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1.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(4): 531-537, 2020 Apr 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895137

RESUMO

OBJECTIVE: To propose a coupled convolutional and graph convolutional network (CCGCN) model for diagnosis of Alzheimer's disease (AD) and its prodromal stage. METHODS: The disease-related brain regions generated by group-wise comparison were used as the input. The convolutional neural networks (CNNs) were used to extract disease-related features from different locations on brain magnetic resonance (MR) images. The generated features via the graph convolutional network (GCN) were processed, and graph pooling was performed to analyze the inherent relationship between the brain topology and the diagnosis task adaptively. Through ADNI dataset, we acquired the accuracy, sensitivity and specificity of the diagnosis tasks for AD and its prodromal stages, followed by an ablation study on the model structure. RESULTS: The CCGCN model outperformed the current state-of-the-art methods and showed a classification accuracy of 92.5% for AD with a sensitivity of 88.1% and a specificity of 96.0%. CONCLUSIONS: Based on the structural and topological features of the brain MR images, the proposed CCGCN model shows excellent performance in AD diagnosis and is expected to provide important assistance to physicians in disease diagnosis.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/diagnóstico por imagem , Encéfalo , Humanos , Imagem por Ressonância Magnética , Redes Neurais de Computação
2.
Neurology ; 95(6): e662-e670, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32636325

RESUMO

OBJECTIVE: Early biomarkers for dementia with Lewy bodies (DLB) are lacking. To determine whether EEG differentiates the prodromal phase of DLB from other causes of mild cognitive impairment (MCI) and whether EEG is predictive for time to conversion from MCI to DLB, we compared EEGs and clinical follow-up of patients with MCI due to DLB with those of patients with MCI due to Alzheimer disease (MCI-AD). METHODS: We compared 37 patients with MCI who developed DLB during follow-up or had an abnormal 123I-PF-CIT SPECT scan (MCI-DLB) with 67 age-matched patients with MCI-AD. EEGs were assessed visually with a score of increasing abnormality (range 1-5). We performed fast Fourier transform to analyze the power spectrum. With survival analyses, EEG characteristics were related to time to progression to dementia. RESULTS: The visual EEG score was higher in MCI-DLB (score >2 in 60%) compared to MCI-AD (score >2 in 8%, p < 0.001). We found frontal intermittent delta activity in 22% of MCI-DLB, not in MCI-AD. Patients with MCI-DLB had a lower peak frequency (7.5 [6.0-9.9] Hz vs 8.8 [6.8-10.2] in MCI-AD, p < 0.001) and more slow-wave activity. Several individual EEG measures showed good performance to discriminate MCI-DLB from MCI-AD (areas under the curve up to 0.94). In MCI-DLB, high visual EEG score, diffuse abnormalities, and low α2 power were related to time to progression to dementia (hazard ratios 4.1, 9.9, 5.1, respectively). CONCLUSIONS: Profound EEG abnormalities are already present in the prodromal stage of DLB and have diagnostic and prognostic value. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that EEG abnormalities are more common in MCI-DLB than MCI-AD.


Assuntos
Eletroencefalografia , Doença por Corpos de Lewy/diagnóstico , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Diagnóstico Diferencial , Progressão da Doença , Diagnóstico Precoce , Feminino , Seguimentos , Análise de Fourier , Humanos , Radioisótopos do Iodo , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/fisiopatologia , Masculino , Pessoa de Meia-Idade , Países Baixos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Estudos Prospectivos , Compostos Radiofarmacêuticos , Avaliação de Sintomas , Fatores de Tempo , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos , Proteínas tau/líquido cefalorraquidiano
3.
PLoS One ; 15(7): e0234255, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726311

RESUMO

'Normal aging' in the brain refers to age-related changes that occur independent of disease, in particular Alzheimer's disease. A major barrier to mapping normal brain aging has been the difficulty in excluding the earliest preclinical stages of Alzheimer's disease. Here, before addressing this issue we first imaged a mouse model and learn that the best MRI measure of dendritic spine loss, a known pathophysiological driver of normal aging, is one that relies on the combined use of functional and structural MRI. In the primary study, we then deployed the combined functional-structural MRI measure to investigate over 100 cognitively-normal people from 20-72 years of age. Next, to cover the tail end of aging, in secondary analyses we investigated structural MRI acquired from cognitively-normal people, 60-84 years of age, who were Alzheimer's-free via biomarkers. Collectively, the results from the primary functional-structural study, and the secondary structural studies revealed that the dentate gyrus is a hippocampal region differentially affected by aging, and that the entorhinal cortex is a region most resistant to aging. Across the cortex, the primary functional-structural study revealed and that the inferior frontal gyrus is differentially affected by aging, however, the secondary structural studies implicated other frontal cortex regions. Together, the results clarify how normal aging may affect the brain and has possible mechanistic and therapeutic implications.


Assuntos
Envelhecimento/fisiologia , Encéfalo/fisiologia , Senescência Celular/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/metabolismo , Mapeamento Encefálico/métodos , Disfunção Cognitiva/fisiopatologia , Espinhas Dendríticas/patologia , Giro Denteado/patologia , Córtex Entorrinal/patologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Camundongos , Pessoa de Meia-Idade
4.
Lancet ; 395(10242): 1988-1997, 2020 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-32593336

RESUMO

BACKGROUND: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome. METHODS: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid ß peptides 1-42 and 1-40 and their ratio (Aß1-42/1-40), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate. FINDINGS: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aß1-42/1-40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life. INTERPRETATION: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments. FUNDING: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health.


Assuntos
Doença de Alzheimer/metabolismo , Biomarcadores/sangue , Síndrome de Down/complicações , Adulto , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/epidemiologia , Peptídeos beta-Amiloides/metabolismo , Amiloidose/diagnóstico por imagem , Amiloidose/patologia , Apolipoproteínas E/metabolismo , Estudos de Casos e Controles , Disfunção Cognitiva/psicologia , Estudos Transversais , Síndrome de Down/epidemiologia , Síndrome de Down/mortalidade , Síndrome de Down/psicologia , Fluordesoxiglucose F18/administração & dosagem , Humanos , Imagem por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons/métodos , Prevalência , Espanha/epidemiologia , Reino Unido/epidemiologia , Proteínas tau/metabolismo
5.
Neuron ; 106(6): 881-883, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32553204
6.
Neurology ; 95(2): e166-e178, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32580974

RESUMO

OBJECTIVE: To investigate sex differences in late-onset Alzheimer disease (AD) risks by means of multimodality brain biomarkers (ß-amyloid load via 11C-Pittsburgh compound B [PiB] PET, neurodegeneration via 18F-fluorodeoxyglucose [FDG] PET and structural MRI). METHODS: We examined 121 cognitively normal participants (85 women and 36 men) 40 to 65 years of age with clinical, laboratory, neuropsychological, lifestyle, MRI, FDG- and PiB-PET examinations. Several clinical (e.g., age, education, APOE status, family history), medical (e.g., depression, diabetes mellitus, hyperlipidemia), hormonal (e.g., thyroid disease, menopause), and lifestyle AD risk factors (e.g., smoking, diet, exercise, intellectual activity) were assessed. Statistical parametric mapping and least absolute shrinkage and selection operator regressions were used to compare AD biomarkers between men and women and to identify the risk factors associated with sex-related differences. RESULTS: Groups were comparable on clinical and cognitive measures. After adjustment for each modality-specific confounders, the female group showed higher PiB ß-amyloid deposition, lower FDG glucose metabolism, and lower MRI gray and white matter volumes compared to the male group (p < 0.05, family-wise error corrected for multiple comparisons). The male group did not show biomarker abnormalities compared to the female group. Results were independent of age and remained significant with the use of age-matched groups. Second to female sex, menopausal status was the predictor most consistently and strongly associated with the observed brain biomarker differences, followed by hormone therapy, hysterectomy status, and thyroid disease. CONCLUSION: Hormonal risk factors, in particular menopause, predict AD endophenotype in middle-aged women. These findings suggest that the window of opportunity for AD preventive interventions in women is early in the endocrine aging process.


Assuntos
Doença de Alzheimer/epidemiologia , Imagem Multimodal , Neuroimagem , Adulto , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologia , Compostos de Anilina , Apolipoproteínas E/genética , Feminino , Fluordesoxiglucose F18 , Hormônios/sangue , Humanos , Estilo de Vida , Imagem por Ressonância Magnética , Masculino , Menopausa/psicologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Fatores de Risco , Fatores Sexuais , Tiazóis
7.
PLoS One ; 15(5): e0232785, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469871

RESUMO

BACKGROUND: Alzheimer's disease (AD) pathology precedes symptoms and its detection can identify at-risk individuals who may benefit from early treatment. Since the retinal nerve fiber layer (RNFL) is depleted in established AD, we tested whether its thickness can predict whether cognitively healthy (CH) individuals have a normal or pathological cerebrospinal fluid (CSF) Aß42 (A) and tau (T) ratio. METHODS: As part of an ongoing longitudinal study, we enrolled CH individuals, excluding those with cognitive impairment and significant ocular pathology. We classified the CH group into two sub-groups, normal (CH-NAT, n = 16) or pathological (CH-PAT, n = 27), using a logistic regression model from the CSF AT ratio that identified >85% of patients with a clinically probable AD diagnosis. Spectral-domain optical coherence tomography (OCT) was acquired for RNFL, ganglion cell-inner plexiform layer (GC-IPL), and macular thickness. Group differences were tested using mixed model repeated measures and a classification model derived using multiple logistic regression. RESULTS: Mean age (± standard deviation) in the CH-PAT group (n = 27; 75.2 ± 8.4 years) was similar (p = 0.50) to the CH-NAT group (n = 16; 74.1 ± 7.9 years). Mean RNFL (standard error) was thinner in the CH-PAT group by 9.8 (2.7) µm; p < 0.001. RNFL thickness classified CH-NAT vs. CH-PAT with 87% sensitivity and 56.3% specificity. CONCLUSIONS: Our retinal data predict which individuals have CSF biomarkers of AD pathology before cognitive deficits are detectable with 87% sensitivity. Such results from easy-to-acquire, objective and non-invasive measurements of the RNFL merit further study of OCT technology to monitor or screen for early AD pathology.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Disfunção Cognitiva/genética , Proteínas tau/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Amiloidose/líquido cefalorraquidiano , Amiloidose/diagnóstico por imagem , Amiloidose/genética , Amiloidose/patologia , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/metabolismo , Fibras Nervosas/patologia , Disco Óptico/diagnóstico por imagem , Disco Óptico/metabolismo , Disco Óptico/patologia , Retina/diagnóstico por imagem , Retina/metabolismo , Retina/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica , Proteínas tau/líquido cefalorraquidiano
8.
Nat Commun ; 11(1): 2612, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32457389

RESUMO

Tau is a hallmark pathology of Alzheimer's disease, and animal models have suggested that tau spreads from cell to cell through neuronal connections, facilitated by ß-amyloid (Aß). We test this hypothesis in humans using an epidemic spreading model (ESM) to simulate tau spread, and compare these simulations to observed patterns measured using tau-PET in 312 individuals along Alzheimer's disease continuum. Up to 70% of the variance in the overall spatial pattern of tau can be explained by our model. Surprisingly, the ESM predicts the spatial patterns of tau irrespective of whether brain Aß is present, but regions with greater Aß burden show greater tau than predicted by connectivity patterns, suggesting a role of Aß in accelerating tau spread. Altogether, our results provide evidence in humans that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain Aß.


Assuntos
Doença de Alzheimer/metabolismo , Proteínas de Membrana/metabolismo , Rede Nervosa/metabolismo , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/fisiologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Conectoma , Feminino , Humanos , Masculino , Modelos Neurológicos , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/patologia , Tomografia por Emissão de Pósitrons
9.
Rinsho Shinkeigaku ; 60(6): 407-413, 2020 Jun 06.
Artigo em Japonês | MEDLINE | ID: mdl-32435042

RESUMO

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are two major types of dementia. Due to shared signs and symptoms, accurate diagnosis of these dementia subtypes is a clinical challenge. We assessed the sensitivity and specificity of the combined use of neuropsychological testing and brain imaging data for the differential diagnosis of these conditions. The study population included 77 patients with either AD or DLB. Ala score was calculated from Mini-Mental State Exam subscores, and the cingulate island sign score (CIScore) was obtained from image analysis of brain perfusion single-photon emission computed tomography. Correlation between Ala score and CIScore values was observed in the subgroup of patients aged ≤79 years (r = 0.485, P = 0.002), and the scatter plot revealed that 70% of DLB patients were within the range of cut-off values for DLB. In the group aged ≥80 years, there was poor correlation between the Ala and CIScores (r = 0.285, P = 0.083), the average CIScore exceeded the cut-off value, and the scatter plot showed lower sensitivity, illustrating the challenge of discriminating AD from DLB in an older patient population. The concurrent use of Ala score and CIScore enhanced the specificity and the area under the curve in both subgroups, indicating the improved ability of these tests to aid in the differential diagnosis of AD from DLB. Our findings suggest that the use of these methodologies in routine medical practice may increase the sensitivity and specificity of the diagnosis of dementia subtypes.


Assuntos
Doença de Alzheimer/diagnóstico , Doença por Corpos de Lewy/diagnóstico , Testes Neuropsicológicos , Tomografia Computadorizada de Emissão de Fóton Único , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Doença por Corpos de Lewy/diagnóstico por imagem , Masculino , Sensibilidade e Especificidade
10.
Ann Neurol ; 88(1): 183-194, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32468646

RESUMO

OBJECTIVE: Preclinical evidence with nilotinib, a US Food and Drug Administration (FDA)-approved drug for leukemia, indicates improvement in Alzheimer's disease phenotypes. We investigated whether nilotinib is safe, and detectable in cerebrospinal fluid, and alters biomarkers and clinical decline in Alzheimer's disease. METHODS: This single-center, phase 2, randomized, double-blind, placebo-controlled study investigated the safety, tolerability, and pharmacokinetics of nilotinib, and measured biomarkers in participants with mild to moderate dementia due to Alzheimer's disease. The diagnosis was supported by cerebrospinal fluid or amyloid positron emission tomography biomarkers. Nilotinib 150 mg versus matching placebo was taken orally once daily for 26 weeks followed by nilotinib 300 mg versus placebo for another 26 weeks. RESULTS: Of the 37 individuals enrolled, 27 were women and the mean (SD) age was 70.7 (6.48) years. Nilotinib was well-tolerated, although more adverse events, particularly mood swings, were noted with the 300 mg dose. In the nilotinib group, central nervous system (CNS) amyloid burden was significantly reduced in the frontal lobe compared to the placebo group. Cerebrospinal fluid Aß40 was reduced at 6 months and Aß42 was reduced at 12 months in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (-27%) at 12 months and phospho-tau-181 was reduced at 6 months and 12 months in the nilotinib group. INTERPRETATION: Nilotinib is safe and achieves pharmacologically relevant cerebrospinal fluid concentrations. Biomarkers of disease were altered in response to nilotinib treatment. These data support a larger, longer, multicenter study to determine the safety and efficacy of nilotinib in Alzheimer's disease. ANN NEUROL 2020 ANN NEUROL 2020;88:183-194.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Proteínas Tirosina Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Resultado do Tratamento , Proteínas tau/líquido cefalorraquidiano
11.
Fortschr Neurol Psychiatr ; 88(4): 266-284, 2020 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-32325519

RESUMO

According to the German S3 guideline dementia every patient with a dementia disorder should have a MRI. The goal is not only to uncover treatable conditions but also to detect region-specific atrophy pattern which are characteristic of primary dementia disorders such as Alzheimer's disease, fronto-temporal lobar degeneration and others. Diagnostic accuracy can be improved by Voxel- and Region-based volumetric analysis of the individual brain compared to age-matched controls.


Assuntos
Demência/diagnóstico por imagem , Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Demência/patologia , Demência/terapia , Degeneração Lobar Frontotemporal/diagnóstico por imagem , Alemanha , Humanos , Imagem por Ressonância Magnética , Guias de Prática Clínica como Assunto
12.
Medicine (Baltimore) ; 99(16): e19620, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32311931

RESUMO

For the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD), variable neuroimaging and neuropsychological tests have been used. We aimed to evaluate the correlation of neuropsychological domain with new amyloid positron emission tomography (PET) study and to validate the availability of new PET tracer.We enrolled 20 patients who underwent C-PiB-PET/CT, new PET tracer F-FC119S PET/CT from November, 2014 to July, 2015. Among them, 10 patients were diagnosed with AD and 10 patients with MCI. The current version of Seoul Neuropsychological Screening Battery (SNSB) II was performed for cognitive evaluation. Each parameter of SNSB was compared between 2 patient groups. Spearman correlation analysis between value of SNSB domain and standardized uptake value ratio (SUVR) of PET was also performed.The AD group presented significant poor z-score in Korean-Boston Naming Test(K-BNT) (P = .01),copy score of Rey Complex Figure Test (RCFT) (P = .049), immediate (P = .028)and delayed memory of Seoul Verbal Learning Test (SVLT) (P = .028), recognition of RCFT (P = .004), "animal" of Controlled Oral Word Association Test (COWAT) (P = .041), color reading of Korean-Color Word Stroop test (K-CWST) (P = .014), and Digit Symbol Coding (DSC) (P = .007) compared with MCI group. That means, except attention domain, all other cognitive domains were relatively impaired in AD compared with MCI. In correlation analysis, we found that poor performances on copy score of RCFT in MCI groups were associated with great beta amyloid burden in frontal area in both C-PiB-PET/CT and F-FC119S PET/CT. In AD group, F-FC119S PET presented more extensive correlation in each cognitive domain with multiple cortical areas compared with C-PiB-PET.The degree of amyloid burden assessed on F-FC119S PET was significantly correlated with neuropsychological test in AD, and also MCI patients. The combination of neuropsychological evaluation with novel F-FC119S PET/CT can be used for valid biomarker for MCI and AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Amiloide/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Compostos de Anilina , Benzotiazóis , Radioisótopos de Carbono , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Feminino , Radioisótopos de Flúor , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Testes Neuropsicológicos , Piridinas , Traçadores Radioativos , Tiazóis
13.
PLoS One ; 15(4): e0231765, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298384

RESUMO

Non-invasive biomarkers will enable widespread screening and early diagnosis of Alzheimer's disease (AD). We hypothesized that the considerable loss of brain tissue in AD will result in detection of brain lipid components in urine, and that these will change in concert with CSF and brain biomarkers of AD. We examined urine dicarboxylic acids (DCA) of carbon length 3-10 to reflect products of oxidative damage and energy generation or balance that may account for changes in brain function in AD. Mean C4-C5 DCAs were lower and mean C7-C10 DCAs were higher in the urine from AD compared to cognitively healthy (CH) individuals. Moreover, mean C4-C5 DCAs were lower and mean C7-C9 were higher in urine from CH individuals with abnormal compared to normal CSF amyloid and Tau levels; i.e., the apparent urine changes in AD also appeared to be present in CH individuals that have CSF risk factors of early AD pathology. In examining the relationship between urine DCAs and AD biomarkers, we found short chain DCAs positively correlated with CSF Aß42, while C7-C10 DCAs negatively correlated with CSF Aß42 and positively correlated with CSF Tau levels. Furthermore, we found a negative correlation of C7-C10 DCAs with hippocampal volume (p < 0.01), which was not found in the occipital volume. Urine measures of DCAs have an 82% ability to predict cognitively healthy participants with normal CSF amyloid/Tau. These data suggest that urine measures of increased lipoxidation and dysfunctional energy balance reflect early AD pathology from brain and CSF biomarkers. Measures of urine DCAs may contribute to personalized healthcare by indicating AD pathology and may be utilized to explore population wellness or monitor the efficacy of therapies in clinical trials.


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Ácidos Dicarboxílicos/urina , Hipocampo/patologia , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Doenças Assintomáticas , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/urina , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/diagnóstico por imagem , Ácidos Dicarboxílicos/química , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Imagem por Ressonância Magnética , Masculino , Análise Multivariada , Fatores de Risco
14.
Neural Netw ; 126: 218-234, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32259762

RESUMO

Convolutional neural network (CNN) models have recently demonstrated impressive performance in medical image analysis. However, there is no clear understanding of why they perform so well, or what they have learned. In this paper, a three-dimensional convolutional neural network (3D-CNN) is employed to classify brain MRI scans into two predefined groups. In addition, a genetic algorithm based brain masking (GABM) method is proposed as a visualization technique that provides new insights into the function of the 3D-CNN. The proposed GABM method consists of two main steps. In the first step, a set of brain MRI scans is used to train the 3D-CNN. In the second step, a genetic algorithm (GA) is applied to discover knowledgeable brain regions in the MRI scans. The knowledgeable regions are those areas of the brain which the 3D-CNN has mostly used to extract important and discriminative features from them. For applying GA on the brain MRI scans, a new chromosome encoding approach is proposed. The proposed framework has been evaluated using ADNI (including 140 subjects for Alzheimer's disease classification) and ABIDE (including 1000 subjects for Autism classification) brain MRI datasets. Experimental results show a 5-fold classification accuracy of 0.85 for the ADNI dataset and 0.70 for the ABIDE dataset. The proposed GABM method has extracted 6 to 65 knowledgeable brain regions in ADNI dataset (and 15 to 75 knowledgeable brain regions in ABIDE dataset). These regions are interpreted as the segments of the brain which are mostly used by the 3D-CNN to extract features for brain disease classification. Experimental results show that besides the model interpretability, the proposed GABM method has increased final performance of the classification model in some cases with respect to model parameters.


Assuntos
Algoritmos , Doença de Alzheimer/diagnóstico por imagem , Transtorno Autístico/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Redes Neurais de Computação , Adolescente , Adulto , Doença de Alzheimer/classificação , Transtorno Autístico/classificação , Evolução Biológica , Criança , Aprendizado Profundo , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética/classificação , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
J Neurosci ; 40(17): 3491-3501, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32265258

RESUMO

Synaptic dysfunction provoking dysregulated cortical neural circuits is currently hypothesized as a key pathophysiological process underlying clinical manifestations in Alzheimer's disease and related neurodegenerative tauopathies. Here, we conducted PET along with postmortem assays to investigate time course changes of excitatory and inhibitory synaptic constituents in an rTg4510 mouse model of tauopathy, which develops tau pathologies leading to noticeable brain atrophy at 5-6 months of age. Both male and female mice were analyzed in this study. We observed that radiosignals derived from [11C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in nontransgenic littermates at 2-3 months of age. In contrast, retentions of (E)-[11C]ABP688, a tracer for mGluR5, were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy. Biochemical and immunohistochemical assessment of postmortem brain tissues demonstrated that inhibitory, but not excitatory, synaptic constituents selectively diminished without overt loss of somas of GABAergic interneurons in the neocortex and hippocampus of rTg4510 mice at 2 months of age, which was concurrent with enhanced immunoreactivity of cFos, a well-characterized immediate early gene, suggesting that impaired inhibitory neurotransmission may cause hyperexcitability of cortical circuits. Our findings indicate that tau-induced disruption of the inhibitory synapse may be a critical trigger of progressive neurodegeneration, resulting in massive neuronal loss, and PET assessments of inhibitory versus excitatory synapses potentially offer in vivo indices for hyperexcitability and excitotoxicity early in the etiologic pathway of neurodegenerative tauopathies.SIGNIFICANCE STATEMENT In this study, we examined the in vivo status of excitatory and inhibitory synapses in the brain of the rTg4510 tauopathy mouse model by PET imaging with (E)-[11C]ABP688 and [11C]flumazenil, respectively. We identified inhibitory synapse as being significantly dysregulated before brain atrophy at 2 months of age, while excitatory synapse stayed relatively intact at this stage. In line with this observation, postmortem assessment of brain tissues demonstrated selective attenuation of inhibitory synaptic constituents accompanied by the upregulation of cFos before the formation of tau pathology in the forebrain at young ages. Our findings indicate that selective degeneration of inhibitory synapse with hyperexcitability in the cortical circuit constitutes the critical early pathophysiology of tauopathy.


Assuntos
Doença de Alzheimer/fisiopatologia , Neurônios GABAérgicos/fisiologia , Hipocampo/fisiopatologia , Neocórtex/fisiopatologia , Sinapses/fisiologia , Tauopatias/fisiopatologia , Proteínas tau/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Neocórtex/diagnóstico por imagem , Neocórtex/metabolismo , Inibição Neural/fisiologia , Tomografia por Emissão de Pósitrons , Tauopatias/diagnóstico por imagem , Tauopatias/metabolismo
16.
BMC Neurol ; 20(1): 148, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32316912

RESUMO

BACKGROUND: Mild cognitive impairment (MCI) is an intermediate stage between normal aging and dementia. Studies on MCI progression are important for Alzheimer's disease (AD) prevention. 18F fluoro-deoxy-glucose positron emission tomography (FDG-PET) has been proven to be a powerful tool for measuring cerebral glucose metabolism. In this study, we proposed a classification framework for MCI prediction with both baseline and multiple follow-up FDG-PET scans as well as cognitive scores of 33 progressive MCI (pMCI) patients and 46 stable MCI (sMCI) patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHOD: First, PET images were normalized using the Yakushev normalization procedure and registered to the Brainnetome Atlas (BNA). The average metabolic intensities of brain regions were defined as static features. Dynamic features were the intensity variation between baseline and the other three time points and change ratios with the intensity obtained at baseline considered as reference. Mini-mental State Examination (MMSE) scores and Alzheimer's disease Assessment Scale-Cognitive section (ADAS-cog) scores of each time point were collected as cognitive features. And F-score was applied for feature selection. Finally, support vector machine (SVM) with radial basis function (RBF) kernel was used for the three above features. RESULTS: Dynamic features showed the best classification performance in accuracy of 88.61% than static features (accuracy of 78.48%). And the combination of cognitive features and dynamic features improved the classification performance in specificity of 95.65% and Area Under Curve (AUC) of 0.9308. CONCLUSION: Our results reported that dynamic features are more representative in longitudinal research for MCI prediction work. And dynamic features and cognitive scores complementarily enhance the classification performance in specificity and AUC. These findings may predict the disease course and clinical changes in individuals with mild cognitive impairment.


Assuntos
Disfunção Cognitiva , Testes de Estado Mental e Demência , Tomografia por Emissão de Pósitrons , Algoritmos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/fisiopatologia , Progressão da Doença , Fluordesoxiglucose F18 , Humanos , Estudos Longitudinais , Prognóstico , Sensibilidade e Especificidade
17.
Ann Neurol ; 88(1): 67-80, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32277502

RESUMO

OBJECTIVE: The study of cortical gyrification in Alzheimer's disease (AD) could help to further understanding of the changes undergone in the brain during neurodegeneration. Here, we aimed to study brain gyrification differences between healthy controls (HC), mild cognitive impairment (MCI) patients, and AD patients, and explore how cerebral gyrification patterns were associated with memory and other cognitive functions. METHODS: We applied surface-based morphometry techniques in 2 large, independent cross-sectional samples, obtained from the Alzheimer's Disease Neuroimaging Initiative project. Both samples, encompassing a total of 1,270 participants, were analyzed independently. RESULTS: Unexpectedly, we found that AD patients presented a more gyrificated entorhinal cortex than HC. Conversely, the insular cortex of AD patients was hypogyrificated. A decrease in the gyrification of the insular cortex was also found in older HC participants as compared with younger HC, which argues against the specificity of this finding in AD. However, an increased degree of folding of the insular cortex was specifically associated with better memory function and semantic fluency, only in AD patients. Overall, MCI patients presented an intermediate gyrification pattern. All these findings were consistently observed in the two samples. INTERPRETATION: The marked atrophy of the medial temporal lobe observed in AD patients may explain the increased folding of the entorhinal cortex. We additionally speculate regarding alternative mechanisms that may also alter its folding. The association between increased gyrification of the insular cortex and memory function, specifically observed in AD, could be suggestive of compensatory mechanisms to overcome the loss of memory function. ANN NEUROL 2020 ANN NEUROL 2020;88:67-80.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Memória/fisiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Cognição/fisiologia , Disfunção Cognitiva/psicologia , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos
18.
Nat Commun ; 11(1): 1148, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123170

RESUMO

Late-onset Alzheimer's disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Sangue/metabolismo , Metaboloma/genética , Idoso , Doença de Alzheimer/diagnóstico por imagem , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Tomografia por Emissão de Pósitrons , Fatores Sexuais
19.
PLoS One ; 15(3): e0230409, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32208428

RESUMO

Machine learning algorithms are currently being implemented in an escalating manner to classify and/or predict the onset of some neurodegenerative diseases; including Alzheimer's Disease (AD); this could be attributed to the fact of the abundance of data and powerful computers. The objective of this work was to deliver a robust classification system for AD and Mild Cognitive Impairment (MCI) against healthy controls (HC) in a low-cost network in terms of shallow architecture and processing. In this study, the dataset included was downloaded from the Alzheimer's disease neuroimaging initiative (ADNI). The classification methodology implemented was the convolutional neural network (CNN), where the diffusion maps, and gray-matter (GM) volumes were the input images. The number of scans included was 185, 106, and 115 for HC, MCI and AD respectively. Ten-fold cross-validation scheme was adopted and the stacked mean diffusivity (MD) and GM volume produced an AUC of 0.94 and 0.84, an accuracy of 93.5% and 79.6%, a sensitivity of 92.5% and 62.7%, and a specificity of 93.9% and 89% for AD/HC and MCI/HC classification respectively. This work elucidates the impact of incorporating data from different imaging modalities; i.e. structural Magnetic Resonance Imaging (MRI) and Diffusion Tensor Imaging (DTI), where deep learning was employed for the aim of classification. To the best of our knowledge, this is the first study assessing the impact of having more than one scan per subject and propose the proper maneuver to confirm the robustness of the system. The results were competitive among the existing literature, which paves the way for improving medications that could slow down the progress of the AD or prevent it.


Assuntos
Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/diagnóstico , Imagem de Tensor de Difusão/métodos , Imagem por Ressonância Magnética/métodos , Idoso , Algoritmos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Aprendizado Profundo , Progressão da Doença , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/fisiologia , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Aprendizado de Máquina , Masculino , Redes Neurais de Computação , Neuroimagem/métodos , Máquina de Vetores de Suporte
20.
Brain ; 143(4): 1249-1260, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32176777

RESUMO

There is both clinical and neuroanatomical variability at the single-subject level in Alzheimer's disease, complicating our understanding of brain-behaviour relationships and making it challenging to develop neuroimaging biomarkers to track disease severity, progression, and response to treatment. Prior work has shown that both group-level atrophy in clinical dementia syndromes and complex neurological symptoms in patients with focal brain lesions localize to brain networks. Here, we use a new technique termed 'atrophy network mapping' to test the hypothesis that single-subject atrophy maps in patients with a clinical diagnosis of Alzheimer's disease will also localize to syndrome-specific and symptom-specific brain networks. First, we defined single-subject atrophy maps by comparing cortical thickness in each Alzheimer's disease patient versus a group of age-matched, cognitively normal subjects across two independent datasets (total Alzheimer's disease patients = 330). No more than 42% of Alzheimer's disease patients had atrophy at any given location across these datasets. Next, we determined the network of brain regions functionally connected to each Alzheimer's disease patient's location of atrophy using seed-based functional connectivity in a large (n = 1000) normative connectome. Despite the heterogeneity of atrophied regions at the single-subject level, we found that 100% of patients with a clinical diagnosis of Alzheimer's disease had atrophy functionally connected to the same brain regions in the mesial temporal lobe, precuneus cortex, and angular gyrus. Results were specific versus control subjects and replicated across two independent datasets. Finally, we used atrophy network mapping to define symptom-specific networks for impaired memory and delusions, finding that our results matched symptom networks derived from patients with focal brain lesions. Our study supports atrophy network mapping as a method to localize clinical, cognitive, and neuropsychiatric symptoms to brain networks, providing insight into brain-behaviour relationships in patients with dementia.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Conectoma/métodos , Idoso , Idoso de 80 Anos ou mais , Atrofia/diagnóstico por imagem , Atrofia/patologia , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética , Masculino
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