Trial of the MIND Diet for Prevention of Cognitive Decline in Older Persons.

BACKGROUND: Findings from observational studies suggest that dietary patterns may offer protective benefits against cognitive decline, but data from clinical trials are limited. The Mediterranean-DASH Intervention for Neurodegenerative Delay, known as the MIND diet, is a hybrid of the Mediterranean diet and the DASH (Dietary Approaches to Stop Hypertension) diet, with modifications to include foods that have been putatively associated with a decreased risk of dementia. METHODS: We performed a two-site, randomized, controlled trial involving older adults without cognitive impairment but with a family history of dementia, a body-mass index (the weight in kilograms divided by the square of the height in meters) greater than 25, and a suboptimal diet, as determined by means of a 14-item questionnaire, to test the cognitive effects of the MIND diet with mild caloric restriction as compared with a control diet with mild caloric restriction. We assigned the participants in a 1:1 ratio to follow the intervention or the control diet for 3 years. All the participants received counseling regarding adherence to their assigned diet plus support to promote weight loss. The primary end point was the change from baseline in a global cognition score and four cognitive domain scores, all of which were derived from a 12-test battery. The raw scores from each test were converted to z scores, which were averaged across all tests to create the global cognition score and across component tests to create the four domain scores; higher scores indicate better cognitive performance. The secondary outcome was the change from baseline in magnetic resonance imaging (MRI)-derived measures of brain characteristics in a nonrandom sample of participants. RESULTS: A total of 1929 persons underwent screening, and 604 were enrolled; 301 were assigned to the MIND-diet group and 303 to the control-diet group. The trial was completed by 93.4% of the participants. From baseline to year 3, improvements in global cognition scores were observed in both groups, with increases of 0.205 standardized units in the MIND-diet group and 0.170 standardized units in the control-diet group (mean difference, 0.035 standardized units; 95% confidence interval, -0.022 to 0.092; P = 0.23). Changes in white-matter hyperintensities, hippocampal volumes, and total gray- and white-matter volumes on MRI were similar in the two groups. CONCLUSIONS: Among cognitively unimpaired participants with a family history of dementia, changes in cognition and brain MRI outcomes from baseline to year 3 did not differ significantly between those who followed the MIND diet and those who followed the control diet with mild caloric restriction. (Funded by the National Institute on Aging; ClinicalTrials.gov number, NCT02817074.).

Age-related and amyloid-beta-independent tau deposition and its downstream effects.

Amyloid-ß (Aß) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aß, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aß-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global/regional Aß in vivo. Immunohistochemistry was used to estimate Aß load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer's disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning. In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for Aß. This was also observed in individuals with low Aß load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of Aß. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer's disease pathology, i.e. early tau and/or Aß pathology (subiculum/Brodmann area 35/precuneus/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including Aß-PET as covariate. Results were validated in the ex vivo cohort showing age-related and Aß-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for Aß density. Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer's disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low Aß pathology.

In vivo effect of LATE-NC on integrity of white matter connections to the hippocampus.

INTRODUCTION: TAR DNA-binding protein 43 (TDP-43) is a highly prevalent proteinopathy that is involved in neurodegenerative processes, including axonal damage. To date, no ante mortem biomarkers exist for TDP-43, and few studies have directly assessed its impact on neuroimaging measures utilizing pathologic quantification. METHODS: Ante mortem diffusion-weighted images were obtained from community-dwelling older adults. Regression models calculated the relationship between post mortem TDP-43 burden and ante mortem fractional anisotropy (FA) within each voxel in connection with the hippocampus, controlling for coexisting Alzheimer's disease and demographics. RESULTS: Results revealed a significant negative relationship (false discovery rate [FDR] corrected p < .05) between post mortem TDP-43 and ante mortem FA in one cluster within the left medial temporal lobe connecting to the parahippocampal cortex, entorhinal cortex, and cingulate, aligning with the ventral subdivision of the cingulum. FA within this cluster was associated with cognition. DISCUSSION: Greater TDP-43 burden is associated with lower FA within the limbic system, which may contribute to impairment in learning and memory. HIGHLIGHTS: Post mortem TDP-43 pathological burden is associated with reduced ante mortem fractional anisotropy. Reduced FA located in the parahippocampal portion of the cingulum. FA in this area was associated with reduced episodic and semantic memory. FA in this area was associated with increased inward hippocampal surface deformation.

Cerebral arteriolosclerosis, lacunar infarcts, and cognition in older Black adults.

INTRODUCTION: Older Black adults are at risk of cerebral small vessel disease (CSVD), which contributes to dementia risk. Two subtypes of CSVD, arteriolosclerosis and ischemic lacunar infarcts, have been independently linked to lower cognition and higher dementia risk, but their combined effects on cognition in older Black adults are unclear. METHODS: Mixed models were used to examine the associations of in vivo measures of arteriolosclerosis (ARTS) and ischemic lacunar infarcts to cognitive level and change in 370 older Black adults without dementia.  RESULTS: Modeled together, higher ARTS load accounted for lower levels of global cognition, episodic memory, semantic memory, and perceptual speed, whereas higher infarct load accounted for lower levels of working memory. There were no associations with rate of cognitive change. DISCUSSION: Both arteriolosclerosis and ischemic infarcts impact the cognitive health of older Black adults, but arteriolosclerosis affects cognition more broadly and offers promise as an in vivo biomarker of dementia risk. HIGHLIGHTS: Older Black adults are at risk of cerebral small vessel disease (CSVD) and dementia. Examined magnetic resonance imaging-derived measure of arteriolosclerosis (ARTS), infarcts, and cognition. ARTS load was widely associated with lower cognition after adjusting for infarct load. Infarct load was specifically associated with lower complex attention. More within-Black in vivo studies of CSVD subtypes and cognition are needed.

High resolution 0.5mm isotropic T1-weighted and diffusion tensor templates of the brain of non-demented older adults in a common space for the MIITRA atlas.

High quality, high resolution T1-weighted (T1w) and diffusion tensor imaging (DTI) brain templates located in a common space can enhance the sensitivity and precision of template-based neuroimaging studies. However, such multimodal templates have not been constructed for the older adult brain. The purpose of this work which is part of the MIITRA atlas project was twofold: (A) to develop 0.5 mm isotropic resolution T1w and DTI templates that are representative of the brain of non-demented older adults and are located in the same space, using advanced multimodal template construction techniques and principles of super resolution on data from a large, diverse, community cohort of 400 non-demented older adults, and (B) to systematically compare the new templates to other standardized templates. It was demonstrated that the new MIITRA-0.5mm T1w and DTI templates are well-matched in space, exhibit good definition of brain structures, including fine structures, exhibit higher image sharpness than other standardized templates, and are free of artifacts. The MIITRA-0.5mm T1w and DTI templates allowed higher intra-modality inter-subject spatial normalization precision as well as higher inter-modality intra-subject spatial matching of older adult T1w and DTI data compared to other available templates. Consequently, MIITRA-0.5mm templates allowed detection of smaller inter-group differences for older adult data compared to other templates. The MIITRA-0.5mm templates were also shown to be most representative of the brain of non-demented older adults compared to other templates with submillimeter resolution. The new templates constructed in this work constitute two of the final products of the MIITRA atlas project and are anticipated to have important implications for the sensitivity and precision of studies on older adults.

Brain and spinal cord arteriolosclerosis and its associations with cerebrovascular disease risk factors in community-dwelling older adults.

Arteriolosclerosis is common in older brains and related to cognitive and motor impairment. We compared the severity of arteriolosclerosis and its associations with cerebrovascular disease risk factors (CVD-RFs) in multiple locations in the brain and spinal cord. Participants (n = 390) were recruited in the context of a longitudinal community-based clinical-pathological study, the Rush Memory and Aging Project. CVD-RFs were assessed annually for an average of 8.7 (SD = 4.3) years before death. The annual assessments included systolic (SBP) and diastolic (DBP) blood pressure, diabetes mellitus (DM), low- and high-density lipoprotein cholesterol, triglyceride, body mass index, and smoking. Postmortem pathological assessments included assessment of arteriolosclerosis severity using the same rating scale in three brain locations (basal ganglia, frontal, and parietal white matter regions) and four spinal cord levels (cervical, thoracic, lumbar and sacral levels). A single measure was used to summarize the severity of spinal arteriolosclerosis assessments at the four levels due to their high correlations. Average age at death was 91.5 (SD = 6.2) years, and 73% were women. Half showed arteriolosclerosis in frontal white matter and spinal cord followed by parietal white matter (38%) and basal ganglia (27%). The severity of arteriolosclerosis in all three brain locations showed mild-to-moderate correlations. By contrast, spinal arteriolosclerosis was associated with brain arteriolosclerosis only in frontal white matter. Higher DBP was associated with more severe arteriolosclerosis in all three brain locations. DM was associated with more severe arteriolosclerosis only in frontal white matter. Controlling for DBP, higher SBP was inversely associated with arteriolosclerosis in parietal white matter. Blood cholesterol and triglyceride, high body mass index, or smoking were not related to the severity of arteriolosclerosis in any brain region. None of the CVD-RFs were associated with the severity of spinal arteriolosclerosis. These data indicate that severity of arteriolosclerosis and its associations with CVD-RFs may vary in different CNS locations.

LATE-NC staging in routine neuropathologic diagnosis: an update.

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

The Relationship of MRI-Derived Alzheimer's and Cerebrovascular-Related Signatures With Level of and Change in Health and Financial Literacy.

OBJECTIVE: The cortical thickness "signature" of Alzheimer's disease (AD-CT) and white matter hyperintensity (WMH) burden have each been associated with cognitive aging and incident AD and related dementias. Less is known about how these structural neuroimaging markers associate with other critical behaviors. We investigated associations of AD-CT and WMH volumes with a composite index of health and financial literacy given that the ability to access, understand, and utilize health and financial information significantly influences older adults' health outcomes. DESIGN, SETTING, PARTICIPANTS: Participants were 303 adults without dementia (age∼80 years; 74% women) from the Rush Memory and Aging Project. MEASUREMENTS: Baseline 3T MRI T1-weighted structural and T2-weighted FLAIR data were used to assess AD-CT and WMH volumes, respectively. Literacy was measured using questions designed to assess comprehension of health and financial information and concepts, yielding a total literacy score. Multivariable linear mixed effects regression models determined the relationship of each neuroimaging marker, first separately and then combined, with the level of and change in literacy. RESULTS: Reduced AD-CT and higher WMH at baseline were each associated with lower levels of literacy; only AD-CT was associated with the rate of decline in literacy over time. The association of AD-CT with change in literacy persisted when both neuroimaging markers were included in the same model. CONCLUSIONS: The cortical thickness signature of AD predicts changes in health and financial literacy in nondemented older adults suggesting that the multidimensional construct of health and financial literacy relies on specific brain networks implicated in AD.

Neuropathology of Vascular Brain Health: Insights From Ex Vivo Magnetic Resonance Imaging-Histopathology Studies in Cerebral Small Vessel Disease.

Sporadic cerebral small vessel disease (SVD) is a major contributor to vascular cognitive impairment and dementia in the aging human brain. On neuropathology, sporadic SVD is characterized by abnormalities to the small vessels of the brain predominantly in the form of cerebral amyloid angiopathy and arteriolosclerosis. These pathologies frequently coexist with Alzheimer disease changes, such as plaques and tangles, in a single brain. Conversely, during life, magnetic resonance imaging (MRI) only captures the larger manifestations of SVD in the form of parenchymal brain abnormalities. There appears to be a major knowledge gap regarding the underlying neuropathology of individual MRI-detectable SVD abnormalities. Ex vivo MRI in postmortem human brain tissue is a powerful tool to bridge this gap. This review summarizes current insights into the histopathologic correlations of MRI manifestations of SVD, their underlying cause, presumed pathophysiology, and associated secondary tissue injury. Moreover, we discuss the advantages and limitations of ex vivo MRI-guided histopathologic investigations and make recommendations for future studies.

Complex Profiles of Cerebrovascular Disease Pathologies in the Aging Brain and Their Relationship With Cognitive Decline.

BACKGROUND AND PURPOSE: Cerebrovascular disease (CVD) pathologies including vessel disease (atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy) and tissue injury (macroinfarcts and microinfarcts) each contribute to Alzheimer and other forms of dementia. CVD is often a complex mix of neuropathologies, with little known about the frequencies of differing combinations or their associations with cognition. METHODS: We investigated 32 possible CVD combinations (3 types of vessel disease and 2 types of tissue injury) using autopsy data from 1474 decedents (≈88 years at death; 65% female) of Rush Alzheimer's Disease Center studies. We determined frequencies of all 32 CVD combinations and their relationships with global and domain-specific cognitive decline using mixed-effect models adjusted for demographics, neuropathologies, time before death, and interactions of these variables with time. RESULTS: Of the 1184 decedents with CVD neuropathology (80% of the total sample), 37% had a single CVD (67-148 decedents/group) while 63% had mixed CVD profiles (11-54 decedents/group). When considered as 2 distinct groups, the mixed CVD profile group (but not the single CVD profile group) showed a faster cognitive decline across all domains assessed compared with decedents without CVD neuropathology. Most mixed CVD profiles, especially those involving both atherosclerosis and arteriolosclerosis, showed faster cognitive decline than any single CVD profile considered alone; specific mixed CVD profiles differentially associated with individual cognitive domains. CONCLUSIONS: Mixed CVD, more common than single CVD, is associated with cognitive decline, and distinct mixed CVD profiles show domain-specific associations with cognitive decline. CVD is not monolithic but consists of heterogenous person-specific combinations with distinct contributions to cognitive decline.

Development and evaluation of a high resolution 0.5mm isotropic T1-weighted template of the older adult brain.

Investigating the structure of the older adult brain at high spatial resolution is of high significance, and a dedicated older adult structural brain template with sub-millimeter resolution is currently lacking. Therefore, the purpose of this work was twofold: (A) to develop a 0.5mm isotropic resolution standardized T1-weighted template of the older adult brain by applying principles of super resolution to high quality MRI data from 222 older adults (65-95 years of age), and (B) to systematically compare the new template to other standardized and study-specific templates in terms of image quality and performance when used as a reference for alignment of older adult data. The new template exhibited higher spatial resolution and improved visualization of fine structural details of the older adult brain compared to a template constructed using a conventional template building approach and the same data. In addition, the new template exhibited higher image sharpness and did not contain image artifacts observed in some of the other templates considered in this work. Due to the above enhancements, the new template provided higher inter-subject spatial normalization precision for older adult data compared to the other templates, and consequently enabled detection of smaller inter-group morphometric differences in older adult data. Finally, the new template was among those that were most representative of older adult brain data. Overall, the new template constructed here is an important resource for studies of aging, and the findings of the present work have important implications in template selection for investigations on older adults.

Development of high quality T1-weighted and diffusion tensor templates of the older adult brain in a common space.

High-quality T1-weighted (T1w) and diffusion tensor imaging (DTI) brain templates that are representative of the individuals under study enhance the accuracy of template-based neuroimaging investigations, and when they are also located in a common space they facilitate optimal integration of information on brain morphometry and diffusion characteristics. However, such multimodal templates have not been constructed for the brain of older adults. The purpose of this work was threefold: (A) to introduce an iterative method for construction of multimodal T1w and DTI templates that aims at maximizing the quality of each template separately as well as the spatial matching between templates, (B) to use this method to develop T1w and DTI templates of the older adult brain in a common space, and (C) to evaluate the performance of the method across iterations and compare it to the performance of state-of-the-art approaches based on multichannel registration. It was demonstrated that more iterations of the proposed method enhanced the characteristics and spatial matching of the resulting T1w and DTI templates. The templates of the older adult brain generated by the final iteration of the proposed method provided better delineation of brain structures, higher discriminability between tissues, and higher image sharpness near the cortex compared to templates generated with approaches employing multichannel registration. In addition, the spatial matching between the T1w and DTI templates constructed by the proposed method approximated the template alignment achieved with methods employing multichannel registration. Finally, when using the templates generated by the proposed method as references for spatial normalization of older adult T1w and DTI data, both the intra-modality inter-subject normalization precision and the inter-modality spatial matching were higher in most metrics than those achieved with templates constructed with other methods. Overall, the present work brought new insights into multimodal template construction, generated much-needed high quality T1w and DTI templates of the older adult brain in a common space, and conducted a thorough, quantitative evaluation of available multimodal template construction methods.

Cognitive decline and hippocampal functional connectivity within older Black adults.

While there has been a proliferation of neuroimaging studies on cognitive decline in older non-Hispanic White adults, there is a dearth of knowledge regarding neuroimaging correlates of cognitive decline in Black adults. Resting-state functional neuroimaging approaches may be particularly sensitive to early cognitive decline, but there are no studies that we know of that apply this approach to examining associations of brain function to cognition in older Black adults. We investigated the association of cognitive decline with whole-brain voxel-wise functional connectivity to the hippocampus, a key brain region functionally implicated in early Alzheimer's dementia, in 132 older Black adults without dementia participating in the Minority Aging Research Study and Rush Memory and Aging Project, two longitudinal studies of aging that include harmonized annual cognitive assessments and magnetic resonance imaging brain imaging. In models adjusted for demographic factors (age, education, sex), global cognitive decline was associated with functional connectivity of the hippocampus to three clusters in the right and left frontal regions of the dorsolateral prefrontal cortex. In domain-specific analyses, decline in semantic memory was associated with functional connectivity of the hippocampus to bilateral clusters in the precentral gyrus, and decline in perceptual speed was inversely associated with connectivity of the hippocampus to the bilateral intracalcarine cortex and the right fusiform gyrus. These findings elucidate neurobiological mechanisms underlying cognitive decline in older Black adults and may point to specific targets of intervention for Alzheimer's disease.

Relationship of Blood Pressure and White Matter Hyperintensity Burden With Level of and Change in Cognition in Older Black Adults.

OBJECTIVE: Elevations in blood pressure (BP) and associated white matter hyperintensities (WMHs) are chronic comorbid conditions among older Black adults. We investigated whether WMHs modify the association between late-life BP and cognition within older Black adults. METHODS: A total of 167 Black adults (age, ~75 years; without dementia at baseline) participating in neuroimaging studies at the Rush Alzheimer's Disease Center were evaluated for BP markers of cardiovascular health, including systolic BP, diastolic BP, pulse pressure, mean arterial pressure (MAP), and hypertension, and were assessed for global and domain-specific cognition at baseline and annually for up to 8 years. WMHs adjusted for intracranial volume were quantified at baseline. RESULTS: Models adjusted for relevant confounders and the interaction of these variables with time revealed differential associations between BP markers and baseline cognition; however, only elevated diastolic BP predicted faster cognitive, that is, episodic memory, decline (estimate = -0.002, standard error = 0.0009, p = .002). Although WMH burden did not modify the association between diastolic BP and episodic memory decline, it did interact with diastolic BP to lower episodic memory at baseline (estimate = -0.051, standard error = 0.012, p = .0001); that is, greater WMHs combined with higher diastolic BP resulted in the lowest baseline episodic memory scores. A similar profile was noted for WMHs, MAP, and baseline episodic memory. Hypertension was neither associated with cognition nor modified by WMH burden after multiple comparisons correction. CONCLUSION: Late-life diastolic BP was associated with faster rates of episodic memory decline in older Black adults; together with higher WMH burden, it (and MAP) lowered the point at which individuals begin their course of decline toward pathological aging.

Properties of the Cognitive Function Battery for the MIND Diet Intervention to Prevent Alzheimer's Disease.

OBJECTIVE: To evaluate the properties of the cognitive battery used in the MIND Diet Intervention to Prevent Alzheimer's Disease. The MIND Diet Intervention is a randomized control trial to determine the relative effectiveness of the MIND diet in slowing cognitive decline and reducing brain atrophy in older adults at risk for Alzheimer's dementia. METHODS: The MIND cognitive function battery was administered at baseline to 604 participants of an average age of 70 years, who agreed to participate in the diet intervention study, and was designed to measure change over time. The battery included 12 cognitive tests, measuring the 4 cognitive domains of executive function, perceptual speed, episodic memory, and semantic memory. We conducted a principal component analysis to examine the consistency between our theoretical domains and the statistical performance of participants in each domain. To further establish the validity of each domain, we regressed the domain scores against a late-life cognitive activity score, controlling for age, race, sex, and years of education. RESULTS: Four factors emerged in the principal component analyses that were similar to the theoretical domains. In regression equations, we found the expected associations with age, education, and late-life cognitive activity with each of the four cognitive domains. CONCLUSIONS: These results indicate that the MIND cognitive battery is a comprehensive and valid battery of four separate domains of cognitive function that can be used in diet intervention trials for older adults.

To what degree is late life cognitive decline driven by age-related neuropathologies?

The ageing brain is vulnerable to a wide array of neuropathologies. Prior work estimated that the three most studied of these, Alzheimer's disease, infarcts, and Lewy bodies, account for ∼40% of the variation in late life cognitive decline. However, that estimate did not incorporate many other diseases that are now recognized as potent drivers of cognitive decline [e.g. limbic predominant age-related TDP-43 encephalopathy (LATE-NC), hippocampal sclerosis, other cerebrovascular conditions]. We examined the degree to which person-specific cognitive decline in old age is driven by a wide array of neuropathologies. Deceased participants (n = 1164) from two longitudinal clinical-pathological studies, the Rush Memory and Aging Project and Religious Orders Study, completed up to 24 annual evaluations including 17 cognitive performance tests and underwent brain autopsy. Neuropathological examinations provided 11 pathological indices, including markers of Alzheimer's disease, non- Alzheimer's disease neurodegenerative diseases (i.e. LATE-NC, hippocampal sclerosis, Lewy bodies), and cerebrovascular conditions (i.e. macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis). Mixed effects models examined the linear relation of pathological indices with global cognitive decline, and random change point models examined the relation of the pathological indices with the onset of terminal decline and rates of preterminal and terminal decline. Cognition declined an average of about 0.10 unit per year (estimate = -0.101, SE = 0.003, P < 0.001) with considerable heterogeneity in rates of decline (variance estimate for the person-specific slope of decline was 0.0094, P < 0.001). When considered separately, 10 of 11 pathological indices were associated with faster decline and accounted for between 2% and 34% of the variation in decline, respectively. When considered simultaneously, the 11 pathological indices together accounted for 43% of the variation in decline; Alzheimer's disease-related indices accounted for 30-36% of the variation, non-Alzheimer's disease neurodegenerative indices 4-10%, and cerebrovascular indices 3-8%. Finally, the 11 pathological indices combined accounted for less than a third of the variation in the onset of terminal decline (28%) and rates of preterminal (32%) and terminal decline (19%). Although age-related neuropathologies account for a large proportion of the variation in late life cognitive decline, considerable variation remains unexplained even after considering a wide array of neuropathologies. These findings highlight the complexity of cognitive ageing and have important implications for the ongoing effort to develop effective therapeutics and identify novel treatment targets.

Regionconnect: Rapidly extracting standardized brain connectivity information in voxel-wise neuroimaging studies.

Reporting white matter findings in voxel-wise neuroimaging studies typically lacks specificity in terms of brain connectivity. Therefore, the purpose of this work was to develop an approach for rapidly extracting standardized brain connectivity information for white matter regions with significant findings in voxel-wise neuroimaging studies. The new approach was named regionconnect and is based on precalculated average healthy adult brain connectivity information stored in standard space in a fashion that allows fast retrieval and integration. Towards this goal, the present work first generated and evaluated the white matter connectome of the IIT Human Brain Atlas v.5.0. It was demonstrated that the edges of the atlas connectome are representative of those of individual participants of the Human Connectome Project in terms of the spatial organization of streamlines and spatial patterns of track-density. Next, the new white matter connectome was used to develop multi-layer, connectivity-based labels for each white matter voxel of the atlas, consistent with the fact that each voxel may contain axons from multiple connections. The regionconnect algorithm was then developed to rapidly integrate information contained in the multi-layer labels across voxels of a white matter region and to generate a list of the most probable connections traversing that region. Usage of regionconnect does not require high angular resolution diffusion MRI or any MRI data. The regionconnect algorithm as well as the white matter tractogram and connectome, multi-layer, connectivity-based labels, and associated resources developed for the IIT Human Brain Atlas v.5.0 in this work are available at www.nitrc.org/projects/iit. An interactive, online version of regionconnect is also available at www.iit.edu/~mri.

Development and evaluation of a high performance T1-weighted brain template for use in studies on older adults.

Τhe accuracy of template-based neuroimaging investigations depends on the template's image quality and representativeness of the individuals under study. Yet a thorough, quantitative investigation of how available standardized and study-specific T1-weighted templates perform in studies on older adults has not been conducted. The purpose of this work was to construct a high-quality standardized T1-weighted template specifically designed for the older adult brain, and systematically compare the new template to several other standardized and study-specific templates in terms of image quality, performance in spatial normalization of older adult data and detection of small inter-group morphometric differences, and representativeness of the older adult brain. The new template was constructed with state-of-the-art spatial normalization of high-quality data from 222 older adults. It was shown that the new template (a) exhibited high image sharpness, (b) provided higher inter-subject spatial normalization accuracy and (c) allowed detection of smaller inter-group morphometric differences compared to other standardized templates, (d) had similar performance to that of study-specific templates constructed with the same methodology, and (e) was highly representative of the older adult brain.

Vitamin D Intake and Brain Cortical Thickness in Community-Dwelling Overweight Older Adults: A Cross-Sectional Study.

BACKGROUND: Vitamin D is critical to brain health and a promising candidate to prevent cognitive decline and onset of Alzheimer disease (AD), although the underlying brain mechanisms are unclear. OBJECTIVES: This study aimed to determine the association between vitamin D intake and brain cortical thickness in older adults. METHODS: This was a cross-sectional investigation of 263 cognitively unimpaired participants, aged 65 y and older, participating in the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) trial (an ongoing study testing the effects of a 3-y diet intervention on cognitive decline). Vitamin D intake, from diet and supplements, was ascertained from an FFQ. Linear regression analysis, adjusted for age, sex, race, education, income, cognitive and physical activities, and cardiovascular disease risk factors, was used to determine the association between vitamin D intake and cortical thickness of the whole brain, lobes, and AD signature. RESULTS: Total vitamin D intake was associated with cortical thickness of the temporal lobe and AD signature. Compared with individuals in the lowest quartile of total vitamin D intake [median: 140 international units (IU)/d], those in the highest quartile (median: 1439 IU/d) had a 0.038-mm (95% CI: 0.006, 0.069 mm) thicker temporal lobe and 0.041-mm (95% CI: 0.012, 0.070 mm) thicker AD signature. Most vitamin D intake was from supplements, and supplemental intake was also associated with cortical thickness. Compared with those who used no supplement, individuals taking 800-1000 IU/d and >1000 IU/d of supplemental vitamin D had a 0.039-mm (95% CI: 0.013, 0.066 mm) and 0.047-mm (95% CI: 0.013, 0.081 mm) thicker temporal lobe and a 0.037-mm (95% CI: 0.013, 0.061 mm) and 0.046-mm (95% CI: 0.015, 0.077 mm) thicker AD signature, respectively. Dietary vitamin D was not related to brain cortical thickness in our sample. CONCLUSIONS: In cognitively unimpaired older adults, total and supplemental vitamin D intakes were associated with cortical thickness in regions vulnerable to AD.This trial was registered at clinicaltrials.gov as NCT02817074.

The "cognitive clock": A novel indicator of brain health.

INTRODUCTION: We identified a "cognitive clock," a novel indicator of brain health that provides person-specific estimates of cognitive age, and tested the hypothesis that cognitive age is a better predictor of brain health than chronological age in two independent datasets. METHODS: The initial analyses were based on 1057 participants from the Rush Memory and Aging Project and the Religious Orders Study who began without impairment and underwent cognitive assessments up to 24 years. A shape invariant model characterized the latent pattern of cognitive decline, conceptualized here as the "cognitive clock," and yielded person-specific estimates of cognitive age. Survival analyses examined cognitive versus chronological age for predicting Alzheimer's disease dementia, mild cognitive impairment and mortality, and regression analyses examined associations of cognitive versus chronological age with neuropathology and brain atrophy. Finally, we applied the cognitive clock to an independent validation sample of 2592 participants from the Chicago Health and Aging Project, a biracial population-based study, to confirm the predictive utility of cognitive age. RESULTS: The "cognitive clock" showed that cognition remained stable until a cognitive age of about 80, then declined moderately until 90, then declined precipitously. In the initial dataset, cognitive age was a better predictor of dementia, mild cognitive impairment and mortality than chronological age, and was more strongly associated with neuropathology and brain atrophy. Application of the cognitive clock to the independent validation sample provided further support for the utility of cognitive age as a strong prognostic indicator of adverse outcomes. DISCUSSION: Cognitive age is a robust prognostic indicator of adverse health outcomes and may serve as a useful biomarker in aging research.