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1.
Acta Neuropathol Commun ; 9(1): 71, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33858515

RESUMO

Insulin is an important hormone for brain function, and alterations in insulin metabolism may be associated with neuropathology. We examined associations of molecular markers of brain insulin signaling with cerebrovascular disease. Participants were enrolled in the Religious Orders Study (ROS), an ongoing epidemiologic community-based, clinical-pathologic study of aging from across the United States. Using cross-sectional analyses, we studied a subset of ROS: 150 persons with or without diabetes, matched 1:1 by sex on age-at-death and education. We used ELISA, immunohistochemistry, and ex vivo stimulation with insulin, to document insulin signaling in postmortem midfrontal gyrus cortex tissue. Postmortem neuropathologic data identified cerebrovascular disease including brain infarcts, classified by number (as none for the reference; one; and more than one), size (gross and microscopic infarcts), and brain region/location (cortical and subcortical). Cerebral vessel pathologies were assessed, including severity of atherosclerosis, arteriolosclerosis, and amyloid angiopathy. In separate regression analyses, greater AKT1 phosphorylation at T308 following ex vivo stimulation with insulin (OR = 1.916; estimate = 0.650; p = 0.007) and greater pS616IRS1 immunolabeling in neuronal cytoplasm (OR = 1.610; estimate = 0.476; p = 0.013), were each associated with a higher number of brain infarcts. Secondary analyses showed consistent results for gross infarcts and microinfarcts separately, but no other association including by infarct location (cortical or subcortical). AKT S473 phosphorylation following insulin stimulation was associated with less amyloid angiopathy severity, but not with other vessel pathology including atherosclerosis and arteriolosclerosis. In summary, insulin resistance in the human brain, even among persons without diabetes, is associated with cerebrovascular disease and especially infarcts. The underlying pathophysiologic mechanisms need further elucidation. Because brain infarcts are known to be associated with lower cognitive function and dementia, these data are relevant to better understanding the link between brain metabolism and brain function.

2.
Mol Neurodegener ; 16(1): 26, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863362

RESUMO

BACKGROUND: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known. METHODS: Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress. RESULTS: Greater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of patients with AD carrying APOE3/E4 compared to APOE3/E3. Greater cPLA2 phosphorylation was also observed in human postmortem frontal cortical synaptosomes and primary astrocytes after treatment with recombinant ApoE4 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition. CONCLUSIONS: Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

3.
Neurology ; 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33853892

RESUMO

OBJECTIVE: We tested the hypothesis that an inverse association exists between diabetes mellitus (DM) and hemoglobin A1C (A1C) with Transactive response DNA binding protein 43 (TDP-43) levels in older adults. METHODS: We leveraged antemortem and postmortem data of decedents from three community-based clinical-pathological studies. DM status, A1C levels, and medications for DM were documented annually. TDP-43 cytoplasmic inclusions, evaluated in 6 brain regions using immunohistochemistry, were used to obtain a semiquantitative TDP-43 score (0-5) in each region, and scores were averaged across regions to obtain a TDP-43 severity score. We used linear regressions to test the association of DM and A1C with the TDP-43 severity score. RESULTS: On average, participants (n=817) were 90 years old at the time of death, three fourth were women, and one fourth had DM. The mean A1C was 6.0% (SD=0.6). TDP-43 was observed in 54% of participants, and the mean TDP-43 score was 0.7 (range 0-4.5). A higher level of A1C was associated with a lower TDP-43 score (estimate=-0.156, S.E.=0.060, p=0.009) while DM had a borderline inverse association with the TDP-43 score (estimate=-0.163, S.E.=0.087, p=0.060). The association of higher levels of A1C with lower TDP-43 scores persisted after further adjustment by Apolipoprotein ε4, vascular risk factors, stroke, and hypoglycemic medications. Exclusion of the oldest old participants did not change the results. CONCLUSION: Overall, the results suggest that a high level of A1C is associated with less TDP-43 proteinopathy in older persons while the relationship of DM with TDP-43 needs further study.

4.
Stroke ; : STROKEAHA120030226, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33840227

RESUMO

BACKGROUND AND PURPOSE: The general cardiovascular Framingham risk score (FRS) identifies adults at increased risk for stroke. We tested the hypothesis that baseline FRS is associated with the presence of postmortem cerebrovascular disease (CVD) pathologies. METHODS: We studied the brains of 1672 older decedents with baseline FRS and measured CVD pathologies including macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. We employed a series of logistic regressions to examine the association of baseline FRS with each of the 5 CVD pathologies. RESULTS: Average age at baseline was 80.5±7.0 years and average age at death was 89.2±6.7 years. A higher baseline FRS was associated with higher odds of macroinfarcts (odds ratio, 1.10 [95% CI, 1.07-1.13], P<0.001), microinfarcts (odds ratio, 1.04 [95% CI, 1.01-1.07], P=0.009), atherosclerosis (odds ratio, 1.07 [95% CI, 1.04-1.11], P<0.001), and arteriolosclerosis (odds ratio, 1.04 [95% CI, 1.01-1.07], P=0.005). C statistics for these models ranged from 0.537 to 0.595 indicating low accuracy for predicting CVD pathologies. FRS was not associated with the presence of cerebral amyloid angiopathy. CONCLUSIONS: A higher FRS score in older adults is associated with higher odds of some, but not all, CVD pathologies, with low discrimination at the individual level. Further work is needed to develop a more robust risk score to identify adults at risk for accumulating CVD pathologies.

5.
Contemp Clin Trials ; 101: 106254, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33383230

RESUMO

INTRODUCTION: Cognitive impairment (CI) and cardiovascular disease (CVD) disproportionately affect women compared to men, and CVD increases risk of CI. Physical activity and cognitive training can improve cognition in older adults and may have additive or synergistic effects. However, no combined intervention has targeted women with CVD or utilized a sustainable lifestyle approach. The purpose of the trial is to evaluate efficacy of MindMoves, a 24-week multimodal physical activity and cognitive training intervention, on cognition and serum biomarkers in older women with CVD. Three serum biomarkers (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor [VEGF], and insulin-like growth factor 1 [IGF-1]) were selected as a priori hypothesized indicators of the effects of physical activity and/or cognitive training on cognition. METHODS: The study design is a randomized controlled trial with a 2 × 2 factorial design, to determine independent and combined efficacies of Mind (tablet-based cognitive training) and Move (lifestyle physical activity with goal-setting and group meetings) on change in cognition (primary outcome) and serum biomarkers (secondary outcomes). We will recruit 254 women aged ≥65 years with CVD and without CI from cardiology clinics. Women will be randomized to one of four conditions: (1) Mind, (2) Move, (3) MindMoves, or (4) usual care. Data will be obtained from participants at baseline, 24, 48, and 72 weeks. DISCUSSION: This study will test efficacy of a lifestyle-focused intervention to prevent or delay cognitive impairment in older women with CVD and may identify relevant serum biomarkers that could be used as early indicators of intervention response.

6.
Curr Neurol Neurosci Rep ; 20(12): 64, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33150490

RESUMO

PURPOSE OF REVIEW: Research has consistently shown that type 2 diabetes (T2D) is associated with increased risk of all-cause dementia. Because one of the most common clinical presentations of early stage dementia is memory impairment, we examined the relationship of T2D with memory function, using the recently published scientific literature. RECENT FINDINGS: We conducted a structured review to identify studies of "T2D and memory" published since 2015. After review of the 129 articles retrieved, we identified 14 studies meeting the inclusion and exclusion criteria. Among the eight studies with a single assessment of memory function in time (mostly cross-sectional), six found an association of T2D with lower memory function, but mostly in select subgroups of persons. Separately, six studies included repeated measures of memory (longitudinal design). Four out of six longitudinal studies found that T2D was related with a faster decline in memory, while two did not. Among the four studies showing a relation with memory decline, two had sample sizes of 9000-10,000 persons. Further, three longitudinal studies controlled for hypertension and stroke as covariates, and results suggested that common vascular risk factors and diseases do not account for the relation. While mechanistic studies clearly support a role for cerebrovascular disease in the relation of T2D with cognition, emerging data suggest that insulin resistance in the brain itself may also play a role. Most, but not all, recently published studies suggest that T2D is associated with a lower level and faster decline in memory function. This association does not appear to be fully accounted for by common vascular processes. More research will clarify the mechanisms linking T2D to memory and dementia.

7.
J Alzheimers Dis ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33185594

RESUMO

BACKGROUND: Vascular mechanisms may contribute to the accumulation of AD pathology. OBJECTIVE: We examined whether the burden of vascular risk factors proximate to death is associated with amyloid-ß and tau levels or modified their known association. METHODS: We examined the brains of 1, 585 participants from two longitudinal community-based studies of older adults. Amyloid-ß and tau were quantified by postmortem examination. The burden of vascular risk factors was summarized by calculating the Framingham general cardiovascular risk score (FRS) proximate to death. Using linear regressions, we examined the association of the FRS with the amyloid-ß and tau levels and examined if the FRS modified the association of the amyloid-ß with tau. RESULTS: On average, participants were nearly 90 years old and two-thirds were women. The FRS was not associated with amyloid-ß (Spearman r  = -0.00, p  = 0.918) or tau (r = 0.01, p = 0.701). However, the FRS as a whole (estimate = -0.022, SE = 0.008, p = 0.009), and specifically the systolic blood pressure (SBP) component (estimate = -0.033, SE = 0.012, p = 0.009), modified the association of the amyloid-ß with tau. Further analysis showed that the association between amyloid-ß and tau was stronger at lower levels of SBP. CONCLUSION: Late-life vascular risk scores were not related to postmortem levels of amyloid-ß or tau. However, lower levels of vascular risk scores and SBP were associated with a stronger association between amyloid-ß and tau. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another.

8.
J Am Geriatr Soc ; 68(11): 2662-2667, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32978794

RESUMO

BACKGROUND/OBJECTIVES: The purpose of this study was to: (1) examine relationships between body mass index (BMI) stability and cognitive decline in older African Americans; and (2) investigate differences in the relationships between women and men. DESIGN: The present study is a secondary data analysis of the Minority Aging Research Study, which is a longitudinal, cohort study of risk factors for cognitive decline and Alzheimer's disease among older African Americans living in the Chicago, IL, area. The study entails annual clinical evaluations, including measures of 19 neuropsychological tests that represent five cognitive domains, including episodic, semantic, and working memory, perceptual speed, and visuospatial ability. PARTICIPANTS: Participants (n = 671; mean age = 73.5 years; standard deviation = 6.2 years) were included in the present analysis if they were dementia free at baseline and completed at least two clinical evaluations, on average 1 year apart, that included valid cognitive and BMI assessments. RESULTS: Mixed-effects models showed higher baseline BMI was related to slower global cognitive decline, whereas changes in BMI (instability) were related to faster global cognitive decline. These effects were the same for four of five cognitive domains and remained after controlling for various health characteristics. However, women and men did not differ in any of the relationships. CONCLUSION: Higher BMI is related to slower cognitive decline in older African Americans, but greater BMI instability is related to faster decline. Stability of BMI should be considered in the cognitive aging of African Americans.

9.
Ann Neurol ; 88(3): 513-525, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32557841

RESUMO

OBJECTIVE: To examine associations of molecular markers of brain insulin signaling with Alzheimer disease (AD) and cognition among older persons with or without diabetes. METHODS: This clinical-pathologic study was derived from a community-based cohort study, the Religious Orders Study. We studied 150 individuals (mean age at death =87 years, 48% women): 75 with and 75 without diabetes (matched by sex on age at death and education). Using enzyme-linked immunosorbent assay, immunohistochemistry, and ex vivo stimulation of brain tissue with insulin, we assessed insulin signaling in the postmortem middle frontal gyrus cortex. Postmortem data documented AD neuropathology. Clinical evaluations documented cognitive function proximate to death, based on 17 neuropsychological tests. In adjusted regression analyses, we examined associations of brain insulin signaling with diabetes, AD, and level of cognition. RESULTS: Brain insulin receptor substrate-1 (IRS1) phosphorylation (pS307 IRS1/total IRS1) and serine/threonine-protein kinase (AKT) phosphorylation (pT308 AKT1/total AKT1) were similar in persons with or without diabetes. AKT phosphorylation was associated with the global AD pathology score (p = 0.001). In contrast, IRS1 phosphorylation was not associated with AD (p = 0.536). No other associations of insulin signaling were found with the global AD score, including when using the ex vivo brain insulin stimulation method. In secondary analyses, normalized pT308 AKT1 was positively correlated with both the amyloid burden and tau tangle density, and no other associations of brain insulin signaling with neuropathology were observed. Moreover, normalized pT308 AKT1 was associated with a lower level of global cognitive function (estimate = -0.212, standard error = 0.097; p = 0.031). INTERPRETATION: Brain AKT phosphorylation, a critical node in the signaling of insulin and other growth factors, is associated with AD neuropathology and lower cognitive function. ANN NEUROL 2020;88:513-525.

10.
J Clin Endocrinol Metab ; 105(4)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32083676

RESUMO

CONTEXT: Metabolic syndrome (MetS) affects cognitive function in late life, particularly in women. But longitudinal research is scarce on associations of MetS with cognitive function during midlife. OBJECTIVE: To determine associations between MetS exposure and cognitive function trajectories in midlife women. DESIGN AND SETTING: This is a 17-year prospective, longitudinal study of multiracial/ethnic women in 7 US communities, with annual/biennial assessments. PARTICIPANTS: Participants were 2149 US women traversing menopause. EXPOSURE: Exposure consisted of MetS assessments (median 4 assessments over 4 years). MAIN OUTCOME MEASURES: Main outcome measures were assessments of cognitive function in 3 domains: perceptual speed (symbol digit modalities test, SDMT), episodic memory (East Boston Memory Test, EBMT), and working memory (Digit Span Backward Test, DSB). RESULTS: By their first cognitive assessment (age 50.7 ± 2.9 years), 29.5% met the criteria for MetS. Women completed a median (interquartile range [IQR]) of 6 (IQR 4-7) follow-up cognitive assessments over 11.2 (IQR 9.2-11.5) years. Women with MetS, compared with those without, had a larger 10-year decline in SDMT z-score (estimate -0.087, 95% confidence interval, -0.150 to -0.024; P = 0.007), after adjustment for cognitive testing practice effects, sociodemographics, lifestyle, mood, and menopause factors. As such, MetS accelerated the 10-year loss of perceptual speed by 24%. MetS did not differentially affect the rate of decline in either immediate (P = 0.534) or delayed (P = 0.740) episodic memory or in working memory (P = 0.584). CONCLUSIONS: In midlife women MetS exposure was associated with accelerated decline in perceptual speed, but not episodic or working memory.

11.
J Gerontol B Psychol Sci Soc Sci ; 75(4): 783-791, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-30102393

RESUMO

OBJECTIVE: To test whether race (specifically Black or White) moderates the relationship between memory complaints and depressive symptoms in cognitively normal older adults, and if these relationships vary by memory complaint characteristics. METHODS: Data from Black (n = 551) and White (n = 1,158) cognitively intact participants (Mage = 77.1, SD = 7.5; 76.6% female) in the Minority Aging Research Study and the Rush Memory and Aging Project were used. Participants completed annual clinical evaluations, including the Center for Epidemiologic Studies Depression scale and two memory complaint questions, over periods of up to 18 years. Ordinal mixed effects models were used to examine within-person relationships between memory complaints and depressive symptoms over time, as well as whether race moderated these associations. RESULTS: Reports of greater memory change over time were associated with more depressive symptoms for both Black and White older adults. However, reports of greater frequency of memory problems were related to depressive symptoms for Black older adults only. CONCLUSION: Findings suggest differential associations between memory complaints and depressive symptoms in cognitively normal Black and White older adults and call for future research to examine the influence of race and related factors on memory complaints and depressive symptoms.


Assuntos
Afro-Americanos/estatística & dados numéricos , Envelhecimento/etnologia , Transtornos Cognitivos/etnologia , Depressão/etnologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Transtornos da Memória/etnologia , Afro-Americanos/psicologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/psicologia , Cognição , Depressão/psicologia , Grupo com Ancestrais do Continente Europeu/psicologia , Feminino , Humanos , Masculino , Transtornos da Memória/psicologia , Fatores de Risco , Autorrelato
13.
JAMA ; 322(16): 1589-1599, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31638686

RESUMO

Importance: Worldwide, 47 million people live with dementia and, by 2050, the number is expected to increase to 131 million. Observations: Dementia is an acquired loss of cognition in multiple cognitive domains sufficiently severe to affect social or occupational function. In the United States, Alzheimer disease, one cause of dementia, affects 5.8 million people. Dementia is commonly associated with more than 1 neuropathology, usually Alzheimer disease with cerebrovascular pathology. Diagnosing dementia requires a history evaluating for cognitive decline and impairment in daily activities, with corroboration from a close friend or family member, in addition to a thorough mental status examination by a clinician to delineate impairments in memory, language, attention, visuospatial cognition such as spatial orientation, executive function, and mood. Brief cognitive impairment screening questionnaires can assist in initiating and organizing the cognitive assessment. However, if the assessment is inconclusive (eg, symptoms present, but normal examination findings), neuropsychological testing can help determine whether dementia is present. Physical examination may help identify the etiology of dementia. For example, focal neurologic abnormalities suggest stroke. Brain neuroimaging may demonstrate structural changes including, but not limited to, focal atrophy, infarcts, and tumor, that may not be identified on physical examination. Additional evaluation with cerebrospinal fluid assays or genetic testing may be considered in atypical dementia cases, such as age of onset younger than 65 years, rapid symptom onset, and/or impairment in multiple cognitive domains but not episodic memory. For treatment, patients may benefit from nonpharmacologic approaches, including cognitively engaging activities such as reading, physical exercise such as walking, and socialization such as family gatherings. Pharmacologic approaches can provide modest symptomatic relief. For Alzheimer disease, this includes an acetylcholinesterase inhibitor such as donepezil for mild to severe dementia, and memantine (used alone or as an add-on therapy) for moderate to severe dementia. Rivastigmine can be used to treat symptomatic Parkinson disease dementia. Conclusions and Relevance: Alzheimer disease currently affects 5.8 million persons in the United States and is a common cause of dementia, which is usually accompanied by other neuropathology, often cerebrovascular disease such as brain infarcts. Causes of dementia can be diagnosed by medical history, cognitive and physical examination, laboratory testing, and brain imaging. Management should include both nonpharmacologic and pharmacologic approaches, although efficacy of available treatments remains limited.


Assuntos
Demência/diagnóstico , Demência/terapia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/terapia , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Memantina/efeitos adversos , Memantina/uso terapêutico , Neuroimagem , Testes Neuropsicológicos
14.
Neurobiol Aging ; 84: 119-130, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31539648

RESUMO

Aberrant insulin and adipokine signaling has been implicated in cognitive decline associated with both type 2 diabetes mellitus and neurodegenerative diseases. We established methods that reliably measure insulin, adiponectin and leptin signaling, and their crosstalk, in thawed postmortem mid-frontal cortical tissue from cognitively normal older subjects with a short postmortem interval. Insulin-evoked insulin receptor (IR) activation increases activated, tyrosine-phosphorylated IRß on tyrosine residues 960, 1150, and 1151, insulin receptor substrate-1 recruitment to IRß and phosphorylated RAC-α-serine/threonine-protein kinase. Adiponectin augments, but leptin inhibits, insulin signaling. Adiponectin activates adiponectin receptors to induce APPL1 binding to adiponectin receptor 1 and 2 and T-cadherin and downstream adenosine monophosphate-dependent protein kinase phosphorylation. Insulin inhibited adiponectin-induced signaling. In addition, leptin-induced leptin receptor (OB-R) signaling promotes Janus kinase 2 recruitment to OB-R and Janus kinase 2 and downstream signal transducer and activator of transcription 3 phosphorylation. Insulin enhanced leptin signaling. These data demonstrate insulin and adipokine signaling interactions in human brain. Future studies can use these methods to examine insulin, adiponectin, and leptin metabolic dysregulation in aging and disease states, such as type 2 diabetes and Alzheimer's disease-related dementias.


Assuntos
Adipocinas/metabolismo , Encéfalo/patologia , Insulina/metabolismo , Transdução de Sinais , Envelhecimento/metabolismo , Encéfalo/metabolismo , Humanos , Leptina/metabolismo , Mudanças Depois da Morte
15.
Curr Neurol Neurosci Rep ; 19(8): 58, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300920

RESUMO

PURPOSE OF REVIEW: Type 2 diabetes (T2D) is a well-established risk factor for the development of dementia. Dementia and T2D share some underlying pathophysiology that has led to interest in the potential to repurpose drugs used in the management of T2D to benefit brain health. This review describes the scientific data available on the use of T2D medications for the risk reduction or management of dementia, in people with and without T2D. RECENT FINDINGS: Results from basic laboratory research support the potential for commonly-used medications for T2D, including those with direct glucose-lowering properties, to have a beneficial effect on brain health. However, human studies have been mostly observational in nature and report conflicting results. Preliminary data suggest that intranasal insulin, metformin, and GLP-1 agonists show promise for dementia, but confirmatory evidence for their benefit in dementia is still lacking. Current evidence does not support the repurposing of T2D medications for dementia risk reduction or management. Research in the field of T2D and dementia is active, and further data are required before definitive conclusions can be drawn.


Assuntos
Demência/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Reposicionamento de Medicamentos , Hipoglicemiantes/uso terapêutico , Glicemia , Encéfalo , Humanos , Insulina , Fatores de Risco
16.
Neuroepidemiology ; 53(1-2): 100-107, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31067547

RESUMO

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.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico por imagem , Transtornos Motores/sangue , Transtornos Motores/diagnóstico por imagem , Neuroimagem/métodos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Coortes , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Neuropatologia
18.
J Affect Disord ; 250: 313-318, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30875674

RESUMO

BACKGROUND: Brain proteins, including Insulin-like Growth Factor Binding Protein 5 (IGFBP-5), have been associated with cognitive dysfunction in aging. Mechanisms linking depression with cognition are poorly understood. We hypothesize that the association of depressive symptoms with cognition is mediated or modified by brain proteins. METHODS: IGFBP-5, HSPB2, AK4, ITPK1 and PLXNB1 were measured in dorsolateral prefrontal cortex in 1057 deceased participants, who underwent annual assessments of depressive symptoms and cognition for a mean of 8.9 years. The average number of depressive symptoms per year before a dementia diagnosis was calculated for each person. RESULTS: A one standard deviation above the mean IGFBP-5 was associated with a 14% higher odds of having more depressive symptoms (p < 0.031). Higher IGFBP-5 was associated with faster decline in global cognition (p < 0.001) and five cognitive domains (p < 0.008), controlling for depressive symptoms. IGFBP-5 moderated the association of depressive symptoms with decline in global cognition (p = 0.045). IGFBP-5 mediated ten percent or less of the total effect of depressive symptoms on decline in global cognition and the cognitive domains (p > 0.070). LIMITATIONS: Participants were volunteers and self-selection bias limits the generalizability of our findings. In addition, we used self-reported data on depressive symptoms. However, we also used data on depression medications as sensitivity analyses to confirm findings. CONCLUSIONS: In old age, brain IGFBP-5 is associated with depressive symptoms and cognition. The association of depressive symptoms with cognitive decline is conditional on IGFBP-5.


Assuntos
Encéfalo/metabolismo , Transtornos Cognitivos/metabolismo , Transtorno Depressivo/metabolismo , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/psicologia , Transtorno Depressivo/psicologia , Feminino , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Masculino , Córtex Pré-Frontal , Proteômica
19.
Acta Neuropathol ; 136(6): 887-900, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30334074

RESUMO

Alzheimer's dementia is significantly more common in women than in men. However, few pathological studies have addressed sex difference in Alzheimer's disease (AD) and other brain pathologies. We leveraged postmortem data from 1453 persons who participated in one of two longitudinal community-based studies of older adults, the Religious Orders Study and the Rush Memory and Aging Project. Postmortem examination identified AD pathologies, neocortical Lewy bodies, DNA-binding protein 43 (TDP-43), hippocampal sclerosis, gross and micro infarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. Linear and logistic regressions examined the association of sex with each of the pathologic measures. Two-thirds of subjects were women (n = 971; 67%), with a mean age at death of 89.8 (SD = 6.6) years in women and 87.3 (SD = 6.6) in men. Adjusted for age and education, women had higher levels on a global measure of AD pathology (estimate = 0.102, SE = 0.022, p < 0.001), and tau tangle density in particular (estimate = 0.334, SE = 0.074, p < 0.001), and there was a borderline difference between women and men in amyloid-ß load (estimate = 0.124, SE = 0.065, p = 0.056). In addition, compared to men, women were more likely to have more severe arteriolosclerosis (OR = 1.28, 95% CI:1.04-1.58, p = 0.018), and less likely to have gross infarcts (OR = 0.78, 95% CI:0.61-0.98, p = 0.037), although the association with gross infarct was attenuated after controlling for vascular risk factors. These data help elucidate the neuropathologic footprint of sex difference in AD and other common brain pathologies of aging.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Encéfalo/patologia , Caracteres Sexuais , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteína E4/genética , Arteriolosclerose/complicações , Arteriolosclerose/patologia , Autopsia , Encéfalo/metabolismo , Distribuição de Qui-Quadrado , Estudos Transversais , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo
20.
Neurology ; 91(6): e517-e525, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-29997190

RESUMO

OBJECTIVE: To examine associations of average and change in late-life blood pressure (BP) with cerebrovascular and Alzheimer disease (AD) neuropathology in a large group of decedents followed longitudinally in vivo. METHODS: This clinical-pathologic study was derived from prospective, community-based cohort studies of aging with similar design and data collection. Measurements of systolic BP (SBP) and diastolic BP (DBP) were obtained annually (mean follow-up 8 years, SD = 4.8). Postmortem neuropathologic evaluations documented diseases of aging. Using regression analyses, we examined associations of average and decline in late-life SBP, and separately in DBP, with neuropathology. RESULTS: In 1,288 persons (mean age at death = 88.6 years; 65% women), the mean standardized person-specific SBP across the study was 134 (SD = 13) and DBP was 71 (SD = 8) mm Hg. The odds of brain infarcts were increased for participants with a higher mean SBP. Specifically, a person with a 1 SD SBP above the mean (147 vs 134 mm Hg) would have a 46% increased odds of having one or more infarcts, and an increased odds of gross infarct (46%) and microinfarct (36%). Furthermore, a more rapidly declining SBP slope over time increased the odds of one or more infarcts. Mean DBP, not slope, was related to brain infarcts. AD pathology analyses showed an association of a higher mean SBP with higher number of tangles (p = 0.038) but not plaques or other pathology (all p > 0.06). Changes in BP were not significantly related to AD pathology. CONCLUSIONS: Higher average late-life SBP and DBP, and independently a faster decline in SBP, are associated with increasing number of brain infarcts, including gross and microinfarcts. We found some evidence for a relation of SBP with AD, specifically tangles. Both average and decline in BP are related to brain disease.


Assuntos
Doença de Alzheimer/patologia , Pressão Sanguínea/fisiologia , Encéfalo/patologia , Transtornos Cerebrovasculares/patologia , Hipertensão/patologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/epidemiologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Masculino , Estudos Prospectivos , Fatores de Risco
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