Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.676
Filtrar
1.
Neurology ; 95(12): e1640-e1649, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32759190

RESUMO

OBJECTIVE: To examine whether neuropathologic burden is associated with hearing impairment. METHODS: We studied 2,755 autopsied participants ≥55 years of age from the National Alzheimer's Coordinating Center database. Participants had at least 1 clinical evaluation at US National Institute on Aging-funded Alzheimer's Disease Center no more than 2 years before death. Patients were classified as hearing impaired by clinician report at baseline. Common dementia neuropathologies included Alzheimer disease pathologic change (Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque density, neurofibrillary degeneration Braak stage), Lewy body disease, gross infarcts, and microinfarcts. Logistic regression models predicted impaired hearing with adjustment for age at death, sex, race, education, center, and follow-up time. Relative risks were calculated with the use of marginal standardization. RESULTS: Impaired hearing was common (32%). In participants who were cognitively normal at baseline (n = 580), impaired hearing was associated with higher Braak stage (relative risk [RR] 1.33 per 2-stage increase, 95% confidence interval [CI] 1.06-1.66) but not other pathologies. In participants with dementia (n = 2,175), impaired hearing was positively associated with microinfarcts (RR 1.18, 95% CI 1.00-1.39) and inversely associated with neuritic plaque density (RR 0.91 per score increase, 95% CI 0.85-0.99). Development of impaired hearing in those with cognitive impairment was associated with neocortical Lewy bodies (1.26, 95% CI 1.02-1.55). CONCLUSIONS: Impaired hearing, reported before the onset of cognitive impairment, was associated with increased neurofibrillary tangle burden. Impaired hearing in those with cognitive impairment was associated with microinfarcts and neocortical Lewy bodies but not typical Alzheimer disease pathologic change. Functional hearing problems may be a preclinical marker of neurofibrillary neurodegeneration, although replication is needed.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Perda Auditiva/patologia , Placa Amiloide/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Autopsia , Feminino , Perda Auditiva/complicações , Humanos , Corpos de Lewy/patologia , Masculino , Emaranhados Neurofibrilares/patologia
2.
Neurology ; 95(5): e545-e553, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32493717

RESUMO

OBJECTIVE: To investigate in vivo whether synaptic loss and neurofibrillary tangle load spatially overlap and correlate with clinical symptoms in patients with amnestic mild cognitive impairment (aMCI). METHODS: In this cross-sectional study, 10 patients with aMCI and 10 healthy controls underwent triple PET-MRI with 11C-UCB-J (synaptic vesicle protein 2A), 18F-MK-6240 (tau deposition), and 11C-Pittsburgh compound B (ß-amyloid) and neuropsychological assessment. Gray matter atrophy was assessed by voxel-based morphometry with T1-weighted MRIs. Voxel-wise and volume-of-interest analyses were conducted on PET data. The interrelationship of synaptic density and tau deposition was investigated. We also investigated correlations of 18F-MK-6240 and 11C-UCB-J binding with cognitive performance. RESULTS: Compared to controls, patients with aMCI showed a decreased 11C-UCB-J binding mainly in substructures of the medial temporal lobe (MTL; 48%-51%, p cluster = 0.02). Increased 18F-MK6240 binding in the same region was observed (42%-44%, p cluster = 0.0003), spreading to association cortices. In the MTL, higher 18F-MK-6240 binding inversely related to lower 11C-UCB-J binding (p = 0.02, r = -0.76). Decreased performance on cognitive tests was associated with both increased 18F-MK-6240 and decreased 11C-UCB-J binding in the hippocampus (p < 0.01, r > 0.7), although in a multivariate analysis only 18F-MK-6240 binding was significantly related to cognitive performance. CONCLUSIONS: Patients with aMCI have high tau deposition and synaptic density loss mainly in key regions known to be involved in early cognitive impairment, indicating that these are interrelated in the MTL, while tau binding had already spread toward association cortices. Longitudinal data are needed to provide further insight into the temporal aspects of this relationship.


Assuntos
Encéfalo/patologia , Disfunção Cognitiva/patologia , Emaranhados Neurofibrilares/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Tomografia por Emissão de Pósitrons
3.
Nat Med ; 26(8): 1256-1263, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32572268

RESUMO

Alzheimer's disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline1. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity2,3. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with 'typical' AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD.


Assuntos
Doença de Alzheimer/genética , Disfunção Cognitiva/genética , Agregação Patológica de Proteínas/genética , Proteínas tau/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Disfunção Cognitiva/patologia , Feminino , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Agregação Patológica de Proteínas/patologia , Índice de Gravidade de Doença
4.
Neurology ; 95(2): e155-e165, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32561678

RESUMO

OBJECTIVE: To determine whether Lewy body disease subgroups have different clinical profiles. METHODS: Participants had dementia, autopsy-confirmed transitional or diffuse Lewy body disease (TLBD or DLBD) (n = 244), or Alzheimer disease (AD) (n = 210), and were seen at least twice (mean follow-up 6.2 ± 3.8 years). TLBD and DLBD groups were partitioned based on the presence or absence of neocortical neurofibrillary tangles using Braak staging. Four Lewy body disease subgroups and AD were compared on clinical features, dementia trajectory, and onset latency of probable dementia with Lewy bodies (DLB) or a DLB syndrome defined as probable DLB or dementia with one core feature of parkinsonism or probable REM sleep behavior disorder. RESULTS: In TLBD and DLBD without neocortical tangles, diagnostic sensitivity was strong for probable DLB (87% TLBD, 96% DLBD) and the DLB syndrome (97% TLBD, 98% DLBD) with median latencies <1 year from cognitive onset, and worse baseline attention-visual processing but better memory-naming scores than AD. In DLBD with neocortical tangles, diagnostic sensitivity was 70% for probable DLB and 77% for the DLB syndrome with respective median latencies of 3.7 years and 2.7 years from cognitive onset, each associated with tangle distribution. This group had worse baseline attention-visual processing than AD, but comparable memory-naming impairment. TLBD with neocortical tangles had 48% diagnostic sensitivity for probable DLB and 52% for the DLB syndrome, with median latencies >6 years from cognitive onset, and were cognitively similar to AD. Dementia trajectory was slowest for TLBD without neocortical tangles, and fastest for DLBD with neocortical tangles. CONCLUSIONS: The phenotypic expression of DLB was associated with the distribution of α-synuclein and tau pathology.


Assuntos
Doença por Corpos de Lewy/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Atenção , Cognição , Progressão da Doença , Feminino , Humanos , Doença por Corpos de Lewy/classificação , Doença por Corpos de Lewy/psicologia , Masculino , Memória , Pessoa de Meia-Idade , Neocórtex/patologia , Emaranhados Neurofibrilares/patologia , Desempenho Psicomotor , Sensibilidade e Especificidade
5.
Adv Exp Med Biol ; 1233: 177-194, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274757

RESUMO

Tauopathies are a heterogeneous group of neurodegenerative dementias involving perturbations in the levels, phosphorylation or mutations of the neuronal microtubule-binding protein Tau. Tauopathies are characterized by accumulation of hyperphosphorylated Tau leading to formation of a range of aggregates including macromolecular ensembles such as Paired Helical filaments and Neurofibrilary Tangles whose morphology characterizes and differentiates these disease states. Why nonphysiological Tau proteins elude the surveillance normal proteostatic mechanisms and eventually form these macromolecular assemblies is a central mostly unresolved question of cardinal importance for diagnoses and potential therapeutic interventions. We discuss the response of the Ubiquitin-Proteasome system, autophagy and the Endoplasmic Reticulum-Unfolded Protein response in Tauopathy models and patients, revealing interactions of components of these systems with Tau, but also of the effects of pathological Tau on these systems which eventually lead to Tau aggregation and accumulation. These interactions point to potential disease biomarkers and future potential therapeutic targets.


Assuntos
Proteostase , Tauopatias/metabolismo , Tauopatias/patologia , Demência/genética , Demência/metabolismo , Demência/patologia , Humanos , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Tauopatias/genética , Ubiquitina/metabolismo , Proteínas tau/química , Proteínas tau/genética , Proteínas tau/metabolismo
6.
J Neuropathol Exp Neurol ; 79(2): 163-175, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913466

RESUMO

The pathological process underlying Alzheimer disease (AD) unfolds predominantly in the cerebral cortex with the gradual appearance and regional progression of abnormal tau. Intraneuronal tau pathology progresses from the temporal transentorhinal and entorhinal regions into neocortical fields/areas of the temporal allocortex. Here, based on 95 cases staged for AD-related neurofibrillary changes, we propose an ordered progression of abnormal tau in the temporal allocortex. Initially, abnormal tau was limited to distal dendritic segments followed by tau in cell bodies of projection neurons of the transentorhinal/entorhinal layer pre-α. Next, abnormal distal dendrites accumulated in the prosubiculum and extended into the CA1 stratum oriens and lacunosum. Subsequently, altered dendrites developed in the CA2/CA3 stratum oriens and stratum lacunosum-moleculare, combined with tau-positive thorny excrescences of CA3/CA4 mossy cells. Finally, granule cells of the dentate fascia became involved. Such a progression might recapitulate a sequence of transsynaptic spreading of abnormal tau from 1 projection neuron to the next: From pre-α cells to distal dendrites in the prosubiculum and CA1; then, from CA1 or prosubicular pyramids to CA2 principal cells and CA3/CA4 mossy cells; finally, from CA4 mossy cells to dentate granule cells. The lesions are additive: Those from the previous steps persist.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Emaranhados Neurofibrilares/patologia , Neurônios/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Córtex Cerebral/patologia , Dendritos/patologia , Giro Denteado/patologia , Progressão da Doença , Córtex Entorrinal/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Temporal/patologia
7.
Biochemistry ; 59(4): 341-342, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31944100

RESUMO

The deposition of amyloid-ß (Aß) plaques and tau-based neurofibrillary tangles is a neuropathological feature of Alzheimer's disease (AD). While studies have shown that the Aß and tau interaction results in elevated AD pathology, the molecular linkage and mechanism of interaction of Aß and tau are unclear. A recent study demonstrated the direct interaction between the Aß core and specific regions of tau that facilitates pathological cross-seeding via a shared epitope. The data suggest that targeting the common epitope could be a more effective treatment strategy rather than targeting only Aß or only tau. The findings have an important clinical significance for AD and related tauopathies.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Emaranhados Neurofibrilares/patologia , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/imunologia , Animais , Epitopos , Humanos , Emaranhados Neurofibrilares/imunologia , Tauopatias/patologia , Proteínas tau/imunologia
8.
J Neuropathol Exp Neurol ; 79(1): 22-33, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31750914

RESUMO

BRCA1 plays an important roles in several biological events during the DNA damage response (DDR). Recently, some reports have indicated that BRCA1 dysfunction is involved in the pathogenesis of Alzheimer disease (AD). Furthermore, it has also been reported that BRCA1 accumulates within neurofibrillary tangles (NFTs) in the AD brain. In this study, we examined the immunohistochemical distribution of BRCA1 and another DDR protein, p53-Binding Protein 1 (53BP1), in AD, Pick disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration, and frontotemporal dementia with parkinsonism linked to chromosome 17. In control subjects, neither BRCA1 nor phosphorylated BRCA1 (pBRCA1; Ser1524) immunoreactivity was observed in neurons or glial cells; and that for pBRCA1 (Ser1423) and 53BP1 were slightly detected in neuronal nuclei. The immunoreactivity for both BRCA1 and pBRCA1 (Ser1423) was localized within phosphorylated tau inclusions in all tauopathies, whereas that for pBRCA1 (Ser1524) was mainly associated with Pick bodies in PiD and to a lesser extent with NFTs in AD. On the other hand, 53BP1-immunoreactive deposits tended to be increased in the nucleus of neurons in AD and PSP compared with those in control cases. Our results suggest that DDR dysfunction due to cytoplasmic sequestration of BRCA1 could be involved in the pathogenesis of tauopathies.


Assuntos
Doença de Alzheimer/metabolismo , Proteína BRCA1/metabolismo , Tauopatias/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Proteína BRCA1/genética , Feminino , Humanos , Imuno-Histoquímica , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Masculino , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Emaranhados Neurofibrilares/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Tauopatias/genética , Tauopatias/patologia , Bancos de Tecidos , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética
9.
J Neuropathol Exp Neurol ; 79(1): 3-21, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31748784

RESUMO

We found evidence of late-onset Alzheimer disease (LOAD)-associated genetic polymorphism within an exon of Mucin 6 (MUC6) and immediately downstream from another gene: Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2). PCR analyses on genomic DNA samples confirmed that the size of the MUC6 variable number tandem repeat (VNTR) region was highly polymorphic. In a cohort of autopsied subjects with quantitative digital pathology data (n = 119), the size of the polymorphic region was associated with the severity of pTau pathology in neocortex. In a separate replication cohort of autopsied subjects (n = 173), more pTau pathology was again observed in subjects with longer VNTR regions (p = 0.031). Unlike MUC6, AP2A2 is highly expressed in human brain. AP2A2 expression was lower in a subset analysis of brain samples from persons with longer versus shorter VNTR regions (p = 0.014 normalizing with AP2B1 expression). Double-label immunofluorescence studies showed that AP2A2 protein often colocalized with neurofibrillary tangles in LOAD but was not colocalized with pTau proteinopathy in progressive supranuclear palsy, or with TDP-43 proteinopathy. In summary, polymorphism in a repeat-rich region near AP2A2 was associated with neocortical pTau proteinopathy (because of the unique repeats, prior genome-wide association studies were probably unable to detect this association), and AP2A2 was often colocalized with neurofibrillary tangles in LOAD.


Assuntos
Complexo 2 de Proteínas Adaptadoras/genética , Subunidades alfa do Complexo de Proteínas Adaptadoras/genética , Doença de Alzheimer/genética , Mucina-6/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Autopsia , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Repetições Minissatélites , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/patologia , Polimorfismo Genético/genética , Polimorfismo de Nucleotídeo Único , Proteinopatias TDP-43/genética , Proteinopatias TDP-43/patologia
10.
Alzheimers Res Ther ; 11(1): 107, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847886

RESUMO

BACKGROUND: Alzheimer disease (AD) is characterized by the accumulation of beta-amyloid (Aß) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline. Current therapeutic approaches have primarily aimed to reduce pathological aggregates of either Aß or tau, yet phase 3 clinical trials of these approaches have thus far failed to delay disease progression in humans. Strong preclinical evidence indicates that these two abnormally aggregated proteins interact synergistically to drive downstream neurodegeneration. Therefore, combinatorial therapies that concurrently target both Aß and tau might be needed for effective disease modification. METHODS: A combinatorial vaccination approach was designed to concurrently target both Aß and tau pathologies. Tau22/5xFAD (T5x) bigenic mice that develop both pathological Aß and tau aggregates were injected intramuscularly with a mixture of two MultiTEP epitope vaccines: AV-1959R and AV-1980R, targeting Aß and tau, respectively, and formulated in AdvaxCpG, a potent polysaccharide adjuvant. Antibody responses of vaccinated animals were measured by ELISA, and neuropathological changes were determined in brain homogenates of vaccinated and control mice using ELISA and Meso Scale Discovery (MSD) multiplex assays. RESULTS: T5x mice immunized with a mixture of Aß- and tau-targeting vaccines generated high Aß- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles/neuropil threads in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aß42, within the brains of bigenic T5x mice. CONCLUSIONS: AV-1959R and AV-1980R formulated with AdvaxCpG adjuvant are immunogenic and therapeutically potent vaccines that in combination can effectively reduce both of the hallmark pathologies of AD in bigenic mice. Taken together, these findings warrant further development of this vaccine technology for ultimate testing in human AD.


Assuntos
Doença de Alzheimer/terapia , Vacinas contra Alzheimer , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia
11.
J. optom. (Internet) ; 12(3): 198-207, jul.-sept. 2019.
Artigo em Espanhol | IBECS | ID: ibc-185371

RESUMO

Alzheimer's disease (AD) is a neurodegenerative dementia characterized by the deposition of extracellular β-amyloid (Aβ) plaques and the presence of neurofibrillary tangles. Until now, the techniques used to analyze these deposits have been difficult to access, invasive, and expensive. This leads us to consider new access routes to the central nervous system (CNS), allowing us to diagnose the disease before the first symptoms appear. Recent studies have shown that microglial and macroglial cell activation could play a role in the development of this disease. Glial cells in the CNS can respond to various damages, such as neurodegenerative pathologies, with morphological and functional changes. These changes are a common feature in neurodegenerative diseases, including AD. The retina is considered an extension of the CNS and has a population of glial cells similar to that of the CNS. When glial cells are activated, various molecules are released and changes in glial cell expression occur, which can be indicators of neuronal damage. The objective of this review is to compile the most relevant findings in the last 10 years relating to alterations in the eye in AD, and the role that glial cells play in the degenerative process in the retina in the context of neurodegeneration


La enfermedad de Alzheimer (EA) es una demencia neurodegenerativa que se caracteriza por la deposición de placas beta-amiloides (βA) extracelulares, y la presencia de ovillos neurofibrilares. Hasta ahora, las técnicas utilizadas para analizar estos depósitos han sido poco accesibles, invasivas y costosas. Esto nos lleva a considerar nuevas vías de acceso al sistema nervioso central (SNC) que nos permitan diagnosticar la enfermedad antes de la aparición de sus primeros síntomas. Los estudios recientes han reflejado que la activación de las células microgliales y macrogliales podría desempeñar un papel en el desarrollo de esta enfermedad. Las células gliales del SNC pueden responder a diversos daños, tales como patologías neurodegenerativas, con cambios morfológicos y funcionales. Dichos cambios son una característica común en las enfermedades neurodegenerativas, incluyendo la EA. La retina se considera una extensión del SNC, y cuenta con una población de células gliales similar a la de dicho sistema. Cuando las células gliales se activan, se liberan diversas moléculas, y se producen diversos cambios en la expresión de las células gliales, que pueden ser indicadores de daño neuronal. El objetivo de esta revisión es recopilar los hallazgos más relevantes de los últimos diez años, con relación a las alteraciones oculares en la EA, y el papel que juegan las células gliales en el proceso degenerativo de la retina en el contexto de la neurodegeneración


Assuntos
Humanos , Doença de Alzheimer/patologia , Neuroglia/patologia , Retina/patologia , Emaranhados Neurofibrilares/patologia
12.
BMC Neurol ; 19(1): 211, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464590

RESUMO

BACKGROUND: THK5351 and flortaucipir tau ligands have high affinity for paired helical filament tau, yet diverse off-target bindings have been reported. Recent data support the hypothesis that THK5351 binds to monoamine oxidase B (MAO-B) expressed from reactive astrocytes and that flortaucipir has an affinity toward MAO-A and B; however, pathological evidence is lacking. We performed a head-to-head comparison of the two tau ligands in a sporadic Creutzfeldt-Jakob disease (CJD) patient and performed an imaging-pathological correlation study. CASE PRESENTATION: A 67-year-old man visited our clinic a history of 6 months of rapidly progressive dementia, visual disturbance, and akinetic mutism. Diffusion-weighted imaging showed cortical diffusion restrictions in the left temporo-parieto-occipital regions. 18F-THK5351 PET, but not 18F-flortaucipir PET showed high uptake in the left temporo-parieto-occipital regions, largely overlapping with the diffusion restricted areas. Cerebrospinal fluid analysis was weakly positive for 14-3-3 protein and pathogenic prion protein was found. The patient showed rapid cognitive decline along with myoclonic seizures and died 13 months after his first visit. A post-mortem study revealed immunoreactivity for PrPsc, no evidence of neurofibrillary tangles, and abundant astrocytosis which was reactive for MAO-B antibody. CONCLUSIONS: Our findings add pathological evidence that increased THK5351 uptake in sporadic CJD patients might be caused by an off-target binding driven by its high affinity for MAO-B.


Assuntos
Aminopiridinas/farmacologia , Carbolinas/farmacologia , Síndrome de Creutzfeldt-Jakob/diagnóstico por imagem , Síndrome de Creutzfeldt-Jakob/patologia , Tomografia por Emissão de Pósitrons/métodos , Quinolinas/farmacologia , Idoso , Autopsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Humanos , Masculino , Monoaminoxidase/metabolismo , Emaranhados Neurofibrilares/patologia , Proteínas tau/metabolismo
13.
Ann Clin Transl Neurol ; 6(9): 1782-1796, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31448566

RESUMO

OBJECTIVE: To identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD-GRN) and chromosome 9 open reading frame 72 (FTLD-C9ORF72). METHODS: We performed quantitative neuropathologic comparison of 17 FTLD-C9ORF72 and 15 FTLD-GRN with a focus on microglia. For clinical comparisons, only cases with high quality medical documentation and concurring diagnoses by at least two neurologists were included (14 FTLD-GRN and 13 FTLD-C9ORF72). Neuropathological analyses were limited to TDP-43 Type A to assure consistent assessment between the groups, acknowledging that Type A is a minority of C9ORF72 patients. Furthermore, only cases with sufficient tissue from all regions were studied (11 FTLD-GRN and 11 FTLD-C9ORF72). FTLD cases were also compared to age- and sex-matched normal controls. Immunohistochemistry was performed for pTDP-43, IBA-1, CD68, and GFAP. Morphological characterization of microglia was performed in sections of cortex blinded to clinical and genetic information. RESULTS: FTLD-GRN patients had frequent asymmetric clinical features, including aphasia and apraxia, as well as more asymmetric cortical atrophy. Neuropathologically, FTLD-C9ORF72 had greater hippocampal tau pathology and more TDP-43 neuronal cytoplasmic inclusions. FTLD-GRN had more neocortical microvacuolation, as well as more IBA-1-positive ameboid microglia in superficial cortical layers and in subcortical white matter. FTLD-GRN also had more microglia with nuclear condensation, possibly indicating apoptosis. Microglial morphology with CD68 immunohistochemistry in FTLD-GRN and FTLD-C9ORF72 differed from controls. INTERPRETATION: Our findings underscore differences in microglial response in FTLD-C9ORF72 and FTLD-GRN as shown by significant differences in ameboid microglia in gray and white matter. These results suggest the differential contribution of microglial dysfunction in FTLD-GRN and FTLD-C9ORF72 and suggest that clinical, neuroimaging and pathologic differences could in part be related to differences in microglia response.


Assuntos
Encéfalo/patologia , Proteína C9orf72/genética , Degeneração Lobar Frontotemporal/patologia , Microglia/patologia , Mutação , Progranulinas/genética , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Feminino , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/metabolismo , Humanos , Masculino , Microglia/metabolismo , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Proteínas tau/metabolismo
14.
Adv Exp Med Biol ; 1173: 67-104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456206

RESUMO

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition associated with pathological accumulation of amyloid plaques and with the appearance of deposit of neurofibrillary tangles. Increasing evidence suggests that disorders of metal ion metabolism in the brain are one of the risk factors for the pathogenesis of AD. Iron, one of the endogenous metal ions, involves in many important physiological activities in the brain. Iron metabolism mainly depends on iron regulatory proteins including ferritin, transferrin and transferrin receptor, hepcidin, ferroportin, lactoferrin. Abnormal iron metabolism generates hydroxyl radicals through the Fenton reaction, triggers oxidative stress reactions, damages cell lipids, protein and DNA structure and function, leads to cell death, and ultimately influences the process of ß-amyloid (Aß) misfolding and plaque aggregation. Although the results are different, in general, iron has deposition in different brain regions of AD patients, which may impair normal cognitive function and behavior. Therefore, neuroimaging changes have so far been largely attributed to focal iron deposition accompanying the plaques at preclinical stages of AD, and iron-targeted therapeutic strategies have become a new direction. Iron chelators have received a great deal of attention and have obtained good results in scientific experiments and some clinical trials. Future research will also focus on iron as an opportunity to study the mechanism of the occurrence and development of AD from the iron steady state to more fully clarify the etiology and prevention strategies.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/metabolismo , Ferro/metabolismo , Peptídeos beta-Amiloides , Encéfalo/fisiopatologia , Humanos , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia
15.
Orv Hetil ; 160(33): 1289-1295, 2019 Aug.
Artigo em Húngaro | MEDLINE | ID: mdl-31401858

RESUMO

The ever-growing average age of the society significantly increases the occurrence of Alzheimer's disease. The increased prevalence represents considerable social and economic burden, which urges the development of diagnostic and therapeutic methods in the field. The most common cause of dementia is Alzheimer's disease, the typical histopathological abnormality of which are well known. The detection of functional changes results in the early diagnosis of the disease, which precedes the morphological changes by years. Positron-emission tomography plays an important role in the demonstration of metabolic changes. The glucose metabolic pattern differs significantly in each clinical form of dementia. The most important ß-amyloid-binding radiopharmaceuticals that should be highlighted are [11C]Pittsburgh compound B that is widely used in the research and [18F]florbetapir that is commonly approved in diagnostics. Tracers visualising neurofibrillary tangles consisting of tau protein appeared most recently. The development continues; newer and newer radiopharmaceuticals appear. These tracers play an important role in both the research and the diagnostics. Orv Hetil. 2019; 160(33): 1289-1295.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Imagem Molecular , Emaranhados Neurofibrilares/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Progressão da Doença , Humanos , Emaranhados Neurofibrilares/patologia , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/metabolismo , Placa Amiloide/patologia
16.
Neurology ; 93(8): e778-e790, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31320469

RESUMO

OBJECTIVE: To identify heterogeneity in cognitive profiles of patients with probable Alzheimer disease (AD) who have mild to moderate dementia and satisfy inclusion and exclusion criteria for a typical AD clinical trial, and to determine whether cognitive profiles are systematically related to the clinical course and neuropathologic features of the disease. METHODS: Neuropsychological test data from patients with mild to moderate probable AD (n = 4,711) were obtained from the National Alzheimer's Coordinating Center. Inclusion and exclusion criteria usually used in AD clinical trials were applied. Principal component analysis and model-based clustering were used to identify cognitive profiles in a subset of patients with autopsy-verified AD (n = 800) and validated in the overall (nonautopsy) sample and an independent cohort with similar test data. Relationships between cognitive profile, clinical characteristics, and rate of decline were examined with mixed-effects models. RESULTS: In the autopsy-confirmed sample, 79.6% of patients had a typical AD cognitive profile (greater impairment of episodic memory than other cognitive functions), and 20.4% had an atypical profile (comparable impairment across cognitive domains). Similar results were obtained in the overall (typical 79.8%, atypical 20.2%) and validation (typical 71.8%, atypical 28.2%) samples. Atypicality was associated with younger age, male sex, lower probability of APOE ε4, less severe global dementia, higher depression scores, lower Braak stage at autopsy, and slower cognitive decline. CONCLUSION: We can reliably identify distinct cognitive profiles among patients with clinically diagnosed probable AD that are associated with tangle pathology and with different rates of decline. This may have implications for clinical trials in AD, especially therapies targeting tau.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Cognição , Demência/patologia , Demência/psicologia , Fatores Etários , Idoso , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Demência/complicações , Progressão da Doença , Feminino , Humanos , Masculino , Emaranhados Neurofibrilares/patologia , Testes Neuropsicológicos , Placa Amiloide/patologia , Fatores de Risco , Fatores Sexuais
17.
BMC Neurol ; 19(1): 168, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319800

RESUMO

BACKGROUND: The coexistence of distinct neurodegenerative diseases in single cases has recently attracted greater attention. The phenotypic co-occurrence of progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) has been documented in several cases. That said, the clinicopathological comorbidity of these two diseases has not been demonstrated. CASE PRESENTATION: A 77-year-old man presented with gait disturbance for 2 years, consistent with PSP with progressive gait freezing. At 79 years old, he developed muscle weakness compatible with ALS. The disease duration was 5 years after the onset of PSP and 5 months after the onset of ALS. Neuropathological findings demonstrated the coexistence of PSP and ALS. Immunohistochemical examination confirmed 4-repeat tauopathy, including globose-type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. Immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands (64 and 68 kDa) and C-terminal fragments (33 kDa), supporting the diagnosis of PSP and excluding other parkinsonian disorders, such as corticobasal degeneration. Genetic studies showed no abnormalities in genes currently known to be related to ALS or PSP. CONCLUSIONS: Our case demonstrates the clinicopathological comorbidity of PSP and ALS in a sporadic patient. The possibility of multiple proteinopathies should be considered when distinct symptoms develop during the disease course.


Assuntos
Esclerose Amiotrófica Lateral/complicações , Encéfalo/patologia , Paralisia Supranuclear Progressiva/complicações , Idoso , Esclerose Amiotrófica Lateral/diagnóstico por imagem , Esclerose Amiotrófica Lateral/patologia , Astrócitos/patologia , Encéfalo/diagnóstico por imagem , Comorbidade , Proteínas de Ligação a DNA , Evolução Fatal , Humanos , Masculino , Transtornos dos Movimentos/etiologia , Emaranhados Neurofibrilares/patologia , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/patologia , Proteínas tau/análise
18.
Eur J Med Chem ; 177: 291-301, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158745

RESUMO

Based on our previous research on the fluorinated phenylquinoxaline scaffold, in this study, different positions of N,N-dimethyl amino group, and alkyl linkers with various lengths were introduced into this scaffold to regulate their lipophilicity and binding affinity to Tau. Four novel 99mTc/Re complexes with diethyl iminodiacetate chelator were synthesized and evaluated as Tau imaging tracers in the brain of Alzheimer's disease. Their specific binding to neurofibrillary tangles was verified by in vitro fluorescence staining and further confirmed by the results of immunofluorescence staining on the same brain sections from AD patient and Tg-tau mice. From in vitro binding assay using recombinant Tau aggregates, complex 4.2 with 6-N(CH3)2 and longer carbon chain (n = 4) displayed the highest affinity (Kd = 59.95 nM). [99mTc]4.2 was achieved by the ligand exchange reaction between dicarboxylic precursor and [99mTc(CO)3(H2O)3]+ intermediate with radiochemical yield over 45%. Ex vivo biodistribution studies on normal ICR mice revealed that [99mTc]4.2 exhibited moderate initial brain uptake (0.61% ID/g) and more structure optimizations are still required to improve the blood-brain barrier permeability.


Assuntos
Doença de Alzheimer/diagnóstico , Complexos de Coordenação/química , Corantes Fluorescentes/química , Compostos de Organotecnécio/química , Quinoxalinas/química , Proteínas tau/metabolismo , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Quelantes/síntese química , Quelantes/química , Quelantes/metabolismo , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Feminino , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Humanos , Iminoácidos/síntese química , Iminoácidos/química , Iminoácidos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Estrutura Molecular , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/metabolismo , Fragmentos de Peptídeos/metabolismo , Quinoxalinas/síntese química , Quinoxalinas/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Rênio/química , Distribuição Tecidual
19.
Acta Neuropathol Commun ; 7(1): 71, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060611

RESUMO

Neurofibrillary tangles (NFTs), are shared between progressive supranuclear palsy (PSP) and Alzheimer disease (AD). Histological distinction of PSP and AD is possible based on the distribution of NFTs. However, neuropathologists may encounter diagnostic difficulty with comorbidity of PSP and AD. In this study, we tried to circumvent this difficulty by analyzing five autopsied brains harboring both PSP and AD pathology. Tau-positive lesions were sorted based on their cell type (neuron versus glia), and tau isoforms: three-repeat (3R) versus four-repeat (4R) tau. 16 regions were selected to map these lesions throughout the brain. 4R-tau lesions were present in all areas examined. Among them, 3R-tau lesions were absent in some areas. These 4R selective (4R+/3R-) areas dictate prototypic distribution of PSP, not usually found in AD, such as pontine nucleus, red nucleus, inferior olivary nucleus, dentate nucleus, globus pallidus and putamen, each contained both glial and neuronal lesions. In contrast, additional 3R-tau lesions were found in hippocampal formation to neocortex, where 3R immunoreactivity (IR) was predominant over the 4R counterpart mainly in neurons as found in AD but not in PSP. Although tau lesions in central grey matter, substantia nigra and locus coeruleus are found in both AD and PSP, 4R-selectivity with glial component suggests PSP origin. Even if the presence of 3 R IR in these areas suggests AD pathology, it does not exclude the involvement of PSP-type lesion because distinction of 4R IR into PSP or AD is not yet possible. Further demixing may be possible if biochemical difference of 4R tau between PSP and AD is identified.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Emaranhados Neurofibrilares/patologia , Paralisia Supranuclear Progressiva/patologia , Proteínas tau/metabolismo , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Comorbidade , Feminino , Humanos , Masculino , Neurônios/metabolismo , Isoformas de Proteínas/metabolismo , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/metabolismo
20.
Adv Exp Med Biol ; 1128: 45-83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31062325

RESUMO

The standard practice in neuropathology is to diagnose Alzheimer's disease (AD) based on the distribution and abundance of neurofibrillary tangles and Aß deposits. However, other significant abnormalities including neuroinflammation, gliosis, white matter degeneration, non-Aß microvascular disease, and insulin-related metabolic dysfunction require further study to understand how they could be targeted to more effectively remediate AD. This review addresses non-Aß and non-pTau AD-associated pathologies, highlighting their major features, roles in neurodegeneration, and etiopathic links to deficits in brain insulin and insulin-like growth factor signaling and cognitive impairment. The discussion delineates why AD with its most characteristic clinical and pathological phenotypic profiles should be regarded as a brain form of diabetes, i.e., type 3 diabetes, and entertains the hypothesis that type 3 diabetes is just one of the categories of insulin resistance diseases that can occur independently or overlap with one or more of the others, including type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Diabetes Mellitus/patologia , Resistência à Insulina , Humanos , Insulina , Emaranhados Neurofibrilares/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA