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1.
J Nucl Med ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420499

RESUMO

Emerging evidence supports a hypothesized role of the α7-nicotinic acetylcholine receptor (α7-nAChR) in the pathophysiology of Alzheimer's disease (AD). 18F-ASEM is a radioligand for estimating availability of the α7-nAChR in the brain in vivo with positron emission tomography (PET). Methods: In this cross-sectional study, 14 patients with mild cognitive impairment (MCI), a prodromal stage to dementia, and 17 cognitively intact, elderly controls completed 18F-ASEM PET. For each participant, binding in each region of interest was estimated using Logan graphical analysis with a metabolite-corrected arterial input function. Results: Higher 18F-ASEM binding was observed in MCI compared to controls across all regions, supporting higher availability of the α7-nAChR in MCI. 18F-ASEM binding was not associated with verbal memory in this small MCI sample. Conclusion: These data support use of 18F-ASEM PET to examine further the relationship between α7-nAChR availability and MCI.

2.
Diabetes Care ; 42(7): 1248-1254, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31221696

RESUMO

OBJECTIVE: We sought to examine associations in older adults among diabetes, glycemic control, diabetes duration, and biomarkers of hyperglycemia with incident mild cognitive impairment (MCI) and incident dementia. RESEARCH DESIGN AND METHODS: We conducted a prospective analysis of 5,099 participants from the Atherosclerosis Risk in Communities (ARIC) Study who attended the fifth (2011-2013) exam. Cognitive status was assessed during follow-up via telephone calls, death certificate codes, surveillance, and a follow-up examination (2016-2017). We defined incident cognitive impairment as incident MCI or incident dementia in persons dementia-free at the index examination; we also examined each outcome separately. Diabetes was defined using self-report, medications, or HbA1c ≥6.5%; poor glycemic control in persons with diabetes was defined as HbA1c ≥7%. We examined the following biomarkers of hyperglycemia: HbA1c, fructosamine, glycated albumin, and 1,5-anhydroglucitol. RESULTS: Mean age at baseline was 76 years, 59% were female, and 21% were black. Diabetes (hazard ratio [HR] 1.14 [95% CI 1.00, 1.31]), poor glycemic control in persons with diabetes (HR 1.31 [95% CI 1.05, 1.63]), and longer diabetes duration (≥5 vs. <5 years; HR 1.59 [95% CI 1.23, 2.07]) were significantly associated with incident cognitive impairment. We found a J-shaped association between HbA1c and incident dementia. Glycated albumin and fructosamine were also associated with incident dementia, independently of HbA1c. HbA1c and fructosamine were also associated with incident MCI. CONCLUSIONS: Diabetes status, poor glycemic control, and longer diabetes duration were associated with worse cognitive outcomes over a median follow-up of 5 years.

3.
Neurobiol Aging ; 76: 214.e1-214.e9, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30528841

RESUMO

Molecular genetic research provides unprecedented opportunities to examine genotype-phenotype correlations underlying complex syndromes. To investigate pathogenic mutations and genotype-phenotype relationships in diverse neurodegenerative conditions, we performed a rare variant analysis of damaging mutations in autopsy-confirmed neurodegenerative cases from the Johns Hopkins Brain Resource Center (n = 1243 patients). We used NeuroChip genotyping and C9orf72 hexanucleotide repeat analysis to rapidly screen our cohort for disease-causing mutations. In total, we identified 42 individuals who carried a pathogenic mutation in LRRK2, GBA, APP, PSEN1, MAPT, GRN, C9orf72, SETX, SPAST, or CSF1R, and we provide a comprehensive description of the diverse clinicopathological features of these well-characterized cases. Our study highlights the utility of high-throughput genetic screening arrays to establish a molecular diagnosis in individuals with complex neurodegenerative syndromes, to broaden disease phenotypes and to provide insights into unexpected disease associations.

4.
Alzheimers Dement ; 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30465754

RESUMO

INTRODUCTION: Primary age-related tauopathy (PART) is a recently described entity that can cause cognitive impairment in the absence of Alzheimer's disease (AD). Here, we compared neuropathological features, tau haplotypes, apolipoprotein E (APOE) genotypes, and cognitive profiles in age-matched subjects with PART and AD pathology. METHODS: Brain autopsies (n = 183) were conducted on participants 85 years and older from the Baltimore Longitudinal Study of Aging and Johns Hopkins Alzheimer's Disease Research Center. Participants, normal at enrollment, were followed with periodic cognitive evaluations until death. RESULTS: Compared with AD, PART subjects showed significantly slower rates of decline on measures of memory, language, and visuospatial performance. They also showed lower APOE ε4 allele frequency (4.1% vs. 17.6%, P = .0046). DISCUSSION: Our observations suggest that PART is separate from AD and its distinction will be important for the clinical management of patients with cognitive impairment and for public health care planning.

5.
Alzheimers Dement (N Y) ; 4: 499-507, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364572

RESUMO

Introduction: Hearing impairment is highly prevalent and independently associated with cognitive decline. The Aging and Cognitive Health Evaluation in Elders study is a multicenter randomized controlled trial to determine efficacy of hearing treatment in reducing cognitive decline in older adults. Clinicaltrials.gov Identifier: NCT03243422. Methods: Eight hundred fifty participants without dementia aged 70 to 84 years with mild-to-moderate hearing impairment recruited from four United States field sites and randomized 1:1 to a best-practices hearing intervention or health education control. Primary study outcome is 3-year change in global cognitive function. Secondary outcomes include domain-specific cognitive decline, incident dementia, brain structural changes on magnetic resonance imaging, health-related quality of life, physical and social function, and physical activity. Results: Trial enrollment began January 4, 2018 and is ongoing. Discussion: When completed in 2022, Aging and Cognitive Health Evaluation in Elders study should provide definitive evidence of the effect of hearing treatment versus education control on cognitive decline in community-dwelling older adults with mild-to-moderate hearing impairment.

6.
Int Psychogeriatr ; : 1-9, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30303065

RESUMO

ABSTRACTObjective:There is increasing evidence of an association between depressive symptoms and mild cognitive impairment (MCI) in cross-sectional studies, but the longitudinal association between depressive symptoms and risk of MCI onset is less clear. The authors investigated whether baseline symptom severity of depression was predictive of time to onset of symptoms of MCI. METHOD: These analyses included 300 participants from the BIOCARD study, a cohort of individuals who were cognitively normal at baseline (mean age = 57.4 years) and followed for up to 20 years (mean follow-up = 2.5 years). Depression symptom severity was measured using the Hamilton Depression Scale (HAM-D). The authors assessed the association between dichotomous and continuous HAM-D and time to onset of MCI within 7 years versus after 7 years from baseline (reflecting the mean time from baseline to onset of clinical symptoms in the cohort) using Cox regression models adjusted for gender, age, and education. RESULTS: At baseline, subjects had a mean HAM-D score of 2.2 (SD = 2.8). Higher baseline HAM-D scores were associated with an increased risk of progression from normal cognition to clinical symptom onset ≤ 7 years from baseline (p = 0.043), but not with progression > 7 years from baseline (p = 0.194). These findings remained significant after adjustment for baseline cognition. CONCLUSIONS: These results suggest that low levels of depressive symptoms may be predictive of clinical symptom onset within approximately 7 years among cognitively normal individuals and may be useful in identifying persons at risk for MCI due to Alzheimer's disease.

7.
Alzheimers Dement ; 14(11): 1406-1415, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29763593

RESUMO

INTRODUCTION: The interplay between midlife vascular risk factors and midlife cognitive function with later life mild cognitive impairment (MCI) and dementia (DEM) is not well understood. METHODS: In the Atherosclerosis Risk in Communities Study, cardiovascular risk factors and cognition were assessed in midlife, ages 45-64 years. In 2011-2013, 20-25 years later, all consenting Atherosclerosis Risk in Communities participants underwent a cognitive and neurological evaluation and were given adjudicated diagnoses of cognitively normal, MCI, or DEM. RESULTS: In 5995 participants with complete covariate data, midlife diabetes, hypertension, obesity, and hypercholesterolemia were associated with late-life MCI and DEM. Low midlife cognition function was also associated with greater likelihood of late-life MCI or DEM. Both midlife vascular risk factors and midlife cognitive function remained associated with later life MCI or DEM when both were in the model. DISCUSSION: Later life MCI and DEM were independently associated with midlife vascular risk factors and midlife cognition.

8.
Parkinsonism Relat Disord ; 50: 29-36, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29478836

RESUMO

INTRODUCTION: Identification of factors associated with progression of cognitive symptoms in Parkinson's disease (PD) is important for treatment planning, clinical care, and design of future clinical trials. The current study sought to identify whether prediction of cognitive progression is aided by examining baseline cognitive features, and whether this differs according to stage of cognitive disease. METHODS: Participants with PD in the Pacific Udall Center Clinical Consortium who had longitudinal data available and were nondemented at baseline were included in the study (n = 418). Logistic and Cox regression models were utilized to examine the relationship between cognitive, demographic, and clinical variables with risk and time to progression from no cognitive impairment to mild cognitive impairment (PD-MCI) or dementia (PDD), and from PD-MCI to PDD. RESULTS: Processing speed (OR = 1.05, p = 0.009) and working memory (OR = 1.01, p = 0.03) were associated with conversion to PDD among those with PD-MCI at baseline, over and above demographic variables. Conversely, the primary predictive factor in the transition from no cognitive impairment to PD-MCI or PDD was male sex (OR = 4.47, p = 0.004), and males progressed more rapidly than females (p = 0.01). Further, among females with shorter disease duration, progression was slower than for their male counterparts, and poor baseline performance on semantic verbal fluency was associated with shorter time to cognitive impairment in females but not in males. CONCLUSIONS: This study provides evidence for sex differences in the progression to cognitive impairment in PD, while specific cognitive features become more important indicators of progression with impending conversion to PDD.

9.
Gerontologist ; 58(5): e311-e324, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-28575230

RESUMO

Purpose of the Study: Interest in cognitive training for healthy older adults to reduce cognitive decline has grown considerably over the past few decades. Given the shift toward a more diverse society, the purpose of this review is to examine the extent of race/ethnic minority participation in cognitive training studies and characteristics of studies that included race/ethnic minority participants. Design and Methods: This review considered peer-reviewed studies reporting cognitive training studies for cognitively healthy, community-dwelling older adults (age 55+) in the United States published in English before December 31, 2015. A total of 31 articles published between 1986 and 2015 meeting inclusion criteria were identified and included in the review. Results: A total of 6,432 participants were recruited across all of the studies, and ranged in age from 55 to 99 years. Across all studies examined, 39% reported racial/ethnic background information. Only 3 of these studies included a substantial number of minorities (26.7% in the ACTIVE study; 28.4% in the SeniorWISE study; 22.7% in the TEAM study). Race/ethnic minority older adults were disproportionately underrepresented in cognitive training studies. Implications: Further research should aim to enroll participants representative of various race/ethnic minority populations. Strategies for recruitment and retention of ethnic minority participants in cognitive training research are discussed, which could lead to the development of more culturally appropriate and perhaps more effective cognitive interventions.

10.
Stroke ; 48(11): 2964-2972, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29018129

RESUMO

BACKGROUND AND PURPOSE: Cerebral microbleed (CMB) location (deep versus strictly lobar) may elucidate underlying pathology with deep CMBs being more associated with hypertensive vascular disease and lobar CMBs being more associated with cerebral amyloid angiopathy. The objective of this study was to determine whether neuroimaging signs of vascular disease and Alzheimer pathology are associated with different types of CMBs. METHODS: Among 1677 nondemented ARIC (Atherosclerosis Risk in Communities) participants (mean age=76±5 years; 40% men; 26% black) with 3-Tesla MRI scans at the fifth examination (2011-2013), we fit multinomial logistic regression models to quantify relationships of brain volumes (Alzheimer disease signature regions, total gray matter, frontal gray matter, and white matter hyperintensity volumes), infarct frequencies (lacunar, nonlacunar, and total), and apolipoprotein E (number of ε4 alleles) with CMB location (none, deep/mixed, or strictly lobar CMBs). Models were weighted for the sample selection scheme and adjusted for age, sex, education, hypertension, ever smoking status, diabetes mellitus, race site membership, and estimated intracranial volume (brain volume models only). RESULTS: Deep/mixed and strictly lobar CMBs had prevalences of 8% and 16%, respectively. Larger white matter hyperintensity burden, greater total infarct frequency, smaller frontal volumes (in women only), and smaller total gray matter volume were associated with greater risk of both deep and lobar CMBs relative to no CMBs. Greater white matter hyperintensity volume was also associated with greater risk of deep relative to lobar CMBs. Higher lacunar and nonlacunar infarct frequencies were associated with higher risk of deep CMBs, whereas smaller Alzheimer disease signature region volume and apolipoprotein E ε4 homozygosity were associated with greater risk of lobar CMBs. CONCLUSIONS: CMBs are a common vascular pathology in the elderly. Markers of hypertensive small-vessel disease may contribute to deep CMBs while cerebral amyloid angiopathy may drive development of lobar CMBs.


Assuntos
Aterosclerose/diagnóstico por imagem , Aterosclerose/epidemiologia , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/epidemiologia , Neuroimagem , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/complicações , Hemorragia Cerebral/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
11.
Alzheimers Dement (N Y) ; 3(3): 410-415, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29067347

RESUMO

INTRODUCTION: Hearing loss (HL) is prevalent and independently related to cognitive decline and dementia. There has never been a randomized trial to test if HL treatment could reduce cognitive decline in older adults. METHODS: A 40-person (aged 70-84 years) pilot study in Washington County, MD, was conducted. Participants were randomized 1:1 to a best practices hearing or successful aging intervention and followed for 6 months. clinicaltrials.gov Identifier: NCT02412254. RESULTS: The Aging and Cognitive Health Evaluation in Elders Pilot (ACHIEVE-P) Study demonstrated feasibility in recruitment, retention, and implementation of interventions with no treatment-related adverse events. A clear efficacy signal of the hearing intervention was observed in perceived hearing handicap (mean of 0.11 to -1.29 standard deviation [SD] units; lower scores better) and memory (mean of -0.10 SD to 0.38 SD). DISCUSSION: ACHIEVE-P sets the stage for the full-scale ACHIEVE trial (N = 850, recruitment beginning November 2017), the first randomized trial to determine efficacy of a best practices hearing (vs. successful aging) intervention on reducing cognitive decline in older adults with HL.

12.
JAMA Neurol ; 74(10): 1246-1254, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28783817

RESUMO

Importance: Vascular risk factors have been associated with cognitive decline. Midlife exposure to these factors may be most important in conferring late-life risk of cognitive impairment. Objectives: To examine Atherosclerosis Risk in Communities (ARIC) participants in midlife and to explore associations between midlife vascular risk factors and 25-year dementia incidence. Design, Setting, and Participants: This prospective cohort investigation of the Atherosclerosis Risk in Communities (ARIC) Study was conducted from 1987-1989 through 2011-2013. The dates of this analysis were April 2015 through August 2016. The setting was ARIC field centers (Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis suburbs, Minnesota). The study comprised 15 744 participants (of whom 27.1% were black and 72.9% white) who were aged 44 to 66 years at baseline. Main Outcomes and Measures: Demographic and vascular risk factors were measured at baseline (obesity, smoking, diabetes, prehypertension, hypertension, and hypercholesterolemia) as well as presence of the APOE ε4 genotype. After the baseline visit, participants had 4 additional in-person visits, for a total of 5 in-person visits, hospitalization surveillance, telephone calls, and repeated cognitive evaluations. Most recently, in 2011-2013, through the ARIC Neurocognitive Study (ARIC-NCS), participants underwent a detailed neurocognitive battery, informant interviews, and adjudicated review to define dementia cases. Additional cases were identified through the Telephone Interview for Cognitive Status-Modified or informant interview, for participants not attending the ARIC-NCS visit, or by an International Classification of Diseases, Ninth Revision dementia code during a hospitalization. Fully adjusted Cox proportional hazards regression was used to evaluate associations of baseline vascular and demographic risk factors with dementia. Results: In total, 1516 cases of dementia (57.0% female and 34.9% black, with a mean [SD] age at visit 1 of 57.4 [5.2] years) were identified among 15 744 participants. Black race (hazard ratio [HR], 1.36; 95% CI, 1.21-1.54), older age (HR, 8.06; 95% CI, 6.69-9.72 for participants aged 60-66 years), lower educational attainment (HR, 1.61; 95% CI, 1.28-2.03 for less than a high school education), and APOE ε4 genotype (HR, 1.98; 95% CI, 1.78-2.21) were associated with increased risk of dementia, as were midlife smoking (HR, 1.41; 95% CI, 1.23-1.61), diabetes (HR, 1.77; 95% CI, 1.53-2.04), prehypertension (HR, 1.31; 95% CI, 1.14-1.51), and hypertension (HR, 1.39; 95% CI, 1.22-1.59). The HR for dementia for diabetes was almost as high as that for APOE ε4 genotype. Conclusions and Relevance: Midlife vascular risk factors are associated with increased risk of dementia in black and white ARIC Study participants. Further studies are needed to evaluate the mechanism of and opportunities for prevention of the cognitive sequelae of these risk factors in midlife.


Assuntos
Aterosclerose/epidemiologia , Transtornos Cognitivos/epidemiologia , Demência/epidemiologia , Características de Residência , Doenças Vasculares/epidemiologia , Adulto , Grupo com Ancestrais do Continente Africano , Fatores Etários , Idoso , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco
13.
Alzheimers Dement (Amst) ; 8: 147-155, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28653035

RESUMO

INTRODUCTION: We established a method for diagnostic harmonization across multiple studies of preclinical Alzheimer's disease and validated the method by examining its relationship with clinical status and cognition. METHODS: Cognitive and clinical data were used from five studies (N = 1746). Consensus diagnoses established in each study used criteria to identify progressors from normal cognition to mild cognitive impairment. Correspondence was evaluated between these consensus diagnoses and three algorithmic classifications based on (1) objective cognitive impairment in 2+ tests only; (2) a Clinical Dementia Rating (CDR) of ≥0.5 only; and (3) both. Associations between baseline cognitive performance and cognitive change were each tested in relation to progression to algorithm-based classifications. RESULTS: In each study, an algorithmic classification based on both cognitive testing cutoff scores and a CDR ≥0.5 provided optimal balance of sensitivity and specificity (areas under the curve: 0.85-0.95). Over an average 6.6 years of follow-up (up to 28 years), N = 186 initially cognitively normal participants aged on average 64 years at baseline progressed (incidence rate: 15.3 people/1000 person-years). Baseline cognitive scores and cognitive change were associated with future diagnostic status using this algorithmic classification. DISCUSSION: Both cognitive tests and CDR ratings can be combined across multiple studies to obtain a reliable algorithmic classification with high specificity and sensitivity. This approach may be applicable to large cohort studies and to clinical trials focused on preclinical Alzheimer's disease because it provides an alternative to implementation of a time-consuming adjudication panel.

14.
Arch Gerontol Geriatr ; 72: 39-44, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28544945

RESUMO

Type II diabetes mellitus (DM) is associated with increased risk of dementia; however, few studies have examined the longitudinal association between DM and cognitive outcomes in large nationally representative cohorts. We investigated these associations in 7605 participants enrolled in the National Health and Aging Trends Study, a nationally representative prospective study of Medicare beneficiaries ≥65, from 2011 to 2015. Participants or proxy respondents reported DM and dementia diagnosis, and participants completed immediate and delayed recall word list learning tests and the Clock Drawing Test. In multivariable-adjusted generalized linear mixed models, baseline DM diagnosis was associated with decline on immediate and delayed word recall and the Clock Drawing Test. In Cox proportional hazards models, DM also predicted incident dementia in older age groups at baseline. These findings further support the notion that DM is associated with cognitive outcomes, suggesting that treatment and prevention of DM may reduce the risk of these outcomes. However, more studies are needed to better understand whether DM treatments affect this relationship.


Assuntos
Disfunção Cognitiva/etiologia , Demência/etiologia , Diabetes Mellitus Tipo 2/complicações , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Lineares , Masculino , Modelos de Riscos Proporcionais , Estudos Prospectivos
15.
Neurology ; 88(18): 1751-1758, 2017 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-28381516

RESUMO

OBJECTIVE: To examine the variability in performance among placebo groups in randomized controlled trials for mild cognitive impairment (MCI). METHODS: Placebo group data were obtained from 2 National Institute on Aging (NIA) MCI randomized controlled trials, the Alzheimer's Disease Cooperative Study (ADCS) MCI trial and the Alzheimer's Disease Neuroimaging Initiative (ADNI), which is a simulated clinical trial, in addition to industry-sponsored clinical trials involving rivastigmine, galantamine, rofecoxib, and donepezil. The data were collated for common measurement instruments. The performance of the placebo participants from these studies was tracked on the Alzheimer's Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination, and Clinical Dementia Rating-sum of boxes, and for progression on these measures to prespecified clinical study endpoints. APOE status, where available, was also analyzed for its effects. RESULTS: The progression to clinical endpoints varied a great deal among the trials. The expected performances were seen for the participants in the 2 NIA trials, ADCS and ADNI, with generally worsening of performance over time; however, the industry-sponsored trials largely showed stable or improved performance in their placebo participants. APOE4 carrier status influenced results in an expected fashion on the study outcomes, including rates of progression and cognitive subscales. CONCLUSIONS: In spite of apparently similar criteria for MCI being adopted by the 7 studies, the implementation of the criteria varied a great deal. Several explanations including instruments used to characterize participants and variability among study populations contributed to the findings.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Apolipoproteína E4/genética , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/genética , Progressão da Doença , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Nootrópicos/uso terapêutico , Seleção de Pacientes , Placebos , Índice de Gravidade de Doença
16.
Gerontologist ; 57(2): 348-358, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-26553736

RESUMO

Purpose of the Study: The goal of the study was to examine barriers and facilitators to clinical research participation among African Americans, as well as recommendations for overcoming these. Design and Methods: Eight focus groups were conducted consisting of 64 individuals. These focus groups targeted 2 groups of individuals: (a) community members, including both individuals involved in research and individuals not involved in research, and (b) community leaders, including clergy, community health care providers and service providers who may influence decisions to participate in research. Results: Among participants in both groups, the most common barriers to participation included fear and mistrust of research due to multiple factors, such as a lack of information about research and prevailing knowledge of historical occurrences. Facilitators to research participation included intrinsic factors, such as a desire to help others, and extrinsic factors, such as familiarity with the research recruiter. The focus groups also directly engaged participants in discussions of strategies that might improve recruitment, such as the importance of providing personal stories that enable community members to understand the potential benefits of research. Implications: Findings from these focus groups address the mandate from funding agencies that emphasize the importance of including racially diverse populations in clinical research studies, and offer potential solutions for increasing the recruitment and retention of minority participants.


Assuntos
Afro-Americanos , Doença de Alzheimer , Atitude , Seleção de Pacientes , Idoso , Pesquisa Biomédica , Clero , Serviços de Saúde Comunitária , Feminino , Grupos Focais , Pessoal de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Confiança
17.
Alzheimers Dement (Amst) ; 4: 159-168, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27830173

RESUMO

INTRODUCTION: With expansion of clinical trials to individuals across the spectrum of Alzheimer disease (AD) from preclinical to symptomatic phases, it is increasingly important to quantify AD severity using methods that capture underlying pathophysiology. METHODS: We derived an AD severity measure based on biomarkers from brain imaging, neuropathology, and cognitive testing using latent variable modeling. We used data from ADNI-1 (N = 822) and applied findings to BIOCARD study (N = 349). We evaluated criterion validity for distinguishing diagnostic groups and construct validity by evaluating rates of change in AD severity. RESULTS: The AD severity factor cross-sectionally distinguishes cognitively normal participants from MCI (AUC = 0.87) and AD dementia (AUC = 0.94). Among ADNI MCI subjects, worsening scores predict faster progression to AD dementia (HR = 1.17; 95% CI, 1.13-1.22). In ADNI and BIOCARD, the pace of change in AD severity is steepest among progressors, with persisting differences by baseline diagnosis. DISCUSSION: Our content-valid latent variable measurement model is a reasonable approach for grading AD severity across a broad spectrum beginning at preclinical stages of AD.

18.
JAMA Neurol ; 73(10): 1217-1224, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27571329

RESUMO

Importance: Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets. Objective: To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression. Design, Setting, and Participants: The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state. Main Outcomes and Measures: Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site. Results: Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (ß = 4.65; 95% CI, 1.72-7.58; P = .002), E326K (ß = 3.42; 95% CI, 0.66-6.17; P = .02), and GBA variants combined as a single group (ß = 4.01; 95% CI, 1.95-6.07; P = 1.5 × 10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (ß = 0.38; 95% CI, 0.23-0.53; P = .01) and E326K (ß = 0.64; 95% CI, 0.43-0.86; P = .002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P = .01) and GBA variant carriers (15 of 39 [38.5%]; P = .04) progressed to mild cognitive impairment or dementia. Conclusions and Relevance: GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.


Assuntos
Progressão da Doença , Glucosilceramidase/genética , Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia , Idoso , Disfunção Cognitiva , Demência , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Genético
19.
Neurobiol Dis ; 94: 55-62, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27312774

RESUMO

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value <0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia.


Assuntos
Demência/genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Doença por Corpos de Lewy/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Corpos de Lewy/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , América do Norte
20.
J Neurol Sci ; 365: 89-95, 2016 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-27206882

RESUMO

Type II diabetes mellitus (DM) increases risk for cognitive decline and is associated with brain atrophy in older demented and non-demented individuals. We investigated (1) the cross-sectional association between fasting blood glucose level and cortical thickness in a sample of largely middle-aged, cognitively normal adults, and (2) whether these associations were modified by genes associated with both lipid processing and dementia. To explore possible modifications by genetic status, we investigated the interaction between blood glucose levels and the apolipoprotein E (APOE) ε4 allele and the translocase of the outer mitochondrial membrane (TOMM) 40 '523 genotype on cortical thickness. Cortical thickness measures were based on mean thickness in a subset of a priori-selected brain regions hypothesized to be vulnerable to atrophy in Alzheimer's disease (AD) (i.e., 'AD vulnerable regions'). Participants included 233 cognitively normal subjects in the BIOCARD study who had a measure of fasting blood glucose and cortical thickness measures, quantified by magnetic resonance imaging (MRI) scans. After adjustment for age, sex, race, education, depression, and medical conditions, higher blood glucose was associated with thinner parahippocampal gyri (B=-0.002; 95% CI -0.004, -0.0004) and temporal pole (B=-0.002; 95% CI -0.004, -0.0001), as well as reduced average thickness over AD vulnerable regions (B=-0.001; 95% CI -0.002, -0.0001). There was no evidence for greater cortical thinning in ε4 carriers of the APOE gene or in APOE ε3/3 individuals carrying the TOMM40 VL/VL genotypes. When individuals with glucose levels in the diabetic range (≥126mg/dL), were excluded from the analysis, the associations between glucose levels and cortical thickness were no longer significant. These findings suggest that glucose levels in the diabetic range are associated with reduced cortical thickness in AD vulnerable regions as early as middle age.


Assuntos
Glicemia , Córtex Cerebral/diagnóstico por imagem , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Envelhecimento/psicologia , Apolipoproteínas E/genética , Glicemia/genética , Córtex Cerebral/patologia , Cognição , Estudos Transversais , Jejum , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Tamanho do Órgão
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