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1.
PLoS One ; 15(11): e0242696, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33216815

RESUMO

Diffusion MRI is extensively used to investigate changes in white matter microstructure. However, diffusion measures within white matter tissue can be affected by partial volume effects due to cerebrospinal fluid and white matter hyperintensities, especially in the aging brain. In previous aging studies, the cingulum bundle that plays a central role in the architecture of the brain networks supporting cognitive functions has been associated with cognitive deficits. However, most of these studies did not consider the partial volume effects on diffusion measures. The aim of this study was to evaluate the effect of free water elimination on diffusion measures of the cingulum in a group of 68 healthy elderly individuals. We first determined the effect of free water elimination on conventional DTI measures and then examined the effect of free water elimination on verbal fluency performance over 12 years. The cingulum bundle was reconstructed with a tractography pipeline including a white matter hyperintensities mask to limit the negative impact of hyperintensities on fiber tracking algorithms. We observed that free water elimination increased the ability of conventional DTI measures to detect associations between tissue diffusion measures of the cingulum and changes in verbal fluency in older individuals. Moreover, free water content and mean diffusivity measured along the cingulum were independently associated with changes in verbal fluency. This suggests that both tissue modifications and an increase in interstitial isotropic water would contribute to cognitive decline. These observations reinforce the importance of using free water elimination when studying brain aging and indicate that free water itself could be a relevant marker for age-related cingulum white matter modifications and cognitive decline.


Assuntos
Envelhecimento/metabolismo , Cognição , Disfunção Cognitiva , Imagem de Tensor de Difusão , Água/metabolismo , Substância Branca , Idoso de 80 Anos ou mais , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Feminino , Humanos , Masculino , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo
3.
Sci Rep ; 10(1): 16396, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009473

RESUMO

Alzheimer Disease (AD) is a pathology suffered by millions of people worldwide and it has a great social and economic impact. Previous studies reported a relationship between alterations in different amino acids and derivatives involved in neurotransmission systems and cognitive impairment. Therefore, in this study the neurotransmission impairment associated to early AD has been evaluated. For this purpose, different amino acids and derivatives were determined in saliva samples from AD patients and healthy subjects, by means of an analytical method based on chromatography coupled to tandem mass spectrometry. Results showed statistically significant differences in salivary levels for the compounds myo-inositol, creatine and acetylcholine; and other compounds (myo-inositol, glutamine, creatine, acetylcholine) showed significant correlations with some cognitive tests scores. Therefore, these compounds were included in a multivariate analysis and the corresponding diagnosis model showed promising indices (AUC 0.806, sensitivity 61%, specificity 92%). In conclusion, some amino acids and derivatives involved in neurotransmission impairment could be potential biomarkers in early and non-invasive AD detection.


Assuntos
Doença de Alzheimer/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Transmissão Sináptica/fisiologia , Acetilcolina/metabolismo , Idoso , Doença de Alzheimer/metabolismo , Aminoácidos/metabolismo , Biomarcadores/metabolismo , Disfunção Cognitiva/metabolismo , Creatina/metabolismo , Feminino , Humanos , Inositol/metabolismo , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade
4.
Neurology ; 95(21): e2834-e2844, 2020 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-33077542

RESUMO

OBJECTIVE: To evaluate a novel ß-amyloid (Aß)-PET-based quantitative measure (Aß accumulation index [Aß index]), including the assessment of its ability to discriminate between participants based on Aß status using visual read, CSF Aß42/Aß40, and post-mortem neuritic plaque burden as standards of truth. METHODS: One thousand one hundred twenty-one participants (with and without cognitive impairment) were scanned with Aß-PET: Swedish BioFINDER, n = 392, [18F]flutemetamol; Alzheimer's Disease Neuroimaging Initiative (ADNI), n = 692, [18F]florbetapir; and a phase 3 end-of-life study, n = 100, [18F]flutemetamol. The relationships between Aß index and standardized uptake values ratios (SUVR) from Aß-PET were assessed. The diagnostic performances of Aß index and SUVR were compared with visual reads, CSF Aß42/Aß40, and Aß histopathology used as reference standards. RESULTS: Strong associations were observed between Aß index and SUVR (R 2: BioFINDER 0.951, ADNI 0.943, end-of-life, 0.916). Both measures performed equally well in differentiating Aß-positive from Aß-negative participants, with areas under the curve (AUCs) of 0.979 to 0.991 to detect abnormal visual reads, AUCs of 0.961 to 0.966 to detect abnormal CSF Aß42/Aß40, and AUCs of 0.820 to 0.823 to detect abnormal Aß histopathology. Both measures also showed a similar distribution across postmortem-based Aß phases (based on anti-Aß 4G8 antibodies). Compared to models using visual read alone, the addition of the Aß index resulted in a significant increase in AUC and a decrease in Akaike information criterion to detect abnormal Aß histopathology. CONCLUSION: The proposed Aß index showed a tight association to SUVR and carries an advantage over the latter in that it does not require the definition of regions of interest or the use of MRI. Aß index may thus prove simpler to implement in clinical settings and may also facilitate the comparison of findings using different Aß-PET tracers. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the Aß accumulation index accurately differentiates Aß-positive from Aß-negative participants compared to Aß-PET visual reads, CSF Aß42/Aß40, and Aß histopathology.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/patologia , Doença de Alzheimer/metabolismo , Compostos de Anilina/farmacologia , Benzotiazóis/farmacologia , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/metabolismo , Humanos , Imagem por Ressonância Magnética/métodos , Placa Amiloide/patologia , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacologia
5.
Neurology ; 95(23): e3104-e3116, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-32873693

RESUMO

OBJECTIVE: To determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals. METHODS: Cross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar ß-amyloid (Aß) with PET using the [11C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers. RESULTS: Accelerated changes in CSF Aß1-42 (Aß42) occurred at 48.28 years of age and in Aß42/Aß40 ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippocampal volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aß42 and Aß42/Aß40 ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other. CONCLUSIONS: Our findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral , Disfunção Cognitiva , Proteínas tau/líquido cefalorraquidiano , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina , Biomarcadores/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Estudos Transversais , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Sintomas Prodrômicos , Tiazóis , Adulto Jovem
6.
Nat Commun ; 11(1): 4571, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917871

RESUMO

Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aß) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Disfunção Cognitiva/metabolismo , Serpinas/metabolismo , Proteínas Virais/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal , Disfunção Cognitiva/tratamento farmacológico , Citocinas/metabolismo , Dipeptídeos/sangue , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Encefalite/metabolismo , Encefalite/patologia , Feminino , Humanos , Inflamação/metabolismo , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Serpinas/sangue , Serpinas/farmacologia , Memória Espacial/fisiologia , Proteínas Virais/sangue , Proteínas Virais/farmacologia , para-Aminobenzoatos/sangue , para-Aminobenzoatos/farmacologia
7.
Neurology ; 95(18): e2577-e2585, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-32887774

RESUMO

OBJECTIVE: To determine the extent to which deficits in learning over 6 days are associated with ß-amyloid-positive (Aß+) and hippocampal volume in cognitively normal (CN) adults. METHODS: Eighty CN older adults who had undergone PET neuroimaging to determine Aß status (n = 42 Aß- and 38 Aß+), MRI to determine hippocampal and ventricular volume, and repeated assessment of memory were recruited from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Participants completed the Online Repeatable Cognitive Assessment-Language Learning Test (ORCA-LLT), which required they learn associations between 50 Chinese characters and their English language equivalents over 6 days. ORCA-LLT assessments were supervised on the first day and were completed remotely online for all remaining days. RESULTS: Learning curves in the Aß+ CN participants were significantly worse than those in matched Aß- CN participants, with the magnitude of this difference very large (d [95% confidence interval (CI)] 2.22 [1.64-2.75], p < 0.001), and greater than differences between these groups for memory decline since their enrollment in AIBL (d [95% CI] 0.52 [0.07-0.96], p = 0.021), or memory impairment at their most recent visit. In Aß+ CN adults, slower rates of learning were associated with smaller hippocampal and larger ventricular volumes. CONCLUSIONS: These results suggest that in CN participants, Aß+ is associated more strongly with a deficit in learning than any aspect of memory dysfunction. Slower rates of learning in Aß+ CN participants were associated with hippocampal volume loss. Considered together, these data suggest that the primary cognitive consequence of Aß+ is a failure to benefit from experience when exposed to novel stimuli, even over very short periods.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/patologia , Idoso , Ventrículos Cerebrais/patologia , Feminino , Voluntários Saudáveis/psicologia , Humanos , Imagem por Ressonância Magnética , Masculino , Neuroimagem , Tomografia por Emissão de Pósitrons
8.
Clin Sci (Lond) ; 134(16): 2161-2175, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32794577

RESUMO

Diabetes-associated cognitive impairment (DACI) can increase the risk of major cardiovascular events and death. Neuronal functionality is highly dependent on mitochondria and emerging evidence has shown that mitochondrial transplantation is a potential and effective strategy that can reduce brain injury and associated disorders. Platelets are abundant in blood and can be considered a readily available source of small-size mitochondria. These cells can be easily acquired from the peripheral blood with minimal invasion via simple venipuncture. The present study aimed to investigate whether transplantation of platelet-derived mitochondria (Mito-Plt) could improve DACI. Cognitive behaviors were assessed using the Morris water maze test in db/db mice. The results demonstrated that Mito-Plt was internalized into hippocampal neurons 24 h following intracerebroventricular injection. Importantly, one month following Mito-Plt transplantation, DACI was alleviated in db/db mice and the effect was accompanied with increased mitochondrial number, restored mitochondrial function, attenuated oxidative stress and neuronal apoptosis, as well as decreased accumulation of Aß and Tau in the hippocampus. Taken together, the data demonstrated that transplantation of Mito-Plt attenuated cognitive impairment and mitochondrial dysfunction in db/db mice. This method may be a potential therapeutic application for the treatment of DACI.


Assuntos
Plaquetas/metabolismo , Disfunção Cognitiva/terapia , Diabetes Mellitus Tipo 2/metabolismo , Mitocôndrias/transplante , Animais , Apoptose , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Hipocampo/citologia , Hipocampo/metabolismo , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Neurônios/citologia , Neurônios/metabolismo , Ratos Sprague-Dawley , Transplante Heterólogo
9.
Artigo em Inglês | MEDLINE | ID: mdl-32825289

RESUMO

Trace elements (TE) homeostasis is crucial in normal brain functioning. Although imbalances have the potential to exacerbate events leading neurodegenerative diseases, few studies have directly addressed the eventual relationships between TE levels in the human body and future cognitive status. The present study aimed to assess how different TE body-levels relate to cognitive decline. This exploratory research included a study-group (RES) of 20 elderly individuals living in two Portuguese geographical areas of interest (Estarreja; Mértola), as well as a 20 subjects neuropsychological control-group (CTR). Participants were neuropsychologically assessed through the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) and the RES group was biomonitored for TE through fingernail analysis. After 5 years, the cognitive assessments were repeated. Analyses of the RES neuropsychological data showed an average decrease of 6.5 and 5.27 points in MMSE and MoCA, respectively, but TE contents in fingernails were generally within the referenced values for non-exposed individuals. Higher levels of Nickel and Selenium significantly predicted lesser cognitive decline within 5 years. Such preliminary results evidence an association between higher contents of these TE and higher cognitive scores at follow-up, suggesting their contribution to the maintenance of cognitive abilities. Future expansion of the present study is needed in order to comprehensively assess the potential benefits of these TE.


Assuntos
Disfunção Cognitiva , Oligoelementos , Idoso , Disfunção Cognitiva/metabolismo , Seguimentos , Humanos , Testes de Estado Mental e Demência , Unhas/química , Testes Neuropsicológicos , Oligoelementos/metabolismo
10.
Sci Rep ; 10(1): 13365, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770103

RESUMO

The apolipoprotein E (APOE) e4 allele is the most common genetic variant associated with Alzheimer's disease (AD). We sought to investigate the distribution of APOE genotypes across the full clinical AD spectrum including AD, late-stage amnestic mild cognitive impairment (L-aMCI), early-stage aMCI (E-aMCI), subjective memory impairment (SMI), and controls. We prospectively recruited 713 AD patients, 735 aMCI patients, 575 SMI patients, and 8,260 individuals as controls. The frequency of the APOE e4 allele revealed an ordered fashion in the AD (30.8%), L-aMCI (24.0%), E-aMCI (15.1%), SMI (11.7%), and control (9.1%) groups. APOE e3/e4 and e4/e4 genotype frequencies also appeared in an ordered fashion in the AD group (39.1% of e3/e4 and 10.9% of e4/e4), as well as the L-aMCI (28.3% and 9.4%), E-aMCI (22.3% and 3.7%), SMI (18.3% and 1.9%), and control (15.1% and 0.8%) groups. In the comparisons of APOE e3/e3 vs. e3/e4 genotypes, all patient groups had a higher frequency of APOE e3/e4 relative to the control group. Relative to the SMI and E-aMCI groups, the AD and L-aMCI groups had higher frequency of the APOE e3/e4 genotype, and the AD group had a higher frequency relative to the L-aMCI group. However, there was no significant difference between the E-aMCI and SMI groups. In our longitudinal data, APOE e4 carrier showed a steeper incline slope in a clinical dementia rating sum of boxes (CDR-SB) score than APOE e4 non-carrier in SMI (B = 0.0066, p = 0.0104), E-aMCI (B = 0.0313, p < 0.0001), and L-aMCI (B = 0.0178, p = 0.0007). APOE e4 carrier showed a steeper decline slope in the CDR-SB than APOE e4 non-carrier in AD (B = - 0.0309, p = 0.0003). These findings suggest that E-aMCI and SMI are associated with a similarly increased frequency of the APOE e4 allele compared to controls, suggesting a greater genetic risk for AD and the importance of monitoring the allele more closely.


Assuntos
Apolipoproteína E4/genética , Disfunção Cognitiva/genética , Transtornos da Memória/genética , Idoso , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteína E4/metabolismo , Estudos de Casos e Controles , Disfunção Cognitiva/metabolismo , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Transtornos da Memória/metabolismo , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos
11.
Biomolecules ; 10(8)2020 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-32784855

RESUMO

Zinc therapy is normally utilized for treatment of Wilson disease (WD), an inherited condition that is characterized by increased levels of non-ceruloplasmin bound ('free') copper in serum and urine. A subset of patients with Alzheimer's disease (AD) or its prodromal form, known as Mild Cognitive Impairment (MCI), fail to maintain a normal copper metabolic balance and exhibit higher than normal values of non-ceruloplasmin copper. Zinc's action mechanism involves the induction of intestinal cell metallothionein, which blocks copper absorption from the intestinal tract, thus restoring physiological levels of non-ceruloplasmin copper in the body. On this basis, it is employed in WD. Zinc therapy has shown potential beneficial effects in preliminary AD clinical trials, even though the studies have missed their primary endpoints, since they have study design and other important weaknesses. Nevertheless, in the studied AD patients, zinc effectively decreased non-ceruloplasmin copper levels and showed potential for improved cognitive performances with no major side effects. This review discusses zinc therapy safety and the potential therapeutic effects that might be expected on a subset of individuals showing both cognitive complaints and signs of copper imbalance.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Cobre/metabolismo , Zinco/uso terapêutico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Ceruloplasmina/metabolismo , Disfunção Cognitiva/enzimologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Humanos , Zinco/administração & dosagem , Zinco/efeitos adversos , Zinco/metabolismo
12.
Sci Rep ; 10(1): 10772, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32612165

RESUMO

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß and tau. We previously reported that administration of bone marrow mesenchymal stem cells (BM-MSCs) ameliorates diabetes-induced cognitive impairment by transferring exosomes derived from these cells into astrocytes. Here, we show that intracerebroventricularly injected BM-MSCs improve cognitive impairment in AD model mice by ameliorating astrocytic inflammation as well as synaptogenesis. Although AD model mice showed an increase in NF-κB in the hippocampus, BM-MSC-treated AD model mice did not show this increase but showed an increase in levels of microRNA (miR)-146a in the hippocampus. Intracerebroventricularly injected BM-MSCs were attached to the choroid plexus in the lateral ventricle, and thus, BM-MSCs may secrete exosomes into the cerebrospinal fluid. In vitro experiments showed that exosomal miR-146a secreted from BM-MSCs was taken up into astrocytes, and an increased level of miR-146a and a decreased level of NF-κB were observed in astrocytes. Astrocytes are key cells for the formation of synapses, and thus, restoration of astrocytic function may have led to synaptogenesis and correction of cognitive impairment. The present study indicates that exosomal transfer of miR-146a is involved in the correction of cognitive impairment in AD model mice.


Assuntos
Doença de Alzheimer/terapia , Transtornos Cognitivos/terapia , Hipocampo/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , MicroRNAs/metabolismo , Doença de Alzheimer/metabolismo , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Células da Medula Óssea/citologia , Plexo Corióideo/metabolismo , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Exossomos/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Inflamação , Macrófagos/metabolismo , Masculino , Aprendizagem em Labirinto , Camundongos , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Sinapses
13.
J Neurosci ; 40(32): 6121-6132, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32605939

RESUMO

Redox dysregulation and oxidative stress are final common pathways in the pathophysiology of a variety of psychiatric disorders, including schizophrenia. Oxidative stress causes dysfunction of GABAergic parvalbumin (PV)-positive interneurons (PVI), which are crucial for the coordination of neuronal synchrony during sensory and cognitive processing. Mitochondria are the main source of reactive oxygen species (ROS) in neurons and they control synaptic activity through their roles in energy production and intracellular calcium homeostasis. We have previously shown that in male mice transient blockade of NMDA receptors (NMDARs) during development [subcutaneous injections of 30 mg/kg ketamine (KET) on postnatal days 7, 9, and 11] results in long-lasting alterations in synaptic transmission and reduced PV expression in the adult prefrontal cortex (PFC), contributing to a behavioral phenotype that mimics multiple symptoms associated with schizophrenia. These changes correlate with oxidative stress and impaired mitochondrial function in both PVI and pyramidal cells. Here, we show that genetic deletion (Ppif-/-) of the mitochondrial matrix protein cyclophilin D (CypD) prevents perinatal KET-induced increases in ROS and the resulting deficits in PVI function, and changes in excitatory and inhibitory synaptic transmission in the PFC. Deletion of CypD also prevented KET-induced behavioral deficits in cognitive flexibility, social interaction, and novel object recognition (NOR). Taken together, these data highlight how mitochondrial activity may play an integral role in modulating PVI-mediated cognitive processes.SIGNIFICANCE STATEMENT Mitochondria are important modulators of oxidative stress and cell function, yet how mitochondrial dysfunction affects cell activity and synaptic transmission in psychiatric illnesses is not well understood. NMDA receptor (NMDAR) blockade with ketamine (KET) during development causes oxidative stress, dysfunction of parvalbumin (PV)-positive interneurons (PVI), and long-lasting physiological and behavioral changes. Here we show that mice deficient for the mitochondrial matrix protein cyclophilin D (CypD) show robust protection from PVI dysfunction following perinatal NMDAR blockade. Mitochondria serve as an essential node for a number of stress-induced signaling pathways and our experiments suggest that failure of mitochondrial redox regulation can contribute to PVI dysfunction.


Assuntos
Disfunção Cognitiva/metabolismo , Ciclofilina D/metabolismo , Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Ciclofilina D/genética , Antagonistas de Aminoácidos Excitatórios/toxicidade , Neurônios GABAérgicos/fisiologia , Deleção de Genes , Interneurônios/fisiologia , Ketamina/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Parvalbuminas/genética , Parvalbuminas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo
14.
Life Sci ; 257: 118020, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32603820

RESUMO

Alzheimer's disease (AD) is the most common form of dementia worldwide. ß-amyloid peptide (Aß) is currently assumed to be the main cause of synaptic dysfunction and cognitive impairments in AD, but the molecular signaling pathways underlying its neurotoxic consequences have not yet been completely explored. Additional investigations regarding these pathways will contribute to development of new therapeutic targets. In context, developing evidence suggest that Aß decreases brain-derived neurotrophic factor (BDNF) mostly by lowering phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) protein. In fact, it has been observed that brain or serum levels of BDNF appear to be beneficial markers for cognitive condition. In addition, the participation of transcription mediated by CREB has been widely analyzed in the memory process and AD development. Designing pharmacologic or genetic therapeutic approaches based on the targeting of CREB-BDNF signaling could be a promising treatment potential for AD. In this review, we summarize data demonstrating the role of CREB-BDNF signaling pathway in cognitive status and mediation of Aß toxicity in AD. Finally, we also focus on the developing intervention methods for improvement of cognitive decline in AD based on targeting of CREB-BDNF pathway.


Assuntos
Doença de Alzheimer/terapia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Cognição/fisiologia , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Modelos Animais de Doenças , Humanos , Memória/fisiologia , Neurônios/metabolismo , Fosforilação , Transdução de Sinais
15.
Life Sci ; 258: 118107, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682919

RESUMO

Cognitive impairment has been widely recognized as a common symptom of chronic stress. Ginsenoside Rd (GRd), the major active compound in Panax ginseng, was previously reported in various neurological researches. However, little research is available regarding on the effect of GRd on cognitive improvement in mice subjected to chronic stress. In the present study, we investigated the neuroprotective effects of GRd in chronic restraint stress (CRS)-induced cognitive deficits and explored the potential mechanism in male C57BL/6J mice. Our results demonstrated that oral administration of GRd for 28 days markedly increased the spontaneous alternation in Y-maze and the relative discrimination index in novel object or location recognition tests following CRS. Additionally, GRd treatment considerably increased the antioxidant enzymes activities in the hippocampus. The expression levels of hippocampus and serum inflammation factors in the CRS groups were also counter-regulated by GRd treatment. Meanwhile, GRd treatment could reverse CRS-induced the decrease in phosphorylated phosphoinositide 3-kinase (PI3K), camp-reflecting element binding protein (CREB), brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) expression in the hippocampus. These findings provided evidences that GRd improves cognitive impairment in CRS mice by mitigating oxidative stress and inflammation, while upregulating the hippocampal BDNF-mediated CREB signaling pathway.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ginsenosídeos/uso terapêutico , Restrição Física , Transdução de Sinais , Estresse Psicológico/tratamento farmacológico , Animais , Doença Crônica , Disfunção Cognitiva/sangue , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Ginsenosídeos/química , Ginsenosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Inflamação/sangue , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/sangue , Estresse Psicológico/fisiopatologia
16.
Neurology ; 95(11): e1538-e1553, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32675080

RESUMO

OBJECTIVE: To develop and evaluate a model for staging cortical amyloid deposition using PET with high generalizability. METHODS: Three thousand twenty-seven individuals (1,763 cognitively unimpaired [CU], 658 impaired, 467 with Alzheimer disease [AD] dementia, 111 with non-AD dementia, and 28 with missing diagnosis) from 6 cohorts (European Medical Information Framework for AD, Alzheimer's and Family, Alzheimer's Biomarkers in Daily Practice, Amsterdam Dementia Cohort, Open Access Series of Imaging Studies [OASIS]-3, Alzheimer's Disease Neuroimaging Initiative [ADNI]) who underwent amyloid PET were retrospectively included; 1,049 individuals had follow-up scans. With application of dataset-specific cutoffs to global standard uptake value ratio (SUVr) values from 27 regions, single-tracer and pooled multitracer regional rankings were constructed from the frequency of abnormality across 400 CU individuals (100 per tracer). The pooled multitracer ranking was used to create a staging model consisting of 4 clusters of regions because it displayed a high and consistent correlation with each single-tracer ranking. Relationships between amyloid stage, clinical variables, and longitudinal cognitive decline were investigated. RESULTS: SUVr abnormality was most frequently observed in cingulate, followed by orbitofrontal, precuneal, and insular cortices and then the associative, temporal, and occipital regions. Abnormal amyloid levels based on binary global SUVr classification were observed in 1.0%, 5.5%, 17.9%, 90.0%, and 100.0% of individuals in stage 0 to 4, respectively. Baseline stage predicted decline in Mini-Mental State Examination (MMSE) score (ADNI: n = 867, F = 67.37, p < 0.001; OASIS: n = 475, F = 9.12, p < 0.001) and faster progression toward an MMSE score ≤25 (ADNI: n = 787, hazard ratio [HR]stage1 2.00, HRstage2 3.53, HRstage3 4.55, HRstage4 9.91, p < 0.001; OASIS: n = 469, HRstage4 4.80, p < 0.001). CONCLUSION: The pooled multitracer staging model successfully classified the level of amyloid burden in >3,000 individuals across cohorts and radiotracers and detects preglobal amyloid burden and distinct risk profiles of cognitive decline within globally amyloid-positive individuals.


Assuntos
Amiloidose/diagnóstico por imagem , Radioisótopos de Carbono , Córtex Cerebral/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons/métodos , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Amiloidose/metabolismo , Córtex Cerebral/metabolismo , Disfunção Cognitiva/metabolismo , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade
17.
J Neurosci ; 40(29): 5681-5696, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32513828

RESUMO

Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, which while adaptive, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here, we used bacterial lipopolysaccharide (LPS) in female C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 µg/kg) induced hypoglycemia, which was mimicked by interleukin (IL)-1ß (25 µg/kg) but not prevented in IL-1RI-/- mice, nor by IL-1 receptor antagonist (IL-1RA; 10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentrations, was mitigated by exogenous glucose (2 g/kg), and was exacerbated by 2-deoxyglucose (2-DG) glycolytic inhibition, despite preventing IL-1ß synthesis. Using the ME7 model of chronic neurodegeneration in female mice, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 µg/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition selectively in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in CSF in humans during inflammatory trauma-induced delirium. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with acutely altered brain energy metabolism. Collectively, the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.SIGNIFICANCE STATEMENT Acute systemic inflammation alters behavior and produces disproportionate effects, such as delirium, in vulnerable individuals. Delirium has serious short and long-term sequelae but mechanisms remain unclear. Here, we show that both LPS and interleukin (IL)-1ß trigger hypoglycemia, reduce CSF glucose, and suppress spontaneous activity. Exogenous glucose mitigates these outcomes. Equivalent hypoglycemia, induced by lipopolysaccharide (LPS) or insulin, was sufficient to trigger cognitive impairment selectively in animals with existing neurodegeneration and glucose also mitigated those impairments. Patient CSF from inflammatory trauma-induced delirium also shows altered brain carbohydrate metabolism. The data suggest that the degenerating brain is exquisitely sensitive to acute behavioral and cognitive consequences of disrupted energy metabolism. Thus "bioenergetic stress" drives systemic inflammation-induced dysfunction. Elucidating this may offer routes to mitigating delirium.


Assuntos
Disfunção Cognitiva/metabolismo , Delírio/metabolismo , Metabolismo Energético , Glucose/metabolismo , Inflamação/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Disfunção Cognitiva/etiologia , Delírio/etiologia , Feminino , Fraturas do Quadril/líquido cefalorraquidiano , Fraturas do Quadril/complicações , Humanos , Comportamento de Doença/fisiologia , Inflamação/líquido cefalorraquidiano , Inflamação/etiologia , Interleucina-1beta/administração & dosagem , Lipopolissacarídeos/administração & dosagem , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
18.
Sci Rep ; 10(1): 9391, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32523019

RESUMO

In Alzheimer's disease (AD) amyloid-ß (Aß) deposits may cause impairments in choroid plexus, a specialised brain structure which forms the blood-cerebrospinal fluid (CSF) barrier. We previously carried out a mass proteomic-based study in choroid plexus from AD patients and we found several differentially regulated proteins compared with healthy subjects. One of these proteins, annexin A5, was previously demonstrated implicated in blocking Aß-induced cytotoxicity in neuronal cell cultures. Here, we investigated the effects of annexin A5 on Aß toxicity in choroid plexus. We used choroid plexus tissue samples and CSF from mild cognitive impairment (MCI) and AD patients to analyse Aß accumulation, cell death and annexin A5 levels compared with control subjects. Choroid plexus cell cultures from rats were used to analyse annexin A5 effects on Aß-induced cytotoxicity. AD choroid plexus exhibited progressive reduction of annexin A5 levels along with progressive increased Aß accumulation and cell death as disease stage was higher. On the other hand, annexin A5 levels in CSF from patients were found progressively increased as the disease stage increased in severity. In choroid plexus primary cultures, Aß administration reduced endogenous annexin A5 levels in a time-course dependent manner and simultaneously increased annexin A5 levels in extracellular medium. Annexin A5 addition to choroid plexus cell cultures restored the Aß-induced impairments on autophagy flux and apoptosis in a calcium-dependent manner. We propose that annexin A5 would exert a protective role in choroid plexus and this protection is lost as Aß accumulates with the disease progression. Then, brain protection against further toxic insults would be jeopardised.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Anexina A5/metabolismo , Barreira Hematoencefálica/patologia , Plexo Corióideo/fisiologia , Disfunção Cognitiva/metabolismo , Neurônios/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Animais , Apoptose , Autofagia , Cálcio/metabolismo , Células Cultivadas , Disfunção Cognitiva/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteômica , Ratos , Ratos Wistar
19.
Neurology ; 95(1): e46-e58, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32522798

RESUMO

OBJECTIVE: To investigate the relationship between the ATN classification system (amyloid, tau, neurodegeneration) and risk of dementia and cognitive decline in individuals with subjective cognitive decline (SCD). METHODS: We classified 693 participants with SCD (60 ± 9 years, 41% women, Mini-Mental State Examination score 28 ± 2) from the Amsterdam Dementia Cohort and Subjective Cognitive Impairment Cohort (SCIENCe) project according to the ATN model, as determined by amyloid PET or CSF ß-amyloid (A), CSF p-tau (T), and MRI-based medial temporal lobe atrophy (N). All underwent extensive neuropsychological assessment. For 342 participants, follow-up was available (3 ± 2 years). As a control population, we included 124 participants without SCD. RESULTS: Fifty-six (n = 385) participants had normal Alzheimer disease (AD) biomarkers (A-T-N-), 27% (n = 186) had non-AD pathologic change (A-T-N+, A-T+N-, A-T+N+), 18% (n = 122) fell within the Alzheimer continuum (A+T-N-, A+T-N+, A+T+N-, A+T+N+). ATN profiles were unevenly distributed, with A-T+N+, A+T-N+, and A+T+N+ containing very few participants. Cox regression showed that compared to A-T-N-, participants in A+ profiles had a higher risk of dementia with a dose-response pattern for number of biomarkers affected. Linear mixed models showed participants in A+ profiles showed a steeper decline on tests addressing memory, attention, language, and executive functions. In the control group, there was no association between ATN and cognition. CONCLUSIONS: Among individuals presenting with SCD at a memory clinic, those with a biomarker profile A-T+N+, A+T-N-, A+T+N-, and A+T+N+ were at increased risk of dementia, and showed steeper cognitive decline compared to A-T-N- individuals. These results suggest a future where biomarker results could be used for individualized risk profiling in cognitively normal individuals presenting at a memory clinic.


Assuntos
Doença de Alzheimer , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/classificação , Progressão da Doença , Idoso , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/patologia , Proteínas tau/líquido cefalorraquidiano
20.
Clin Interv Aging ; 15: 743-754, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32546992

RESUMO

Background: Preventative measures have recently been taken to reduce the incidence of Alzheimer's disease worldwide. We previously showed that Met-Lys-Pro (MKP), a casein-derived angiotensin-converting enzyme inhibitory peptide with the potential to cross the blood-brain barrier, attenuated cognitive decline in a mouse model of Alzheimer's disease. However, the effect of MKP on cognitive function improvement in humans remains unknown. This exploratory study sought to investigate whether MKP intake could improve cognitive function in adults without dementia. Methods: A total of 268 community-dwelling adults without dementia participated in this 24-week randomized controlled trial. Participants were randomly allocated to the MKP (n = 134) or placebo (n = 134) group. The MKP group received four tablets daily, each containing 50 µg MKP, while the placebo group received four dextrin tablets containing no detectable MKP for 24 weeks. Scores on the Japanese version of the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) were used as the primary outcome to compare cognitive function between the MKP and placebo groups. The study products were also evaluated for safety. Results: The intention-to-treat analysis showed that there was no significant difference between the groups in terms of the ADAS-cog total score. Orientation, as measured by the respective ADAS-cog subscale, was significantly improved compared to placebo at 24 weeks post-MKP administration (P = 0.022). No serious adverse events due to MKP intake were observed. Conclusion: To the best of our knowledge, this is the first study to report the effects of MKP on human cognition. These preliminary results suggested the safety of daily MKP intake and its potential to improve orientation in adults without dementia. Further clinical studies are needed to confirm the present findings and the benefits of MKP on cognitive function.


Assuntos
Caseínas/farmacologia , Cognição/efeitos dos fármacos , Disfunção Cognitiva , Oligopeptídeos/administração & dosagem , Administração Oral , Idoso , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/prevenção & controle , Método Duplo-Cego , Feminino , Humanos , Vida Independente , Masculino , Testes Neuropsicológicos , Nootrópicos/administração & dosagem , Comprimidos , Resultado do Tratamento
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