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1.
Neurobiol Aging ; 83: 54-62, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31585367

RESUMO

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials.

3.
Brain ; 142(6): 1503-1527, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31039256

RESUMO

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-ß plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

4.
Int J Geriatr Psychiatry ; 34(6): 828-835, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30864178

RESUMO

INTRODUCTION: Sexual minority discrimination might lead to a higher risk of mild cognitive impairment (MCI) and dementia. The aim of this study was to assess the risk of MCI and dementia between older adults in same-sex relationships (SSR) and opposite-sex relationships (OSR). METHODS: We analyzed longitudinal data from the National Alzheimer's Coordinating Center up to September 2017. Analyses included cognitively normal individuals 55+ at baseline who had a spouse, partner, or companion as study partner at any assessment. Associations were calculated using survival analysis adjusting for demographics and APOE-e4 carrier status. RESULTS: Hazard ratios of MCI and dementia did not differ statistically between SSR and OSR individuals in the total sample nor stratified by sex. CONCLUSION: The lack of association between SSR and MCI and dementia warrants future research into their potential resilience mechanisms and the inclusion of sexual minority status questions in research and surveillance studies. The potential recruitment bias caused by nonprobabilistic sampling of the cohort and the reporting and ascertainment bias caused by using SSR to infer sexual minority status may have influenced our findings.

5.
Lab Invest ; 99(7): 1049-1055, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30710118

RESUMO

Primary age-related tauopathy (PART) is increasingly recognized as a pathologic entity distinct from Alzheimer's disease (AD). Given that the diagnosis of PART is an autopsy diagnosis, it is unclear how PART is perceived in clinical practice. Thus, we investigated the presumptive primary and contributing diagnoses in individuals who had cognitive impairment while alive and who met neuropathologic criteria for PART at autopsy. We also compared these clinical diagnoses for people with PART to those with AD neuropathology (ADNP). We used data on 1354 participants from the National Alzheimer's Coordinating Center, restricting to those with no neuritic plaques (PART) or moderate/frequent neuritic plaques (ADNP); clinical visit within two years of autopsy; and mild cognitive impairment (MCI) or dementia at last visit. To assess if PART participants were less likely to receive a clinical diagnosis of AD at their last visit prior to autopsy, we used logistic regression, controlling for age, sex, education, and APOE ε4 status. There were 161 PART individuals (n = 49 MCI; n = 112 dementia) and 1193 individuals with ADNP (n = 75 MCI; n = 1118 dementia). Primary clinical diagnosis of AD was more common in those with ADNP (MCI: 69%; demented: 86%) than PART (MCI: 57%; demented: 52%). In the adjusted analysis, primary and contributing clinical diagnoses of AD remained less likely in PART vs. ADNP participants with dementia (OR: 0.22, 95% CI: 0.13-0.38). This study suggests that clinicians recognize a distinction in the clinical presentation between PART and ADNP, diagnosing AD less frequently in those with PART. Nonetheless, clinical AD was diagnosed greater than 50% of the time in PART participants with MCI or dementia. Ante-mortem criteria for diagnosis of PART need to be established, as PART is a neuropathological entity that is distinct from AD and has its own clinical and cognitive outcomes.

6.
J Neuropathol Exp Neurol ; 78(3): 219-228, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30715383

RESUMO

This study examined differences in neuropsychological test scores between individuals with primary age-related tauopathy (PART) and Alzheimer disease (AD) using cross-sectional data from the National Alzheimer's Coordinating Center. Linear regression tested for differences in 4 cognitive domains stratified by cognitive status (global Clinical Dementia Rating [CDR]). The sample included 240 participants with no neuritic plaques (NP) (definite PART), 186 with sparse NP (possible PART), and 510 with moderate/frequent NP (AD). Four cognitive domain z-score outcome variables (memory, attention, executive function, and semantic memory/language) were calculated using 12 neuropsychological tests. Definite PART participants had a sparing of semantic memory/language compared to those with AD, with a mean adjusted z-score difference of 0.37 (95% confidence interval [CI]: 0.16-0.58) for those with CDR = 0.5 or 1 and of 0.92 (CI: 0.22-1.63) for those with CDR = 2 or 3. Compared to participants with AD, definite PART participants with CDR = 0.5 or 1 had sparing of memory (adjusted z-score difference: 0.61; CI: 0.39-0.84) and definite PART participants with CDR = 2 or 3 had sparing of attention (adjusted z-score difference: 0.76: CI: 0.09-1.43). Patterns of cognitive impairment differed between definite PART and AD, suggesting significant differences in clinical presentation between individuals from these 2 groups.

7.
Alzheimer Dis Assoc Disord ; 33(2): 87-94, 2019 Apr-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30633043

RESUMO

INTRODUCTION: We investigated whether cholinesterase inhibitors (ChEIs) benefit cognitive outcomes in mild cognitive impairment due to Alzheimer disease (MCI-AD) and in mild AD dementia (ADdem). METHODS: Data from 2242 individuals, clinically diagnosed with MCI-AD [Clinical Dementia Rating (CDR), 0 or 0.5] or with mild ADdem (CDR, 0.5 or 1), were available from the National Alzheimer's Coordinating Center's (NACC) Uniform Data Set (UDS). General linear mixed models were used to examine the annual change in the CDR Sum of Boxes (CDR-SB) and in neuropsychological performance. We compared slopes before and after ChEI initiation among ChEI users, and also compared the change in scores of ChEI users versus nonusers. RESULTS: Thirty-four percent of 944 MCI-AD and 72% of 1298 ADdem participants were ChEI users. Cognitive decline was greater after ChEI initiation in MCI-AD and ADdem groups (eg, MCI-AD, CDR-SB: 0.03 points/y before initiation; 0.61 points/y after initiation, P<0.0001). Both MCI-AD and ADdem groups had faster decline after ChEI initiation than nonusers (eg, MCI-AD, CDR-SB: 0.61 points/y, ChEI users; 0.24 points/y, nonusers, P<0.0001). DISCUSSION: This study suggests that ChEI use may not improve the cognitive course in MCI-AD and mild ADdem.

8.
Brain ; 142(2): 460-470, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30689776

RESUMO

Mounting evidence indicates that the polygenic basis of late-onset Alzheimer's disease can be harnessed to identify individuals at greatest risk for cognitive decline. We have previously developed and validated a polygenic hazard score comprising of 31 single nucleotide polymorphisms for predicting Alzheimer's disease dementia age of onset. In this study, we examined whether polygenic hazard scores are associated with: (i) regional tracer uptake using amyloid PET; (ii) regional volume loss using longitudinal MRI; (iii) post-mortem regional amyloid-ß protein and tau associated neurofibrillary tangles; and (iv) four common non-Alzheimer's pathologies. Even after accounting for APOE, we found a strong association between polygenic hazard scores and amyloid PET standard uptake volume ratio with the largest effects within frontal cortical regions in 980 older individuals across the disease spectrum, and longitudinal MRI volume loss within the entorhinal cortex in 607 older individuals across the disease spectrum. We also found that higher polygenic hazard scores were associated with greater rates of cognitive and clinical decline in 632 non-demented older individuals, even after controlling for APOE status, frontal amyloid PET and entorhinal cortex volume. In addition, the combined model that included polygenic hazard scores, frontal amyloid PET and entorhinal cortex volume resulted in a better fit compared to a model with only imaging markers. Neuropathologically, we found that polygenic hazard scores were associated with regional post-mortem amyloid load and neuronal neurofibrillary tangles, even after accounting for APOE, validating our imaging findings. Lastly, polygenic hazard scores were associated with Lewy body and cerebrovascular pathology. Beyond APOE, we show that in living subjects, polygenic hazard scores were associated with amyloid deposition and neurodegeneration in susceptible brain regions. Polygenic hazard scores may also be useful for the identification of individuals at the highest risk for developing multi-aetiological dementia.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Herança Multifatorial/genética , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/genética
9.
Acta Neuropathol Commun ; 6(1): 142, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30567576

RESUMO

TAR-DNA binding protein 43 (TDP-43) proteinopathy is a common brain pathology in elderly persons, but much remains to be learned about this high-morbidity condition. Published stage-based systems for operationalizing disease severity rely on the involvement (presence/absence) of pathology in specific anatomic regions. To examine the comorbidities associated with TDP-43 pathology in aged individuals, we studied data from the National Alzheimer's Coordinating Center (NACC) Neuropathology Data Set. Data were analyzed from 929 included subjects with available TDP-43 pathology information, sourced from 27 different American Alzheimer's Disease Centers (ADCs). Cases with relatively unusual diseases including autopsy-proven frontotemporal lobar degeneration (FTLD-TDP or FTLD-tau) were excluded from the study. Our data provide new information about pathologic features that are and are not associated with TDP-43 pathologies in different brain areas-spinal cord, amygdala, hippocampus, entorhinal cortex/inferior temporal cortex, and frontal neocortex. Different research centers used cite-specific methods including different TDP-43 antibodies. TDP-43 pathology in at least one brain region was common (31.4%) but the pathology was rarely observed in spinal cord (1.8%) and also unusual in frontal cortex (5.3%). As expected, TDP-43 pathology was positively associated with comorbid hippocampal sclerosis pathology and with severe AD pathology. TDP-43 pathology was also associated with comorbid moderate-to-severe brain arteriolosclerosis. The association between TDP-43 pathology and brain arteriolosclerosis appears relatively specific since there was no detected association between TDP-43 pathology and microinfarcts, lacunar infarcts, large infarcts, cerebral amyloid angiopathy (CAA), or circle of Willis atherosclerosis. Together, these observations provide support for the hypothesis that many aged brains are affected by a TDP-43 proteinopathy that is more likely to be seen in brains with AD pathology, arteriolosclerosis pathology, or both.


Assuntos
Doença de Alzheimer/complicações , Encéfalo/metabolismo , Transtornos Cerebrovasculares/complicações , Proteinopatias TDP-43/complicações , Proteinopatias TDP-43/patologia , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Encéfalo/patologia , Transtornos Cerebrovasculares/patologia , Feminino , Humanos , Masculino
10.
PLoS One ; 13(11): e0206803, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30462667

RESUMO

Age-related changes in memory are not uniform, even in the absence of dementia. Characterization of non-disease associated cognitive changes is crucial to gain a more complete understanding of brain aging. Episodic memory was investigated in 13,037 ethnically diverse elderly (ages 72 to 85 years) with two to 15 years of follow-up, and with known dementia status, age, sex, education, and APOE genotypes. Adjusted trajectories of episodic memory performance over time were estimated using Latent Class Mixed Models. Analysis was conducted using two samples at baseline evaluation: i) non-cognitively impaired individuals, and ii) all individuals regardless of dementia status. We calculated the age-specific annual incidence rates of dementia in the non-demented elderly (n = 10,220). Two major episodic memory trajectories were estimated: 1) Stable-consisting of individuals exhibiting a constant or improved memory function, and 2) Decliner-consisting of individuals whose memory function declined. The majority of the study participants maintain their memory performance over time. Compared to those with Stable trajectory, individuals characterized as Decliners were more likely to have non-white ethnic background, fewer years of education, a higher frequency of ε4 allele at APOE gene and five times more likely to develop dementia. The steepest decline in episodic memory was observed in Caribbean-Hispanics compared to non-Hispanic whites (p = 4.3 x 10-15). The highest incident rates of dementia were observed in the oldest age group, among those of Caribbean-Hispanics ancestry and among Decliners who exhibited rates five times higher than those with Stable trajectories (11 per 100 person-years versus 3 per 100 person-years. Age, education, ethnic background and APOE genotype influence the maintenance of episodic memory. Declining memory is one of the strongest predictors of incident dementia.

11.
Science ; 360(6395)2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29930110

RESUMO

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.


Assuntos
Encefalopatias/genética , Transtornos Mentais/genética , Encefalopatias/classificação , Encefalopatias/diagnóstico , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Transtornos Mentais/classificação , Transtornos Mentais/diagnóstico , Fenótipo , Característica Quantitativa Herdável , Fatores de Risco
12.
J Neuropathol Exp Neurol ; 77(8): 717-726, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29945202

RESUMO

Neuropathologic evaluation remains the gold standard for determining the presence and severity of aging-related neurodegenerative diseases. Researchers at U.S. Alzheimer's Disease Centers (ADCs) have worked for >30 years studying human brains, with the goals of achieving new research breakthroughs. Harmonization and sharing among the 39 current and past ADCs is promoted by the National Alzheimer's Coordinating Center (NACC), which collects, audits, and disburses ADC-derived data to investigators on request. The past decades have witnessed revised disease definitions paired with dramatic expansion in the granularity and multimodality of the collected data. The NACC database now includes cognitive test scores, comorbidities, drug history, neuroimaging, and links to genomics. Relatively, recent advances in the neuropathologic diagnoses of Alzheimer's disease, frontotemporal lobar degeneration (FTLD), and vascular contributions to cognitive impairment and dementia catalyzed a 2014 update to the NACC Neuropathology Form completed by all ADCs. New focal points include cerebrovascular disease (including arteriolosclerosis, microbleeds, and microinfarcts), hippocampal sclerosis, TDP-43, and FTLD. Here, we provide summary data and analyses to illustrate the potential for both hypothesis-testing and also generating new hypotheses using the NACC Neuropathology data set, which represents one of the largest multi-center databases of carefully curated neuropathologic information that is freely available to researchers worldwide.

15.
Soc Sci Med ; 200: 27-35, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29355828

RESUMO

Preliminary studies suggest that neighborhood social and built environment (BE) characteristics may affect cognition in older adults. Older adults are particularly vulnerable to the neighborhood environment due to a decreasing range of routine travel with increasing age. We examined if multiple neighborhood BE characteristics are cross-sectionally associated with cognition in a diverse sample of older adults, and if the BE-cognition associations vary by individual-level demographics. The sample included 4539 participants from the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to examine the associations between five BE measures and four cognitive measures, and effect modification by individual-level education and race/ethnicity. In the overall sample, increasing social destination density, walking destination density, and intersection density were associated with worse overall cognition, whereas increasing proportion of land dedicated to retail was associated with better processing speed. Effect modification results suggest that the association between urban density and worse cognition may be limited to or strongest in those of non-white race/ethnicity. Although an increase in neighborhood retail destinations was associated with better cognition in the overall sample, these results suggest that certain BE characteristics in dense urban environments may have a disproportionately negative association with cognition in vulnerable populations. However, our findings must be replicated in longitudinal studies and other regional samples.


Assuntos
Cognição , Planejamento Ambiental/estatística & dados numéricos , Características de Residência/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/etnologia , Escolaridade , Grupos Étnicos/psicologia , Grupos Étnicos/estatística & dados numéricos , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , População Urbana/estatística & dados numéricos
16.
Alzheimer Dis Assoc Disord ; 32(1): 1-9, 2018 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29319603

RESUMO

Over recent decades, epidemiology has made significant contributions to our understanding of dementia, translating scientific discoveries into population health. Here, we propose reframing dementia epidemiology as "population neuroscience," blending techniques and models from contemporary neuroscience with those of epidemiology and biostatistics. On the basis of emerging evidence and newer paradigms and methods, population neuroscience will minimize the bias typical of traditional clinical research, identify the relatively homogenous subgroups that comprise the general population, and investigate broader and denser phenotypes of dementia and cognitive impairment. Long-term follow-up of sufficiently large study cohorts will allow the identification of cohort effects and critical windows of exposure. Molecular epidemiology and omics will allow us to unravel the key distinctions within and among subgroups and better understand individuals' risk profiles. Interventional epidemiology will allow us to identify the different subgroups that respond to different treatment/prevention strategies. These strategies will inform precision medicine. In addition, insights into interactions between disease biology, personal and environmental factors, and social determinants of health will allow us to measure and track disease in communities and improve population health. By placing neuroscience within a real-world context, population neuroscience can fulfill its potential to serve both precision medicine and population health.

17.
Neurobiol Aging ; 62: 64-71, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29107848

RESUMO

Thyroid hormone disease is common among older adults and is associated with cognitive impairment. However, pathologic correlates are not well understood. We studied pathologic and clinical factors associated with hypothyroidism, the most common manifestation of thyroid disease, in research subjects seen annually for clinical evaluations at U.S. Alzheimer's Disease Centers. Thyroid disease and treatment status were assessed during clinician interviews. Among autopsied subjects, there were 555 participants with treated hypothyroidism and 2146 without known thyroid disease; hypothyroidism was associated with severe atherosclerosis (odds ratio: 1.35; 95% confidence interval: 1.02, 1.79) but not Alzheimer's disease pathologies (amyloid plaques or neurofibrillary tangles). Among participants who did not undergo autopsy (4598 with treated hypothyroidism and 20,945 without known thyroid hormone disease), hypercholesterolemia and cerebrovascular disease (stroke and/or transient ischemic attack) were associated with hypothyroidism, complementing findings in the smaller autopsy sample. This is the first large-scale evaluation of neuropathologic concomitants of hypothyroidism in aged individuals. Clinical hypothyroidism was prevalent (>20% of individuals studied) and was associated with cerebrovascular disease but not Alzheimer's disease-type neuropathology.


Assuntos
Transtornos Cerebrovasculares/etiologia , Hipotireoidismo/complicações , Hipotireoidismo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Aterosclerose , Combinação de Medicamentos , Feminino , Humanos , Hipercolesterolemia/etiologia , Masculino , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Índice de Gravidade de Doença , Tiroxina/uso terapêutico , Tri-Iodotironina/uso terapêutico
18.
Alzheimer Dis Assoc Disord ; 32(1): 10-17, 2018 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29240561

RESUMO

INTRODUCTION: The neuropsychological battery of the Uniform Data Set (UDSNB) was implemented in 2005 by the National Institute on Aging (NIA) Alzheimer Disease Centers program to measure cognitive performance in dementia and mild cognitive impairment due to Alzheimer Disease. This paper describes a revision, the UDSNB 3.0. METHODS: The Neuropsychology Work Group of the NIA Clinical Task Force recommended revisions through a process of due diligence to address shortcomings of the original battery. The UDSNB 3.0 covers episodic memory, processing speed, executive function, language, and constructional ability. Data from 3602 cognitively normal participants in the National Alzheimer Coordinating Center database were analyzed. RESULTS: Descriptive statistics are presented. Multivariable linear regression analyses demonstrated score differences by age, sex, and education and were also used to create a normative calculator available online. DISCUSSION: The UDSNB 3.0 neuropsychological battery provides a valuable non proprietary resource for conducting research on cognitive aging and dementia.

19.
Neurology ; 89(17): 1773-1781, 2017 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-28939667

RESUMO

OBJECTIVE: To test whether decline in specific cognitive domains associated with Alzheimer disease neuropathologic change (ADNC) is modified by co-occurrence of other neuropathologies such as Lewy body disease (LBD) or vascular brain injury (VBI). METHODS: Data came from 1,603 autopsied participants evaluated at US Alzheimer's Disease Centers. Standardized z scores in memory, attention, language, and executive function were derived from neuropsychological test scores assessed at each annual visit. Multivariable linear mixed-effects models assessed associations between neuropathologies and longitudinal trajectories of domain scores. RESULTS: Compared to other participants, those with ADNC + LBD generally had worse cognitive trajectories, particularly lower initial executive function and faster attention decline. Participants with ADNC + VBI typically had less impairment and slower decline. Interactions were significant between LBD and ADNC for memory (p = 0.046) and between VBI and ADNC for language (p = 0.03); decline was slower than expected if these neuropathologies acted additively on the rate of decline. In secondary models, these interactions were limited to those with high ADNC (but not intermediate ADNC). In a subset of 260 participants with data on microinfarct location, cortical and subcortical microinfarcts were associated with decline in memory, language, and executive function in those without ADNC, but this effect was reduced among those with ADNC. CONCLUSIONS: ADNC + LBD (but not ADNC + VBI) was associated with poorer executive function and attention compared to other pathology groupings. However, the effect of co-occurring pathologies on cognitive trajectories may depend on the severity of ADNC. Future studies using antemortem biomarkers should seek to replicate these neuropathologic observations.


Assuntos
Encéfalo/patologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/psicologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/psicologia , Atenção , Autopsia , Transtornos Cognitivos/etiologia , Função Executiva , Feminino , Humanos , Linguagem , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/psicologia , Estudos Longitudinais , Masculino , Memória , Testes Neuropsicológicos
20.
Ann Neurol ; 82(3): 484-488, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28940650

RESUMO

Identifying asymptomatic older individuals at elevated risk for developing Alzheimer disease (AD) is of clinical importance. Among 1,081 asymptomatic older adults, a recently validated polygenic hazard score (PHS) significantly predicted time to AD dementia and steeper longitudinal cognitive decline, even after controlling for APOE ɛ4 carrier status. Older individuals in the highest PHS percentiles showed the highest AD incidence rates. PHS predicted longitudinal clinical decline among older individuals with moderate to high Consortium to Establish a Registry for Alzheimer's Disease (amyloid) and Braak (tau) scores at autopsy, even among APOE ɛ4 noncarriers. Beyond APOE, PHS may help identify asymptomatic individuals at highest risk for developing Alzheimer neurodegeneration. Ann Neurol 2017;82:484-488.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Predisposição Genética para Doença , Herança Multifatorial , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Genótipo , Humanos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Medição de Risco , Fatores de Risco
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