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Digital biomarkers are defined as objective, quantifiable physiological and behavioral data that are collected and measured by means of digital devices. Their use has revolutionized clinical research by enabling high-frequency, longitudinal, and sensitive measurements. In the field of neurodegenerative diseases, an example of a digital biomarker-based technology is instrumental activities of daily living (iADL) digital medical application, a predictive biomarker of conversion from mild cognitive impairment (MCI) due to Alzheimer's disease (AD) to dementia due to AD in individuals aged 55 + . Digital biomarkers show promise to transform clinical practice. Nevertheless, their use may be affected by variables such as demographics, genetics, and phenotype. Among these factors, sex is particularly important in Alzheimer's, where men and women present with different symptoms and progression patterns that impact diagnosis. In this study, we explore sex differences in Altoida's digital medical application in a sample of 568 subjects consisting of a clinical dataset (MCI and dementia due to AD) and a healthy population. We found that a biological sex-classifier, built on digital biomarker features captured using Altoida's application, achieved a 75% ROC-AUC (receiver operating characteristic - area under curve) performance in predicting biological sex in healthy individuals, indicating significant differences in neurocognitive performance signatures between males and females. The performance dropped when we applied this classifier to more advanced stages on the AD continuum, including MCI and dementia, suggesting that sex differences might be disease-stage dependent. Our results indicate that neurocognitive performance signatures built on data from digital biomarker features are different between men and women. These results stress the need to integrate traditional approaches to dementia research with digital biomarker technologies and personalized medicine perspectives to achieve more precise predictive diagnostics, targeted prevention, and customized treatment of cognitive decline., Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00284-3., Competing Interests: Conflict of interestES is Director of AI and Machine Learning at Bayer. A.S.C. is an official employee of Biogen International and works as Head of Stakeholder Engagement for Alzheimer disease at Biogen. She is also co-founder and CEO of the Women’s Brain Project., (© The Author(s) 2022.)

Background: Cerebral small vessel disease (SVD) is associated with increased risk of stroke and dementia. Progressive damage to the cerebral microvasculature may also trigger angiogenic processes to promote vessel repair. Elevated levels of circulating endothelial progenitor cells (EPCs) and pro-angiogenic signaling proteins are observed in response to vascular injury. We aimed to examine circulating levels of EPCs and proangiogenic proteins in older adults with evidence of SVD. Methods: Older adults (ages 55-90) free of dementia or stroke underwent venipuncture and brain magnetic resonance imaging (MRI). Flow cytometry quantified circulating EPCs as the number of cells in the lymphocyte gate positively expressing EPC surface markers (CD34+CD133+CD309+). Plasma was assayed for proangiogenic factors (VEGF-A, VEGF-C, VEGF-D, Tie-2, and Flt-1). Total SVD burden score was determined based on MRI markers, including white matter hyperintensities, cerebral microbleeds and lacunes. Results: Sixty-four older adults were included. Linear regression revealed that older adults with higher circulating EPC levels exhibited greater total SVD burden [β = 1.0 × 10 5 , 95% CI (0.2, 1.9), p = 0.019], after accounting for age and sex. Similarly, a positive relationship between circulating VEGF-D and total SVD score was observed, controlling for age and sex [β = 0.001, 95% CI (0.000, 0.001), p = 0.048]. Conclusion: These findings suggest that elevated levels of circulating EPCs and VEGF-D correspond with greater cerebral SVD burden in older adults. Additional studies are warranted to determine whether activation of systemic angiogenic growth factors and EPCs represents an early attempt to rescue the vascular endothelium and repair damage in SVD., Competing Interests: IM was employed by company Chione GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kapoor, Gaubert, Marshall, Meier, Yew, Ho, Blanken, Dutt, Sible, Li, Jang, Brickman, Rodgers and Nation.)

Conventional neuropsychological assessments for Alzheimer's disease are burdensome and inaccurate at detecting mild cognitive impairment and predicting Alzheimer's disease risk. Altoida's Digital Neuro Signature (DNS), a longitudinal cognitive test consisting of two active digital biomarker metrics, alleviates these limitations. By comparison to conventional neuropsychological assessments, DNS results in faster evaluations (10 min vs 45-120 min), and generates higher test-retest in intraindividual assessment, as well as higher accuracy at detecting abnormal cognition. This study comparatively evaluates the performance of Altoida's DNS and conventional neuropsychological assessments in intraindividual assessments of cognition and function by means of two semi-naturalistic observational experiments with 525 participants in laboratory and clinical settings. The results show that DNS is consistently more sensitive than conventional neuropsychological assessments at capturing longitudinal individual-level change, both with respect to intraindividual variability and dispersion (intraindividual variability across multiple tests), across three participant groups: healthy controls, mild cognitive impairment, and Alzheimer's disease. Dispersion differences between DNS and conventional neuropsychological assessments were more pronounced with more advanced disease stages, and DNS-intraindividual variability was able to predict conversion from mild cognitive impairment to Alzheimer's disease. These findings are instrumental for patient monitoring and management, remote clinical trial assessment, and timely interventions, and will hopefully contribute to a better understanding of Alzheimer's disease.

Cerebral microbleeds, observed as small, spherical hypointense regions on gradient echo (GRE) or susceptibility weighted (SWI) magnetic resonance imaging (MRI) sequences, reflect small hemorrhagic infarcts, and are associated with conditions such as vascular dementia, small vessel disease, cerebral amyloid angiopathy, and Alzheimer's disease. The current gold standard for detecting and rating cerebral microbleeds in a research context is visual inspection by trained raters, a process that is both time consuming and subject to poor reliability. We present here a novel method to automate microbleed detection on GRE and SWI images. We demonstrate in a community-based cohort of older adults that the method is highly sensitive (greater than 92% of all microbleeds accurately detected) across both modalities, with reasonable precision (fewer than 20 and 10 false positives per scan on GRE and SWI, respectively). We also demonstrate that the algorithm can be used to identify microbleeds over longitudinal scans with a higher level of sensitivity than visual ratings (50% of longitudinal microbleeds correctly labeled by the algorithm, while manual ratings was 30% or lower). Further, the algorithm identifies the anatomical localization of microbleeds based on brain atlases, and greatly reduces time spent completing visual ratings (43% reduction in visual rating time). Our automatic microbleed detection instrument is ideal for implementation in large-scale studies that include cross-sectional and longitudinal scanning, as well as being capable of performing well across multiple commonly used MRI modalities.

Recent case studies show that the SARS-CoV-2 infectious disease, COVID-19, is associated with accelerated decline of mental health, in particular, cognition in elderly individuals, but also with neurological and neuropsychiatric illness in young people. Recent studies also show a bidirectional link between COVID-19 and mental health in that people with previous history of psychiatric illness have a higher risk for contracting COVID-19 and that COVID-19 patients display a variety of psychiatric illnesses. Risk factors and the response of the central nervous system to the virus show large overlaps with pathophysiological processes associated with Alzheimer's disease, delirium, post-operative cognitive dysfunction and acute disseminated encephalomyelitis, all characterized by cognitive impairment. These similarities lead to the hypothesis that the neurological symptoms could arise from neuroinflammation and immune cell dysfunction both in the periphery as well as in the central nervous system and the assumption that long-term consequences of COVID-19 may lead to cognitive impairment in the well-being of the patient and thus in today's workforce, resulting in large loss of productivity. Therefore, particular attention should be paid to neurological protection during treatment and recovery of COVID-19, while cognitive consequences may require monitoring., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The SARS-CoV-2 global pandemic will disproportionately impact countries with weak economies and vulnerable populations including people with dementia. Latin American and Caribbean countries (LACs) are burdened with unstable economic development, fragile health systems, massive economic disparities, and a high prevalence of dementia. Here, we underscore the selective impact of SARS-CoV-2 on dementia among LACs, the specific strain on health systems devoted to dementia, and the subsequent effect of increasing inequalities among those with dementia in the region. Implementation of best practices for mitigation and containment faces particularly steep challenges in LACs. Based upon our consideration of these issues, we urgently call for a coordinated action plan, including the development of inexpensive mass testing and multilevel regional coordination for dementia care and related actions. Brain health diplomacy should lead to a shared and escalated response across the region, coordinating leadership, and triangulation between governments and international multilateral networks., Competing Interests: Agustin Ibanez is partially supported by grants from CONICET, FONCyT‐PICT 2017‐1818, FONCyT‐PICT 2017 1820, ANID/FONDAP/15150012, INECO Foundation, the Interamerican Development Bank (IDB), GBHI ALZ UK‐20‐639295, and the MULTI‐PARTNER CONSORTIUM TO EXPAND DEMENTIA RESEARCH IN LATIN AMERICA (ReDLat, supported by National Institutes of Health, National Institutes of Aging [R01 AG057234], Alzheimer's Association [SG‐20‐725707], Tau Consortium, and Global Brain Health Institute). Fabricio Ferreira de Oliveira has contributed by way of a grant from FAPESP ‐ The State of São Paulo Research Foundation (grant #2015/10109‐5). Alzheimer's Society Canada and the Weston Brain Institute (to FGF), National Institute for Translational Neuroscience (INNT/Brazil) (to FGF), the Brazilian funding agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (to FGF). Elisa De Paula França Resende received funding from the Alzheimer's Association. Alzheimer's Association Research Grant 2018‐AARG‐591107 and REDI170583 (CDA). María Isabel Behrens is supported by grants from FONDECYT (Fondo de Desarrollo Científico y Tecnológico) Grant 1190958, FONDEF (Fondo de Fomento al Desarrollo Científico y Tecnológico Grant ID19I10302, and URedes URC‐036/17. Andrea Slachevsky is partially supported by grants from ANID/FONDAP/15150012, ANID / Fondecyt/ 1141279. Kenneth S. Kosik has support from the Alzheimer's Association and Tau Consortium. The contents of this publication are solely the responsibility of the authors and do not represent the official views of these Institutions. The other authors declare no conflicts of interest., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Background: Research investigating treatments and interventions for cognitive decline fail due to difficulties in accurately recognizing behavioral signatures in the presymptomatic stages of the disease. For this validation study, we took our previously constructed digital biomarker-based prognostic models and focused on generalizability and robustness of the models., Method: We validated prognostic models characterizing subjects using digital biomarkers in a longitudinal, multi-site, 40-month prospective study collecting data in memory clinics, general practitioner offices, and home environments., Results: Our models were able to accurately discriminate between healthy subjects and individuals at risk to progress to dementia within 3 years. The model was also able to differentiate between people with or without amyloid neuropathology and classify fast and slow cognitive decliners with a very good diagnostic performance., Conclusion: Digital biomarker prognostic models can be a useful tool to assist large-scale population screening for the early detection of cognitive impairment and patient monitoring over time., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.The authors declare the following financial interests/personal relationships which may be considered potential competing interests:, (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of the Alzheimer's Association.)

Objective: To test the hypotheses that hypertension and nocturnal blood pressure are related to white matter hyperintensity (WMH) volume, an MRI marker of small vessel cerebrovascular disease, and that WMH burden statistically mediates the association of hypertension and dipping status with memory functioning, we examined the relationship of hypertension and dipping status on WMH volume and neuropsychological test scores in middle-aged and older adults., Methods: Participants from the community-based Maracaibo Aging Study received ambulatory 24-hour blood pressure monitoring, structural MRI, and neuropsychological assessment. Four hundred thirty-five participants (mean ± SD age 59 ± 13 years, 71% women) with available ambulatory blood pressure, MRI, and neuropsychological data were included in the analyses. Ambulatory blood pressure was used to define hypertension and dipping status (i.e., dipper, nondipper, and reverse dipper based on night/day blood pressure ratio <0.9, 0.9-1, and >1, respectively). Outcome measures included regional WMH and memory functioning derived from a neuropsychological test battery., Results: The majority of the participants (59%) were hypertensive. Ten percent were reverse dippers, and 40% were nondippers. Reverse dipping in the presence of hypertension was associated with particularly elevated periventricular WMH volume ( F 2,423 = 3.78, p = 0.024) and with lowered memory scores ( F 2,423 = 3.911, p = 0.021). Periventricular WMH volume mediated the effect of dipping status and hypertension on memory (β = -4.1, 95% confidence interval -8.7 to -0.2, p < 0.05)., Conclusion: Reverse dipping in the presence of hypertension is associated with small vessel cerebrovascular disease, which, in turn, mediates memory functioning. These results point toward reverse dipping as a marker of poor nocturnal blood pressure control, particularly among hypertensive individuals, with potentially pernicious effects on cerebrovascular health and associated cognitive function., (© 2020 American Academy of Neurology.)

Background: The amyloid cascade hypothesis characterizes the stereotyped progression of pathological changes in Alzheimer's disease (AD) beginning with beta amyloid deposition, but does not address the reasons for amyloid deposition. Brain areas with relatively higher neuronal activity, metabolic demand, and production of reactive oxygen species in earlier life may have higher beta amyloid deposition in later life. The aim of this study was to investigate early life patterns of perfusion and late life patterns of amyloid deposition to determine the extent to which normative cerebral perfusion predisposes specific regions to future beta amyloid deposition., Materials and Methods: One hundred twenty-eight healthy, older human subjects (age: 56-87 years old; 44% women) underwent positron emission tomography (PET) imaging with [ 11 C]PiB for measures of amyloid burden. Cerebral perfusion maps derived from 47 healthy younger adults (age: 22-49; 47%) who had undergone single photon emission computed tomography (SPECT) imaging, were averaged to create a normative template, representative of young, healthy adults. Perfusion and amyloid measures were investigated in 31 cortical regions from the Hammers atlas. We examined the spatial relationship between normative perfusion patterns and amyloid pathophysiology., Results: The pattern of increasing perfusion (temporal lobe < parietal lobe < frontal lobe < insula/cingulate gyrus < occipital lobe; F(4,26) = 7.8, p = 0.0003) in young, healthy adults was not exactly identical to but approximated the pattern of increasing amyloid burden (temporal lobe < occipital lobe < frontal lobe < parietal lobe < insula/cingulate gyrus; F(4,26) = 5.0, p = 0.004) in older adults. However, investigating subregions within cortical lobes provided consistent agreement between ranked normative perfusion patterns and expected Thal staging of amyloid progression in AD (Spearman r = 0.39, p = 0.03)., Conclusion: Our findings suggest that brain areas with normatively greater perfusion may be more susceptible to amyloid deposition in later life, possibly due to higher metabolic demand, and associated levels of oxidative stress and inflammation., Competing Interests: Declaration of Competing Interest Nothing to report.

List learning tests are used in practice for diagnosis and in research to characterize episodic memory, but often suffer from ceiling effects in unimpaired individuals. We developed the Modified Rey Auditory Verbal Learning Test, or ModRey, an episodic memory test for use in normal and preclinical populations. We administered the ModRey to 230 healthy adults and to 86 of the same individuals 102 days later and examined psychometric properties and effects of demographic factors. Primary measures were normally distributed without evidence of ceiling effect. Differences between alternate forms were of very small magnitude and not significant. Test-retest reliability was good. Higher participant age and lower participant education was associated with poorer performance across most outcome measures. We conclude that the ModRey is appropriate for episodic memory characterization in normal populations and could be used as an outcome measure in studies involving preclinical populations.

Objective: This investigation aimed at examining whether circulating inflammatory biomarkers C-reactive protein (CRP), interleukin-6 (IL6), and alpha 1-antichymotrypsin (ACT) were related to cerebrovascular disease (CVD) assessed by MRI., Methods: The study included nondemented elderly participants of a community-based, multiethnic cohort, who received baseline MRI scans and had CRP (n = 508), ACT (435), and IL6 (N = 357) measured by ELISA. Silent brain infarcts and white matter hyperintensities (WMH) were derived from all available MRI scans at baseline, approximately 4.4 years after blood sample collection for inflammatory biomarkers. Repeated assessments of infarcts and WMH, as well as microbleeds assessment, were performed at follow-up MRI visits around 4.5 years later. Cross-sectional and longitudinal relationship between inflammatory biomarkers and CVD were analyzed using appropriate logistic regression models, generalized linear models, or COX models., Results: After adjusting for age, sex, ethnicity, education, APOE genotype, and intracranial volume, 1 SD increase in log 10 IL6 was associated with infarcts on MRI {odds ratio [OR] (95% confidence interval [CI]) = 1.28 [1.02-1.60], p = 0.033}, and 1 SD increase in log 10 CRP and log 10 ACT was associated with microbleeds (OR [95% CI] = 1.46 [1.02-2.09], p = 0.041; and 1.65 [1.11-2.46], p = 0.013; respectively). One SD increase in log 10 ACT was also associated with larger WMH at the follow-up MRI (b = 0.103, p = 0.012) and increased accumulation of WMH volume (b = 0.062, p = 0.041) during follow-up. The associations remained significant after additional adjustment of vascular risk factors and excluding participants with clinical stroke., Conclusions: Among older adults, increased circulating inflammatory biomarkers were associated with the presence of infarcts and microbleeds, WMH burden, and progression of WMH.

Introduction: White matter hyperintensity (WMH) volume on MRI is increased among presymptomatic individuals with autosomal dominant mutations for Alzheimer's disease (AD). One potential explanation is that WMH, conventionally considered a marker of cerebrovascular disease, are a reflection of cerebral amyloid angiopathy (CAA) and that increased WMH in this population is a manifestation of this vascular form of primary AD pathology. We examined whether the presence of cerebral microbleeds, a marker of CAA, mediates the relationship between WMH and estimated symptom onset in individuals with and without autosomal dominant mutations for AD., Participants and Methods: Participants (n = 175, mean age = 41.1 years) included 112 with an AD mutation and 63 first-degree non-carrier controls. We calculated the estimated years from expected symptom onset (EYO) and analyzed baseline MRI data for WMH volume and presence of cerebral microbleeds. Mixed effects regression and tests of mediation were used to examine microbleed and WMH differences between carriers and non-carriers and to test the whether the association between WMH and mutation status is dependent on the presence of microbleeds., Results: Mutation carriers were more likely to have microbleeds than non-carriers (p<0.05) and individuals with microbleeds had higher WMH volume than those without (p<0.05). Total WMH volume was increased in mutation carriers compared with non-carriers, up to 20 years prior to EYO, after controlling for microbleed status, as we demonstrated previously. Formal testing of mediation demonstrated that 21% of the association between mutation status and WMH was mediated by presence of microbleeds (p = 0.03) but a significant direct effect of WMH remained (p = 0.02) after controlling for presence of microbleeds., Discussion: Although there is some co-dependency between WMH and microbleeds, the observed increases in WMH among mutation carriers does not appear to be fully mediated by this marker of CAA. The findings highlight the possibility that WMH represent a core feature of AD independent of vascular forms of beta amyloid.

The incidence and prevalence of Alzheimer's disease (AD) dementia are higher among Caribbean Hispanics than among non-Hispanic Whites. The causes of this health disparity remain elusive, partially because of the relative limited capacity for biomedical research in the developing countries that comprise Caribbean Latin America. To begin to address this issue, we were awarded a Development Research Award from the US NIH and Fogarty International Center in order to establish the local capacity to integrate magnetic resonance imaging (MRI) into studies of cognitive aging and dementia in Dominican Republic, establish collaborations with Dominican investigators, and conduct a pilot study on the role of cerebrovascular markers in the clinical expression of AD. Ninety older adult participants with and without AD dementia and with and without a strong family history of AD dementia received MRI scans and clinical evaluation. We quantified markers of cerebrovascular disease (white matter hyperintensities [WMH], presence of infarct, and presence of microbleed) and neurodegeneration (entorhinal cortex volume) and compared them across groups. Patients with AD dementia had smaller entorhinal cortex and greater WMH volumes compared with controls, regardless of family history status. This study provides evidence for the capacity to conduct MRI studies of cognitive aging and dementia in Dominican Republic. The results are consistent with the hypothesis that small vessel cerebrovascular disease represents a core feature of AD dementia, as affected participants had elevated WMH volumes irrespective of family history status.

Background: The incidence of Alzheimer's disease (AD) strongly relates to advanced age and progressive deposition of cerebral amyloid-beta (Aβ), hyperphosphorylated tau, and iron. The purpose of this study was to investigate the relationship between cerebral dynamic functional connectivity and variability of long-term cognitive performance in healthy, elderly subjects, allowing for local pathology and genetic risk., Methods: Thirty seven participants (mean (SD) age 74 (6.0) years, Mini-Mental State Examination 29.0 (1.2)) were dichotomized based on repeated neuropsychological test performance within 2 years. Cerebral Aβ was measured by 11 C Pittsburgh Compound-B positron emission tomography, and iron by quantitative susceptibility mapping magnetic resonance imaging (MRI) at an ultra-high field strength of 7 Tesla (7T). Dynamic functional connectivity patterns were investigated by resting-state functional MRI at 7T and tested for interactive effects with genetic AD risk (apolipoprotein E (ApoE)-ε4 carrier status)., Results: A relationship between low episodic memory and a lower expression of anterior-posterior connectivity was seen (F(9,27) = 3.23, p < 0.008), moderated by ApoE-ε4 (F(9,27) = 2.22, p < 0.005). Inherent node-strength was related to local iron (F(5,30) = 13.2; p < 0.022)., Conclusion: Our data indicate that altered dynamic anterior-posterior brain connectivity is a characteristic of low memory performance in the subclinical range and genetic risk for AD in the elderly. As the observed altered brain network properties are associated with increased local iron, our findings may reflect secondary neuronal changes due to pathologic processes including oxidative stress.

Recent work suggests that analysis of the cortical thickness in key brain regions can be used to identify individuals at greatest risk for development of Alzheimer's disease (AD). It is unclear to what extent this "signature" is a biological marker of normal memory function - the primary cognitive domain affected by AD. We examined the relationship between the AD signature biomarker and memory functioning in a group of neurologically healthy young and older adults. Cortical thickness measurements and neuropsychological evaluations were obtained in 110 adults (age range 21-78, mean = 46) drawn from the Brain Resource International Database. The cohort was divided into young adult (n = 64, age 21-50) and older adult (n = 46, age 51-78) groups. Cortical thickness analysis was performed with FreeSurfer, and the average cortical thickness extracted from the eight regions that comprise the AD signature. Mean AD-signature cortical thickness was positively associated with performance on the delayed free recall trial of a list learning task and this relationship did not differ between younger and older adults. Mean AD-signature cortical thickness was not associated with performance on a test of psychomotor speed, as a control task, in either group. The results suggest that the AD signature cortical thickness is a marker for memory functioning across the adult lifespan.

Accumulating evidence implicates small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging, in the pathogenesis and diagnosis of Alzheimer's disease (AD). Cross-sectional volumetric measures of WMH, particularly in the parietal lobes, are associated with increased risk of AD. In the present study, we sought to determine whether the longitudinal regional progression of WMH predicts incident AD above-and-beyond traditional radiological markers of neurodegeneration (i.e., hippocampal atrophy and cortical thickness). Three hundred three nondemented older adults (mean age = 79.24 ± 5.29) received high-resolution magnetic resonance imaging at baseline and then again 4.6 years (standard deviation = 1.01) later. Over the follow-up interval 26 participants progressed to AD. Using structural equation modeling, we calculated latent difference scores of parietal and nonparietal WMH, hippocampus volumes, and cortical thickness values in AD-related regions. Within the structural equation modeling framework, we determined whether baseline or change scores or both predicted AD conversion, while controlling for several time-invariant relevant variables. Smaller baseline hippocampus volume, change in hippocampus volume (i.e., atrophy), higher baseline parietal lobe WMH, and increasing parietal lobe WMH volume but not WMH in other regions or measures of cortical thickness, independently predicted progression to AD. The findings provide strong evidence that regionally accumulating WMH predict AD onset in addition to hallmark neurodegenerative changes typically associated with AD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Microbleeds, small perivascular collections of hemosiderin manifested radiologically as hypointensities on gradient-echo magnetic resonance imaging (MRI), are important markers of small vessel pathology. Despite their clinical relevance, little is known about their prevalence and demographic correlates, particularly among ethnically diverse older adults. We examined demographic and clinical correlates of regional microbleeds in a multi-ethnic cohort and examined categorization schemes of microbleed distribution and severity., Methods: Between 2005 and 2007, 769 individuals participated in a MRI study as part of the Washington Heights/Inwood Columbia Aging Project. Approximately four years later, 243 out of 339 participants (mean age=84.50) who returned for a repeat MRI had gradient-echo scans for microbleed assessment and comprised the sample. We examined the association of deep and lobar microbleeds with age, sex, education, vascular factors, cognitive status and markers of small vessel disease., Results: Sixty-seven of the 243 (27%) participants had at least one microbleed. Individuals with microbleeds were more likely to have a history of stroke than individuals without. When categorized as having either no microbleeds, microbleeds in deep regions only, in lobar regions only, and both deep and lobar microbleeds, hypertension, proportion of strokes, and white matter hyperintensity volume (WMH) increased monotonically across the four groups. The number of lobar microbleeds correlated with WMH volume and diastolic blood pressure., Conclusions: Microbleeds in deep and lobar locations are associated with worse outcomes than microbleeds in either location alone, although the presence of lobar microbleeds appears to be more clinically relevant., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Accumulation of amyloid beta (Aβ) may occur during healthy aging and is a risk factor for Alzheimer Disease (AD). While individual Aβ-accumulation can be measured non-invasively using Pittsburgh Compund-B positron emission tomography (PiB-PET), Fluid-attenuated inversion recovery (FLAIR) is a Magnetic Resonance Imaging (MRI) sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR intensity., Methods: Fourteen healthy elderly subjects without known history of cognitive impairment received 11C-PiB-PET for estimation of regional Aβ-load. In addition, whole brain T1-MPRAGE and FLAIR-MRI sequences were acquired at high field strength of 7 Tesla (7T). Volume-normalized intensities of brain regions were assessed by applying an automated subcortical segmentation algorithm for spatial definition of brain structures. Statistical dependence between FLAIR- and PiB-PET intensities was tested using Spearman's rank correlation coefficient (rho), followed by Holm-Bonferroni correction for multiple testing., Results: Neuropsychological testing revealed normal cognitive performance levels in all participants. Mean regional PiB-PET and FLAIR intensities were normally distributed and independent. Significant correlation between volume-normalized PiB-PET signals and FLAIR intensities resulted for Hippocampus (right: rho = 0.86; left: rho = 0.84), Brainstem (rho = 0.85) and left Basal Ganglia vessel region (rho = 0.82)., Conclusions: Our finding of a significant relationship between PiB- and FLAIR intensity mainly observable in the Hippocampus and Brainstem, indicates regional Aβ associated tissue-edema in cognitively normal elderly subjects. Further studies including clinical populations are necessary to clarify the relevance of our findings for estimating individual risk for age-related neurodegenerative processes such as AD.

Background: Normal aging is associated with a decline in cognitive abilities, particularly in the domains of psychomotor speed and executive functioning. However, 'aging,' per se, is not a cause of cognitive decline but rather a variable that likely captures multiple accumulating biological changes over time that collectively affect mental abilities. Recent work has focused on the role of cerebrovascular disease as one of the biological changes. In the current study, we examined whether lobar microbleeds - magnetic resonance imaging (MRI) signal voids due to hemosiderin deposits secondary to cerebral amyloid angiopathy - are associated with cognitive decline in normal aging. Previous studies that reported a relationship between the presence of lobar microbleeds and decreased cognitive abilities have been primarily cross-sectional. Here, we used a retrospective longitudinal design to examine whether the presence of lobar microbleeds is associated with the rate of cognitive decline among non-demented older adults., Methods: Participants came from an ongoing longitudinal community-based aging study, in which subjects are evaluated at 18-24 months intervals and received a full medical, neurological, and neuropsychological examination at each of the follow-up visits. Gradient echo MRI scans were available on 197 non-demented participants (mean age: 84.15 ± 5.02 years). Microbleeds were rated visually on axial view and divided into subcortical (basal ganglia, cerebellum) and lobar (frontal, temporal, parietal, occipital lobe) regions, and confirmed with coronal and sagittal views to exclude artifacts. Cognition was assessed with a neuropsychological battery, providing summary scores for memory, language, executive, and visuospatial abilities. Using general estimating equations (GEE), we compared cognition cross-sectionally between individuals with 2 or more (n = 11) and fewer than 2 (n = 186) lobar microbleeds and examined longitudinal cognitive change beginning 9.47 ± 3.13 years before the MRI scan., Results: Subjects with 2 or more lobar microbleeds had worse executive functioning at the visit closest to the MRI scan (β = -0.044; p < 0.001) and had a faster decline in executive function over time (β = -0.072; p = 0.012) than subjects with fewer than 2 lobar microbleeds. The two groups were similar in age at scan date, education, ethnicity, sex distribution, and cognitive performance at first visit., Conclusions: Lobar microbleeds, a marker of cerebral amyloid angiopathy, are associated with an accelerated rate of executive function decline. The presence of cerebral amyloid angiopathy may be an important source of cognitive decline in aging. Future work should examine how cerebral amyloid angiopathy interacts with neurodegenerative processes, such as Alzheimer's disease., (© 2014 S. Karger AG, Basel.)

Importance: Current hypothetical models emphasize the importance of β-amyloid in Alzheimer disease (AD) pathogenesis, although amyloid alone is not sufficient to account for the dementia syndrome. The impact of small-vessel cerebrovascular disease, visualized as white matter hyperintensities (WMHs) on magnetic resonance imaging scans, may be a key factor that contributes independently to AD presentation., Objective: To determine the impact of WMHs and Pittsburgh Compound B (PIB) positron-emission tomography-derived amyloid positivity on the clinical expression of AD., Design: Baseline PIB-positron-emission tomography values were downloaded from the Alzheimer's Disease Neuroimaging Initiative database. Total WMH volume was derived on accompanying structural magnetic resonance imaging data. We examined whether PIB positivity and total WMHs predicted diagnostic classification of patients with AD (n = 20) and control subjects (n = 21). A second analysis determined whether WMHs discriminated between those with and without the clinical diagnosis of AD among those who were classified as PIB positive (n = 28). A third analysis examined whether WMHs, in addition to PIB status, could be used to predict future risk for AD among subjects with mild cognitive impairment (n = 59)., Setting: The Alzheimer's Disease Neuroimaging Initiative public database., Participants: The study involved data from 21 normal control subjects, 59 subjects with mild cognitive impairment, and 20 participants with clinically defined AD from the Alzheimer Disease's Neuroimaging Initiative database., Main Outcome Measures: Clinical AD diagnosis and WMH volume., Results: Pittsburgh Compound B positivity and increased total WMH volume independently predicted AD diagnosis. Among PIB-positive subjects, those diagnosed as having AD had greater WMH volume than normal control subjects. Among subjects with mild cognitive impairment, both WMH and PIB status at baseline conferred risk for future diagnosis of AD., Conclusions and Relevance: White matter hyperintensities contribute to the presentation of AD and, in the context of significant amyloid deposition, may provide a second hit necessary for the clinical manifestation of the disease. As risk factors for the development of WMHs are modifiable, these findings suggest intervention and prevention strategies for the clinical syndrome of AD.

The retrogenesis hypothesis postulates that late-myelinated white matter fibers are most vulnerable to age- and disease-related degeneration, which in turn mediate cognitive decline. While recent evidence supports this hypothesis in the context of Alzheimer's disease, it has not been tested systematically in normal cognitive aging. In the current study, we examined the retrogenesis hypothesis in a group (n = 282) of cognitively normal individuals, ranging in age from 7 to 87 years, from the Brain Resource International Database. Participants were evaluated with a comprehensive neuropsychological battery and were imaged with diffusion tensor imaging. Fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (DA), measures of white matter coherence, were computed in 2 prototypical early-myelinated fiber tracts (posterior limb of the internal capsule, cerebral peduncles) and 2 prototypical late-myelinated fiber tracts (superior longitudinal fasciculus, inferior longitudinal fasciculus) chosen to parallel previous studies; mean summary values were also computed for other early- and late-myelinated fiber tracts. We examined age-associated differences in FA, RD, and DA in the developmental trajectory (ages 7-30 years) and degenerative trajectory (ages 31-87 years), and tested whether the measures of white matter coherence mediated age-related cognitive decline in the older group. FA and DA values were greater for early-myelinated fibers than for late-myelinated fibers, and RD values were lower for early-myelinated than late-myelinated fibers. There were age-associated differences in FA, RD, and DA across early- and late-myelinated fiber tracts in the younger group, but the magnitude of differences did not vary as a function of early or late myelinating status. FA and RD in most fiber tracts showed reliable age-associated differences in the older age group, but the magnitudes were greatest for the late-myelinated tract summary measure, inferior longitudinal fasciculus (late fiber tract), and cerebral peduncles (early fiber tract). Finally, FA in the inferior longitudinal fasciculus and cerebral peduncles and RD in the cerebral peduncles mediated age-associated differences in an executive functioning factor. Taken together, the findings highlight the importance of white matter coherence in cognitive aging and provide some, but not complete, support for the white matter retrogenesis hypothesis in normal cognitive aging., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Few studies have applied multiple imaging modalities to examine cognitive correlates of white matter. We examined the utility of T2-weighted magnetic resonance imaging (MRI) -derived white matter hyperintensities (WMH) and diffusion tensor imaging-derived fractional anisotropy (FA) to predict cognitive functioning among older adults. Quantitative MRI and neuropsychological evaluations were performed in 112 older participants from an ongoing study of the genetics of Alzheimer's disease (AD) in African Americans. Regional WMH volumes and FA were measured in multiple regions of interest. We examined the association of regional WMH and an FA summary score with cognitive test performance. Differences in WMH and FA were compared across diagnostic groups (i.e., normal controls, mild cognitive impairment, and probable AD). Increased WMH volume in frontal lobes was associated with poorer delayed memory performance. FA did not emerge as a significant predictor of cognition. White matter hyperintensity volume in the frontal and parietal lobes was increased in MCI participants and more so in AD patients relative to controls. These results highlight the importance of regionally distributed small vessel cerebrovascular disease in memory performance and AD among African American older adults. White matter microstructural changes, quantified with diffusion tensor imaging, appear to play a lesser role in our sample.