Sue Leurgans’s research while affiliated with Rush University Medical Center and other places

BACKGROUND The pathological basis underlying motor impairment in older adults is partially accounted for by Alzheimer disease and related dementias pathologies. We tested the hypothesis that arteriolosclerosis, a pathological correlate of small vessel disease, outside the cerebrum is related to motor impairment in older adults above and beyond Alzheimer disease and related dementias pathologies. METHODS The data were from decedents of a community-based clinical-autopsy study. Arteriolosclerosis was assessed in the cerebrum (as 1 of 10 Alzheimer disease and related dementias pathologies), midbrain, cerebellum, pons, and 4 levels of the spinal cord. Parkinsonism was assessed using the Unified Parkinson Disease Rating Scale. Other motor performances included timed-peg placement and finger tapping, grip and pinch strength, walking 8 ft and turning 360° twice, and sensor-derived metrics assessing tandem walk. Multivariate linear regression models were used to examine the association of arteriolosclerosis across varied motor performances. RESULTS The participants (n=403) were on average 91.4 (6.1) years old at death, and 73.2% (n=295) were women. The frequency of moderate/severe arteriolosclerosis varied outside the cerebrum, ranging from 15.5% (40/258) in the pons to 49.6% (200/403) in the spinal cord. The correlation of the severity of arteriolosclerosis between these regions ranged from unrelated to modestly related. Spinal arteriolosclerosis was associated with impaired motor function ( P =0.006), in particular more severe parkinsonism (estimate, 0.170; SE, 0.071; P =0.018) and less hand dexterity (estimate, −0.022; SE, 0.009; P =0.014). Arteriolosclerosis of the cerebellum was associated with impaired tandem walk ( P =0.012), in particular more variability in the acceleration signal in the mediolateral direction (estimate, 0.023; SE, 0.011; P =0.040). Arteriolosclerosis in the pons or midbrain was not associated with motor performances. CONCLUSIONS Arteriolosclerosis severity varies in the central nervous system tissues outside of the cerebrum and is differentially associated with varied motor performances, suggesting that the adverse motor consequences of small vessel disease in older adults may be underestimated by studies focusing only on the brain.

BACKGROUND Few neuropathologic studies focus on the associations of cerebrovascular pathologies with cognition in older Black adults. METHODS We conducted a nested substudy of participants who were enrolled in 1 of 4 harmonized longitudinal cohort studies—the Minority Aging Research Study, African American Clinical Core, Rush Memory and Aging Project, and Religious Order Study before coming to autopsy. Neuropathologic evaluation included assessment of cerebrovascular and neurodegenerative pathologies. We first documented single and mixed cerebrovascular profiles and neurodegenerative pathologies in 112 Black decedents and examined the pathological burden with cognitive function proximate to death. In secondary analyses, we matched 2:1 the 112 Black decedents to 214 White decedents from the same cohorts using Mahalanobis distance matching and conducted linear regression models to examine racial differences in the burden of each vascular pathology and their associations with cognition. RESULTS In older Black decedents, macroscopic infarcts were present in 37%, microinfarcts in 30%, basal ganglia arteriolosclerosis in 20%, cerebral amyloid angiopathy in 32%, and atherosclerosis in 14%. Single cerebrovascular profiles were present in 29% and mixed cerebrovascular profiles in 40%. Microinfarcts (estimate=−0.51, SE=0.23, P =0.03) and arteriolosclerosis in the basal ganglia (estimate =−0.29, SE=0.13, P =0.03) were associated with lower global cognition independent of neurodegenerative pathologies. Further, microinfarcts were associated with lower episodic and semantic memory, and perceptual speed, whereas arteriolosclerosis was associated with only semantic memory. Mixed vascular profiles were also associated with lower episodic memory and perceptual speed. In secondary analyses, the burden of cerebrovascular pathologies and cognitive associations were similar across races. CONCLUSIONS Cerebrovascular pathologies are common in older Black decedents, most often as a mixed cerebrovascular pathology profile. Arteriosclerosis and microinfarcts were associated with lower cognition above and beyond the presence of neurodegenerative pathologies. Burden and cognitive associations with cerebrovascular pathologies were similar across races.

Objective Cerebral amyloid angiopathy (CAA) involves β‐amyloid deposition in the walls of cortical and leptomeningeal small vessels. Transverse relaxation rate (R2) is a major source of contrast in MRI. This study tested the hypothesis that CAA is associated with R2, extracted the spatial pattern of CAA‐related R2 abnormalities, and evaluated R2 at different CAA severity levels in a large number of community‐based older adults. Methods Cerebral hemispheres from 804 older adults who came to autopsy were included. All hemispheres underwent ex vivo MRI and detailed neuropathologic examination. R2 maps were generated from ex vivo MRI data. Voxel‐wise and region‐based regression analyses were conducted to investigate the association of R2 with CAA, controlling for other neuropathologies and demographics. R2 values at different CAA severity levels were also investigated. Results CAA severity was associated with a higher transverse relaxation rate R2 in cortical and juxtacortical frontal and medial temporal lobe regions, and in deep brain structures, independently of other neuropathologies and demographics. R2 abnormalities were significant in severe CAA, but were limited in terms of spatial extent and magnitude in moderate CAA, and were not detectable in mild CAA. Interpretation This is to our knowledge the first investigation of the link between CAA and R2, one of the major contrast mechanisms in MRI. R2 is sensitive to CAA‐related brain abnormalities, primarily in moderate and severe stages of the disease. In vivo detection of CAA is an important challenge, and the present work contributes new knowledge that may aid toward this goal.

Alzheimer’s disease (AD) is a common, devastating disease which carries a heavy economic burden. Accelerated efforts to identify presymptomatic stages of AD and biomarkers to classify the disease are urgent needs. Currently, no biomarkers can perfectly discriminate individuals into multiple disease categories of AD (no cognitive impairment, mild cognitive impairment, and dementia). Although many biomarkers for diagnosis and their various features are being studied, we lack advanced statistical methods which can fully utilize biomarkers to classify AD accurately, thereby facilitating evaluation of putative markers both alone and in combination. In this paper, we propose two approaches: 1) a forward addition procedure in which we adapt an additive logistic regression model to the setting for disease with ordered multiple categories. Using this approach, we select and combine multiple cross-sectional biomarkers to improve diagnostic accuracy, and 2) a method by extending the Neyman-Pearson Lemma to the ordered three disease categories to construct optimal cutoff points to distinguish multiple disease categories. We evaluate the robustness of the proposed model using a simulation study. Then we apply these two methods to data from the Religious Orders Study to examine the feasibility of combining biomarkers, and compare the diagnostic accuracy between the proposed methods and existing methods including model-based methods (ordinal logistic regression and quadratic discriminant analysis), a tree-based method CART, and the Youden index method. The two proposed methods facilitate evaluations of biomarkers for conditions with graded, rather than binary, classifications. The evaluation of the performance of different approaches provides guidance of how to choose approaches to address research questions.

Background Assessments of Alzheimer’s disease pathology do not routinely include lower brainstem, olfactory bulb, and spinal cord. Objective Test if amyloid-β (Aβ) and paired helical filament (PHF) tau-tangles outside the cerebrum are associated with the odds of dementia. Methods Autopsies were obtained in decedents with cognitive testing (n = 300). Aβ plaques and PHF tau-tangles were assessed in 24 sites: cerebrum (n = 14), brainstem (n = 5), olfactory bulb, and four spinal cord levels. Since spinal Aβ were absent in the first 165 cases, it was not assessed in the remaining cases. Results Age at death was 91 years old. About 90% had Aβ in cerebrum and of these, half had Aβ in the brainstem. Of the latter, 85% showed Aβ in the olfactory bulb. All but one participant had tau-tangles in the cerebrum and 86% had brainstem tau-tangles. Of the latter, 80% had tau-tangles in olfactory bulb and 36% tau-tangles in one or more spinal cord levels. About 90% of adults with tau-tangles also had Aβ in one or more regions. In a logistic model controlling for demographics, Aβ and tau-tangles within the cerebrum, the presence of Aβ in olfactory bulb [OR, 1.74(1.00, 3.05)]; tau-tangles in brainstem [OR, 4.00(1.1.57,10.21)]; and spinal cord [OR, 1.87 (1.21,3.11)] were independently associated with higher odds of dementia. Conclusion Regional differences in Aβ and tau-tangle accumulation extend beyond cerebrum to spinal cord and their presence outside the cerebrum are associated with a higher odds of dementia. Further studies are needed to clarify the extent, burden, and consequences of AD pathology outside of cerebrum.

INTRODUCTION This study investigates the inter‐related roles of hippocampal neuronal loss (HNL), limbic‐predominant age‐related TAR‐DNA binding protein of 43 kDa (TDP‐43) encephalopathy neuropathologic changes (LATE‐NC), and Alzheimer's disease neuropathologic changes (ADNC) on cognitive decline. METHODS Participants underwent annual cognitive testing and autopsy. HNL, ADNC, LATE‐NC, and other age‐related pathologies were evaluated. Regression and mixed‐effects models examined the association of HNL with ADNC and LATE‐NC, and separately with cognitive decline. Path analyses examined the extent to which associations of LATE‐NC and ADNC with cognitive decline were attributable to HNL. RESULTS LATE‐NC was associated with more severe HNL, but ADNC was associated only after excluding subjects with hippocampal sclerosis (HS). HNL was associated with faster decline in global cognition and episodic, semantic, and working memory. In path analyses, about 61% of the association of LATE‐NC with cognitive decline was attributable to HNL, whereas for ADNC it was mostly independent of HNL. DISCUSSION HNL has an independent contribution to cognitive decline and acts as a major step in LATE‐NC‐related cognitive decline. Highlights Hippocampal neuronal loss (HNL) is associated with cognitive decline. HNL is a prominent feature of limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic changes (LATE‐NC) and less so with Alzheimer's disease neuropathologic changes (ADNC). HNL acts as a major pathway in cognitive decline for LATE‐NC. Differential mechanisms in hippocampal degeneration are associated with LATE‐NC versus ADNC.

Peak width of skeletonized mean diffusivity (PSMD) is an emerging automated diffusion imaging marker showing clinically relevant changes in cerebral small vessel disease (cSVD), a leading cause of stroke and dementia with no mechanism-based treatment. We conducted a genome-wide association study of PSMD in 58,403 participants from 24 population-based cohorts (89% European, 10% East-Asian, 1% African-American), identifying 31 independent common variant associations. Additionally, a whole-exome sequencing analysis in 32,957 participants yielded associations of PSMD with single and burden of rare coding variants in four novel genes. Mendelian randomization supported causal association of higher blood pressure with larger PSMD values, and of larger PSMD with an increased risk of stroke, especially intracerebral hemorrhage. Strikingly, genetic susceptibility to white matter hyperintensities, an established MRI-marker of cSVD, was associated with higher PSMD from early childhood to older age, with prominent lifespan effects for VCAN and SMG6 . Leveraging unique brain single-cell sequencing resources we showed temporal changes in the cell-type specificity of these genes in the developing brain and overall enrichment of PSMD risk loci in genes expressed in fetal brain endothelial cells. Finally, through extensive integration with multi-omics resources, we provide precious leads for gene prioritization to accelerate drug discovery for cSVD.

Background The ARTS biomarker is a fully automated software container that predicts the presence of arteriolosclerosis based on in‐vivo MRI data and demographic features. The present study describes findings from the instrumental and clinical validation of ARTS conducted by the MarkVCID consortium. Method Instrumental validation of ARTS involved assessment of inter‐rater reliability, test‐retest repeatability, and inter‐scanner reproducibility. Inter‐rater reliability was assessed by means of the intraclass correlation (ICC) between ARTS scores generated from all MarkVCID sites using data on 20 older adults. Test‐retest repeatability was assessed by means of the ICC between test and retest ARTS scores from 41 older adults imaged twice. Inter‐scanner reproducibility was assessed by means of the ICC between ARTS scores on 20 older adults imaged on 4 different scanners. Clinical validation of ARTS included two groups of non‐demented older adults: N = 156 participating in community cohort studies at Rush Alzheimer’s Disease Center; and N = 906 participating in the Atherosclerosis Risk in Communities (ARIC) study. The primary prespecified hypothesis was that change in Trails B score (or perceptual speed score for Rush data) two years after baseline MRI is associated with baseline ARTS score, controlling for years of education. The secondary prespecified hypothesis was that baseline Trails B (or perceptual speed) is associated with baseline ARTS score, controlling for years of education. Results ARTS exhibited excellent inter‐rater reliability (ICC = 0.9999, p<10‐200, CI:[0.99987, 0.99997]), test‐retest repeatability (ICC = 0.996, p<10‐42, CI:[0.993, 0.998]), and inter‐scanner reproducibility (ICC = 0.955, p = 0.00018, CI:[0.622,0.989]). In Rush data, a higher baseline ARTS score was associated with a faster two‐year decline in perceptual speed (beta = ‐0.32, p = 0.04, CI:[‐0.63, ‐0.01]) (Fig.1A) and a lower baseline level of perceptual speed (beta = ‐1.04, p<10‐4, CI:[‐1.48, ‐0.60]) (Fig.1B). In ARIC data, a higher baseline ARTS score was associated with a faster annual increase in Trails B (beta = 3.7, SE = 1.7, p = 0.03) (Fig.2A), and a higher baseline Trails B (beta = 45.5, SE = 5.8, p<10‐4) (Fig.2B). Conclusion ARTS exhibited outstanding technical performance and baseline ARTS score was associated with subsequent decline in cognitive abilities known to be affected by small vessel disease. The above evidence supports ARTS as a marker of the risk of vascular contributions to cognitive impairment and dementia (VCID).