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1.
AIDS Behav ; 2024 May 04.
Article En | MEDLINE | ID: mdl-38703338

Black cisgender sexually minoritized men (SMM) and transgender women (TW) are subgroups at highest risk of HIV and sexually transmitted infections (STIs) in the US. We sought to identify factors facilitating continued conversations - social reinforcement - surrounding HIV/STI prevention among this subgroup. Participants were recruited in Chicago from 2018 to 2019 from community health spaces. Participants provided information about themselves (level 2) and ⩽5 confidants (level 1). We used multinomial multilevel modeling to identify associations with HIV/STI prevention conversation frequency. A total of 370 participants provided information on 987 confidants (mean = 2.6). We found significantly positive associations between having biweekly or more often HIV/STI prevention conversations and a confidant being a kin family member, older by 15 years or more, racially homophilous, and emotionally close. Future interventions should harness social networks by including components that consider racial homophily, respect for elders, and strong ties, in addition to applying kin family systems interventions approaches and decreasing stigma surrounding HIV/STIs.

2.
Acta Neuropathol ; 143(3): 349-362, 2022 03.
Article En | MEDLINE | ID: mdl-35044500

Emerging evidence suggests that small vessel disease (SVD) is a risk factor for clinical dementia and may contribute to AD neuropathological changes. Watershed brain regions are located at the most distal areas between arterial territories, making them vulnerable to SVD-related changes. We examined the association of pathologic markers of SVD, specifically arteriolosclerosis in watershed brain regions, with AD pathologic changes. Participants (N = 982; mean age-at-death = 90; 69% women) were enrolled as part of one of two cohort studies of aging and dementia. At autopsy, neuropathological evaluation included semi-quantitative grading of arteriolosclerosis pathology from 2 cortical watershed regions: the anterior watershed (AWS) and posterior watershed (PWS), densities for cortical ß-amyloid and tau-tangle pathology, and other common age-related pathologies. Linear regression models examined the association of watershed arteriolosclerosis pathology with ß-amyloid and tau-tangle burden. In follow-up analyses, available ex-vivo MRI and proteomics data in a subset of decedents were leveraged to examine the association of whole brain measure of WMH, as a presumed MRI marker of SVD, with ß-amyloid and tau-tangle burden, as well as to examine the association of watershed arteriolosclerosis with proteomic tau. Watershed arteriolosclerosis was common, with 45% of older persons having moderate-to-severe arteriolosclerosis pathology in the AWS region, and 35% in the PWS. In fully adjusted models that controlled for demographics and common age-related pathologies, an increase in severity of PWS arteriolosclerosis was associated with a higher burden of tau-tangle burden, specifically neocortical tau burden, but not with ß-amyloid. AWS arteriolosclerosis was not associated with ß-amyloid or tau pathology. Ex-vivo WMH was associated with greater tau-tangle pathology burden but not ß-amyloid. Furthermore, PWS arteriolosclerosis was associated with higher abundance of tau phosphopeptides, that promote formation of tau aggregates. These data provide compelling evidence that SVD, specifically posterior watershed arteriolosclerosis pathology, is linked with tau pathological changes in the aging brain.


Alzheimer Disease , Proteomics , Aged , Aged, 80 and over , Aging/pathology , Alzheimer Disease/pathology , Amyloid beta-Peptides , Brain/pathology , Female , Humans , Male , tau Proteins/metabolism
3.
Stroke ; 52(3): 1012-1021, 2021 03.
Article En | MEDLINE | ID: mdl-33567873

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.


Amyloid beta-Protein Precursor/metabolism , Brain Infarction/metabolism , Vascular Diseases/metabolism , tau Proteins/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Arteriosclerosis/metabolism , Brain/physiopathology , Brain Infarction/physiopathology , Cerebral Amyloid Angiopathy , Female , Humans , Immunohistochemistry , Male , Regression Analysis , Vascular Diseases/physiopathology
5.
Neuropathol Appl Neurobiol ; 46(5): 458-477, 2020 08.
Article En | MEDLINE | ID: mdl-31970820

AIMS: Brain mural cells (BMC), smooth muscle cells and pericytes, interact closely with endothelial cells and modulate numerous cerebrovascular functions. A loss of BMC function is suspected to play a role in the pathophysiology of Alzheimer's Disease (AD). METHODS: BMC markers, namely smooth muscle alpha actin (α-SMA) for smooth muscle cells, as well as platelet-derived growth factor receptor ß (PDGFRß) and aminopeptidase N (ANPEP or CD13) for pericytes, were assessed by Western immunoblotting in microvessel extracts from the parietal cortex of 60 participants of the Religious Orders study, with ages at death ranging from 75 to 98 years old. RESULTS: Participants clinically diagnosed with AD had lower vascular levels of α-SMA, PDGFRß and CD13. These reductions were correlated with lower cognitive scores for global cognition, episodic and semantic memory, perceptual speed and visuospatial ability. In addition, α-SMA, PDGFRß and CD13 were negatively correlated with vascular Aß40 concentrations. Vascular levels of BMC markers were also inversely correlated with insoluble cleaved phosphorylated transactive response DNA binding protein 43 (TDP-43) (25 kDa) and positively correlated with soluble cleaved phosphorylated TDP-43 (35 kDa) in cortical homogenates, suggesting strong association between BMC loss and cleaved phosphorylated TDP-43 aggregation. CONCLUSIONS: The results of this study highlight a loss of BMC in AD. The associations between α-SMA, PDGFRß and CD13 vascular levels with cognitive scores, TDP-43 aggregation and cerebrovascular accumulation of Aß in the parietal cortex suggest that BMC loss contributes to both AD symptoms and pathology, further strengthening the link between cerebrovascular defects and dementia.


Alzheimer Disease/pathology , Cognitive Dysfunction/pathology , Myocytes, Smooth Muscle/pathology , Parietal Lobe/pathology , Pericytes/pathology , TDP-43 Proteinopathies/pathology , Aged, 80 and over , Alzheimer Disease/complications , Animals , Cognitive Dysfunction/etiology , Female , Humans , Male , Mice
6.
Mol Psychiatry ; 23(6): 1521-1529, 2018 06.
Article En | MEDLINE | ID: mdl-28322283

Tauopathies, including Alzheimer's disease (AD) and other neurodegenerative conditions, are defined by a pathological hallmark: neurofibrillary tangles (NFTs). NFT accumulation is thought to be closely linked to cognitive decline in AD. Here, we perform a genome-wide association study for NFT pathologic burden and report the association of the PTPRD locus (rs560380, P=3.8 × 10-8) in 909 prospective autopsies. The association is replicated in an independent data set of 369 autopsies. The association of PTPRD with NFT is not dependent on the accumulation of amyloid pathology. In contrast, we found that the ZCWPW1 AD susceptibility variant influences NFT accumulation and that this effect is mediated by an accumulation of amyloid ß plaques. We also performed complementary analyses to identify common pathways that influence multiple neuropathologies that coexist with NFT and found suggestive evidence that certain loci may influence multiple different neuropathological traits, including tau, amyloid ß plaques, vascular injury and Lewy bodies. Overall, these analyses offer an evaluation of genetic susceptibility to NFT, a common end point for multiple different pathologic processes.


Neurofibrillary Tangles/genetics , Neurofibrillary Tangles/pathology , Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism , Aged , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Brain/metabolism , Cognitive Dysfunction/metabolism , Female , Genome-Wide Association Study , Hippocampus/metabolism , Humans , Male , Middle Aged , Neurons/metabolism , Neuropathology/methods , Plaque, Amyloid/metabolism , Prospective Studies , Receptor-Like Protein Tyrosine Phosphatases, Class 2/physiology , Tauopathies/metabolism , tau Proteins/metabolism
7.
Soc Networks ; 51: 73-87, 2017 Oct.
Article En | MEDLINE | ID: mdl-29062165

Mass incarceration of young Black men has a significant impact on their network composition and stability that, in turn, may have major implications for health and well-being. A sub-group of young Black men with criminal justice involvement (CJI) identify as gay, bisexual or are non-identified men who have sex with men (hereafter MSM). This paper focuses on the potential effects of CJI on the composition of Black MSM social and sexual networks, their stability over time, and concomitant health and social outcomes. We use data from the UConnect study, a population-based cohort of young Black MSM 16-29 years of age (n=618) selected using respondent-driven sampling in Chicago from 2013-2016. Both confidant and sexual network name generators and interpreters were administered at 9-month intervals over three waves of data collection. Ego and dyadic-level data were collected on behaviors prevalent among MSM and including factors associated with network CJI, network stability, and health outcomes. Generalized Structural Equation Models (GSEM) were utilized to determine the relationship between CJI network composition, network stability and behaviors prevalent among young Black MSM and their networks. In the UConnect cohort, 46% had at least once been detained, arrested or spent time in jail or prison. In addition, 20% of participants reported incident CJI over the study period. Respondents with a history of CJI were significantly more likely to have CJI homophily in their confidant and sexual networks. Multivariate analyses demonstrate that the association between one's history of CJI, housing instability and drug use is partially explained by one's network CJI. In addition, a higher prevalence of network CJI is associated with increased turnover in the confidant network, and this network instability is also related to important health and social outcomes. This analysis describes the networks of criminal justice involved men among a representative sample of young Black MSM and demonstrates the relationship between CJI network homophily, network stability and their impact on several key health and social outcomes relevant to this population.

8.
Mol Psychiatry ; 22(2): 287-295, 2017 02.
Article En | MEDLINE | ID: mdl-27021820

The lack of strong association between brain beta-amyloid deposition and cognitive impairment has been a challenge for the Alzheimer's disease (AD) field. Although beta-amyloid is necessary for the pathologic diagnosis of AD, it is not sufficient to make the pathologic diagnosis or cause dementia. We sought to identify the genetic modifiers of the relation between cortical beta-amyloid burden (measured using [18F]Florbetapir-PET) and cognitive dysfunction (measured using ADAS-cog) by conducting a genome-wide interaction study on baseline data from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) phases GO/2 (n=678). Near genome-wide significant interaction effect was observed for rs73069071 within the IAPP (amylin) and SLCO1A2 genes (P=6.2 × 10-8). Congruent results were found using data from participants followed up from ADNI-1 (Pone-tailed=0.028, n=165). Meta-analysis across ADNI-GO/2 and ADNI-1 revealed a genome-wide significant interaction effect (P=1.1 × 10-8). Our results were further supported by similar interaction effects on temporal lobe cortical thickness (whole-brain voxelwise analysis: familywise error corrected P=0.013) and longitudinal changes in ADAS-cog score and left middle temporal thickness and amygdalar volume (Pone-tailed=0.026, 0.019 and 0.003, respectively). Using postmortem beta-amyloid immunohistochemistry data from 243 AD participants in the Religious Orders Study and Memory and Aging Project, we also observed similar rs73069071-by-beta-amyloid deposition interaction effect on global cognitive function (Pone-tailed=0.005). Our findings provide insight into the complexity of the relationship between beta-amyloid burden and AD-related cognitive impairment. Although functional studies are required to elucidate the role of rs73069071 in AD pathophysiology, our results support the recently growing evidence on the role of amylin in AD.


Alzheimer Disease/genetics , Amyloid beta-Peptides/physiology , Cognition Disorders/pathology , Aged , Amyloid beta-Peptides/metabolism , Brain/anatomy & histology , Brain/metabolism , Cognitive Dysfunction , Dementia/metabolism , Female , Genetic Association Studies/methods , Genome-Wide Association Study , Humans , Islet Amyloid Polypeptide/genetics , Islet Amyloid Polypeptide/metabolism , Male , Neuroimaging , Neuropsychological Tests , Organic Anion Transporters/genetics , Organic Anion Transporters/metabolism , Positron-Emission Tomography/methods , Temporal Lobe
9.
Biochim Biophys Acta ; 1862(5): 878-86, 2016 05.
Article En | MEDLINE | ID: mdl-26769363

There is growing evidence suggesting that vascular pathologies and dysfunction play a critical role in cognitive impairment, clinical Alzheimer's disease, and dementia. Vascular pathologies such as macroinfarcts, microinfarcts, microbleeds, small and large vessel cerebrovascular disease, and white matter disease are common especially in the brains of older persons where they contribute to cognitive impairment and lower the dementia threshold. Vascular dysfunction resulting in decreased cerebral blood flow, and abnormalities in the blood brain barrier may also contribute to the Alzheimer's disease (AD) pathophysiologic process and AD dementia. This review provides a clinical-pathological perspective on the role of vessel disease, vascular brain injury, alterations of the neurovascular unit, and mixed pathologies in the Alzheimer's disease pathophysiologic process and Alzheimer's dementia. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.


Alzheimer Disease/etiology , Cerebrovascular Disorders/complications , Cognitive Dysfunction/etiology , Dementia/etiology , Age Factors , Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Brain/blood supply , Brain/pathology , Brain/physiopathology , Cerebrovascular Disorders/pathology , Cerebrovascular Disorders/physiopathology , Cognitive Dysfunction/pathology , Cognitive Dysfunction/physiopathology , Dementia/pathology , Dementia/physiopathology , Humans , Risk Factors
10.
Obs Stud ; 1(2015): 56-73, 2015 Mar.
Article En | MEDLINE | ID: mdl-25984574

Longitudinal cognitive trajectories and other factors associated with mixed neuropathologies (such as Alzheimer's disease with co-occurring cerebrovascular disease) remain incompletely understood, despite being the rule and not the exception in older populations. The Statistical Modeling of Aging and Risk of Transition study (SMART) is a consortium of 11 different high-quality longitudinal studies of aging and cognition (N=11,541 participants) established for the purpose of characterizing risk and protective factors associated with subtypes of age-associated mixed neuropathologies (N=3,001 autopsies). While brain donation was not required for participation in all SMART cohorts, most achieved substantial autopsy rates (i.e., > 50%). Moreover, the studies comprising SMART have large numbers of participants who were followed from intact cognition and transitioned to cognitive impairment and dementia, as well as participants who remained cognitively intact until death. These data provide an exciting opportunity to apply sophisticated statistical methods, like Markov processes, that require large, well-characterized samples. Thus, SMART will serve as an important resource for the field of mixed dementia epidemiology and neuropathology.

11.
AIDS Care ; 26(10): 1275-82, 2014.
Article En | MEDLINE | ID: mdl-24766079

Rising rates of HIV infection among younger black men who have sex with men (YBMSM) in the USA have generated a public health emergency. Living with HIV requires deep and persistent social support often available only from close confidants. Enlisting endogenous support network members into the care of HIV-infected YBMSM may help shape sustainable supportive environments, leading to long-term improvements in mental and HIV-specific health outcomes. The present study examined trends in support network change over time after new HIV diagnoses among 14 YBMSM. Participants completed a social network survey that utilized sociograms to record support confidants (SCs) preceding HIV diagnosis and at one and nine months postdiagnosis. Reported SCs included family of origin, friends, sex partners, and other associates. Analysis revealed three distinct patterns of change: high gain, high turnover, and stable networks. These patterns offer valuable insights into the social support of YBMSM during the period following diagnosis. This research underscores a growing movement to embrace key support figures in the lives of YBMSM, who may be critical to promoting overall health and adherence to HIV-care.


Black or African American , HIV Infections/ethnology , Homosexuality, Male/ethnology , Social Support , Adult , Black People , HIV Infections/psychology , Homosexuality, Male/psychology , Humans , Male , United States , Young Adult
12.
Mol Psychiatry ; 19(10): 1125-32, 2014 Oct.
Article En | MEDLINE | ID: mdl-24166411

Prior to intervention trials in individuals genetically at-risk for late-onset Alzheimer's disease, critical first steps are identifying where (neuroanatomic effects), when (timepoint in the lifespan) and how (gene expression and neuropathology) Alzheimer's risk genes impact the brain. We hypothesized that variants in the sortilin-like receptor (SORL1) gene would affect multiple Alzheimer's phenotypes before the clinical onset of symptoms. Four independent samples were analyzed to determine effects of SORL1 genetic risk variants across the lifespan at multiple phenotypic levels: (1) microstructural integrity of white matter using diffusion tensor imaging in two healthy control samples (n=118, age 18-86; n=68, age 8-40); (2) gene expression using the Braincloud postmortem healthy control sample (n=269, age 0-92) and (3) Alzheimer's neuropathology (amyloid plaques and tau tangles) using a postmortem sample of healthy, mild cognitive impairment (MCI) and Alzheimer's individuals (n=710, age 66-108). SORL1 risk variants predicted lower white matter fractional anisotropy in an age-independent manner in fronto-temporal white matter tracts in both samples at 5% family-wise error-corrected thresholds. SORL1 risk variants also predicted decreased SORL1 mRNA expression, most prominently during childhood and adolescence, and significantly predicted increases in amyloid pathology in postmortem brain. Importantly, the effects of SORL1 variation on both white matter microstructure and gene expression were observed during neurodevelopmental phases of the human lifespan. Further, the neuropathological mechanism of risk appears to primarily involve amyloidogenic pathways. Interventions targeted toward the SORL1 amyloid risk pathway may be of greatest value during early phases of the lifespan.


Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Brain/metabolism , Genetic Predisposition to Disease , LDL-Receptor Related Proteins/genetics , LDL-Receptor Related Proteins/metabolism , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Aging/genetics , Aging/metabolism , Alzheimer Disease/pathology , Brain/growth & development , Brain/pathology , Child , Child, Preschool , Diffusion Tensor Imaging , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Polymorphism, Single Nucleotide , RNA, Messenger/metabolism , Young Adult
13.
Dalton Trans ; 43(6): 2676-83, 2014 Feb 14.
Article En | MEDLINE | ID: mdl-24336738

Platinum tetrakis(2,4,6-triethylphenyl)porphyrin (Pt-1) was synthesized and its structural (X-ray), electrochemical and photophysical properties were fully characterized. Comparative studies of Pt-1 and its unsubstituted analog PtTPP show the effect of sterically congesting ortho-substituents on the dynamics of the triplet excited states. Lowered quenching rates by 3-4 times were observed for Pt-1vs. PtTPP in the presence of oxygen and perylene, and in concentration (self)-quenching experiments.


Metalloporphyrins/chemistry , Platinum/chemistry , Porphyrins/chemistry , Absorption , Electrochemistry , Models, Molecular , Molecular Conformation , Oxygen/chemistry , Perylene/chemistry , Photochemical Processes
14.
Brain ; 135(Pt 10): 3005-14, 2012 Oct.
Article En | MEDLINE | ID: mdl-23065790

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.


Alzheimer Disease/pathology , Cognition Disorders/diagnosis , Cognition Disorders/pathology , Lewy Bodies/pathology , Aged , Aged, 80 and over , Alzheimer Disease/epidemiology , Comorbidity , Female , Humans , Lewy Body Disease/epidemiology , Lewy Body Disease/pathology , Longitudinal Studies , Male , Neuropsychological Tests
15.
Transl Psychiatry ; 2: e114, 2012 May 15.
Article En | MEDLINE | ID: mdl-22832958

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.


Alzheimer Disease/diagnosis , Alzheimer Disease/physiopathology , Brain/physiopathology , Cognitive Reserve/physiology , Membrane Proteins/physiology , Nerve Tissue Proteins/physiology , Qa-SNARE Proteins/physiology , Synapses/physiology , Synaptosomal-Associated Protein 25/physiology , Adaptor Proteins, Vesicular Transport/physiology , Aged , Aged, 80 and over , Alzheimer Disease/pathology , Atrophy , Brain/pathology , Cerebral Cortex/pathology , Cerebral Cortex/physiopathology , Cerebral Infarction/pathology , Cerebral Infarction/physiopathology , Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/pathology , Cognitive Dysfunction/physiopathology , Female , Humans , Longitudinal Studies , Male , Protein Interaction Domains and Motifs/physiology , R-SNARE Proteins/physiology , Reference Values , Risk Assessment
16.
Neurology ; 78(5): 334-41, 2012 Jan 31.
Article En | MEDLINE | ID: mdl-22262751

OBJECTIVE: Accumulated evidence suggests that a variant within the CR1 gene (single nucleotide polymorphism rs6656401), known to increase risk for Alzheimer disease (AD), influences ß-amyloid (Aß) deposition in brain tissue. Given the biologic overlap between AD and cerebral amyloid angiopathy (CAA), a leading cause of intracerebral hemorrhage (ICH) in elderly individuals, we investigated whether rs6656401 increases the risk of CAA-related ICH and influences vascular Aß deposition. METHODS: We performed a case-control genetic association study of 89 individuals with CAA-related ICH and 280 individuals with ICH unrelated to CAA and compared them with 324 ICH-free control subjects. We also investigated the effect of rs6656401 on risk of recurrent CAA-ICH in a prospective longitudinal cohort of ICH survivors. Finally, association with severity of histopathologic CAA was investigated in 544 autopsy specimens from 2 longitudinal studies of aging. RESULTS: rs6656401 was associated with CAA-ICH (odds ratio [OR] = 1.61, 95% confidence interval [CI] 1.19-2.17, p = 8.0 × 10(-4)) as well as with risk of recurrent CAA-ICH (hazard ratio = 1.35, 95% CI 1.04-1.76, p = 0.024). Genotype at rs6656401 was also associated with severity of CAA pathology at autopsy (OR = 1.34, 95% CI 1.05-1.71, p = 0.009). Adjustment for parenchymal amyloid burden did not cancel this effect, suggesting that, despite the correlation between parenchymal and vascular amyloid pathology, CR1 acts independently on both processes, thus increasing risk of both AD and CAA. CONCLUSION: The CR1 variant rs6656401 influences risk and recurrence of CAA-ICH, as well as the severity of vascular amyloid deposition.


Cerebral Amyloid Angiopathy/epidemiology , Cerebral Amyloid Angiopathy/genetics , Receptors, Complement 3b/genetics , Age Factors , Aged , Aged, 80 and over , Alzheimer Disease/epidemiology , Alzheimer Disease/genetics , Apolipoproteins E/genetics , Autopsy , Confidence Intervals , Data Interpretation, Statistical , Female , Follow-Up Studies , Genetic Variation , Genome-Wide Association Study , Genotype , Humans , Kaplan-Meier Estimate , Longitudinal Studies , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk , Sex Factors
17.
Neuroscience ; 188: 142-7, 2011 Aug 11.
Article En | MEDLINE | ID: mdl-21596102

Plasticity in the spinal dorsal horn is thought to underlie the development of neuropathic pain. Calcineurin (protein phosphatase 3) plays an important role in plasticity in the brain. Here we examined whether chronic constriction injury (CCI) of the sciatic nerve modifies calcineurin expression in the spinal dorsal horn. Male rats were assigned to control (uninjured), sham-operated or CCI groups. CCI animals exhibited both a shift in weight bearing and a reduction in paw withdrawal latencies as signs of pain behavior. At 3 days (3D) the pain behavior was associated with a significant increase in calcineurin gene expression, enzyme activity and content of its Aα isoform in the ipsilateral spinal dorsal horn. In contrast, while the pain behavior persisted at 7 days (7D) calcineurin gene expression returned to control levels and activity and protein content decreased. A single intrathecal injection of MK-801 15 min before the ligation attenuated both signs of pain behavior in 3D but not 7D CCI animals. The same pre-treatment also prevented the CCI-associated increases in calcineurin in these animals. These data suggested an involvement of calcineurin in CCI-elicited neuropathic pain. The time-dependent divergent changes in calcineurin expression may underlie the different phases of neuropathic pain development.


Calcineurin/biosynthesis , Neuralgia/metabolism , Posterior Horn Cells/metabolism , Sciatic Nerve/injuries , Animals , Constriction , Dizocilpine Maleate/pharmacology , Gene Expression/drug effects , Immunoblotting , Male , Neuronal Plasticity/drug effects , Neuronal Plasticity/physiology , Neuroprotective Agents/pharmacology , Posterior Horn Cells/drug effects , RNA, Messenger/analysis , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Sciatic Nerve/metabolism
18.
Curr Alzheimer Res ; 8(4): 336-40, 2011 Jun.
Article En | MEDLINE | ID: mdl-21222592

It is increasingly recognized that the correlation between neuropathological lesions and cognition is modest and accounts for about a quarter of the variance of cognition among older adults. Some individuals maintain normal cognitive functioning amidst significant brain pathology, while others suffer varying degrees of cognitive and neurological deterioration that render them dependent and frail. We present data from the Religious Orders Study and the Memory and Aging Project pertaining to pathology and cognition, and propose a paradigm shift in consideration of the neurobiology of healthy aging and dementia. Factors that modify or mediate the association between neuropathology and cognition are also discussed. It is hypothesized that the concept of resilient aging can serve as a useful entity in understanding mechanisms that underlie healthy aging amidst disease-related pathology.


Aging/pathology , Brain/pathology , Cognition Disorders/pathology , Dementia/pathology , Memory Disorders/pathology , Aging/physiology , Aging/psychology , Cohort Studies , Dementia/physiopathology , Female , Humans , Male , Neuropsychological Tests
19.
Neurology ; 75(12): 1070-8, 2010 Sep 21.
Article En | MEDLINE | ID: mdl-20844243

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.


Aging/pathology , Brain/pathology , Cognition Disorders/pathology , Dementia/pathology , Nerve Degeneration/pathology , Age Factors , Brain/physiopathology , Cognition , Cognition Disorders/physiopathology , Dementia/physiopathology , Disease Progression , Female , Humans , Lewy Bodies/pathology , Longitudinal Studies , Male , Nerve Degeneration/physiopathology , Neurofibrillary Tangles/pathology , Neuropsychological Tests
20.
Int J STD AIDS ; 20(1): 39-45, 2009 Jan.
Article En | MEDLINE | ID: mdl-19103892

The relationships between hygiene, sexual behaviour and HIV infection are poorly understood. We examine these relationships in Indian truck drivers, a group at high risk for HIV infection. Truck drivers (n = 189) were recruited into an integrated HIV and hygiene Information Motivation (IM) programme. Sociodemographic characteristics, sexual and hygiene behaviour and HIV prevalence were determined. Multivariate logistic regression and linear generalized estimating equation models were utilized. At baseline, 2.1% of drivers were HIV infected and 34% who reported having contact with female sex workers (FSWs) had contact within the previous six months. Those who washed their hands postdefecation were less likely to report genital symptoms (OR 0.02; P = 0.01) and have sex with an FSW (OR [odds ratio] 0.21; P = 0.05). After an IM intervention, there were no changes in sexual risk-taking behaviour (coefficient -0.15 to -0.02; P = 0.13-0.75); however, hygiene behaviour improved from baseline (coefficient 0.09-0.31; P < 0.01 to P = 0.03). Personal hygiene habits, like handwashing, seem to be a modifiable behaviour after a modest intervention, whereas HIV risk-taking behaviour was not. The association between hygiene and HIV risk-taking suggests the need for further evaluation of the relationship and that of other hygiene practices in high-risk men in India.


HIV Infections/epidemiology , Hygiene , Risk-Taking , Sexual Behavior , Transportation , Adult , Female , HIV Infections/prevention & control , HIV-1 , Hand Disinfection/methods , Health Knowledge, Attitudes, Practice , Health Surveys , Humans , India , Interviews as Topic , Male , Prevalence , Workforce
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