016. Seventy‐four patients in this cohort presented with non‐traumatic ICH. Medical records including imaging data were reviewed to identify those with CAA and record baseline variables and outcomes of interest; 38 of our 74 patients (51.4%) (mean age 81.5 years) met Modified Boston Criteria for possible or probable CAA. Twenty‐six of 74 patients (35%) died during the first 30 days while 56 of the 74 (76%) patients died by 10 years follow‐up after index ICH. Overall mortality was not significantly different between the CAA and non‐CAA groups at any point of time during follow‐up (P=0.89) even amongst patients restarted on anticoagulation +/− antiplatelet (n=19) (P=0.46) or those patients restarted only on antiplatelet therapy (n=22) (P=0.66). Three of the 41 patients who restarted on antithrombotic therapy had a recurrent ICH; these 3 patients met criteria for possible or probable CAA. Conclusions Although more than half of our patients with atrial fibrillation on antithrombotic therapy and non‐traumatic ICH met Modified Boston Criteria for CAA, CAA did not significantly influence the high mortality seen in this cohort.

Disproportionately enlarged subarachnoid space hydrocephalus (DESH), characterized by ventriculomegaly, high convexity/midline tight sulci, and enlarged sylvian fissures on brain MRI has been increasingly recognized as a distinct diagnostic imaging entity that falls within the larger category of idiopathic normal pressure hydrocephalus. Normal pressure hydrocephalus has been previously characterized as a CSF dynamics disorder based on abnormalities on nuclear medicine cisternography: radiotracer in the lateral ventricles and absent or delayed ascent of radiotracer over the cerebral convexity. The purpose of this work was to evaluate for differences in nuclear medicine cisternography between patients with vs without DESH and thereby provide support for the concept that DESH is a structural imaging marker of a CSF dynamics disorder. The study included 102 patients (mean age 71 years, range 46–86, 38 females), 58 patients with cisternogram performed to evaluate suspected normal pressure hydrocephalus (mean age 73 years, range 46–86 years, 24 female) and 44 patients evaluated for headache (mean age 68 years, range 60–82 years, 14 female). All patients had an MRI of the brain performed within 13 months of the cisternogram. Cisternogram imaging, typically acquired at 0.5, 1, 2, 4, and 24 h post injection, was evaluated for the time at which radiotracer reached the basal cisterns, presence of persistent radiotracer in the lateral ventricles, time radiotracer first entered the lateral ventricles, presence of radiotracer over the cerebral convexity, and time at which radiotracer was first visualized over the cerebral convexity. MRI features of ventriculomegaly (defined as Evans’ index ≥ 0.3) and high convexity tight sulci (HCTS) were recorded. Based on the MRI features, patients were grouped according to presence or absence of DESH (ventriculomegaly and HCTS). Those without DESH were separated into groups of ventriculomegaly alone, HCTS alone, and neither ventriculomegaly nor HCTS. Cisternogram metrics were compared between MR-defined groups. Patients with DESH showed a higher frequency of radiotracer in the lateral ventricles and delayed or absent ascent over the cerebral convexity compared to those without DESH, higher frequency of ventricular radioactivity vs those with HCTS alone, and shorter time to ventricular radioactivity compared to those with ventriculomegaly alone. Patients with ventriculomegaly or HCTS alone had a higher frequency of radiotracer in the lateral ventricles and delayed ascent of radiotracer over the cerebral convexity compared to those with neither ventriculomegaly nor HCTS. These findings support DESH and the individual components of ventriculomegaly and HCTS as markers of disordered CSF dynamics.

BackgroundBrain reserve can be defined as the individual variation in the brain structural characteristics that later in life are likely to modulate cognitive performance. Late midlife represents a point in aging where some structural brain imaging changes have become manifest but the effects of cognitive aging are minimal, and thus may represent an ideal opportunity to determine the relationship between risk factors and brain imaging biomarkers of reserve.ObjectiveWe aimed to assess neuroimaging measures from multiple modalities to broaden our understanding of brain reserve, and the late midlife risk factors that may make the brain vulnerable to age related cognitive disorders.MethodsWe examined multimodal [structural and diffusion Magnetic Resonance Imaging (MRI), FDG PET] neuroimaging measures in 50–65 year olds to examine the associations between risk factors (Intellectual/Physical Activity: education-occupation composite, physical, and cognitive-based activity engagement; General Health Factors: presence of cardiovascular and metabolic conditions (CMC), body mass index, hemoglobin A1c, smoking status (ever/never), CAGE Alcohol Questionnaire (>2, yes/no), Beck Depression Inventory score), brain reserve measures [Dynamic: genu corpus callosum fractional anisotropy (FA), posterior cingulate cortex FDG uptake, superior parietal cortex thickness, AD signature cortical thickness; Static: intracranial volume], and cognition (global, memory, attention, language, visuospatial) from a population-based sample. We quantified dynamic proxies of brain reserve (cortical thickness, glucose metabolism, microstructural integrity) and investigated various protective/risk factors.ResultsEducation-occupation was associated with cognition and total intracranial volume (static measure of brain reserve), but was not associated with any of the dynamic neuroimaging biomarkers. In contrast, many general health factors were associated with the dynamic neuroimaging proxies of brain reserve, while most were not associated with cognition in this late middle aged group.ConclusionBrain reserve, as exemplified by the four dynamic neuroimaging features studied here, is itself at least partly influenced by general health status in midlife, but may be largely independent of education and occupation.

Background: Idiopathic normal pressure hydrocephalus (iNPH) is an important and treatable cause of neurologic impairment. Diagnosis is complicated due to symptoms overlapping with other age related disorders. The pathophysiology underlying iNPH is not well understood. We explored FDG-PET abnormalities in iNPH patients in order to determine if FDG-PET may serve as a biomarker to differentiate iNPH from common neurodegenerative disorders. Methods: We retrospectively compared 18F-FDG PET-CT imaging patterns from seven iNPH patients (mean age 74 ± 6 years) to age and sex matched controls, as well as patients diagnosed with clinical Alzheimer's disease dementia (AD), Dementia with Lewy Bodies (DLB) and Parkinson's Disease Dementia (PDD), and behavioral variant frontotemporal dementia (bvFTD). Partial volume corrected and uncorrected images were reviewed separately. Results: Patients with iNPH, when compared to controls, AD, DLB/PDD, and bvFTD, had significant regional hypometabolism in the dorsal striatum, involving the caudate and putamen bilaterally. These results remained highly significant after partial volume correction. Conclusions: In this study, we report a FDG-PET pattern of hypometabolism in iNPH involving the caudate and putamen with preserved cortical metabolism. This pattern may differentiate iNPH from degenerative diseases and has the potential to serve as a biomarker for iNPH in future studies. These findings also further our understanding of the pathophysiology underlying the iNPH clinical presentation. Keywords: FDG-PET, Normal pressure hydrocephalus, Hypometabolism, Caudate, Biomarker

Visually preserved metabolism in posterior cingulate cortex relative to hypometabolism in precuneus and cuneus, the cingulate island sign, is a feature of dementia with Lewy bodies (DLB) on FDG-PET. Lower cingulate island sign ratio (posterior cingulate cortex/cuneus+precuneus; FDG-CISr) values have been associated with a higher Braak neurofibrillary tangle stage in autopsied DLB. Using voxel-wise analysis, we assessed the patterns of regional cortical perfusion and metabolism, and using an atlas-based approach, we measured perfusion cingulate island sign ratio on arterial spin labeling MRI (ASL-CISr), and its associations with FDG-CISr, uptake on tau-PET and clinical severity in DLB. Our study sample (n = 114) included clinically probable DLB patients (n = 19), age-matched patients with probable Alzheimer's disease dementia (AD; n = 19) and matched controls (n = 76) who underwent MRI with 3-dimensional pseudo-continuous arterial spin labeling, 18F-FDG-PET and 18F-AV-1451 tau PET. Patterns of cortical perfusion and metabolism were derived from quantitative maps using Statistical Parametric Mapping. DLB patients showed hypoperfusion on ASL-MRI in precuneus, cuneus and posterior parieto-occipital cortices, compared to controls, and relatively spared posterior cingulate gyrus, similar to pattern of hypometabolism on FDG-PET. DLB patients had higher ASL-CISr and FDG-CISr than AD patients (p

Objective: To characterize the clinical, EEG, and neuroimaging profiles of transient epileptic amnesia (TEA).Methods: We performed a retrospective analysis of patients diagnosed with TEA at the Mayo Clinic Minnesota from January 1, 1998 to September 21, 2017. Diagnostic criteria included the presence of recurrent episodes of transient amnesia with preservation of other cognitive functions and evidence for epilepsy [epileptiform abnormalities on EEG, clinical features of seizures, or symptomatic response to anti-seizure medications (ASMs)].Results: Nineteen patients were identified (14 men, 5 women) with median onset age 66 years and median time to diagnosis 2 years. Thirteen patients (68%) reported persistent cognitive/behavioral symptoms, including 4 (21%) for whom these were the chief presenting complaints. EEG revealed epileptiform abnormalities involving the frontal and/or temporal regions in 12/19 individuals (63%), including activation during sleep in all of these cases. In numerous cases, sleep and prolonged EEG evaluations identified abnormalities not previously seen on shorter or awake-state studies. Brain MRI revealed focal abnormalities in only 4/19 cases (21%). FDG-PET identified focal hypometabolism in 2/8 cases where it was performed, both involving the frontal and/or temporal regions. Anti-seizure therapy, most often with a single agent, resulted in improvement (reduction in spell frequency and/or subjective improvement in interictal cognitive/behavioral complaints) in all 17 cases with available follow-up.Conclusions: TEA is a treatable cause of amnestic spells in older adults. This syndrome is frequently associated with persistent interictal cognitive/behavioral symptoms and thus can be mistaken for common mimics. In the appropriate clinical context, our findings support the use of early prolonged EEG with emphasis on sleep monitoring as a key diagnostic tool. FDG-PET may also complement MRI in distinguishing TEA from neurodegenerative disease when suspected.

Importance: Prior studies evaluating opening pressure (OP) have mostly involved lumbar puncture (LP) for diagnosis of neurologic disease or small cohorts of healthy volunteers and therefore the normal OP is not well-defined.Objective: The goal of this study was to establish the normal range of OP in a community-based population using the Mayo Clinic Study of Aging (MCSA) and to evaluate factors that contribute to OP variability.Design: LP OP were obtained from participants aged 32–95 years between 11/1/07 and 10/1/17, as part of routine data collection for the MCSA, a longitudinal, population-based study of residents of Olmsted County, Minnesota.Setting: A longitudinal, population-based study of residents of Olmsted County, Minnesota.Participants: There were 639 participants (56.8% male; 98.5% white) who underwent LP with recorded OP as part of the MCSA.Intervention: LP.Main Outcome(s) and Measure(s): LP OP was recorded along with variables that could possibly influence its variability, including age, body mass index (BMI), and obstructive sleep apnea (OSA).Results: Six hundred thirty-nine participants (56.8% men) underwent LP with recorded OP; average age was 71.0 years (SD 10.9) with a mean BMI of 28.0 (SD 4.6). Mean OP was 155.4 mmH2O (SD 41.9) with a 95% reference interval of 82–242 mmH2O (range 60–314; Q1, Q3: 124, 182). Increasing age was associated with lower OP (p < 0.001), while increasing BMI was associated with higher OP (p < 0.001). Twelve (2%) participants had OP ≥ 250 mmH2O; they were younger [58.5 (SD 8.2), p < 0.001], had higher BMI [33.6 (SD 4.6), p < 0.001], and were more likely to have OSA (75%, p < 0.001). Among the 79 participants with repeat LPs within 2.5 years, the coefficient of repeatability (CR) was 64.9. Ten (12.7%) had an OP difference ≥50 mmH2O between serial LPs.Conclusions and Relevance: This large population-based study showed that LP OP can vary significantly among individuals. Higher OPs were associated with higher BMI and younger age.

The aims of this study were: to examine regional rates of change in tau-PET uptake and grey matter volume in atypical Alzheimer's disease (AD); to investigate the role of age in such changes; to describe multimodal regional relationships between tau accumulation and atrophy. Thirty atypical AD patients underwent baseline and one-year follow-up MRI, [18F]AV-1451 PET and PiB PET. Region- and voxel-level rates of tau accumulation and grey matter atrophy relative to cognitively unimpaired individuals, and the influence of age on such rates, were assessed. Univariate and multivariate analyses were performed between baseline measurements and rates of change, between baseline tau and atrophy, and between the two rates of change. Regional patterns of change in tau and volume differed, with highest rates of tau accumulation in frontal lobe and highest rates of atrophy in temporoparietal regions. Age had a negative effect on disease progression, predominantly on tau, with younger patients having a more rapid accumulation. Baseline tau uptake and regions of tau accumulation were disconnected, with high baseline tau uptake across the cortex correlated with high rates of tau accumulation in frontal and sensorimotor regions. In contrast, baseline volume and atrophy were locally related in the occipitoparietal regions. Higher tau uptake at baseline was locally related to higher rates of atrophy in frontal and occipital lobes. Tau accumulation rates positively correlated with rates of atrophy. In summary, our study showed that tau accumulation and atrophy presented different regional patterns in atypical AD, with tau spreading into the frontal lobes while atrophy remains in temporoparietal and occipital cortex, suggesting a temporal disconnect between protein deposition and neurodegeneration. Keywords: Longitudinal tau-PET, Atrophy, Atypical AD, Multimodal imaging

Objective: Create an automated classifier for imaging characteristics of disproportionately enlarged subarachnoid space hydrocephalus (DESH), a neuroimaging phenotype of idiopathic normal pressure hydrocephalus (iNPH). Methods: 1597 patients from the Mayo Clinic Study of Aging (MCSA) were reviewed for imaging characteristics of DESH. One core feature of DESH, the presence of tightened sulci in the high-convexities (THC), was used as a surrogate for the presence of DESH as the expert clinician-defined criterion on which the classifier was trained. Anatomical MRI scans were automatically segmented for cerebrospinal fluid (CSF) and overlaid with an atlas of 123 named sulcal regions. The volume of CSF in each sulcal region was summed and normalized to total intracranial volume. Area under the receiver operating characteristic curve (AUROC) values were computed for each region individually, and these values determined feature selection for the machine learning model. Due to class imbalance in the data (72 selected scans out of 1597 total scans) adaptive synthetic sampling (a technique which generates synthetic examples based on the original data points) was used to balance the data. A support vector machine model was then trained on the regions selected. Results: Using the automated classification model, we were able to classify scans for tightened sulci in the high convexities, as defined by the expert clinician, with an AUROC of about 0.99 (false negative ≈ 2%, false positive ≈ 5%). Ventricular volumes were among the classifier's most discriminative features but are not specific for DESH. The inclusion of regions outside the ventricles allowed specificity from atrophic neurodegenerative diseases that are also accompanied by ventricular enlargement. Conclusion: Automated detection of tight high convexity, a key imaging feature of DESH, is possible by using support vector machine models with selected sulcal CSF volumes as features. Keywords: Normal pressure ydrocephalus, Disproportionately enlarged subarachnoid hydrocephalus, Support vector machines, Computer-aided diagnosis, Tight high-convexity