Aß (Amyloid Beta) and Tau Tangle Pathology Modifies the Association Between Small Vessel Disease and Cortical Microinfarcts.

BACKGROUND AND PURPOSE: There is increasing recognition of the importance of cortical microinfarcts to overall brain health, cognition, and Alzheimer dementia. Cerebral small vessel pathologies are associated with microinfarcts and frequently coexist with Alzheimer disease; however, the extent to which Aß (amyloid beta) and tau pathology modulates microvascular pathogenesis is not fully understood. Study objective was to examine the relationship of small vessel pathologies, arteriolosclerosis, and cerebral amyloid angiopathy, with cortical microinfarcts in people with differing levels of Aß or tau tangle burden. METHODS: Participants were 1489 autopsied older people (mean age at death, 89 years; 67% women) from 1 of 3 ongoing clinical-pathological cohort studies of aging. Neuropathological evaluation identified cortical Aß and tau tangle burden using immunohistochemistry in 8 brain regions, provided semiquantitative grading of cerebral vessel pathologies, and identified the presence of cortical microinfarcts. Logistic regression models adjusted for demographics and atherosclerosis and examined whether Aß or tau tangle burden modified relations between small vessel pathologies and cortical microinfarcts. RESULTS: Cortical microinfarcts were present in 17% of older people, moderate-to-severe cerebral amyloid angiopathy pathology in 36%, and arteriolosclerosis in 34%. In logistic regression models, we found interactions with Aß and tau tangles, reflecting that the association between arteriolosclerosis and cortical microinfarcts was stronger in the context of greater Aß (estimate, 0.15; SE=0.07; P=0.02) and tau tangle burden (estimate, 0.13; SE=0.06; P=0.02). Interactions also emerged for cerebral amyloid angiopathy, suggesting that the association between cerebral amyloid angiopathy and cortical microinfarcts is more robust in the presence of higher Aß (estimate, 0.27; SE=0.07; P<0.001) and tangle burden (estimate, 0.16; SE=0.06; P=0.005). CONCLUSIONS: These findings suggest that in the presence of elevated Aß or tangle pathology, small vessel pathologies are associated with greater microvascular tissue injury, highlighting a potential link between neurodegenerative and vascular mechanisms.

Entorhinal Cortex: Antemortem Cortical Thickness and Postmortem Neurofibrillary Tangles and Amyloid Pathology.

BACKGROUND AND PURPOSE: The entorhinal cortex, a critical gateway between the neocortex and hippocampus, is one of the earliest regions affected by Alzheimer disease-associated neurofibrillary tangle pathology. Although our prior work has automatically delineated an MR imaging-based measure of the entorhinal cortex, whether antemortem entorhinal cortex thickness is associated with postmortem tangle burden within the entorhinal cortex is still unknown. Our objective was to evaluate the relationship between antemortem MRI measures of entorhinal cortex thickness and postmortem neuropathological measures. MATERIALS AND METHODS: We evaluated 50 participants from the Rush Memory and Aging Project with antemortem structural T1-weighted MR imaging and postmortem neuropathologic assessments. Here, we focused on thickness within the entorhinal cortex as anatomically defined by our previously developed MR imaging parcellation system (Desikan-Killiany Atlas in FreeSurfer). Using linear regression, we evaluated the association between entorhinal cortex thickness and tangles and amyloid-ß load within the entorhinal cortex and medial temporal and neocortical regions. RESULTS: We found a significant relationship between antemortem entorhinal cortex thickness and entorhinal cortex (P = .006) and medial temporal lobe tangles (P = .002); we found no relationship between entorhinal cortex thickness and entorhinal cortex (P = .09) and medial temporal lobe amyloid-ß (P = .09). We also found a significant association between entorhinal cortex thickness and cortical tangles (P = .003) and amyloid-ß (P = .01). We found no relationship between parahippocampal gyrus thickness and entorhinal cortex (P = .31) and medial temporal lobe tangles (P = .051). CONCLUSIONS: Our findings indicate that entorhinal cortex-associated in vivo cortical thinning may represent a marker of postmortem medial temporal and neocortical Alzheimer disease pathology.

Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodies.

Lewy bodies are common in the ageing brain and often co-occur with Alzheimer's disease pathology. There is little known regarding the independent role of Lewy body pathology in cognition impairment, decline and fluctuations in community-dwelling older persons. We examined the contribution of Lewy body pathology to dementia, global cognition, cognitive domains, cognitive decline and fluctuations in 872 autopsied subjects (mean age = 87.9 years) from the Rush Religious Order Study (n = 491) and Memory and Aging Project (n = 381) longitudinal community-based clinical-pathological studies. Dementia was based on a clinical evaluation; annual cognitive performance tests were used to create a measure of global cognition and five cognitive domains. Lewy body type was determined by using α-synuclein immunostained sections of substantia nigra, limbic and neocortical regions. Statistical models included multiple regression models for dementia and cognition and mixed effects models for decline. Cognitive fluctuations were estimated by comparing standard deviations of individual residuals from mean trajectories of decline in those with and without Lewy bodies. All models controlled for age, sex, education, Alzheimer's disease pathology and infarcts. One hundred and fifty-seven subjects (18%) exhibited Lewy body pathology (76 neocortical-type, 54 limbic-type and 27 nigra-predominant). One hundred and three (66%) subjects with Lewy body pathology had a pathologic diagnosis of Alzheimer's disease. Neocortical-type, but not nigral-predominant or limbic-type Lewy body pathology was related to an increased odds of dementia (odds ratio = 3.21; 95% confidence interval = 1.78-5.81) and lower cognition (P < 0.001) including episodic memory function (P < 0.001) proximate to death. Neocortical-type Lewy body pathology was also related to a faster decline in global cognition (P < 0.001), decline in all five specific cognitive domains (all P-values < 0.001), and to fluctuations in decline of working and semantic memory (P-values < 0.001). Limbic-type Lewy body pathology was related to lower and faster decline in visuospatial skills (P = 0.042). The relationship of Lewy body pathology to cognition and dementia was not modified by Alzheimer's disease pathology. Neocortical-type Lewy body pathology is associated with increased odds of dementia; lower and more rapid decline in all cognitive domains including episodic memory and fluctuations in decline in semantic and working memory. Limbic-type Lewy body pathology is specifically associated with lower and more rapid decline in visuospatial skills. The effect of Lewy body pathology on cognition appears to be independent of Alzheimer's disease pathology.

Cognitive reserve, presynaptic proteins and dementia in the elderly.

Differences in cognitive reserve may contribute to the wide range of likelihood of dementia in people with similar amounts of age-related neuropathology. The amounts and interactions of presynaptic proteins could be molecular components of cognitive reserve, contributing resistance to the expression of pathology as cognitive impairment. We carried out a prospective study with yearly assessments of N = 253 participants without dementia at study entry. Six distinct presynaptic proteins, and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25) and syntaxin, were measured in post-mortem brains. We assessed the contributions of Alzheimer's disease (AD) pathology, cerebral infarcts and presynaptic proteins to odds of dementia, level of cognitive function and cortical atrophy. Clinical dementia was present in N = 97 (38.3%), a pathologic diagnosis of AD in N = 142 (56.1%) and cerebral infarcts in N = 77 (30.4%). After accounting for AD pathology and infarcts, greater amounts of vesicle-associated membrane protein, complexins I and II and the SNAP-25/syntaxin interaction were associated with lower odds of dementia (odds ratio = 0.36-0.68, P < 0.001 to P = 0.03) and better cognitive function (P < 0.001 to P = 0.03). Greater cortical atrophy, a putative dementia biomarker, was not associated with AD pathology, but was associated with lower complexin-II (P = 0.01) and lower SNAP-25/syntaxin interaction (P < 0.001). In conclusion, greater amounts of specific presynaptic proteins and distinct protein-protein interactions may be structural or functional components of cognitive reserve that reduce the risk of dementia with aging.

Hemoglobin level in older persons and incident Alzheimer disease: prospective cohort analysis.

OBJECTIVE: To test the hypothesis that level of hemoglobin is associated with incident Alzheimer disease (AD). METHODS: A total of 881 community-dwelling older persons participating in the Rush Memory and Aging Project without dementia and a measure of hemoglobin level underwent annual cognitive assessments and clinical evaluations for AD. RESULTS: During an average of 3.3 years of follow-up, 113 persons developed AD. In a Cox proportional hazards model adjusted for age, sex, and education, there was a nonlinear relationship between baseline level of hemoglobin such that higher and lower levels of hemoglobin were associated with AD risk (hazard ratio [HR] for the quadratic of hemoglobin 1.06, 95% confidence interval [CI] 1.01-1.11). Findings were unchanged after controlling for multiple covariates. When compared to participants with clinically normal hemoglobin (n = 717), participants with anemia (n = 154) had a 60% increased hazard for developing AD (95% CI 1.02-2.52), as did participants with clinically high hemoglobin (n = 10, HR 3.39, 95% CI 1.25-9.20). Linear mixed-effects models showed that lower and higher hemoglobin levels were associated with a greater rate of global cognitive decline (parameter estimate for quadratic of hemoglobin = -0.008, SE -0.002, p < 0.001). Compared to participants with clinically normal hemoglobin, participants with anemia had a -0.061 z score unit annual decline in global cognitive function (SE 0.012, p < 0.001), as did participants with clinically high hemoglobin (-0.090 unit/year, SE 0.038, p = 0.018). CONCLUSIONS: In older persons without dementia, both lower and higher hemoglobin levels are associated with an increased hazard for developing AD and more rapid cognitive decline.

Neurodegenerative basis of age-related cognitive decline.

OBJECTIVE: To assess the contribution of dementia-related neuropathologic lesions to age-related and disease-related change in cognitive function. METHODS: A total of 354 Catholic nuns, priests, and brothers had annual clinical evaluations for up to 13 years, died, and underwent brain autopsy. The clinical evaluations included detailed testing of cognitive function from which previously established composite measures of global cognition and specific cognitive functions were derived. As part of a uniform neuropathologic evaluation, the density of neurofibrillary tangles was summarized in a composite measure and the presence of Lewy bodies and gross and microscopic cerebral infarction was noted. RESULTS: During follow-up, rate of global cognitive decline was gradual at first and then more than quadrupled in the last 4 to 5 years of life consistent with the onset of progressive dementia. Neurofibrillary tangles, cerebral infarction, and neocortical Lewy bodies all contributed to gradual age-related cognitive decline and little age-related decline was evident in the absence of these lesions. Neurofibrillary tangles and neocortical Lewy bodies contributed to precipitous disease-related cognitive decline, but substantial disease-related decline was evident even in the absence of these lesions. CONCLUSION: Mild age-related decline in cognitive function is mainly due to the neuropathologic lesions traditionally associated with dementia.

Kidney function is associated with the rate of cognitive decline in the elderly.

OBJECTIVE: We tested the hypothesis that impaired kidney function in the elderly is associated with a more rapid rate of cognitive decline. METHODS: Baseline serum was used to calculate estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease formula, for 886 elderly without dementia participating in the Rush Memory and Aging Project, a prospective, observational cohort study. Kidney function was also dichotomized into impairment or no impairment based on eGFR < or >or=60 mL/min/1.73 m(2). Structured cognitive testing was performed at baseline and at annual evaluations, using a battery of 19 cognitive tests summarized into global cognition and 5 cognitive domains. RESULTS: In mixed-effects models adjusted for age, sex, and education, a lower eGFR at baseline was associated with a more rapid rate of cognitive decline (estimate 0.0008, SE <0.001, p = 0.017). The increased rate of cognitive decline associated with a 15-mL/min/1.73 m(2) lower eGFR at baseline (approximately 1 SD) was similar to the effect of being 3 years older at baseline. Impaired kidney function at baseline was associated with a more rapid rate of cognitive decline (estimate -0.028, SE <0.009, p = 0.003). The increased rate of cognitive decline associated with impaired kidney function at baseline was approximately 75% the effect of ApoE4 allele on the rate of cognitive decline. Baseline kidney function was associated with declines in semantic memory, episodic memory, and working memory but not visuospatial abilities or perceptual speed. CONCLUSION: Impaired kidney function is associated with a more rapid rate of cognitive decline in old age.

Effect of donepezil on motor and cognitive function in Huntington disease.

Striatal cholinergic dysfunction may be important in Huntington disease (HD). We studied whether donepezil improves chorea, cognition, and quality of life (QoL) in HD. Thirty patients were randomly assigned to treatment with donepezil or placebo. At the doses studied, donepezil did not improve chorea, cognition, or QoL. Adverse events were similar between both groups. Based on this small sample study, donepezil was not an effective treatment for HD.

Focal neurological deficits and West Nile virus infection.

Our experience with West Nile virus infection revealed that 54% of 28 patients had a focal neurological deficit at presentation. A meningitis or encephalitis syndrome was absent in 47% of patients with focal deficits. Details of the variety of deficits, the time to development of deficits, and the associated radiological and laboratory findings are also discussed in the present report.

Biomechanical risk factors for occupationally related low back disorders.

A continuing challenge for ergonomists has been to determine quantitatively the types of trunk motion and how much trunk motion contributes to the risk of occupationally-related low back disorder (LBD). It has been difficult to include this motion information in workplace assessments since the speed at which trunk motion becomes dangerous has not been determined. An in vivo study was performed to assess the contribution of three-dimensional dynamic trunk motions to the risk of LBD during occupational lifting in industry. Over 400 industrial lifting jobs were studied in 48 varied industries. The medical records in these industries were examined so that specific jobs historically categorized as either low, medium, or high risk for occupationally-related LBD could be identified. A tri-axial electrogoniometer was worn by workers and documented the three-dimensional angular position, velocity, and acceleration characteristics of the lumbar spine while workers worked at these low, medium, or high risk jobs. Workplace and individual characteristics were also documented for each of the repetitive lifting tasks. A multiple logistic regression model indicated that a combination of five trunk motion and workplace factors predicted well both medium risk and high risk occupational-related LBD. These factors included lifting frequency, load moment, trunk lateral velocity, trunk twisting velocity, and trunk sagittal angle. Increases in the magnitude of these factors significantly increased the risk of LBD. The analyses have enabled us to determine the LBD risk associated with combined changes in the magnitudes of the five factors. The results indicate that by suitably varying these five factors observed during the lift collectively, the odds of high risk group membership may decrease by over ten times. These results were related to the biomechanical, ergonomic, and epidemiologic literature. The five trunk motion and workplace factors could be used as quantitative, objective measures to redesign the workplace so that the risk of occupationally-related LBD is minimized.

Industrial wrist motions and incidence of hand/wrist cumulative trauma disorders.

One of the major research voids in the study of occupational hand/wrist cumulative trauma disorders (CTDs) is the lack of quantification of the relationship between the known kinematic risk factors, such as wrist angle and repetition, and CTD risk. A previously published article in this journal (Marras and Schoenmarklin 1993) reported the descriptive results from a quantitative surveillance study performed in industry in which worker's wrist motions were monitored on the factory floor. The wrist motion components that were monitored on each subject were position, velocity, and acceleration measures in each plane of movement (radial/ulnar, flexion/extension, and pronation/supination). The objective of this article was to form a metric that associates the degree of incidence of hand/wrist CTDs with those types of wrist motions that were significant in the earlier paper. Of all the kinematic parameters measured, multivariate analysis of the motion data revealed that acceleration in the flexion/extension plane discriminated the best between groups of low and high incidence rates of CTDs. The epidemiological association between flexion/extension acceleration and CTD incidence rate is compatible with results from empirical studies and theoretical models in the physiologic and biomechanical literature. The flexion/extension acceleration values from this study can serve as preliminary motion benchmarks that establish relative risk levels of CTDs for hand-intensive, highly repetitive jobs that do not require hand tools. Industrial practitioners can use this methodology, along with other accepted tools, to enhance ergonomic assessments of jobs.

The role of dynamic three-dimensional trunk motion in occupationally-related low back disorders. The effects of workplace factors, trunk position, and trunk motion characteristics on risk of injury.

Current ergonomic techniques for controlling the risk of occupationally-related low back disorder consist of static assessments of spinal loading during lifting activities. This may be problematic because several biomechanical models and epidemiologic studies suggest that the dynamic characteristics of a lift increase spine loading and the risk of occupational low back disorder. It has been difficult to include this motion information in workplace assessments because the speed at which trunk motion becomes dangerous has not been determined. An in vivo study was performed to assess the contribution of three-dimensional dynamic trunk motions to the risk of low back disorder during occupational lifting in industry. More than 400 repetitive industrial lifting jobs were studied in 48 varied industries. Existing medical and injury records in these industries were examined so that specific jobs historically categorized as either high-risk or low-risk for reported occupationally-related low back disorder could be identified. A triaxial electrogoniometer was worn by workers and documented the three-dimensional angular position, velocity, and acceleration characteristics of the lumbar spine while workers lifted in these high-risk or low-risk jobs. Workplace and individual characteristics were also documented for each of the repetitive lifting tasks. A multiple logistic regression model was developed, based on biomechanical plausibility, and indicated that a combination of five trunk motion and workplace factors distinguished between high and low risk of occupationally-related low back disorder risk well (odds ratio: 10.7). These factors included 1) lifting frequency, 2) load moment, 3) trunk lateral velocity, 4) trunk twisting velocity, and 5) the trunk sagittal angle. This analysis implies that by suitably varying these five factors observed during the lift collectively, the odds of high-risk group membership may decrease by almost 11 times. The predictive power of this model was found to be more than three times greater than that of current lifting guidelines. This study, though not proving causality, indicates an association between the biomechanical factors and low back disorder risk. This model could be used as a quantitative, objective measure to design the workplace so that the risk of occupationally-related low back disorder is minimized.