Publications by authors named "Konstantinos Arfanakis"

103 Publications

Association of White Matter Hyperintensities With Pathology and Progression of Parkinsonism in Aging.

JAMA Neurol 2021 Nov 1. Epub 2021 Nov 1.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.

Importance: Progressive parkinsonism is common in older adults without a diagnosis of Parkinson disease and is associated with adverse health outcomes, but its pathologic basis is controversial.

Objective: To examine if the burden of cerebral white matter hyperintensity (WMH), a common manifestation of cerebrovascular disease pathologies, is associated with the rate of progressive parkinsonism.

Design, Setting, And Participants: This community-based cohort study included participants recruited in 3 ongoing cohorts that began enrollment in 1994, 1997, and 2004. Prior to death, participants were observed for a mean of 7.5 years, with annual clinical assessments. From 4427 participants enrolled in the 3 cohorts, 2134 died. Postmortem autopsy was performed in 1725 decedents, and 598 also had ex vivo brain magnetic resonance imaging. Participants were excluded if they were missing any of the 9 postmortem pathology indices (n = 22) or repeated parkinsonism assessment (n = 41) or had received a clinical diagnosis of Parkinson disease at any point before or during the study (n = 19). Data were analyzed from April 2020 to August 2021.

Exposures: WMH burden was assessed using a modified Fazekas rating scale.

Main Outcomes And Measures: Parkinsonism was assessed annually using 26 items of a modified motor portion of the Unified Parkinson's Disease Rating Scale. A summary score was developed from the item scores, with higher scores indicating more severe parkinsonism.

Results: Of 516 included decedents, 364 (70.5%) were female, and the mean (SD) age at death was 90.2 (6.4) years. Higher WMH was associated with faster progressive parkinsonism (estimate, 0.024; SE, 0.008; P = .002). The attenuation of this association was greater when controlling for indices of cerebrovascular disease pathologies than when controlling for neurodegenerative pathologies (cerebrovascular disease: estimate, 0.019; SE, 0.008; P = .02; neurodegenerative: estimate, 0.022; SE, 0.008; P = .003), but both remained significant.

Conclusions And Relevance: In this cohort study, higher levels of both WMH and indices of cerebrovascular disease pathologies in aging brains were associated with more rapid progressive parkinsonism. Further studies are needed to determine if in vivo brain imaging of older adults for evidence of WMH and aggressive medical treatment of vascular risk factors and diseases can reduce the occurrence or severity of late-life parkinsonism.
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http://dx.doi.org/10.1001/jamaneurol.2021.3996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561430PMC
November 2021

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

J Int Neuropsychol Soc 2021 Oct 6:1-8. Epub 2021 Oct 6.

Department of Neurological Sciences, Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

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.
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http://dx.doi.org/10.1017/S1355617721001089DOI Listing
October 2021

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

Stroke 2021 Oct 4:STROKEAHA121034814. Epub 2021 Oct 4.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL. (M.L., S.L., A.K., L.L.B., P.A.B., D.A.B., K.A., J.A.S.).

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.
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http://dx.doi.org/10.1161/STROKEAHA.121.034814DOI Listing
October 2021

The association of Lewy bodies with limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes and their role in cognition and Alzheimer's dementia in older persons.

Acta Neuropathol Commun 2021 09 25;9(1):156. Epub 2021 Sep 25.

Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W. Harrison street, Suite 1000, Chicago, IL, 60612, USA.

Lewy bodies (LBs) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) are common in older persons and associated with cognitive impairment. However, little is known about the relationship between LBs and LATE-NC and their combined roles in cognitive impairment and Alzheimer's dementia in community-dwelling participants. The study included 1670 community-based participants (mean age-at-death, 89.5 years (SD = 6.65); 69% females) who underwent annual assessments of cognition to create summary measures of global cognition and cognitive domains and evaluation for Alzheimer's dementia. Systematic neuropathologic evaluations were performed to assess LBs, LATE-NC, and Alzheimer's disease (AD) pathology. We excluded cases with pathologically confirmed frontotemporal lobar degeneration in this study. Logistic and linear regression analyses were used, adjusted for demographics and AD pathology. LBs were present in 428 (25.6%) decedents (29 nigra-predominant, 165 limbic-type, and 234 neocortical-type) while 865 (51.7%) decedents exhibited LATE-NC (307 stage 1, 167 stage 2, and 391 stage 3). LBs combined with LATE-NC were common (15% of all participants) and in those with Alzheimer's dementia (25%). Neocortical-type, but not nigral-predominant or limbic-type LBs increased the odds of stage 2/3 LATE-NC (odds ratio = 1.70; 95% confidence interval = 1.26-2.30). The association between neocortical-type LBs and stage 2/3 LATE-NC was stronger in those under 90 years of age and in women. In analyses of cognition and Alzheimer's dementia, LATE-NC and neocortical-type LBs, separately, were related to lower global cognition, five specific cognitive domains, and an increased odds of Alzheimer's dementia, above and beyond the AD pathology. Limbic-type LBs were related to lower global cognition, and the domains of episodic, working, and semantic memory, and increased odds of Alzheimer's dementia. Furthermore, there was no interaction between limbic/neocortical-type LBs and LATE-NC on cognitive function, cognitive domains, or Alzheimer's dementia. These findings suggest that neocortical-type LBs are associated with LATE-NC, specifically in the younger old and in women. Limbic/neocortical-type LBs and LATE-NC have separate and additive effects on cognitive function and odds of Alzheimer's dementia.
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http://dx.doi.org/10.1186/s40478-021-01260-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466680PMC
September 2021

ARTS: A novel In-vivo classifier of arteriolosclerosis for the older adult brain.

Neuroimage Clin 2021 24;31:102768. Epub 2021 Jul 24.

Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Dept. of Diagnostic Radiology & Nuc Med, Rush University Medical Center, Chicago, IL, USA. Electronic address:

Brain arteriolosclerosis, one of the main pathologies of cerebral small vessel disease, is common in older adults and has been linked to lower cognitive and motor function and higher odds of dementia. In spite of its frequency and associated morbidity, arteriolosclerosis can only be diagnosed at autopsy. Therefore, the purpose of this work was to develop an in-vivo classifier of arteriolosclerosis based on brain MRI. First, an ex-vivo classifier of arteriolosclerosis was developed based on features related to white matter hyperintensities, diffusion anisotropy and demographics by applying machine learning to ex-vivo MRI and pathology data from 119 participants of the Rush Memory and Aging Project (MAP) and Religious Orders Study (ROS), two longitudinal cohort studies of aging that recruit non-demented older adults. The ex-vivo classifier showed good performance in predicting the presence of arteriolosclerosis, with an average area under the receiver operating characteristic curve AUC = 0.78. The ex-vivo classifier was then translated to in-vivo based on available in-vivo and ex-vivo MRI data on the same participants. The in-vivo classifier was named ARTS (short for ARTerioloSclerosis), is fully automated, and provides a score linked to the likelihood a person suffers from arteriolosclerosis. The performance of ARTS in predicting the presence of arteriolosclerosis in-vivo was tested in a separate, 91% dementia-free group of 79 MAP/ROS participants and exhibited an AUC = 0.79 in persons with antemortem intervals shorter than 2.4 years. This level of performance in mostly non-demented older adults is notable considering that arteriolosclerosis can only be diagnosed at autopsy. The scan-rescan reproducibility of the ARTS score was excellent, with an intraclass correlation of 0.99, suggesting that application of ARTS in longitudinal studies may show high sensitivity in detecting small changes. Finally, higher ARTS scores in non-demented older adults were associated with greater decline in cognition two years after baseline MRI, especially in perceptual speed which has been linked to arteriolosclerosis and small vessel disease. This finding was shown in a separate group of 369 non-demented MAP/ROS participants and was validated in 72 non-demented Black participants of the Minority Aging Research Study (MARS) and also in 244 non-demented participants of the Alzheimer's Disease Neuroimaging Initiative 2 and 3. The results of this work suggest that ARTS may have broad implications in the advancement of diagnosis, prevention and treatment of arteriolosclerosis. ARTS is publicly available at https://www.nitrc.org/projects/arts/.
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http://dx.doi.org/10.1016/j.nicl.2021.102768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329541PMC
September 2021

Physical activity, brain tissue microstructure, and cognition in older adults.

PLoS One 2021 7;16(7):e0253484. Epub 2021 Jul 7.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, United States of America.

Objective: To test whether postmortem MRI captures brain tissue characteristics that mediate the association between physical activity and cognition in older adults.

Methods: Participants (N = 318) were older adults from the Rush Memory and Aging Project who wore a device to quantify physical activity and also underwent detailed cognitive and motor testing. Following death, cerebral hemispheres underwent MRI to quantify the transverse relaxation rate R2, a metric related to tissue microstructure. For analyses, we reduced the dimensionality of the R2 maps from approximately 500,000 voxels to 30 components using spatial independent component analysis (ICA). Via path analysis, we examined whether these R2 components attenuated the association between physical activity and cognition, controlling for motor abilities and indices of common brain pathologies.

Results: Two of the 30 R2 components were associated with both total daily physical activity and global cognition assessed proximate to death. We visualized these components by highlighting the clusters of voxels whose R2 values contributed most strongly to each. One of these spatial signatures spanned periventricular white matter and hippocampus, while the other encompassed white matter of the occipital lobe. These two R2 components partially mediated the association between physical activity and cognition, accounting for 12.7% of the relationship (p = .01). This mediation remained evident after controlling for motor abilities and neurodegenerative and vascular brain pathologies.

Conclusion: The association between physically activity and cognition in older adults is partially accounted for by MRI-based signatures of brain tissue microstructure. Further studies are needed to elucidate the molecular mechanisms underlying this pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253484PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262790PMC
November 2021

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

J Nutr 2021 Sep;151(9):2760-2767

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

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.
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http://dx.doi.org/10.1093/jn/nxab168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417916PMC
September 2021

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

Alzheimers Dement 2021 Jun 1. Epub 2021 Jun 1.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.

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.
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http://dx.doi.org/10.1002/alz.12351DOI Listing
June 2021

Bootstrap approach for meta-synthesis of MRI findings from multiple scanners.

J Neurosci Methods 2021 08 27;360:109229. Epub 2021 May 27.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, 60612, United States; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, 60612, United States; Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL 60612, United States.

Background: Neuroimaging data from large epidemiologic cohort studies often come from multiple scanners. The variations of MRI measurements due to differences in magnetic field strength, image acquisition protocols, and scanner vendors can influence the interpretation of aggregated data. The purpose of the present study was to compare methods that meta-analyze findings from a small number of different MRI scanners.

Methods: We proposed a bootstrap resampling method using individual participant data and compared it with two common random effects meta-analysis methods, DerSimonian-Laird and Hartung-Knapp, and a conventional pooling method that combines MRI data from different scanners. We first performed simulations to compare the power and coverage probabilities of the four methods in the absence and presence of scanner effects on measurements. We then examined the association of age with white matter hyperintensity (WMH) volumes from 787 participants.

Results: In simulations, the bootstrap approach performed better than the other three methods in terms of coverage probability and power when scanner differences were present. However, the bootstrap approach was consistent with pooling, the optimal approach, when scanner differences were absent. In the association of age with WMH volume, we observed that age was significantly associated with WMH volumes using the bootstrap approach, pooling, and the DerSimonian-Laird method, but not using the Hartung-Knapp method (p < 0.0001 for the bootstrap approach, DerSimonian-Laird, and pooling but p = 0.1439 for the Hartung-Knapp approach).

Conclusion: The bootstrap approach using individual participant data is suitable for integrating outcomes from multiple MRI scanners regardless of absence or presence of scanner effects on measurements.
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http://dx.doi.org/10.1016/j.jneumeth.2021.109229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324567PMC
August 2021

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

Brain 2021 08;144(7):2166-2175

Rush University Medical Center, Rush Alzheimer's Disease Center, Chicago, IL 60612, USA.

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.
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http://dx.doi.org/10.1093/brain/awab092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370442PMC
August 2021

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change and microvascular pathologies in community-dwelling older persons.

Brain Pathol 2021 05 23;31(3):e12939. Epub 2021 Feb 23.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) and microvascular pathologies, including microinfarcts, cerebral amyloid angiopathy (CAA), and arteriolosclerosis are common in old age. A relationship between LATE-NC and arteriolosclerosis has been reported in some but not all studies. The objectives of this study were to investigate the frequency of co-occurring LATE-NC and microvascular pathologies and test the hypothesis that arteriolosclerosis, specifically, is related to LATE-NC in brains from community-dwelling older persons. Analyses included 749 deceased participants with completed data on LATE-NC and microvascular pathology from 3 longitudinal clinical pathologic studies of aging. Given the specific interest in arteriolosclerosis, we expanded the examination of arteriolosclerosis to include not only the basal ganglia but also two additional white matter regions from anterior and posterior watershed territories. Ordinal logistic regression models examined the association of microvascular pathology with LATE-NC. LATE-NC was present in 409 (54.6%) decedents, of which 354 (86.5%) had one or multiple microvascular pathologies including 132 (32.3%) with moderate-severe arteriolosclerosis in basal ganglia, 195 (47.6%) in anterior watershed, and 144 (35.2%) in posterior watershed; 170 (41.5%) with moderate-severe CAA, and 150 (36.6%) with microinfarcts. In logistic regression models, only posterior watershed arteriolosclerosis, but not other regions of arteriolosclerosis was associated with a higher odds of more advanced LATE-NC stages (Odds Ratio = 1.12; 95% Confidence Interval = 1.01-1.25) after controlling for demographics, AD, and other age-related pathologies. Capillary CAA, but not the severity of CAA was associated with an increased odds of LATE-NC burden (Odds Ratio = 1.71; 95% Confidence Interval = 1.13-2.58). Findings were unchanged in analyses controlling for APOE ε4, vascular risk factors, or vascular diseases. These findings suggest that LATE-NC with microvascular pathology is a very common mixed pathology and small vessel disease pathology may contribute to LATE-NC in the aging brain.
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http://dx.doi.org/10.1111/bpa.12939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363209PMC
May 2021

MarkVCID cerebral small vessel consortium: II. Neuroimaging protocols.

Alzheimers Dement 2021 04 21;17(4):716-725. Epub 2021 Jan 21.

Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

The MarkVCID consortium was formed under cooperative agreements with the National Institute of Neurologic Diseases and Stroke (NINDS) and National Institute on Aging (NIA) in 2016 with the goals of developing and validating biomarkers for the cerebral small vessel diseases associated with the vascular contributions to cognitive impairment and dementia (VCID). Rigorously validated biomarkers have consistently been identified as crucial for multicenter studies to identify effective strategies to prevent and treat VCID, specifically to detect increased VCID risk, diagnose the presence of small vessel disease and its subtypes, assess prognosis for disease progression or response to treatment, demonstrate target engagement or mechanism of action for candidate interventions, and monitor disease progression during treatment. The seven project sites and central coordinating center comprising MarkVCID, working with NINDS and NIA, identified a panel of 11 candidate fluid- and neuroimaging-based biomarker kits and established harmonized multicenter study protocols (see companion paper "MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols" for full details). Here we describe the MarkVCID neuroimaging protocols with specific focus on validating their application to future multicenter trials. MarkVCID procedures for participant enrollment; clinical and cognitive evaluation; and collection, handling, and instrumental validation of fluid samples are described in detail in a companion paper. Magnetic resonance imaging (MRI) has long served as the neuroimaging modality of choice for cerebral small vessel disease and VCID because of its sensitivity to a wide range of brain properties, including small structural lesions, connectivity, and cerebrovascular physiology. Despite MRI's widespread use in the VCID field, there have been relatively scant data validating the repeatability and reproducibility of MRI-based biomarkers across raters, scanner types, and time intervals (collectively defined as instrumental validity). The MRI protocols described here address the core MRI sequences for assessing cerebral small vessel disease in future research studies, specific sequence parameters for use across various research scanner types, and rigorous procedures for determining instrumental validity. Another candidate neuroimaging modality considered by MarkVCID is optical coherence tomography angiography (OCTA), a non-invasive technique for directly visualizing retinal capillaries as a marker of the cerebral capillaries. OCTA has theoretical promise as a unique opportunity to visualize small vessels derived from the cerebral circulation, but at a considerably earlier stage of development than MRI. The additional OCTA protocols described here address procedures for determining OCTA instrumental validity, evaluating sources of variability such as pupil dilation, and handling data to maintain participant privacy. MRI protocol and instrumental validation The core sequences selected for the MarkVCID MRI protocol are three-dimensional T1-weighted multi-echo magnetization-prepared rapid-acquisition-of-gradient-echo (ME-MPRAGE), three-dimensional T2-weighted fast spin echo fluid-attenuated-inversion-recovery (FLAIR), two-dimensional diffusion-weighted spin-echo echo-planar imaging (DWI), three-dimensional T2*-weighted multi-echo gradient echo (3D-GRE), three-dimensional T -weighted fast spin-echo imaging (T2w), and two-dimensional T2*-weighted gradient echo echo-planar blood-oxygenation-level-dependent imaging with brief periods of CO inhalation (BOLD-CVR). Harmonized parameters for each of these core sequences were developed for four 3 Tesla MRI scanner models in widespread use at academic medical centers. MarkVCID project sites are trained and certified for their instantiation of the consortium MRI protocols. Sites are required to perform image quality checks every 2 months using the Alzheimer's Disease Neuroimaging Initiative phantom. Instrumental validation for MarkVCID MRI-based biomarkers is operationally defined as inter-rater reliability, test-retest repeatability, and inter-scanner reproducibility. Assessments of these instrumental properties are performed on individuals representing a range of cerebral small vessel disease from mild to severe. Inter-rater reliability is determined by distribution of an independent dataset of MRI scans to each analysis site. Test-retest repeatability is determined by repeat MRI scans performed on individual participants on a single MRI scanner after a short (1- to 14-day) interval. Inter-scanner reproducibility is determined by repeat MRI scans performed on individuals performed across four MRI scanner models. OCTA protocol and instrumental validation The MarkVCID OCTA protocol uses a commercially available, Food and Drug Administration-approved OCTA apparatus. Imaging is performed on one dilated and one undilated eye to assess the need for dilation. Scans are performed in quadruplicate. MarkVCID project sites participating in OCTA validation are trained and certified by this biomarker's lead investigator. Inter-rater reliability for OCTA is assessed by distribution of OCTA datasets to each analysis site. Test-retest repeatability is assessed by repeat OCTA imaging on individuals on the same day as their baseline OCTA and a different-day repeat session after a short (1- to 14-day) interval. Methods were developed to allow the OCTA data to be de-identified by the sites before transmission to the central data management system. The MarkVCID neuroimaging protocols, like the other MarkVCID procedures, are designed to allow translation to multicenter trials and as a template for outside groups to generate directly comparable neuroimaging data. The MarkVCID neuroimaging protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the neuroimaging MarkVCID kits will undergo biological validation to determine its ability to measure important aspects of VCID such as cognitive function. The analytic methods for the neuroimaging-based kits and the results of these validation studies will be published separately. The results will ultimately determine the neuroimaging kits' potential usefulness for multicenter interventional trials in small vessel disease-related VCID.
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http://dx.doi.org/10.1002/alz.12216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627001PMC
April 2021

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

Hum Brain Mapp 2021 04 15;42(6):1758-1776. Epub 2021 Jan 15.

Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois, USA.

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.
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http://dx.doi.org/10.1002/hbm.25327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978143PMC
April 2021

Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) study: Rationale, design and baseline characteristics of a randomized control trial of the MIND diet on cognitive decline.

Contemp Clin Trials 2021 03 9;102:106270. Epub 2021 Jan 9.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, United States of America; Department of Neurology, Rush University Medical Center, Chicago, IL, United States of America. Electronic address:

Alzheimer's dementia (AD) is the sixth leading cause of death in the U.S., with an estimated $305 billion cost of care in 2020. Currently there are no cures or therapies to ameliorate the disease progression and symptoms. Growing evidence links a diet characterized by high antioxidant components with benefits to cognitive function, which is indicative of the preventative potential of dietary inteventions. The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) study is a 3-year, multicenter, randomized controlled trial to test the effects of the MIND diet on cognitive function in 604 individuals at risk for AD. Men and women ages 65 to 84 years were recruited. Eligible participants were randomized to either the MIND diet with mild caloric restriction or their usual diet with mild caloric restriction. Cognitive assessments, medical history, blood pressure, anthropometric measurements, and blood and urine sample collections will be taken at baseline and follow-up visits. MRI scans will be completed on approximately half of the enrolled participants at the start and end of the study. Unique features of the MIND study include: 1) a dietary pattern, rather than single nutrient or food, tested in an at-risk population; 2) foods featured as key components of the MIND diet (i.e. extra-virgin olive oil, blueberries, and nuts) provided for participants; and 3) MRI scans of brain structure and volume that may provide potential mechanistic evidence on the effects of the diet. Results from the study will be crucial to the development of dietary guidelines for the prevention of AD.
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http://dx.doi.org/10.1016/j.cct.2021.106270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042655PMC
March 2021

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

Neuroimage 2021 01 16;225:117462. Epub 2020 Oct 16.

Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, United States; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, United States; Department of Diagnostic Radiology and Nuclear Medicine, Rush University Medical Center, Chicago, IL, United States. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811895PMC
January 2021

Common Brain Structural Alterations Associated with Cardiovascular Disease Risk Factors and Alzheimer's Dementia: Future Directions and Implications.

Neuropsychol Rev 2020 12 3;30(4):546-557. Epub 2020 Oct 3.

Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison Street, Suite 1000, Chicago, IL, 60612, USA.

Recent reports suggest declines in the age-specific risk of Alzheimer's dementia in higher income Western countries. At the same time, investigators believe that worldwide trends of increasing mid-life modifiable risk factors [e.g., cardiovascular disease (CVD) risk factors] coupled with the growth of the world's oldest age groups may nonetheless lead to an increase in Alzheimer's dementia. Thus, understanding the overlap in neuroanatomical profiles associated with CVD risk factors and AD may offer more relevant targets for investigating ways to reduce the growing dementia epidemic than current targets specific to isolated AD-related neuropathology. We hypothesized that a core group of common brain structural alterations exist between CVD risk factors and Alzheimer's dementia. Two co-authors conducted independent literature reviews in PubMed using search terms for CVD risk factor burden (separate searches for 'cardiovascular disease risk factors', 'hypertension', and 'Type 2 diabetes') and 'aging' or 'Alzheimer's dementia' with either 'grey matter volumes' or 'white matter'. Of studies that reported regionally localized results, we found support for our hypothesis, determining 23 regions commonly associated with both CVD risk factors and Alzheimer's dementia. Within this context, we outline future directions for research as well as larger cerebrovascular implications for these commonalities. Overall, this review supports previous as well as more recent calls for the consideration that both vascular and neurodegenerative factors contribute to the pathogenesis of dementia.
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http://dx.doi.org/10.1007/s11065-020-09460-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718308PMC
December 2020

Neuropathologic and Cognitive Correlates of Enlarged Perivascular Spaces in a Community-Based Cohort of Older Adults.

Stroke 2020 09 6;51(9):2825-2833. Epub 2020 Aug 6.

Department of Biomedical Engineering, Illinois Institute of Technology, Chicago (C.J.P., N.M., K.A.).

Background And Purpose: Enlarged perivascular spaces (EPVS) have been associated with aging, increased stroke risk, decreased cognitive function, and vascular dementia. However, the relationship of EPVS with age-related neuropathologies is not well understood. Therefore, the purpose of this study was to assess the neuropathologic correlates of EPVS in a large community-based cohort of older adults. The cognitive correlates of EPVS over and beyond those of other pathologies were also assessed.

Methods: This study included 654 older deceased and autopsied participants of 3 longitudinal community-based studies of aging that had available data on cognition, ex vivo brain magnetic resonance imaging, and detailed neuropathologic examination. EPVS seen on ex vivo magnetic resonance imaging were histologically validated. Experienced observers rated EPVS burden in ex vivo magnetic resonance imaging using a semiquantitative 4-level scale. Elastic-net regularized ordinal logistic regression was used to investigate associations of EPVS burden with age-related neuropathologies. Mixed-effects models of cognition controlling for neuropathologies, demographics, and clinical factors, were used to determine whether EPVS burden has additional contributions to cognitive decline.

Results: EPVS burden in the whole group was associated with gross infarcts (odds ratio=1.67, =0.0017) and diabetes mellitus (odds ratio=1.73, =0.004). When considering only nondemented participants (with mild or no cognitive impairment), EPVS burden was associated with gross infarcts (odds ratio=1.74, =0.016) and microscopic infarcts (odds ratio=1.79, =0.013). EPVS burden was associated with faster decline in visuospatial abilities (estimate=-0.009, =0.028), in the whole group, as well as lower levels of semantic memory (estimate=-0.13, =0.048) and visuospatial abilities (estimate=-0.11, =0.016) at the time of death.

Conclusions: EPVS and infarcts may share similar neurobiological pathways regardless of dementia status. EPVS burden is linked to diabetes mellitus independently of neuropathologies, extending recent findings in animal studies implicating diabetes mellitus in impairment of the glymphatic system. Finally, EPVS burden may reflect additional brain tissue injury that may contribute to cognitive decline, not captured with traditional neuropathologic measures.
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http://dx.doi.org/10.1161/STROKEAHA.120.029388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484322PMC
September 2020

Self-reported experiences of discrimination in older black adults are associated with insula functional connectivity.

Brain Imaging Behav 2021 Aug;15(4):1718-1727

Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL, 60612, USA.

Self-reported experiences of discrimination are associated with a number of negative health outcomes. However, the neurobiological correlates of discrimination remain elusive. Recent neuroimaging work suggests that the amygdala is sensitive to forms of social adversity and the insula is involved in assessments of trust. We hypothesized that functional connectivity (FC) of these brain regions may be associated with discrimination in older Black adults. One-hundred and twenty-four nondemented older Black adults participating in the Minority Aging Research Study or the Clinical Core study of the Rush Alzheimer's Disease Center completed a measure of self-reported experiences of discrimination and a 3T MRI brain scan including structural T1 and resting-state fMRI EPIBOLD sequences. The right and left amygdala and insula regions were anatomically delineated as ROIs according to the Harvard-Oxford Brain Atlas and whole-brain voxelwise FC analyses were conducted using default parameters in the CONN toolbox. In regression analyses controlling for demographics and global cognition, self-reported experiences of discrimination were associated with greater FC between the left insula and the bilateral intracalcarine cortex, weaker FC between the left insula and the left dorsolateral prefrontal cortex, and weaker FC between the right insula and the left supplementary motor area. Amygdala analyses yielded no significant findings. Greater self-reported experiences of discrimination are associated with differential insula functional connectivity in older adults. More specifically, results suggest that discrimination is associated with differential connectivity of a key region (the insula) involved in trust perception.
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http://dx.doi.org/10.1007/s11682-020-00365-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854830PMC
August 2021

Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons.

JAMA Psychiatry 2020 Nov;77(11):1172-1180

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.

Importance: Identifying genes and proteins for cognitive resilience (ie, targets that may be associated with slowing or preventing cognitive decline regardless of the presence, number, or combination of common neuropathologic conditions) provides a complementary approach to developing novel therapeutics for the treatment and prevention of Alzheimer disease and related dementias.

Objective: To identify proteins associated with cognitive resilience via a proteome-wide association study of the human dorsolateral prefrontal cortex.

Design, Setting, And Participants: This study used data from 391 community-dwelling older persons who participated in the Religious Orders Study and the Rush Memory and Aging Project. The Religious Orders Study began enrollment January 1, 1994, and the Rush Memory and Aging Project began enrollment September 1, 1997, and data were collected and analyzed through October 23, 2019.

Exposures: Participants had undergone annual detailed clinical examinations, postmortem evaluations, and tandem mass tag proteomics analyses.

Main Outcomes And Measures: The outcome of cognitive resilience was defined as a longitudinal change in cognition over time after controlling for common age-related neuropathologic indices, including Alzheimer disease, Lewy bodies, transactive response DNA-binding protein 43, hippocampal sclerosis, infarcts, and vessel diseases. More than 8000 high abundance proteins were quantified from frozen dorsolateral prefrontal cortex tissue using tandem mass tag and liquid chromatography-mass spectrometry.

Results: There were 391 participants (273 women); their mean (SD) age was 79.7 (6.7) years at baseline and 89.2 (6.5) years at death. Eight cortical proteins were identified in association with cognitive resilience: a higher level of NRN1 (estimate, 0.140; SE, 0.024; P = 7.35 × 10-9), ACTN4 (estimate, 0.321; SE, 0.065; P = 9.94 × 10-7), EPHX4 (estimate, 0.198; SE, 0.042; P = 2.13 × 10-6), RPH3A (estimate, 0.148; SE, 0.031; P = 2.58 × 10-6), SGTB (estimate, 0.211; SE, 0.045; P = 3.28 × 10-6), CPLX1 (estimate, 0.136; SE, 0.029; P = 4.06 × 10-6), and SH3GL1 (estimate, 0.179; SE, 0.039; P = 4.21 × 10-6) and a lower level of UBA1 (estimate, -0.366; SE, 0.076; P = 1.43 × 10-6) were associated with greater resilience.

Conclusions And Relevance: These protein signals may represent novel targets for the maintenance of cognition in old age.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.1807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330835PMC
November 2020

Late-life cognitive decline is associated with hippocampal volume, above and beyond its associations with traditional neuropathologic indices.

Alzheimers Dement 2020 01;16(1):209-218

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.

Introduction: Reduced hippocampal volume is associated with late-life cognitive decline, but prior studies have not determined whether this association persists after accounting for Alzheimer's disease (AD) and other neuropathologies.

Methods: Participants were 531 deceased older adults from community-based cohort studies of aging who had undergone annual cognitive evaluations. At death, brain tissue underwent neuropathologic examination and magnetic resonance imaging (MRI). Linear mixed models examined whether hippocampal volume measured via MRI accounted for variation in decline rate of global cognition and five cognitive domains, above and beyond neuropathologic indices.

Results: Demographics and indices of AD, cerebrovascular disease, Lewy body disease, hippocampal sclerosis, TDP-43, and atherosclerosis accounted for 42.6% of the variation in global cognitive decline. Hippocampal volume accounted for an additional 5.4% of this variation and made similar contributions in four of the five cognitive domains.

Discussion: Hippocampal volume is associated with late-life cognitive decline, above and beyond contributions from common neuropathologic indices.
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http://dx.doi.org/10.1002/alz.12009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953608PMC
January 2020

Neuropathologic Correlates of White Matter Hyperintensities in a Community-Based Cohort of Older Adults.

J Alzheimers Dis 2020 ;73(1):333-345

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Background: The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood.

Objective: The objective of this work was to elucidate the neuropathologic correlates of WMH in a large community-based cohort of older adults.

Methods: Cerebral hemispheres from 603 community-based older adults were imaged with MRI ex vivo. All participants underwent annual clinical evaluation, cognitive assessment, and neuropathologic examination. WMH burden was assessed using a modified Fazekas rating scale. Multiple ordinal logistic regression was used to test the association of WMH burden with an array of age-related neuropathologies, adjusting for demographics. Mixed effects models of cognition controlling for neuropathologies and demographics were used to determine whether WMH burden contributes to cognitive decline beyond measured pathologies.

Results: WMH burden in the whole group was associated with both vascular and Alzheimer's disease (AD) pathologies: arteriolosclerosis (p < 10-4), gross (p < 10-4), and microscopic infarcts (p = 0.04), and amyloid-β plaques (p = 0.028). In non-demented participants (mild or no cognitive impairment) (N = 332), WMH burden was related to gross infarcts (p = 10-4) and arteriolosclerosis (p < 10-4), but not to AD pathology. Similarly, in those with no cognitive impairment (N = 178), WMH burden was related to gross infarcts (p = 8×10-4) and arteriolosclerosis (p = 0.014). WMH burden was associated with faster decline in perceptual speed in both the whole (p = 0.038) and non-demented (p = 0.006) groups.

Conclusion: WMH burden has independent associations with vascular pathologies in older adults regardless of clinical status, and with AD pathology later in the progression of AD. Moreover, WMH burden may reflect additional tissue injury not captured with traditional neuropathologic indices.
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http://dx.doi.org/10.3233/JAD-190687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996196PMC
April 2021

Contribution of TDP and hippocampal sclerosis to hippocampal volume loss in older-old persons.

Neurology 2020 01 22;94(2):e142-e152. Epub 2019 Nov 22.

From the Rush Alzheimer's Disease Center (L.Y., P.A.B., R.J.D., D.A.B., K.A., J.A.S.), Department of Neurological Sciences (L.Y., D.A.B., J.A.S.), Department of Behavioral Sciences (P.A.B.), Department of Diagnostic Radiology and Nuclear Medicine (R.J.D., K.A.), and Department of Pathology (J.A.S.), Rush University Medical Center; and Department of Biomedical Engineering (K.A.), Illinois Institute of Technology, Chicago.

Objective: To investigate the contribution of Alzheimer disease (AD) vs non-AD neuropathologies to hippocampal atrophy.

Methods: The Religious Orders Study and Rush Memory and Aging Project are clinicopathologic cohort studies of aging. The current study included 547 participants who had undergone brain autopsy and postmortem hippocampal volume measurement by November 1, 2018. Hippocampal volume was measured with postmortem MRI via a 3D region of interest applied to the hippocampal formation. Neuropathologies were measured via uniform structured evaluations. Linear regression analyses estimated the proportion of variance of hippocampal volume attributable to AD and non-AD neuropathologies.

Results: The average age at death was 90 years, and the average hippocampal volume was 2.1 mL. AD, transactive response DNA-binding protein 43 (TDP), hippocampal sclerosis (HS), and atherosclerosis were associated with hippocampal volume. After demographics and total hemisphere volume were controlled for, 7.0% of the variance (95% bootstrapped confidence interval [CI] 4.3%-10.5%) of hippocampal volume was attributable to AD pathology. TDP/HS explained an additional 4.5% (95% CI 2.2%-7.6%). Among individuals with Alzheimer dementia (n = 232), 3.1% (95% CI 0.6%-7.7%) of the variance was attributable to AD pathology, and TDP/HS explained an additional 6.1% (95% CI 2.2%-11.6%). Among those without Alzheimer dementia (n = 307), 3.2% (95% CI 0.9%-7.3%) of the variance was attributable to AD pathology, and TDP/HS explained an additional 1.1%, which did not reach statistical significance. Lewy bodies and vascular diseases had modest contribution to the variance of hippocampal volume.

Conclusions: Both AD and TDP/HS contribute to hippocampal volume loss in older-old persons, with TDP/HS more strongly associated with hippocampal volume than AD in Alzheimer dementia.
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http://dx.doi.org/10.1212/WNL.0000000000008679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988988PMC
January 2020

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019

Microstructural changes in the brain mediate the association of AK4, IGFBP5, HSPB2, and ITPK1 with cognitive decline.

Neurobiol Aging 2019 12 26;84:17-25. Epub 2019 Jul 26.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.

The associations of 4 proteins-AK4, ITPK1, HSPB2, and IGFBP5-with cognitive function in older adults were largely unexplained by known brain pathologies. We examined the extent to which individual protein associations with cognitive decline were attributable to microstructural changes in the brain. This study included 521 participants (mean age 90.3, 65.9-108.3) with the postmortem reciprocal of transverse relaxation time (R) magnetic resonance image. All participants came from one of the 2 ongoing longitudinal cohorts of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project. Higher abundance of AK4, HSPB2, and IGFBP5 was associated with faster cognitive decline and mediated through lower postmortem R in the frontal and temporal white matter regions. In contrast, higher abundance of ITPK1 was associated with slower cognitive decline and mediated through higher postmortem R in the frontal and temporal white matter regions. The associations of 4 proteins-AK4, ITPK1, IGFBP5, and HSPB2-with cognition in late life were explained via microstructural changes in the brain.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077920PMC
December 2019

A genome-wide association study identifies genetic loci associated with specific lobar brain volumes.

Commun Biol 2019 2;2:285. Epub 2019 Aug 2.

17Department of Biomedical Data Sciences, Statistical Genetics, Leiden University Medical Center, Leiden, 2333ZA the Netherlands.

Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications ( and ), or close to genes causing Mendelian brain-related diseases ( and ). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes.
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http://dx.doi.org/10.1038/s42003-019-0537-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677735PMC
April 2020

Human Hippocampal Neurogenesis Persists in Aged Adults and Alzheimer's Disease Patients.

Cell Stem Cell 2019 06 23;24(6):974-982.e3. Epub 2019 May 23.

Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA. Electronic address:

Whether hippocampal neurogenesis persists throughout life in the human brain is not fully resolved. Here, we demonstrate that hippocampal neurogenesis is persistent through the tenth decade of life and is detectable in patients with mild cognitive impairments and Alzheimer's disease. In a cohort of 18 participants with a mean age of 90.6 years, NestinSox2 neural progenitor cells (NPCs) and DCX neuroblasts and immature neurons were detected, but their numbers greatly varied between participants. Nestin cells localize in the anterior hippocampus, and NPCs, neuroblasts, and immature neurons are evenly distributed along the anterior to posterior axis. The number of DCXPCNA cells is reduced in mild cognitive impairments, and higher numbers of neuroblasts are associated with better cognitive status. The number of DCXPCNA cells correlates with functional interactions between presynaptic SNARE proteins. Our results suggest that hippocampal neurogenesis persists in the aged and diseased human brain and that it is possibly associated with cognition.
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http://dx.doi.org/10.1016/j.stem.2019.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608595PMC
June 2019

Antiphospholipid Antibodies: Cognitive and Motor Decline, Neuroimaging and Neuropathology.

Neuroepidemiology 2019 8;53(1-2):100-107. Epub 2019 May 8.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.

Background: Few data are available on associations of antiphospholipid (aPL) antibodies with cognitive and motor decline in aging, and cerebrovascular disease on in vivo neuroimaging and postmortem neuropathology.

Methods: This longitudinal, clinical-pathologic study (aPL antibodies, brain infarcts, and cognitive and motor decline in aging), was derived from 2 ongoing community-based cohort studies. A panel of 3 aPL antibodies was assayed in serum from 956 older individuals (mean age = 81.1 years; 72% women). Serum was also tested in a subset for markers of inflammation (C-reactive protein [CRP]) and blood-brain barrier breakdown (matrix metalloproteinases, MMPs). Annual clinical evaluations documented cognitive (17 neuropsychological tests) and motor function including parkinsonism. Cerebrovascular disease data were derived from in vivo neuroimaging and postmortem neuropathologic evaluations (699 individuals). We examined associations of aPL with cognitive and motor decline, other serum markers, neuroimaging, and neuropathology.

Results: Of 956 individuals, 197 (20.6%) had aPL positivity, defined as positivity on any of the assays, at the time of first measurement. During a mean follow-up of 6.6 years (SD 4), overall aPL positivity was not associated with change in global cognition (estimate = -0.005, SE 0.011; p = 0.622) or parkinsonian signs (estimate = -0.003, SE 0.017; p = 0.860). aPL were not associated with serum CRP or MMPs (both p > 0.268). aPL were not associated with in vivo brain magnetic resonance imaging white matter hyperintensities or infarcts (both p > 0.376). Among those autopsied, aPL were not associated with pathologically confirmed brain infarcts, or cerebral atherosclerosis or arteriolosclerosis (all p≥ 0.447).

Conclusions: In older individuals followed longitudinally, aPL do not relate to cognitive or motor decline, inflammation, or cerebrovascular disease on in vivo neuroimaging or postmortem neuropathology.
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http://dx.doi.org/10.1159/000500157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698409PMC
June 2020

Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.

Brain 2019 06;142(6):1503-1527

University of California, San Diego, CA, USA.

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.
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http://dx.doi.org/10.1093/brain/awz099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536849PMC
June 2019

White matter correlates of scam susceptibility in community-dwelling older adults.

Brain Imaging Behav 2020 Oct;14(5):1521-1530

Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison Street, Suite 1000, Chicago, IL, 60612, USA.

Scam susceptibility places older adults - even those with intact cognition - at great risk. Lower grey matter volumes, particularly within right medial temporal regions, are associated with higher scam susceptibility; however, very little is known about white matter associates. We investigated associations between white matter integrity measured using diffusion tensor imaging (DTI) and scam susceptibility in 302 non-demented older adults (75% female; mean years: age = 81.3 + 7.5, education = 15.7 + 2.9). Participants completed comprehensive neuroimaging (including DTI, T1- and T2-weighted imaging), a self-report measure of scam susceptibility, and neuropsychological testing. Tract-Based Spatial Statistics (TBSS) investigated associations of DTI-derived measures of fractional anisotropy (FA), trace of the diffusion tensor, axial and radial diffusivity (separately) with scam susceptibility adjusting for age, sex, education, and white matter hyperintensities (WMH; total volume and voxelwise separately). Statistical significance was determined at p < 0.05, Family Wise Error corrected. TBSS revealed significant negative associations between FA in tracts connecting a number of right hemisphere white matter regions and scam susceptibility, particularly after additional adjustment for global cognitive functioning. The pathways implicated were mainly in right temporal-parietal and temporal-occipital regions. Association of trace, axial, and radial diffusivity with scam susceptibility were not significant in fully-adjusted models. Lower white matter integrity within right hemisphere tracts was associated with higher scam susceptibility independent of relevant confounds including global cognition. Thus, a right hemisphere brain network that includes key structures implicated in multi-sensory processing of immediate and future consequences may serve as a neurobiologic substrate of scam susceptibility in vulnerable older adults.
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http://dx.doi.org/10.1007/s11682-019-00079-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754317PMC
October 2020
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