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1.
Neuroimage Clin ; 22: 101687, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30710872

RESUMO

Alzheimer's disease is considered a disconnection syndrome, motivating the use of brain network measures to detect changes in whole-brain resting state functional connectivity (FC). We investigated changes in FC within and among resting state networks (RSN) across four different stages in the Alzheimer's disease continuum. FC changes were examined in two independent cohorts of individuals (84 and 58 individuals, respectively) each comprising control, subjective cognitive decline, mild cognitive impairment and Alzheimer's dementia groups. For each participant, FC was computed as a matrix of Pearson correlations between pairs of time series from 278 gray matter brain regions. We determined significant differences in FC modular organization with two distinct approaches, network contingency analysis and multiresolution consensus clustering. Network contingency analysis identified RSN sub-blocks that differed significantly across clinical groups. Multiresolution consensus clustering identified differences in the stability of modules across multiple spatial scales. Significant modules were further tested for statistical association with memory and executive function cognitive domain scores. Across both analytic approaches and in both participant cohorts, the findings converged on a pattern of FC that varied systematically with diagnosis within the frontoparietal network (FP) and between the FP network and default mode network (DMN). Disturbances of modular organization were manifest as greater internal coherence of the FP network and stronger coupling between FP and DMN, resulting in less segregation of these two networks. Our findings suggest that the pattern of interactions within and between specific RSNs offers new insight into the functional disruption that occurs across the Alzheimer's disease spectrum.

2.
Neuroimage Clin ; 21: 101574, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30553759

RESUMO

BACKGROUND: Imaging techniques used to measure hippocampal atrophy are key to understanding the clinical progression of Alzheimer's disease (AD). Various semi-automated hippocampal segmentation techniques are available and require human expert input to learn how to accurately segment new data. Our goal was to compare 1) the performance of our automated hippocampal segmentation technique relative to manual segmentations, and 2) the performance of our automated technique when provided with a training set from two different raters. We also explored the ability of hippocampal volumes obtained using manual and automated hippocampal segmentations to predict conversion from MCI to AD. METHODS: We analyzed 161 1.5 T T1-weighted brain magnetic resonance images (MRI) from the ADCS Donepezil/Vitamin E clinical study. All subjects carried a diagnosis of mild cognitive impairment (MCI). Three different segmentation outputs (one produced by manual tracing and two produced by a semi-automated algorithm trained with training sets developed by two raters) were compared using single measure intraclass correlation statistics (smICC). The radial distance method was used to assess each segmentation technique's ability to detect hippocampal atrophy in 3D. We then compared how well each segmentation method detected baseline hippocampal differences between MCI subjects who remained stable (MCInc) and those who converted to AD (MCIc) during the trial. Our statistical maps were corrected for multiple comparisons using permutation-based statistics with a threshold of p < .01. RESULTS: Our smICC analyses showed significant agreement between the manual and automated hippocampal segmentations from rater 1 [right smICC = 0.78 (95%CI 0.72-0.84); left smICC = 0.79 (95%CI 0.72-0.85)], the manual segmentations from rater 1 versus the automated segmentations from rater 2 [right smICC = 0.78 (95%CI 0.7-0.84); left smICC = 0.78 (95%CI 0.71-0.84)], and the automated segmentations of rater 1 versus rater 2 [right smICC = 0.97 (95%CI 0.96-0.98); left smICC = 0.97 (95%CI 0.96-0.98)]. All three segmentation methods detected significant CA1 and subicular atrophy in MCIc compared to MCInc at baseline (manual: right pcorrected = 0.0112, left pcorrected = 0.0006; automated rater 1: right pcorrected = 0.0318, left pcorrected = 0.0302; automated rater 2: right pcorrected = 0.0029, left pcorrected = 0.0166). CONCLUSIONS: The hippocampal volumes obtained with a fast semi-automated segmentation method were highly comparable to the ones obtained with the labor-intensive manual segmentation method. The AdaBoost automated hippocampal segmentation technique is highly reliable allowing the efficient analysis of large data sets.

3.
Acta Neuropathol Commun ; 6(1): 114, 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30373672

RESUMO

This study aimed to determine the pattern of [18F]flortaucipir uptake in individuals affected by Gerstmann-Sträussler-Scheinker disease (GSS) associated with the PRNP F198S mutation. The aims were to: 1) determine the pattern of [18F]flortaucipir uptake in two GSS patients; 2) compare tau distribution by [18F]flortaucipir PET imaging among three groups: two GSS patients, two early onset Alzheimer's disease patients (EOAD), two cognitively normal older adults (CN); 3) validate the PET imaging by comparing the pattern of [18F]flortaucipir uptake, in vivo, with that of tau neuropathology, post-mortem. Scans were processed to generate standardized uptake value ratio (SUVR) images. Regional [18F]flortaucipir SUVR was extracted and compared between GSS patients, EOADs, and CNs. Neuropathology and tau immunohistochemistry were carried out post-mortem on a GSS patient who died 9 months after the [18F]flortaucipir scan. The GSS patients were at different stages of disease progression. Patient A was mildly to moderately affected, suffering from cognitive, psychiatric, and ataxia symptoms. Patient B was moderately to severely affected, suffering from ataxia and parkinsonism accompanied by psychiatric and cognitive symptoms. The [18F]flortaucipir scans showed uptake in frontal, cingulate, and insular cortices, as well as in the striatum and thalamus. Uptake was greater in Patient B than in Patient A. Both GSS patients showed greater uptake in the striatum and thalamus than the EOADs and greater uptake in all evaluated regions than the CNs. Thioflavin S fluorescence and immunohistochemistry revealed that the anatomical distribution of tau pathology is consistent with that of [18F]flortaucipir uptake. In GSS patients, the neuroanatomical localization of pathologic tau, as detected by [18F]flortaucipir, suggests correlation with the psychiatric, motor, and cognitive symptoms. The topography of uptake in PRNP F198S GSS is strikingly different from that seen in AD. Further studies of the sensitivity, specificity, and anatomical patterns of tau PET in diseases with tau pathology are warranted.

4.
Neurobiol Dis ; 114: 120-128, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29501530

RESUMO

Synaptic neurodegeneration is thought to be an early event initiated by soluble ß-amyloid (Aß) aggregates that closely correlates with cognitive decline in Alzheimer disease (AD). Apolipoprotein ε4 (APOE4) is the most common genetic risk factor for both familial AD (FAD) and sporadic AD; it accelerates Aß aggregation and selectively impairs glutamate receptor function and synaptic plasticity. However, its molecular mechanisms remain elusive and these synaptic deficits are difficult to monitor. AD- and APOE4-dependent plasma biomarkers have been proposed, but synapse-related plasma biomarkers are lacking. We evaluated neuronal pentraxin 1 (NP1), a potential CNS-derived plasma biomarker of excitatory synaptic pathology. NP1 is preferentially expressed in brain and involved in glutamate receptor internalization. NP1 is secreted presynaptically induced by Aß oligomers, and implicated in excitatory synaptic and mitochondrial deficits. Levels of NP1 and its fragments were increased in a correlated fashion in both brain and plasma of 7-8 month-old E4FAD mice relative to E3FAD mice. NP1 was also found in exosome preparations and reduced by dietary DHA supplementation. Plasma NP1 was higher in E4FAD+ (APOE4+/+/FAD+/-) relative to E4FAD- (non-carrier; APOE4+/+/FAD-/-) mice, suggesting NP1 is modulated by Aß expression. Finally, relative to normal elderly, plasma NP1 was also elevated in patients with mild cognitive impairment (MCI) and elevated further in the subset who progressed to early-stage AD. In those patients, there was a trend towards increased NP1 levels in APOE4 carriers relative to non-carriers. These findings indicate that NP1 may represent a potential synapse-derived plasma biomarker relevant to early alterations in excitatory synapses in MCI and early-stage AD.

5.
JAMA Neurol ; 75(3): 328-341, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29340569

RESUMO

Importance: Late-onset Alzheimer disease (AD) is highly heritable. Genome-wide association studies have identified more than 20 AD risk genes. The precise mechanism through which many of these genes are associated with AD remains unknown. Objective: To investigate the association of the top 20 AD risk variants with brain amyloidosis. Design, Setting, and Participants: This study analyzed the genetic and florbetapir F 18 data from 322 cognitively normal control individuals, 496 individuals with mild cognitive impairment, and 159 individuals with AD dementia who had genome-wide association studies and 18F-florbetapir positron emission tomographic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a prospective, observational, multisite tertiary center clinical and biomarker study. This ongoing study began in 2005. Main Outcomes and Measures: The study tested the association of AD risk allele carrier status (exposure) with florbetapir mean standard uptake value ratio (outcome) using stepwise multivariable linear regression while controlling for age, sex, and apolipoprotein E ε4 genotype. The study also reports on an exploratory 3-dimensional stepwise regression model using an unbiased voxelwise approach in Statistical Parametric Mapping 8 with cluster and significance thresholds at 50 voxels and uncorrected P < .01. Results: This study included 977 participants (mean [SD] age, 74 [7.5] years; 535 [54.8%] male and 442 [45.2%] female) from the ADNI-1, ADNI-2, and ADNI-Grand Opportunity. The adenosine triphosphate-binding cassette subfamily A member 7 (ABCA7) gene had the strongest association with amyloid deposition (χ2 = 8.38, false discovery rate-corrected P < .001), after apolioprotein E ε4. Significant associations were found between ABCA7 in the asymptomatic and early symptomatic disease stages, suggesting an association with rapid amyloid accumulation. The fermitin family homolog 2 (FERMT2) gene had a stage-dependent association with brain amyloidosis (FERMT2 × diagnosis χ2 = 3.53, false discovery rate-corrected P = .05), which was most pronounced in the mild cognitive impairment stage. Conclusions and Relevance: This study found an association of several AD risk variants with brain amyloidosis. The data also suggest that AD genes might differentially regulate AD pathologic findings across the disease stages.

6.
Brain Imaging Behav ; 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29305751

RESUMO

The hippocampus has been widely studied using neuroimaging, as it plays an important role in memory and learning. However, hippocampal subfield information is difficult to capture by standard magnetic resonance imaging (MRI) techniques. To facilitate morphometric study of hippocampal subfields, ADNI introduced a high resolution (0.4 mm in plane) T2-weighted turbo spin-echo sequence that requires 8 min. With acceleration, the protocol can be acquired in 4 min. We performed a comparative study of hippocampal subfield volumes using standard and accelerated protocols on a Siemens Prisma 3T MRI in an independent sample of older adults that included 10 cognitively normal controls, 9 individuals with subjective cognitive decline, 10 with mild cognitive impairment, and 6 with a clinical diagnosis of Alzheimer's disease (AD). The Automatic Segmentation of Hippocampal Subfields (ASHS) software was used to segment 9 primary labeled regions including hippocampal subfields and neighboring cortical regions. Intraclass correlation coefficients were computed for reliability tests between 4 and 8 min scans within and across the four groups. Pairwise group analyses were performed, covaried for age, sex and total intracranial volume, to determine whether the patterns of group differences were similar using 4 vs. 8 min scans. The 4 and 8 min protocols, analyzed by ASHS segmentation, yielded similar volumetric estimates for hippocampal subfields as well as comparable patterns of differences between study groups. The accelerated protocol can provide reliable imaging data for investigation of hippocampal subfields in AD-related MRI studies and the decreased scan time may result in less vulnerability to motion.

7.
Alzheimer Dis Assoc Disord ; 32(1): 35-42, 2018 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29140859

RESUMO

INTRODUCTION: Few studies to date have explored patient and caregiver views on the clinical use of amyloid positron emission tomography (PET). METHODS: A 7-item questionnaire assessing patient and caregiver views (510 total respondents) toward amyloid PET imaging was advertised broadly through alz.org/trialmatch. RESULTS: We received 510 unique responses from 48 US states, 2 Canadian provinces, the Dominican Republic, and Greece. Both patients and caregivers indicated that they would want to receive amyloid imaging if offered the opportunity. Over 88% of respondents had a positive response (∼10% with neutral and 2% with negative responses) to whether amyloid PET should be offered routinely and be reimbursed. Such information was felt to be useful for long-term legal, financial, and health care planning. Respondents identifying with early age cognitive decline (younger than 65 y) were more likely to explore options for disability insurance (P=0.03). Responders from the Midwest were more likely to utilize information from amyloid imaging for legal planning (P=0.02), disability insurance (P=0.02), and life insurance (P=0.04) than other US regions. DISCUSSION: Patients and caregivers supported the use of amyloid PET imaging in clinical practice and felt that the information would provide significant benefits particularly in terms of future planning.

8.
Alzheimers Dement (Amst) ; 9: 57-66, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29159268

RESUMO

Introduction: We investigated the association between olfactory identification and Alzheimer's disease biomarkers, including amyloid, tau, and neurodegeneration. Methods: Thirty-four older adults, including 19 cognitively normal (CN), 10 subjective cognitive decline (SCD), and 5 mild cognitive impairment, underwent amyloid positron emission tomography, magnetic resonance imaging, and the University of Pennsylvania Smell Identification Test (UPSIT). Twenty-six also underwent tau positron emission tomography. Associations between the UPSIT and regionally sampled amyloid, tau, and temporal atrophy were evaluated. Voxel-wise regression models were also utilized. Analyses were conducted with the full sample and only CN/SCD. Results: Lower UPSIT scores were associated with increased temporal and parietal tau burden in regional and voxel-wise analyses in the full sample and in CN and SCD only. Temporal lobe atrophy was associated with lower UPSIT score. Amyloid was not associated with the UPSIT. Discussion: Impairment on the UPSIT may be a good marker for tau and neurodegeneration in preclinical or prodromal Alzheimer's disease.

9.
Brain Lang ; 172: 22-29, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28577822

RESUMO

Language impairment is common in prodromal stages of Alzheimer's disease (AD) and progresses over time. However, the genetic architecture underlying language performance is poorly understood. To identify novel genetic variants associated with language performance, we analyzed brain MRI and performed a genome-wide association study (GWAS) using a composite measure of language performance from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=1560). The language composite score was associated with brain atrophy on MRI in language and semantic areas. GWAS identified GLI3 (GLI family zinc finger 3) as significantly associated with language performance (p<5×10-8). Enrichment of GWAS association was identified in pathways related to nervous system development and glutamate receptor function and trafficking. Our results, which warrant further investigation in independent and larger cohorts, implicate GLI3, a developmental transcription factor involved in patterning brain structures, as a putative gene associated with language dysfunction in AD.


Assuntos
Doença de Alzheimer/genética , Estudo de Associação Genômica Ampla , Linguagem , Idoso , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Feminino , Humanos , Fatores de Transcrição Kruppel-Like/genética , Imagem por Ressonância Magnética , Masculino , Proteínas do Tecido Nervoso/genética , Neuroimagem , Sintomas Prodrômicos , Receptores de Glutamato/metabolismo , Proteína Gli3 com Dedos de Zinco
10.
Alzheimers Res Ther ; 9(1): 35, 2017 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-28472970

RESUMO

BACKGROUND: Mild cognitive impairment (MCI) has an uncertain etiology and prognosis and may be challenging for clinicians to discuss with patients and families. Amyloid imaging may aid specialists in determining MCI etiology and prognosis, but creates novel challenges related to disease labeling. METHODS: We convened a workgroup to formulate recommendations for clinicians providing care to MCI patients. RESULTS: Clinicians should use the MCI diagnosis to validate patient and family concerns and educate them that the patient's cognitive impairment is not normal for his or her age and education level. The MCI diagnosis should not be used to avoid delivering a diagnosis of dementia. For patients who meet Appropriate Use Criteria after standard-of-care clinical workup, amyloid imaging may position specialists to offer more information about etiology and prognosis. Clinicians must set appropriate expectations, including ensuring that patients and families understand the limitations of amyloid imaging. Communication of negative results should include that patients remain at elevated risk for dementia and that negative scans do not indicate a specific diagnosis or signify brain health. Positive amyloid imaging results should elicit further monitoring and conversations about appropriate advance planning. Clinicians should offer written summaries, including referral to appropriate social services. CONCLUSIONS: In patients with MCI, there is a need to devote considerable time and attention to patient education and shared decision-making. Amyloid imaging may be a tool to aid clinicians. Careful management of patient expectations and communication of scan results will be critical to the appropriate use of amyloid imaging information.


Assuntos
Proteínas Amiloidogênicas/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Imagem Molecular/métodos , Neuroimagem/métodos , Biomarcadores/metabolismo , Medicina Baseada em Evidências , Humanos , Tomografia por Emissão de Pósitrons/métodos
11.
Neuroimage Clin ; 15: 56-61, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28491492

RESUMO

Hippocampal atrophy, amyloid plaques, and neurofibrillary tangles are established pathologic markers of Alzheimer's disease. We analyzed the temporal lobes of 9 Alzheimer's dementia (AD) and 7 cognitively normal (NC) subjects. Brains were scanned post-mortem at 7 Tesla. We extracted hippocampal volumes and radial distances using automated segmentation techniques. Hippocampal slices were stained for amyloid beta (Aß), tau, and cresyl violet to evaluate neuronal counts. The hippocampal subfields, CA1, CA2, CA3, CA4, and subiculum were manually traced so that the neuronal counts, Aß, and tau burden could be obtained for each region. We used linear regression to detect associations between hippocampal atrophy in 3D, clinical diagnosis and total as well as subfield pathology burden measures. As expected, we found significant correlations between hippocampal radial distance and mean neuronal count, as well as diagnosis. There were subfield specific associations between hippocampal radial distance and tau in CA2, and cresyl violet neuronal counts in CA1 and subiculum. These results provide further validation for the European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP).


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Imagem por Ressonância Magnética/estatística & dados numéricos , Lobo Temporal/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Atrofia/diagnóstico por imagem , Atrofia/patologia , Estudos de Coortes , Feminino , Hipocampo/patologia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Lobo Temporal/patologia , Adulto Jovem
12.
Nat Rev Neurol ; 13(6): 321-322, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28452353
13.
Alzheimers Dement (Amst) ; 6: 171-181, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28275699

RESUMO

INTRODUCTION: Both theoretical and statistically derived approaches have been used in research settings for predicting cognitive decline. METHODS: Fifty-eight cognitively normal (NC) and 71 mild cognitive impairment (MCI) subjects completed a comprehensive cognitive battery for up to 5 years of follow-up. Composite indices of cognitive function were derived using a classic theoretical approach and exploratory factor analysis (EFA). Cognitive variables comprising each factor were averaged to form the EFA composite indices. Logistic regression was used to investigate whether these cognitive composites can reliably predict cognitive outcomes. RESULTS: Neither method predicted decline in NC. The theoretical memory, executive, attention, and language composites and the EFA-derived "attention/executive" and "verbal memory" composites were significant predictors of decline in MCI. The best models achieved an area under the curve of 0.94 in MCI. CONCLUSIONS: The theoretical and the statistically derived cognitive composite approaches are useful in predicting decline in MCI but not in NC.

14.
Alzheimers Dement ; 13(8): 924-932, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28174068

RESUMO

INTRODUCTION: Amyloid imaging is a tool that has recently become available to dementia specialists evaluating patients with possible Alzheimer's disease. Studies have assessed the impact of amyloid imaging on diagnostic and treatment decisions, but patient and family perspectives have received less attention. METHODS: To examine how amyloid imaging affects the diagnostic experience of patients and families, we interviewed members of 26 patient-caregiver dyads with whom a neurologist discussed the option of amyloid positron emission tomography. RESULTS: Most participants who chose to undergo amyloid imaging would choose to do so again. Regardless of the scan outcome, patients and caregivers commonly expressed relief on learning the scan results. Some participants expressed expectations that were beyond scan capabilities. DISCUSSION: Amyloid imaging may provide information that patients and their families find useful. Clinicians must set correct expectations and ensure that families understand the limitations of amyloid imaging.


Assuntos
Amiloide/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Cuidadores/psicologia , Satisfação do Paciente , Tomografia por Emissão de Pósitrons/psicologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Compostos de Anilina , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Etilenoglicóis , Feminino , Humanos , Entrevistas como Assunto , Masculino , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/metabolismo , Transtornos da Memória/psicologia , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos
15.
Neurotherapeutics ; 14(1): 62-68, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27873182

RESUMO

In vivo imaging of the tau protein has the potential to aid in quantitative diagnosis of Alzheimer's disease, corroborate or dispute the amyloid hypothesis, and demonstrate biomarker engagement in clinical drug trials. A host of tau positron emission tomography agents have been designed, validated, and tested in humans. Several agents have characteristics approaching the ideal imaging tracer with some limitations, primarily regarding off-target binding. Dozens of clinical trials evaluating imaging techniques and several pharmaceutical trials have begun to integrate tau imaging into their protocols.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Proteínas tau/metabolismo , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ensaios Clínicos como Assunto , Humanos
16.
J Alzheimers Dis ; 56(1): 229-237, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27911294

RESUMO

BACKGROUND: Donepezil is an acetylcholinesterase inhibitor frequently prescribed for the treatment of mild cognitive impairment (MCI) though not approved by the Food and Drug Administration for this indication. In Alzheimer's disease, butyrylcholinesterase (BChE) activity increases with disease progression and may replace acetylcholinesterase function. The most frequent polymorphism of BChE is the K-variant, which is associated with lower acetylcholine-hydrolyzing activity. BChE-K polymorphism has been studied in Alzheimer's disease progression and donepezil therapy, and has led to contradictory results. OBJECTIVES: To determine whether BChE-K genotype predicts response to donepezil in MCI. METHODS: We examined the association between BChE-K genotype and changes in cognitive function using the data collected during the ADCS vitamin E/donepezil clinical trial in MCI. RESULTS: We found significant interactions between BChE-K genotype and the duration of donepezil treatment, with increased changes in MMSE and CDR-SB scores compared to the common allele in MCI subjects treated during the 3-year trial. We found faster MMSE decline and CDR-SB rise in BChE-K homozygous individuals treated with donepezil compared to the untreated. We observed similar interactions between BChE-K genotype and steeper changes in MMSE and CDR-SB scores in APOE4 carriers treated with donepezil compared to controls. CONCLUSION: BChE-K polymorphisms are associated with deleterious changes in cognitive decline in MCI patients treated with donepezil for 3 years. This indicates that BChE-K genotyping should be performed to help identify subsets of subjects at risk for donepezil therapy, like those carrying APOE4. BChE-K and APOE4 carriers should not be prescribed off-label donepezil therapy for MCI management.


Assuntos
Butirilcolinesterase/genética , Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/genética , Indanos/uso terapêutico , Piperidinas/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/genética , Progressão da Doença , Donepezila , Feminino , Frequência do Gene , Genótipo , Humanos , Estudos Longitudinais , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Testes Neuropsicológicos , Avaliação de Resultados (Cuidados de Saúde) , Farmacognosia , Fatores de Tempo
17.
Dement Geriatr Cogn Dis Extra ; 6(3): 508-517, 2016 Sep-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27920794

RESUMO

INTRODUCTION: We investigated the effect dance experience may have on cortical gray matter thickness and cognitive performance in elderly participants with and without mild cognitive impairment (MCI). METHODS: 39 cognitively normal and 48 MCI elderly participants completed a questionnaire regarding their lifetime experience with music, dance, and song. Participants identified themselves as either dancers or nondancers. All participants received structural 1.5-tesla MRI scans and detailed clinical and neuropsychological evaluations. An advanced 3D cortical mapping technique was then applied to calculate cortical thickness. RESULTS: Despite having a trend-level significantly thinner cortex, dancers performed better in cognitive tasks involving learning and memory, such as the California Verbal Learning Test-II (CVLT-II) short delay free recall (p = 0.004), the CVLT-II long delay free recall (p = 0.003), and the CVLT-II learning over trials 1-5 (p = 0.001). DISCUSSION: Together, these results suggest that dance may result in an enhancement of cognitive reserve in aging, which may help avert or delay MCI.

18.
Neurobiol Aging ; 47: 201-209, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27614114

RESUMO

The mechanisms underlying presenilin 1 (PSEN1) mutation-associated spastic paraparesis (SP) are not clear. We compared diffusion and volumetric magnetic resonance measures between 3 persons with SP associated with the A431E mutation and 7 symptomatic persons with PSEN1 mutations without SP matched for symptom duration. We performed amyloid imaging and central motor and somatosensory conduction studies in 1 subject with SP. We found decreases in fractional anisotropy and increases in mean diffusivity in widespread white-matter areas including the corpus callosum, occipital, parietal, and frontal lobes in PSEN1 mutation carriers with SP. Volumetric measures were not different, and amyloid imaging showed low signal in sensorimotor cortex and other areas in a single subject with SP. Electrophysiological studies demonstrated both slowed motor and sensory conduction in the lower extremities in this same subject. Our results suggest that SP in carriers of the A431E PSEN1 mutation is a manifestation of widespread white-matter abnormalities not confined to the corticospinal tract that is at most indirectly related to the mutation's effect on amyloid precursor protein processing and amyloid deposition.


Assuntos
Estudos de Associação Genética , Mutação , Condução Nervosa , Paraparesia Espástica/diagnóstico por imagem , Paraparesia Espástica/genética , Presenilina-1/genética , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Anisotropia , Imagem de Tensor de Difusão , Fenômenos Eletrofisiológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Motor/fisiopatologia , Paraparesia Espástica/patologia , Paraparesia Espástica/fisiopatologia , Córtex Somatossensorial/fisiopatologia , Substância Branca/metabolismo , Substância Branca/fisiopatologia
19.
Alzheimers Dement (Amst) ; 2: 113-22, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27239542

RESUMO

INTRODUCTION: The objective of this study was to assess the utility of novel verbal fluency scores for predicting conversion from mild cognitive impairment (MCI) to clinical Alzheimer's disease (AD). METHOD: Verbal fluency lists (animals, vegetables, F, A, and S) from 107 MCI patients and 51 cognitively normal controls were transcribed into electronic text files and automatically scored with traditional raw scores and five types of novel scores computed using methods from machine learning and natural language processing. Additional scores were derived from structural MRI scans: region of interest measures of hippocampal and ventricular volumes and gray matter scores derived from performing ICA on measures of cortical thickness. Over 4 years of follow-up, 24 MCI patients converted to AD. Using conversion as the outcome variable, ensemble classifiers were constructed by training classifiers on the individual groups of scores and then entering predictions from the primary classifiers into regularized logistic regression models. Receiver operating characteristic curves were plotted, and the area under the curve (AUC) was measured for classifiers trained with five groups of available variables. RESULTS: Classifiers trained with novel scores outperformed those trained with raw scores (AUC 0.872 vs 0.735; P < .05 by DeLong test). Addition of structural brain measurements did not improve performance based on novel scores alone. CONCLUSION: The brevity and cost profile of verbal fluency tasks recommends their use for clinical decision making. The word lists generated are a rich source of information for predicting outcomes in MCI. Further work is needed to assess the utility of verbal fluency for early AD.

20.
Continuum (Minneap Minn) ; 22(2 Dementia): 419-34, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27042902

RESUMO

PURPOSE OF REVIEW: This article discusses the recent advances in the diagnosis and treatment of Alzheimer disease (AD). RECENT FINDINGS: In recent years, significant advances have been made in the fields of genetics, neuroimaging, clinical diagnosis, and staging of AD. One of the most important recent advances in AD is our ability to visualize amyloid pathology in the living human brain. The newly revised criteria for diagnosis of AD dementia embrace the use for biomarkers as supportive evidence for the underlying pathology. Guidelines for the responsible use of amyloid positron emission tomography (PET) have been developed, and the clinical and economic implications of amyloid PET imaging are actively being explored. SUMMARY: Our improved understanding of the clinical onset, progression, neuroimaging, pathologic features, genetics, and other risk factors for AD impacts the approaches to clinical diagnosis and future therapeutic interventions.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/terapia , Doença de Alzheimer/epidemiologia , Transtornos Cognitivos/etiologia , Progressão da Doença , Humanos , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica
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