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1.
Chem Biol Interact ; 328: 109144, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32653415

RESUMO

The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional antiepileptics to further deteriorate cognitive function are areas of growing concern. Glucagon-like peptide-1 (GLP-1) deficiency has been linked to reduced seizure threshold as well as cognitive dysfunction. Here, we tested whether sitagliptin (SITA), by virtue of its neuroprotective properties, could alleviate both epilepsy and associated cognitive dysfunction in a rat model of kindling epilepsy. Chemical kindling was induced by subconvulsive doses of pentylenetetrazol (PTZ) (30 mg/kg; i.p). SITA (50 mg/kg; p.o) was administered 1 h before PTZ injections. SITA conceivably attenuated PTZ hippocampal histological insult, preserved neuronal integrity and amended neurotransmitter perturbations in rat hippocampi paralleled with enhanced hippocampal GLP-1 levels as well as the downstream cAMP content and protein kinase A (PKA) activity. Moreover, SITA improved cognitive functioning of rats in the Morris water maze which was coupled with hampered hippocampal p(Ser404)-tau and ß-amyloid proteins. SITA replenished p(Ser9)-glycogen synthase kinase-3ß (GSK-3ß). It also opposed the boosted matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) levels associated with PTZ administration along with mitigation of both ß-secretase-1 (BACE1) immunoreactivity and receptor for advanced glycation end products (RAGE) protein level in rat hippocampi. In conclusion, SITA subdues epileptic and cognitive upshots of PTZ kindling in rats, which might correspond to the modulation of BACE1, amyloidogenic/RAGE axis as well as GSK-3ß/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Excitação Neurológica/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Fosfato de Sitagliptina/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/patologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neurotransmissores/metabolismo , Pentilenotetrazol , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/patologia , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Proteínas tau/metabolismo
2.
BMC Psychiatry ; 20(1): 334, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32580716

RESUMO

BACKGROUND: Dysfunction in brain network dynamics has been found to correlate with many psychiatric disorders. However, there is limited research regarding resting electroencephalogram (EEG) brain network and its association with cognitive process for patients with methamphetamine use disorder (MUD). This study aimed at using EEG microstate analysis to determine whether brain network dynamics in patients with MUD differ from those of healthy controls (HC). METHODS: A total of 55 MUD patients and 27 matched healthy controls were included for analysis. The resting brain activity was recorded by 64-channel electroencephalography. EEG microstate parameters and intracerebral current sources of each EEG microstate were compared between the two groups. Generalized linear regression model was used to explore the correlation between significant microstates with drug history and cognitive functions. RESULTS: MUD patients showed lower mean durations of the microstate classes A and B, and a higher global explained variance of the microstate class C. Besides, MUD patients presented with different current density power in microstates A, B, and C relative to the HC. The generalized linear model showed that MA use frequency is negatively correlated with the MMD of class A. Further, the generalized linear model showed that MA use frequency, scores of Two-back task, and the error rate of MA word are correlated with the MMD and GEV of class B, respectively. CONCLUSIONS: Intracranial current source densities of resting EEG microstates are disrupted in MUD patients, hence causing temporal changes in microstate topographies, which are correlated with attention bias and history of drug use.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/fisiopatologia , Eletroencefalografia , Metanfetamina/efeitos adversos , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/patologia , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/patologia , Feminino , Humanos , Masculino
3.
Ann Biol Clin (Paris) ; 78(3): 243-252, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32540813

RESUMO

Adiponectin is a major adipokine involved in energy homeostasis that exerts insulin-sensitizing properties. The level of adiponectin is reduced in situations of insulin resistance and is negatively associated with several pathophysiological situations including abdominal obesity, metabolic syndrome, steatosis and non-alcoholic steatohepatitis, type 2 diabetes, some cancers and cognitive diseases. These aspects are discussed in this review.


Assuntos
Adiponectina/fisiologia , Animais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Obesidade/metabolismo , Obesidade/patologia , Obesidade/fisiopatologia
4.
Nat Commun ; 11(1): 2484, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32424276

RESUMO

DNA damage contributes to brain aging and neurodegenerative diseases. However, the factors stimulating DNA repair to stave off functional decline remain obscure. We show that HDAC1 modulates OGG1-initated 8-oxoguanine (8-oxoG) repair in the brain. HDAC1-deficient mice display age-associated DNA damage accumulation and cognitive impairment. HDAC1 stimulates OGG1, a DNA glycosylase known to remove 8-oxoG lesions that are associated with transcriptional repression. HDAC1 deficiency causes impaired OGG1 activity, 8-oxoG accumulation at the promoters of genes critical for brain function, and transcriptional repression. Moreover, we observe elevated 8-oxoG along with reduced HDAC1 activity and downregulation of a similar gene set in the 5XFAD mouse model of Alzheimer's disease. Notably, pharmacological activation of HDAC1 alleviates the deleterious effects of 8-oxoG in aged wild-type and 5XFAD mice. Our work uncovers important roles for HDAC1 in 8-oxoG repair and highlights the therapeutic potential of HDAC1 activation to counter functional decline in brain aging and neurodegeneration.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Encéfalo/patologia , Dano ao DNA , DNA Glicosilases/metabolismo , Histona Desacetilase 1/metabolismo , Estresse Oxidativo , Acetilação , Envelhecimento/genética , Doença de Alzheimer/complicações , Doença de Alzheimer/fisiopatologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Sequência de Bases , Benzofenonas/farmacologia , Cognição/efeitos dos fármacos , Transtornos Cognitivos/complicações , Transtornos Cognitivos/patologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Ontologia Genética , Guanina/análogos & derivados , Guanina/metabolismo , Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Regiões Promotoras Genéticas/genética
5.
Neurology ; 94(19): e2005-e2013, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32277059

RESUMO

OBJECTIVE: To determine if survival and cognitive profile is affected by initial presentation in amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) (motor vs cognitive), we compared survival patterns in ALS-FTD based on initial phenotypic presentation and their cognitive profile compared to behavioral variant FTD (bvFTD). METHODS: Cognitive/behavioral profiles were examined in 98 patients (59 ALS-FTD and 39 bvFTD). The initial presentation of ALS-FTD was categorized into either motor or cognitive. Survival was calculated from initial symptom onset. MRI brain atrophy patterns were examined using a validated visual rating scale. RESULTS: In the ALS-FTD group, 41 (69%) patients were categorized as having an initial cognitive presentation and 18 (31%) a motor presentation. Patients with motor presentation experienced a significantly shorter median survival of 2.7 years compared to 4.4 years (p < 0.001) in those with a cognitive presentation. No differences between motor vs cognitive onset ALS-FTD were found on cognitive testing. When compared to bvFTD, ALS-FTD-cognitive presentation was characterized by reduced language function (p < 0.001), verbal fluency (p = 0.001), and naming (p = 0.007). Both motor and cognitive onset ALS-FTD showed reduced emotion processing (p = 0.01) and exhibited greater motor cortex and dorsal lateral prefrontal cortex atrophy than bvFTD. Increased motor cortex atrophy was associated with 1.5-fold reduction in survival. CONCLUSIONS: Initial motor presentation in ALS-FTD leads to faster progression than in those with a cognitive presentation, despite similar overall cognitive deficits. These findings suggest that disease progression in ALS-FTD may be critically linked to physiologic and motor changes.


Assuntos
Esclerose Amiotrófica Lateral/psicologia , Variação Biológica da População , Transtornos Cognitivos/diagnóstico , Demência Frontotemporal/psicologia , Análise de Sobrevida , Esclerose Amiotrófica Lateral/complicações , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/patologia , Atrofia/complicações , Transtornos Cognitivos/complicações , Transtornos Cognitivos/patologia , Feminino , Demência Frontotemporal/complicações , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Motor/patologia , Neuroimagem , Testes Neuropsicológicos , Córtex Pré-Frontal/patologia
6.
J Neurol Neurosurg Psychiatry ; 91(4): 418-425, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32079673

RESUMO

BACKGROUND: Dementia is common in Parkinson's disease (PD) but measures that track cognitive change in PD are lacking. Brain tissue iron accumulates with age and co-localises with pathological proteins linked to PD dementia such as amyloid. We used quantitative susceptibility mapping (QSM) to detect changes related to cognitive change in PD. METHODS: We assessed 100 patients with early-stage to mid-stage PD, and 37 age-matched controls using the Montreal Cognitive Assessment (MoCA), a validated clinical algorithm for risk of cognitive decline in PD, measures of visuoperceptual function and the Movement Disorders Society Unified Parkinson's Disease Rating Scale part 3 (UPDRS-III). We investigated the association between these measures and QSM, an MRI technique sensitive to brain tissue iron content. RESULTS: We found QSM increases (consistent with higher brain tissue iron content) in PD compared with controls in prefrontal cortex and putamen (p<0.05 corrected for multiple comparisons). Whole brain regression analyses within the PD group identified QSM increases covarying: (1) with lower MoCA scores in the hippocampus and thalamus, (2) with poorer visual function and with higher dementia risk scores in parietal, frontal and medial occipital cortices, (3) with higher UPDRS-III scores in the putamen (all p<0.05 corrected for multiple comparisons). In contrast, atrophy, measured using voxel-based morphometry, showed no differences between groups, or in association with clinical measures. CONCLUSIONS: Brain tissue iron, measured using QSM, can track cognitive involvement in PD. This may be useful to detect signs of early cognitive change to stratify groups for clinical trials and monitor disease progression.


Assuntos
Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/diagnóstico por imagem , Ferro/metabolismo , Doença de Parkinson/diagnóstico por imagem , Idoso , Encéfalo/metabolismo , Encéfalo/patologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Progressão da Doença , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Índice de Gravidade de Doença
7.
Genes (Basel) ; 11(2)2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033187

RESUMO

The hippocampus is involved in learning and memory and undergoes significant growth and maturation during the neonatal period. Environmental insults during this developmental timeframe can have lasting effects on brain structure and function. This study assessed hippocampal DNA methylation and gene transcription from two independent studies reporting reduced cognitive development stemming from early life environmental insults (iron deficiency and porcine reproductive and respiratory syndrome virus (PRRSv) infection) using porcine biomedical models. In total, 420 differentially expressed genes (DEGs) were identified between the reduced cognition and control groups, including genes involved in neurodevelopment and function. Gene ontology (GO) terms enriched for DEGs were associated with immune responses, angiogenesis, and cellular development. In addition, 116 differentially methylated regions (DMRs) were identified, which overlapped 125 genes. While no GO terms were enriched for genes overlapping DMRs, many of these genes are known to be involved in neurodevelopment and function, angiogenesis, and immunity. The observed altered methylation and expression of genes involved in neurological function suggest reduced cognition in response to early life environmental insults is due to altered cholinergic signaling and calcium regulation. Finally, two DMRs overlapped with two DEGs, VWF and LRRC32, which are associated with blood brain barrier permeability and regulatory T-cell activation, respectively. These results support the role of altered hippocampal DNA methylation and gene expression in early life environmentally-induced reductions in cognitive development across independent studies.


Assuntos
Biomarcadores/análise , Transtornos Cognitivos/etiologia , Metilação de DNA , Exposição Ambiental/efeitos adversos , Epigênese Genética , Hipocampo/patologia , Animais , Animais Recém-Nascidos , Diferenciação Celular , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Ilhas de CpG , Feminino , Hipocampo/metabolismo , Suínos
8.
Brain ; 143(2): 635-649, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32040564

RESUMO

Age being the main risk factor for Alzheimer's disease, it is particularly challenging to disentangle structural changes related to normal brain ageing from those specific to Alzheimer's disease. Most studies aiming to make this distinction focused on older adults only and on a priori anatomical regions. Drawing on a large, multi-cohort dataset ranging from young adults (n = 468; age range 18-35 years), to older adults with intact cognition (n = 431; age range 55-90 years) and with Alzheimer's disease (n = 50 with late mild cognitive impairment and 71 with Alzheimer's dementia, age range 56-88 years), we investigated grey matter organization and volume differences in ageing and Alzheimer's disease. Using independent component analysis on all participants' structural MRI, we first derived morphometric networks and extracted grey matter volume in each network. We also derived a measure of whole-brain grey matter pattern organization by correlating grey matter volume in all networks across all participants from the same cohort. We used logistic regressions and receiver operating characteristic analyses to evaluate how well grey matter volume in each network and whole-brain pattern could discriminate between ageing and Alzheimer's disease. Because increased heterogeneity is often reported as one of the main features characterizing brain ageing, we also evaluated interindividual heterogeneity within morphometric networks and across the whole-brain organization in ageing and Alzheimer's disease. Finally, to investigate the clinical validity of the different grey matter features, we evaluated whether grey matter volume or whole-brain pattern was related to clinical progression in cognitively normal older adults. Ageing and Alzheimer's disease contributed additive effects on grey matter volume in nearly all networks, except frontal lobe networks, where differences in grey matter were more specific to ageing. While no networks specifically discriminated Alzheimer's disease from ageing, heterogeneity in grey matter volumes across morphometric networks and in the whole-brain grey matter pattern characterized individuals with cognitive impairments. Preservation of the whole-brain grey matter pattern was also related to lower risk of developing cognitive impairment, more so than grey matter volume. These results suggest both ageing and Alzheimer's disease involve widespread atrophy, but that the clinical expression of Alzheimer's disease is uniquely associated with disruption of morphometric organization.


Assuntos
Envelhecimento , Doença de Alzheimer/patologia , Encéfalo/patologia , Disfunção Cognitiva/patologia , Demência/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Disfunção Cognitiva/metabolismo , Demência/complicações , Progressão da Doença , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Brain ; 143(2): 611-621, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31942622

RESUMO

Primary age-related tauopathy is increasingly recognized as a separate neuropathological entity different from Alzheimer's disease. Both share the neuropathological features of tau aggregates and neuronal loss in the temporal lobe, but primary age-related tauopathy lacks the requisite amyloid plaques central to Alzheimer's disease. While both have similar clinical presentations, individuals with symptomatic primary age-related tauopathy are commonly of more advanced ages with milder cognitive dysfunction. Direct comparison of the neuropsychological trajectories of primary age-related tauopathy and Alzheimer's disease has not been thoroughly evaluated and thus, our objective was to determine how cognitive decline differs longitudinally between these two conditions after the onset of clinical symptoms. Data were obtained from the National Alzheimer's Coordinating Center on participants with mild cognitive impairment at baseline and either no neuritic plaques (i.e. primary age-related tauopathy) or moderate to frequent neuritic plaques (i.e. Alzheimer neuropathological change) at subsequent autopsy. For patients with Alzheimer's disease and primary age-related tauopathy, we compared rates of decline in the sum of boxes score from the CDR® Dementia Staging Instrument and in five cognitive domains (episodic memory, attention/working memory, executive function, language/semantic memory, and global composite) using z-scores for neuropsychological tests that were calculated based on scores for participants with normal cognition. The differences in rates of change were tested using linear mixed-effects models accounting for clinical centre clustering and repeated measures by individual. Models were adjusted for sex, age, education, baseline test score, Braak stage, apolipoprotein ε4 (APOE ε4) carrier status, family history of cognitive impairment, and history of stroke, hypertension, or diabetes. We identified 578 participants with a global CDR of 0.5 (i.e. mild cognitive impairment) at baseline, 126 with primary age-related tauopathy and 452 with Alzheimer's disease. Examining the difference in rates of change in CDR sum of boxes and in all domain scores, participants with Alzheimer's disease had a significantly steeper decline after becoming clinically symptomatic than those with primary age-related tauopathy. This remained true after adjusting for covariates. The results of this analysis corroborate previous studies showing that primary age-related tauopathy has slower cognitive decline than Alzheimer's disease across multiple neuropsychological domains, thus adding to the understanding of the neuropsychological burden in primary age-related tauopathy. The study provides further evidence to support the hypothesis that primary age-related tauopathy has distinct neuropathological and clinical features compared to Alzheimer's disease.


Assuntos
Transtornos Cognitivos/patologia , Cognição/fisiologia , Disfunção Cognitiva/patologia , Tauopatias/patologia , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Disfunção Cognitiva/diagnóstico , Função Executiva/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
PLoS One ; 15(1): e0227879, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929603

RESUMO

Accumulating evidence suggests that Alzheimer's disease is associated with brain insulin resistance, as are some other types of dementia. Intranasal insulin administration has been suggested as a potential approach to overcoming brain insulin resistance and improving cognitive functions. Islet transplantation into the cranial subarachnoid cavity was used as an alternative route for insulin delivery into the brain. Recently, the authors showed the short-term beneficial cognitive effect of a small number of intracranially grafted islets in rats with cognitive dysfunction induced by intracerebroventricular administration of streptozotocin (icv-STZ). This was associated with continuous and safe insulin delivery to the rat brain. The current study investigated the long-term effect of intracranial grafting of islets on cognitive functioning in icv-STZ rats. Severe dementia, associated with obesity and cerebral amyloid-ß angiopathy, was induced in Lewis inbred rats by icv-STZ. Two months after icv-STZ, one hundred syngeneic islets were transplanted into the cranial subarachnoid space. Two and six months later, cognitive alterations were assessed by Morris water-maze tests. Islet graft survival was evaluated by immunohistochemical and biochemical assays. Improvement was found in spatial learning and memory of grafted rats as opposed to the sham-operated icv-STZ rats. The grafted islets showed intact morphology, intensive expression of insulin, glucagon and glucose transporter 2. Normoglycemic obesity and cerebral amyloid-ß angiopathy were found in both grafted and sham-operated icv-STZ rats. In conclusion, islet grafting into cranial subarachnoid space provides an efficient and safe approach for insulin delivery to the brain, leading to a long-term attenuation of icv-STZ-induced cognitive dysfunction.


Assuntos
Doença de Alzheimer/terapia , Transtornos Cognitivos/terapia , Insulina/biossíntese , Transplante das Ilhotas Pancreáticas/métodos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/cirurgia , Cognição/fisiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/cirurgia , Humanos , Ilhotas Pancreáticas/metabolismo , Aprendizagem em Labirinto , Memória/fisiologia , Ratos
11.
Neurology ; 94(1): e42-e50, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31792096

RESUMO

OBJECTIVE: To estimate the proportion of late-life cognitive loss attributable to impending death. METHODS: Older persons (n = 1,071) in a longitudinal cohort study without dementia at enrollment underwent annual cognitive assessments (mean 10.6 years, SD 4.6, range 4-24) prior to death. We estimated the onset of terminal acceleration in cognitive decline and rates of decline before and after this point in change point models that allowed calculation of the percent of cognitive loss attributable to terminal decline. Outcomes were composite measures of global and specific cognitive functions. We also estimated dementia and mild cognitive impairment (MCI) incidence before and during the terminal period. RESULTS: A mean of 3.7 years before death (95% credible interval [CI] -3.8 to -3.5), the rate of global cognitive decline accelerated to -0.313 unit per year (95% CI -0.337 to -0.290), a more than 7-fold increase indicative of terminal decline. The mean global cognitive score dropped 0.377 unit (SD 0.516) assuming no terminal decline and 1.192 units (SD 1.080) with terminal decline. As a result, 71% (95% bootstrapped CI 0.70, 0.73) of overall global cognitive loss was terminal. In subsequent analyses, terminal decline accounted for 70% of episodic memory loss, 65% of semantic memory loss, 57% of working memory loss, 52% of perceptual speed loss, and 53% of visuospatial loss. MCI incidence in the preterminal and terminal periods was similar, but dementia incidence was more than 6-fold higher in the terminal period than preterminal. CONCLUSION: Most late-life cognitive loss is driven by terminal decline.


Assuntos
Transtornos Cognitivos/patologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/psicologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Estudos de Coortes , Morte , Demência/patologia , Demência/psicologia , Escolaridade , Feminino , Humanos , Estudos Longitudinais , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/psicologia , Memória de Curto Prazo , Testes de Estado Mental e Demência , Testes Neuropsicológicos , Desempenho Psicomotor , Percepção Espacial
12.
Alzheimers Dement ; 16(2): 354-364, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31786129

RESUMO

INTRODUCTION: To date, the clinical relevance of comorbid amyloid-ß (Aß) pathology in patients with vascular cognitive disorders (VCD) is largely unknown. METHODS: We included 218 VCD patients with available cerebrospinal fluid Aß42 levels. Patients were divided into Aß+ mild-VCD (n = 84), Aß- mild-VCD (n = 68), Aß+ major-VCD (n = 31), and Aß- major-VCD (n = 35). We measured depression with the Geriatric Depression Scale, cognition with a neuropsychological test battery and derived white matter hyperintensities (WMH) and gray matter atrophy from MRI. RESULTS: Aß- patients showed more depressive symptoms than Aß+. In the major-VCD group, Aß- patients performed worse on attention (P = .02) and executive functioning (P = .008) than Aß+. We found no cognitive differences in patients with mild VCD. In the mild-VCD group, Aß- patients had more WMH than Aß+ patients, whereas conversely, in the major-VCD group, Aß+ patients had more WMH. Atrophy patterns did not differ between Aß+ and Aß- VCD group. DISCUSSION: Comorbid Aß pathology affects the manifestation of VCD, but effects differ by severity of VCD.


Assuntos
Peptídeos beta-Amiloides , Transtornos Cognitivos/patologia , Demência Vascular/patologia , Imagem por Ressonância Magnética , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/classificação , Demência Vascular/diagnóstico por imagem , Função Executiva , Feminino , Substância Cinzenta/patologia , Humanos , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Estudos Retrospectivos , Índice de Gravidade de Doença , Substância Branca/patologia
13.
Brain Imaging Behav ; 14(1): 51-61, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30259291

RESUMO

Cerebral White Matter Hyperintensity (WMH) lesions have been identified as markers of cerebrovascular diseases and they are associated with increased risk of cognitive impairment. In this study, we investigated the relationship between midlife cardiovascular risk factors and late life WMH volumes two decades later, and examined their association with cognitive performance. 135 participants from the Women's Healthy Ageing Project had completed midlife cardiovascular risk measurement in 1992 and late life brain MRI scan and cognitive assessment in 2012. In these community-dwelling normal aging women, we found that higher midlife Framingham Cardiovascular Risk Profile (FCRP) score was associated with greater WMH volume two decades later, and was predominantly driven by the impact of HDL cholesterol level, controlling for age, education and APOE ε4 status. Structural equation modelling demonstrated that the relationship between midlife FCRP score and late life executive function was mediated by WMH volume. These findings suggest intervention strategies that target major cardiovascular risk factors at midlife might be effective in reducing the development of WMH lesions and thus late life cognitive decline.


Assuntos
Cognição/fisiologia , Leucoaraiose/fisiopatologia , Substância Branca/patologia , Idoso , Envelhecimento/patologia , Encéfalo/patologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/diagnóstico por imagem , HDL-Colesterol/efeitos adversos , HDL-Colesterol/análise , Transtornos Cognitivos/patologia , Disfunção Cognitiva/patologia , Feminino , Humanos , Leucoaraiose/diagnóstico por imagem , Estudos Longitudinais , Imagem por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de Risco , Substância Branca/diagnóstico por imagem
14.
Autophagy ; 16(3): 512-530, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31234698

RESUMO

Macroautophagy/autophagy is generally regarded as a cytoprotective mechanism, and it remains a matter of controversy whether autophagy can cause cell death in mammals. Here, we show that chronic restraint stress suppresses adult hippocampal neurogenesis in mice by inducing autophagic cell death (ACD) of hippocampal neural stem cells (NSCs). We generated NSC-specific, inducible Atg7 conditional knockout mice and found that they had an intact number of NSCs and neurogenesis level under chronic restraint stress and were resilient to stress- or corticosterone-induced cognitive and mood deficits. Corticosterone treatment of adult hippocampal NSC cultures induced ACD via SGK3 (serum/glucocorticoid regulated kinase 3) without signs of apoptosis. Our results demonstrate that ACD is biologically important in a mammalian system in vivo and would be an attractive target for therapeutic intervention for psychological stress-induced disorders.Abbreviations: AAV: adeno-associated virus; ACD: autophagic cell death; ACTB: actin, beta; Atg: autophagy-related; ASCL1/MASH1: achaete-scute family bHLH transcription factor 1; BafA1: bafilomycin A1; BrdU: Bromodeoxyuridine/5-bromo-2'-deoxyuridine; CASP3: caspase 3; cKO: conditional knockout; CLEM: correlative light and electron microscopy; CORT: corticosterone; CRS: chronic restraint stress; DAB: 3,3'-diaminobenzidine; DCX: doublecortin; DG: dentate gyrus; GC: glucocorticoid; GFAP: glial fibrillary acidic protein; HCN: hippocampal neural stem; i.p.: intraperitoneal; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MKI67/Ki67: antigen identified by monoclonal antibody Ki 67; MWM: Morris water maze; Nec-1: necrostatin-1; NES: nestin; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NSC: neural stem cell; PCD: programmed cell death; PFA: paraformaldehyde; PX: Phox homology; PtdIns3P: phosphatidylinositol-3-phosphate; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SGK: serum/glucocorticoid-regulated kinases; SGZ: subgranular zone; SOX2: SRY (sex determining region Y)-box 2; SQSTM1: sequestosome 1; STS: staurosporine; TAM: tamoxifen; Ulk1: unc-51 like kinase 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VIM: vimentin; WT: wild type; ZFYVE1: zinc finger, FYVE domain containing 1; Z-VAD/Z-VAD-FMK: pan-caspase inhibitor.


Assuntos
Autofagia , Transtornos Cognitivos/patologia , Hipocampo/patologia , Células-Tronco Neurais/patologia , Neurogênese , Estresse Fisiológico , Animais , Ansiedade/complicações , Apoptose , Proteína 7 Relacionada à Autofagia/deficiência , Proteína 7 Relacionada à Autofagia/metabolismo , Transtornos Cognitivos/complicações , Corticosterona/administração & dosagem , Depressão/complicações , Deleção de Genes , Inativação Gênica , Proteínas Imediatamente Precoces/metabolismo , Camundongos Knockout , Necroptose , Células-Tronco Neurais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo
15.
Autophagy ; 16(3): 531-547, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31204559

RESUMO

Mutations in the macroautophagy/autophagy gene WDR45 cause ß-propeller protein-associated neurodegeneration (BPAN); however the molecular and cellular mechanism of the disease process is largely unknown. Here we generated constitutive wdr45 knockout (KO) mice that displayed cognitive impairments, abnormal synaptic transmission and lesions in several brain regions. Immunohistochemistry analysis showed loss of neurons in prefrontal cortex and basal ganglion in aged mice, and increased apoptosis in prefrontal cortex, recapitulating a hallmark of neurodegeneration. Quantitative proteomic analysis showed accumulation of endoplasmic reticulum (ER) proteins in KO mouse. At the cellular level, accumulation of ER proteins due to WDR45 deficiency resulted in increased ER stress and impaired ER quality control. The unfolded protein response (UPR) was elevated through ERN1/IRE1 or EIF2AK3/PERK pathway, and eventually led to neuronal apoptosis. Suppression of ER stress or activation of autophagy through MTOR inhibition alleviated cell death. Thus, the loss of WDR45 cripples macroautophagy machinery in neurons and leads to impairment in organelle autophagy, which provides a mechanistic understanding of cause of BPAN and a potential therapeutic strategy to treat this genetic disorder.Abbreviations: 7-ADD: 7-aminoactinomycin D; ASD: autistic spectrum disorder; ATF6: activating transcription factor 6; ATG: autophagy-related; BafA1: bafilomycin A1; BCAP31: B cell receptor associated protein 31; BPAN: ß-propeller protein-associated neurodegeneration; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CDIPT: CDP-diacylglycerol-inositol 3-phosphatidyltransferase (phosphatidylinositol synthase); DDIT3/CHOP: DNA-damage inducible transcript 3; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GFP: green fluorescent protein; HIP: hippocampus; HSPA5/GRP78: heat shock protein family A (HSP70) member 5; KO: knockout; LAMP1: lysosomal-associated membrane 1; mEPSCs: miniature excitatory postsynaptic currents; MG132: N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal; MIB: mid-brain; MTOR: mechanistic target of rapamycin kinase; PCR: polymerase chain reaction; PFA: paraformaldehyde; PFC: prefrontal cortex; PRM: parallel reaction monitoring; RBFOX3/NEUN: RNA binding protein, fox-1 homolog [C. elegans] 3; RTN3: reticulon 3; SEC22B: SEC22 homolog B, vesicle trafficking protein; SEC61B: SEC61 translocon beta subunit; SEM: standard error of the mean; SNR: substantia nigra; SQSTM1/p62: sequestosome 1; TH: tyrosine hydroxylase; Tm: tunicamycin; TMT: tandem mass tag; TUDCA: tauroursodeoxycholic acid; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; UPR: unfolded protein response; WDR45: WD repeat domain 45; WT: wild type; XBP1: X-box binding protein 1.


Assuntos
Proteínas de Transporte/metabolismo , Retículo Endoplasmático/metabolismo , Homeostase , Degeneração Neural/patologia , Neurônios/patologia , Animais , Apoptose , Autofagia , Sequência de Bases , Encéfalo/patologia , Morte Celular , Transtornos Cognitivos/complicações , Transtornos Cognitivos/patologia , Estresse do Retículo Endoplasmático , Lisossomos/metabolismo , Camundongos Knockout , Degeneração Neural/complicações , Neurônios/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Mapas de Interação de Proteínas , Proteólise
16.
Brain ; 143(2): 503-511, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31840744

RESUMO

Adult-onset leukoencephalopathy with spheroids and pigmented glia (ALSP) is an autosomal dominant leukoencephalopathy caused by mutations in colony stimulating factor 1 receptor (CSF1R). Here we report clinical and imaging outcomes following allogeneic haematopoietic stem cell transplantation (HSCT) in two patients with ALSP at the University of California, San Francisco between January 2016 and December 2017. Patient 1 proceeded to transplantation at age 53 with a haplo-identical sibling donor. Patient 2, whose sister and mother had died of the disease, proceeded to transplantation at age 49 with a 12/12 human leukocyte antigen-matched unrelated donor. Both patients received reduced intensity conditioning regimens. At 28 and 26 months post-HSCT, respectively, both patients were alive, without evidence of graft-versus-host disease, with major infection at 1 year in one and new-onset seizures in the other. In both cases, neurological worsening continued post-HSCT; however, the progression in cognitive deficits, overall functional status and gait impairment gradually stabilized. There was continued progression of parkinsonism in both patients. On brain MRI, within 1 year there was stabilization of T2/FLAIR abnormalities, and after 2 years there was complete resolution of abnormal multifocal reduced diffusion. In summary, after >2 years of follow-up, allogeneic HSCT in ALSP led to interval resolution of diffusion MRI abnormalities, stabilization of T2/FLAIR MRI abnormalities, and partial clinical stabilization, supportive of treatment response. Allogeneic HSCT may be beneficial in ALSP by providing a supply of bone marrow-derived brain-engrafting myeloid cells with donor wild-type CSF1R to repopulate the microglial niche.


Assuntos
Encéfalo/fisiopatologia , Leucoencefalopatias/genética , Microglia/patologia , Neuroglia/citologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Progressão da Doença , Feminino , Humanos , Leucoencefalopatias/terapia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos
17.
Life Sci ; 241: 117163, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837337

RESUMO

AIMS: The high sugar and lipid content of the Western diet (WD) is associated with metabolic dysfunction, non-alcoholic steatohepatitis, and it is an established risk factor for neuropsychiatric disorders. Our previous studies reported negative effects of the WD on rodent emotionality, impulsivity, and sociability in adulthood. Here, we investigated the effect of the WD on motor coordination, novelty recognition, and affective behavior in mice as well as molecular and cellular endpoints in brain and peripheral tissues. MAIN METHODS: Female C57BL/6 J mice were fed the WD for three weeks and were investigated for glucose tolerance, insulin resistance, liver steatosis, and changes in motor coordination, object recognition, and despair behavior in the swim test. Lipids and liver injury markers, including aspartate-transaminase, alanine-transaminase and urea were measured in blood. Serotonin transporter (SERT) expression, the density of Iba1-positive cells and concentration of malondialdehyde were measured in brain. KEY FINDINGS: WD-fed mice exhibited impaired glucose tolerance and insulin resistance, a loss of motor coordination, deficits in novel object exploration and recognition, increased helplessness, dyslipidemia, as well as signs of a non-alcoholic steatohepatitis (NASH)-like syndrome: liver steatosis and increased liver injury markers. Importantly, these changes were accompanied by decreased SERT expression, elevated numbers of microglia cells and malondialdehyde levels in, and restricted to, the prefrontal cortex. SIGNIFICANCE: The WD induces a spectrum of behaviors that are more reminiscent of ADHD and ASD than previously recognized and suggests that, in addition to the impairment of impulsivity and sociability, the consumption of a WD might be expected to exacerbate motor dysfunction that is also known to be associated with adult ADHD and ASD.


Assuntos
Transtornos Cognitivos/etiologia , Dieta Ocidental/efeitos adversos , Inflamação/etiologia , Transtornos Motores/etiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Córtex Pré-Frontal/patologia , Animais , Comportamento Animal , Transtornos Cognitivos/patologia , Feminino , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Motores/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Córtex Pré-Frontal/imunologia
18.
Diabetes Care ; 43(1): 201-208, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31601638

RESUMO

OBJECTIVE: Prediabetes and type 2 diabetes are associated with structural brain abnormalities, often observed in cognitive disorders. Besides visible lesions, (pre)diabetes might also be associated with alterations of the intrinsic organization of the white matter. In this population-based cohort study, the association of prediabetes and type 2 diabetes with white matter network organization was assessed. RESEARCH DESIGN AND METHODS: In the Maastricht Study, a type 2 diabetes-enriched population-based cohort study (1,361 subjects with normal glucose metabolism, 348 with prediabetes, and 510 with type 2 diabetes assessed by oral glucose tolerance test; 52% men; aged 59 ± 8 years), 3 Tesla structural and diffusion MRI was performed. Whole-brain white matter tractography was used to assess the number of connections (node degree) between 94 brain regions and the topology (graph measures). Multivariable linear regression analyses were used to investigate the associations of glucose metabolism status with network measures. Associations were adjusted for age, sex, education, and cardiovascular risk factors. RESULTS: Prediabetes and type 2 diabetes were associated with lower node degree after full adjustment (standardized [st]ßPrediabetes = -0.055 [95% CI -0.172, 0.062], stßType2diabetes = -0.256 [-0.379, -0.133], P trend < 0.001). Prediabetes was associated with lower local efficiency (stß = -0.084 [95% CI -0.159, -0.008], P = 0.033) and lower clustering coefficient (stß = -0.097 [95% CI -0.189, -0.005], P = 0.049), whereas type 2 diabetes was not. Type 2 diabetes was associated with higher communicability (stß = 0.148 [95% CI 0.042, 0.253], P = 0.008). CONCLUSIONS: These findings indicate that prediabetes and type 2 diabetes are associated with fewer white matter connections and weaker organization of white matter networks. Type 2 diabetes was associated with higher communicability, which was not yet observed in prediabetes and may reflect the use of alternative white matter connections.


Assuntos
Transtornos Cognitivos/diagnóstico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/psicologia , Rede Nervosa/diagnóstico por imagem , Estado Pré-Diabético/complicações , Estado Pré-Diabético/psicologia , Substância Branca/diagnóstico por imagem , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/fisiopatologia , Transtornos Cognitivos/complicações , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Estudos de Coortes , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Teste de Tolerância a Glucose , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Países Baixos , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/patologia , Substância Branca/patologia , Substância Branca/fisiopatologia
19.
Int J Mol Sci ; 20(24)2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31817864

RESUMO

Vascular cognitive impairment (VCI) or vascular dementia occurs as a result of brain ischemia and represents the second most common type of dementia after Alzheimer's disease. To explore the underlying mechanisms of VCI, several animal models of chronic cerebral hypoperfusion have been developed in rats, mice, and primates. We established a mouse model of chronic cerebral hypoperfusion by narrowing the bilateral common carotid arteries with microcoils, eventually resulting in hippocampal atrophy. In addition, a mouse model of white matter infarct-related damage with cognitive and motor dysfunction has also been established by asymmetric common carotid artery surgery. Although most experiments studying chronic cerebral hypoperfusion have been performed in rodents because of the ease of handling and greater ethical acceptability, non-human primates appear to represent the best model for the study of VCI, due to their similarities in much larger white matter volume and amyloid ß depositions like humans. Therefore, we also recently developed a baboon model of VCI through three-vessel occlusion (both the internal carotid arteries and the left vertebral artery). In this review, several animal models of chronic cerebral hypoperfusion, from mouse to primate, are extensively discussed to aid in better understanding of pathophysiology of VCI.


Assuntos
Isquemia Encefálica/complicações , Transtornos Cognitivos/patologia , Demência Vascular/patologia , Modelos Animais de Doenças , Animais , Doença Crônica , Transtornos Cognitivos/etiologia , Demência Vascular/etiologia , Camundongos , Primatas
20.
BMC Cancer ; 19(1): 1243, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870331

RESUMO

BACKGROUND: The gut microbiota is an important modulator of immune, metabolic, psychological and cognitive mechanisms. Chemotherapy adversely affects the gut microbiota, inducing acute dysbiosis, and alters physiological and psychological function. Cancer among young adults has risen 38% in recent decades. Understanding chemotherapy's long-term effects on gut microbiota and psycho-physiological function is critical to improve survivors' physical and mental health, but remains unexamined. Restoration of the gut microbiota via targeted therapies (e.g. probiotics) could potentially prevent or reverse the psycho-physiological deficits often found in young survivors following chemotherapy, ultimately leading to reduced symptom burden and improved health. METHODS: This longitudinal study investigates chemotherapy induced long-term gut dysbiosis, and associations between gut microbiota, and immune, metabolic, cognitive and psychological parameters using data collected at < 2 month (T1), 3-4 months (T2), and 5-6 months (T3) post-chemotherapy. Participants will be 18-39 year old blood or solid tumor cancer survivors (n = 50), and a healthy sibling, partner or friend as a control (n = 50). Gut microbiota composition will be measured from fecal samples using 16 s RNA sequencing. Psychological and cognitive patient reported outcome measures will include depression, anxiety, post-traumatic stress disorder symptoms, pain, fatigue, and social and cognitive function. Dual-energy X-ray Absorptiometry (DXA) will be used to measure fat and lean mass, and bone mineral concentration. Pro-inflammatory cytokines, C-reactive protein (CRP), lipopolysaccharide (LPS), serotonin, and brain derived neurotrophic factor (BDNF) will be measured in serum, and long-term cortisol will be assayed from hair. Regression and linear mixed model (LMM) analyses will examine associations across time points (T1 - T3), between groups, and covariates with gut microbiota, cognitive, psychological, and physiological parameters. CONCLUSION: Knowing what bacterial species are depleted after chemotherapy, how long these effects last, and the physiological mechanisms that may drive psychological and cognitive issues among survivors will allow for targeted, integrative interventions to be developed, helping to prevent or reverse some of the late-effects of treatment that many young cancer survivors face. This protocol has been approved by the Health Research Ethics Board of Alberta Cancer Committee (ID: HREBA.CC-19-0018).


Assuntos
Antineoplásicos/efeitos adversos , Composição Corporal/efeitos dos fármacos , Sobreviventes de Câncer/psicologia , Transtornos Cognitivos/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/microbiologia , Adolescente , Adulto , Antineoplásicos/administração & dosagem , Estudos de Casos e Controles , Protocolos Clínicos , Transtornos Cognitivos/patologia , Citocinas/metabolismo , Feminino , Microbioma Gastrointestinal/imunologia , Humanos , Estudos Longitudinais , Masculino , Neoplasias/imunologia , Neoplasias/psicologia , Qualidade de Vida , Adulto Jovem
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