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1.
Eur J Neurol ; 29(5): 1324-1334, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35007366

RESUMO

BACKGROUND AND PURPOSE: Abnormal mitochondrial metabolism has been described in the Alzheimer's disease (AD) brain. However, the relationship between AD pathophysiology and key mitochondrial processes remains elusive. The purpose of this study was to investigate whether mitochondrial complex I dysfunction is associated with amyloid aggregation or glucose metabolism and brain atrophy in patients with mild AD using positron emission tomography (PET). METHODS: Amyloid- and tau-positive symptomatic AD patients with clinical dementia rating 0.5 or 1 (N = 30; mean age ± standard deviation: 71.8 ± 7.6 years) underwent magnetic resonance imaging and PET scans with [18 F]2-tert-butyl-4-chloro-5-2H-pyridazin-3-one (BCPP-EF), [11 C]Pittsburgh Compound-B (PiB) and [18 F]fluorodeoxyglucose (FDG) to assess brain atrophy, mitochondrial complex I dysfunction, amyloid deposition, and glucose metabolism, respectively. Local cortical associations among these biomarkers and gray matter volume were evaluated with voxel-based regressions models. RESULTS: [18 F]BCPP-EF standardized uptake value ratio (SUVR) was positively correlated with [18 F]FDG SUVR in the widespread brain area, while its associations with gray matter volume were restricted to the parahippocampal gyrus. Reductions in [18 F]BCPP-EF SUVR were associated with domain-specific cognitive performance. We did not observe regional associations between mitochondrial dysfunction and amyloid burden. CONCLUSIONS: In symptomatic cases, although mitochondrial complex I reduction is linked to a wide range of downstream neurodegenerative processes such as hypometabolism, atrophy, and cognitive decline, a link to amyloid was not observable. The data presented here support [18 F]BCPP-EF as an excellent imaging tool to investigate mitochondrial dysfunction in AD.


Assuntos
Doença de Alzheimer , Amiloidose , Disfunção Cognitiva , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Amiloidose/metabolismo , Compostos de Anilina , Atrofia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Fluordesoxiglucose F18/metabolismo , Glucose/metabolismo , Humanos , Tomografia por Emissão de Pósitrons/métodos
2.
Cogn Behav Neurol ; 33(4): 288-293, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33264158

RESUMO

The frontal variant of Alzheimer disease (fvAD) is characterized by behavioral and/or dysexecutive impairments that can resemble those of behavioral-variant frontotemporal dementia (bvFTD). This overlap, in addition to the lack of consensus clinical criteria for fvAD, complicates its identification. We provide the first case report of fvAD differentiated in vivo from bvFTD using amyloid-beta and tau PET imaging. The patient, a right-handed woman, presented with forgetfulness at age 60. Cognitive testing at that time revealed mild impairments in memory, attention, and executive functions. Three years later, her family reported that she was displaying socially inappropriate behaviors, inertia, diminished social interest, and altered food preferences-the sum of which met the criteria for possible bvFTD. PET using an amyloid-beta tracer (F-AZD4694) identified diffuse amyloid plaques across the cerebral cortex. PET using a tau tracer specific for neurofibrillary tangles (F-MK6240) identified substantial tau pathology in the brain's frontal lobes. Together with the clinical findings, these images supported the diagnosis of fvAD rather than bvFTD. Considering past and emerging evidence that tau topography in Alzheimer disease (AD) matches the clinical features of AD, we discuss the potential utility of in vivo tau imaging using F-MK6240 for identifying fvAD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/diagnóstico , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/diagnóstico , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Diagnóstico Diferencial , Feminino , Demência Frontotemporal/patologia , Humanos , Pessoa de Meia-Idade
3.
EBioMedicine ; 102: 105046, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38471397

RESUMO

BACKGROUND: Blood-based biomarkers of Alzheimer's disease (AD) have become increasingly important as scalable tools for diagnosis and determining clinical trial eligibility. P-tau217 is the most promising due to its excellent sensitivity and specificity for AD-related pathological changes. METHODS: We compared the performance of two commercially available plasma p-tau217 assays (ALZpath p-tau217 and Janssen p-tau217+) in 294 individuals cross-sectionally. Correlations with amyloid PET and tau PET were assessed, and Receiver Operating Characteristic (ROC) analyses evaluated both p-tau217 assays for identifying AD pathology. FINDINGS: Both plasma p-tau217 assays were strongly associated with amyloid and tau PET. Furthermore, both plasma p-tau217 assays identified individuals with AD vs other neurodegenerative diseases (ALZpath AUC = 0.95; Janssen AUC = 0.96). Additionally, plasma p-tau217 concentrations rose with AD severity and their annual changes correlated with tau PET annual change. INTERPRETATION: Both p-tau217 assays had excellent diagnostic performance for AD. Our study supports the future clinical use of commercially-available assays for p-tau217. FUNDING: This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR), Canadian Consortium on Neurodegeneration in Aging, the Alzheimer's Association, Brain Canada Foundation, the Fonds de Recherche du Québec - Santé and the Colin J. Adair Charitable Foundation.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico , Canadá , Plasma , Envelhecimento , Bioensaio , Proteínas tau , Biomarcadores , Peptídeos beta-Amiloides
4.
Alzheimers Dement (Amst) ; 15(1): e12408, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36968620

RESUMO

Background: Risk factors for dementia have distinct frequency and impact in relation to race. Our aim was to identify differences in modifiable risk factors of dementia related to races and estimate their population attributable fraction (PAF). Methods: An epidemiological cohort was used to estimate the prevalence of 10 modifiable risk factors for dementia among five races-White, Black, Brown, Asian, and Indigenous. Sample weighting was used to estimate the prevalence and PAF of each risk factor in each race. Results: A total of 9070 individuals were included. Overall adjusted PAF was the lowest in Indigenous (38.9%), and Asian individuals (41.2%). Race-related prevalence of individual risk factors was widely variable in our population, but hearing loss was the most important contributor to the overall PAF in all races. Conclusions: Public policies aiming to reduce preventable risk factors for dementia should take into consideration the race of the target populations. HIGHLIGHTS: Preventable risk factors for dementia vary according to race.Hearing loss presented the highest prevalence among all races studied.Indigenous and Asian individuals presented the lowest population attributable fractions.Black and Brown individuals were more vulnerable to social determinants.

5.
Brain Sci ; 13(2)2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36831775

RESUMO

Associations between pathophysiological events and cognitive measures provide insights regarding brain networks affected during the clinical progression of Alzheimer's disease (AD). In this study, we assessed patients' scores in two delayed episodic memory tests, and investigated their associations with regional amyloid deposition and brain metabolism across the clinical spectrum of AD. We assessed the clinical, neuropsychological, structural, and positron emission tomography (PET) baseline measures of participants from the Alzheimer's Disease Neuroimaging Initiative. Subjects were classified as cognitively normal (CN), or with early (EMCI) or late (LMCI) mild cognitive impairment, or AD dementia. The memory outcome measures of interest were logical memory 30 min delayed recall (LM30) and Rey Auditory Verbal Learning Test 30 min delayed recall (RAVLT30). Voxel-based [18F]florbetapir and [18F]FDG uptake-ratio maps were constructed and correlations between PET images and cognitive scores were calculated. We found that EMCI individuals had LM30 scores negatively correlated with [18F]florbetapir uptake on the right parieto-occipital region. LMCI individuals had LM30 scores positively associated with left lateral temporal lobe [18F]FDG uptake, and RAVLT30 scores positively associated with [18F]FDG uptake in the left parietal lobe and in the right enthorhinal cortex. Additionally, LMCI individuals had LM30 scores negatively correlated with [18F]florbetapir uptake in the right frontal lobe. For the AD group, [18F]FDG uptake was positively correlated with LM30 in the left temporal lobe and with RAVLT30 in the right frontal lobe, and [18F]florbetapir uptake was negatively correlated with LM30 scores in the right parietal and left frontal lobes. The results show that the association between regional brain metabolism and the severity of episodic memory deficits is dependent on the clinical disease stage, suggesting a dynamic relationship between verbal episodic memory deficits, AD pathophysiology, and clinical disease stages.

6.
Nat Rev Neurol ; 18(7): 400-418, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35585226

RESUMO

Well-authenticated biomarkers can provide critical insights into the biological basis of Alzheimer disease (AD) to enable timely and accurate diagnosis, estimate future burden and support therapeutic trials. Current cerebrospinal fluid and molecular neuroimaging biomarkers fulfil these criteria but lack the scalability and simplicity necessary for widespread application. Blood biomarkers of adequate effectiveness have the potential to act as first-line diagnostic and prognostic tools, and offer the possibility of extensive population screening and use that is not limited to specialized centres. Accelerated progress in our understanding of the biochemistry of brain-derived tau protein and advances in ultrasensitive technologies have enabled the development of AD-specific phosphorylated tau (p-tau) biomarkers in blood. In this Review we discuss how new information on the molecular processing of brain p-tau and secretion of specific fragments into biofluids is informing blood biomarker development, enabling the evaluation of preanalytical factors that affect quantification, and informing harmonized protocols for blood handling. We also review the performance of blood p-tau biomarkers in the context of AD and discuss their potential contexts of use for clinical and research purposes. Finally, we highlight outstanding ethical, clinical and analytical challenges, and outline the steps that need to be taken to standardize inter-laboratory and inter-assay measurements.


Assuntos
Doença de Alzheimer , Proteínas tau , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides , Biomarcadores/líquido cefalorraquidiano , Humanos , Neuroimagem
7.
Mol Neurodegener ; 16(1): 28, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33902654

RESUMO

BACKGROUND: Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer's disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [18F]BCPP-EF. METHODS: Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [18F]BCPP-EF mitochondrial function, [11C]PBB3 for tau deposition, and [11C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed. RESULTS: The [18F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [11C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [18F]BCPP-EF SUVR and [11C]PBB3 BPND (R = 0.2679, p = 0.04), but not [11C] PiB SUVR. CONCLUSIONS: Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [11C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.


Assuntos
Doença de Alzheimer/metabolismo , Complexo I de Transporte de Elétrons/análise , Proteínas tau/análise , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Aminopiridinas/farmacocinética , Compostos de Anilina/farmacocinética , Benzotiazóis/farmacocinética , Química Encefálica , Radioisótopos de Carbono , Córtex Entorrinal/química , Córtex Entorrinal/diagnóstico por imagem , Feminino , Radioisótopos de Flúor , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Neuroimagem , Tomografia por Emissão de Pósitrons , Piridazinas/farmacocinética , Piridinas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Índice de Gravidade de Doença , Avaliação de Sintomas , Tiazóis/farmacocinética
8.
Case Rep Oncol Med ; 2013: 306983, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23533871

RESUMO

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic entity characterized by headaches, altered mental status, seizures, visual loss, and characteristic imaging pattern in brain MRI. The cause of PRES is not yet understood. We report a case of a 27-year-old woman that developed PRES after the use of FOLFOX 5 (oxaliplatin/5-Fluoracil/Leucovorin) chemotherapy for a colorectal cancer.

9.
J Neuroimaging ; 23(4): 535-6, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23551823

RESUMO

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic entity not yet understood, that is present with transient neurologic symptoms and particular radiological findings. The most common imaging pattern in PRES is the presence of edema in the white matter of the posterior portions of both cerebral hemispheres. The cause of PRES is unclear. We report a case of 13-year-old male who was stung by a scorpion and developed a severe headache, visual disturbance, and seizures and had the diagnosis of PRES with a good outcome. Numerous factors can trigger this syndrome, most commonly: acute elevation of blood pressure, abnormal renal function, and immunosuppressive therapy. There are many cases described showing the relationship between PRES and eclampsia, transplantation, neoplasia and chemotherapy treatment, systemic infections, renal disease acute, or chronic. However, this is the first case of PRES following a scorpion sting.


Assuntos
Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Síndrome da Leucoencefalopatia Posterior/patologia , Picadas de Escorpião/complicações , Picadas de Escorpião/patologia , Adolescente , Humanos , Masculino
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