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BACKGROUND: Monoclonal antibodies that target amyloid-beta (Aß) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aß IgG1 monoclonal antibody with highest affinity for aggregated Aß that has been tested for the treatment of Alzheimer's disease. METHODS: We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. RESULTS: A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aß42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. CONCLUSIONS: Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.).
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Doença de Alzheimer , Anticorpos Monoclonais Humanizados , Humanos , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Tomografia por Emissão de Pósitrons , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou maisRESUMO
Resveratrol, a naturally occurring polyphenol that activates sirtuin 1 (SIRT1), has been shown to reduce overall levels of matrix metalloprotease-9 (MMP-9) in cerebrospinal fluid (CSF) samples from patients with Alzheimer's dementia (AD). Depending on the site of release, however, MMP-9 has the potential to improve or impair cognition. In particular, its release from microglia or pericytes proximal to the blood brain barrier can damage the basement membrane, while neuronal activity-dependent release of this protease from glutamatergic neurons can instead promote dendritic spine expansion and long-term potentiation of synaptic plasticity. In the present study, we test the hypothesis that resveratrol reduces overall MMP-9 levels in CSF samples from patients with APOE4, an allele associated with increased glial inflammation. We also examine the possibility that resveratrol reduces inflammation-associated MMP release from cultured glia but spares neuronal activity-dependent release from cultured cortical neurons. We observe that resveratrol decreases overall levels of MMP-2 and MMP-9 in CSF samples from AD patients. Resveratrol also reduces CSF levels of tissue inhibitor of metalloproteinases-1 (TIMP-1), glial-derived protein that restricts long-term potentiation of synaptic transmission, in individuals homozygous for APOE4. Consistent with these results, we observe that resveratrol reduces basal and lipopolysaccharide (LPS)-stimulated MMP and TIMP-1 release from cultured microglia and astrocytes. In contrast, however, resveratrol does not inhibit release of MMP-9 from cortical neurons. Overall, these results are consistent with the possibility that while resveratrol reduces potentially maladaptive MMP and TIMP-1 release from activated glia, neuroplasticity-promoting MMP release from neurons is spared. In contrast, resveratrol reduces release of neurocan and brevican, extracellular matrix components that restrict neuroplasticity, from both neurons and glia. These data underscore the diversity of resveratrol's actions with respect to affected cell types and molecular targets and also suggest that further studies may be warranted to determine if its effects on glial MMP release could make it a useful adjunct for AD- and/or anti-amyloid therapy-related damage to the blood brain barrier.
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INTRODUCTION: Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aß) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. METHODS: Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 µg (n = 42) or placebo (n = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aß positron emission tomography (PET) scans at 18 to 24 months. RESULTS: CAD106 induced measurable serum Aß immunoglobulin G titers in 41/42 participants, slower rates of Aß plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P < 0.001), and three amyloid-related imaging abnormality cases (one symptomatic). DISCUSSION: Despite early termination, these findings support the potential value of conducting larger prevention trials of Aß active immunotherapies in individuals at risk for AD. HIGHLIGHTS: This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Humanos , Pessoa de Meia-Idade , Idoso , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/terapia , Doença de Alzheimer/tratamento farmacológico , Homozigoto , Apolipoproteína E4/genética , Placa Amiloide , Amiloide/metabolismo , Tomografia por Emissão de Pósitrons , Imunoterapia , Encéfalo/metabolismoRESUMO
The APOE4 allele increases the risk for Alzheimer's disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murine APOE with human APOE3 or APOE4, the latter show reduced neuronal dendritic complexity and impaired learning. APOE4 TR mice also show reduced gamma oscillation power, a neuronal population activity which is important to learning and memory. Published work has shown that brain extracellular matrix (ECM) can reduce neuroplasticity as well as gamma power, while attenuation of ECM can instead enhance this endpoint. In the present study we examine human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 individuals and brain lysates from APOE3 and APOE4 TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples from APOE4 individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased in APOE4 CSF as well as astrocyte supernatants brain lysates from APOE4 TR mice. Importantly, as compared to APOE4/wild-type heterozygotes, APOE4/CCR5 knockout heterozygotes show reduced TIMP levels and enhanced EEG gamma power. The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target for APOE4 individuals.
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Doença de Alzheimer , Apolipoproteína E4 , Camundongos , Humanos , Animais , Idoso , Apolipoproteína E4/genética , Memória de Curto Prazo , Apolipoproteína E3/genética , Camundongos Transgênicos , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Receptores CCR5RESUMO
Discoidin Domain Receptor (DDR)-1 is activated by collagen. Nilotinib is a tyrosine kinase inhibitor that is FDA-approved for leukemia and potently inhibits DDR-1. Individuals diagnosed with mild-moderate Alzheimer's disease (AD) treated with nilotinib (versus placebo) for 12 months showed reduction of amyloid plaque and cerebrospinal fluid (CSF) amyloid, and attenuation of hippocampal volume loss. However, the mechanisms are unclear. Here, we explored unbiased next generation whole genome miRNA sequencing from AD patients CSF and miRNAs were matched with their corresponding mRNAs using gene ontology. Changes in CSF miRNAs were confirmed via measurement of CSF DDR1 activity and plasma levels of AD biomarkers. Approximately 1050 miRNAs are detected in the CSF but only 17 miRNAs are specifically altered between baseline and 12-month treatment with nilotinib versus placebo. Treatment with nilotinib significantly reduces collagen and DDR1 gene expression (upregulated in AD brain), in association with inhibition of CSF DDR1. Pro-inflammatory cytokines, including interleukins and chemokines are reduced along with caspase-3 gene expression. Specific genes that indicate vascular fibrosis, e.g., collagen, Transforming Growth Factors (TGFs) and Tissue Inhibitors of Metalloproteases (TIMPs) are altered by DDR1 inhibition with nilotinib. Specific changes in vesicular transport, including the neurotransmitters dopamine and acetylcholine, and autophagy genes, including ATGs, indicate facilitation of autophagic flux and cellular trafficking. Inhibition of DDR1 with nilotinib may be a safe and effective adjunct treatment strategy involving an oral drug that enters the CNS and adequately engages its target. DDR1 inhibition with nilotinib exhibits multi-modal effects not only on amyloid and tau clearance but also on anti-inflammatory markers that may reduce cerebrovascular fibrosis.
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Doença de Alzheimer , MicroRNAs , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Receptores com Domínio Discoidina , Pirimidinas/farmacologia , Colágeno/uso terapêutico , Fibrose , Inflamação/tratamento farmacológicoRESUMO
INTRODUCTION: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. DISCUSSION: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. HIGHLIGHTS: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Reprodutibilidade dos Testes , Lobo Temporal/patologia , Imageamento por Ressonância Magnética/métodos , Atrofia/patologia , BiomarcadoresRESUMO
INTRODUCTION: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants. METHODS: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study. RESULTS: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases. DISCUSSION: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases. HIGHLIGHTS: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Proteína C9orf72/genética , Testes Genéticos , Estudos Longitudinais , Mutação , Presenilina-1/genética , Presenilina-2/genéticaRESUMO
BACKGROUND: Missing data are a notable problem in Alzheimer's disease clinical trials. One cause of missing data is participant dropout. The Research Attitudes Questionnaire is a 7-item instrument that measures an individual's attitudes toward biomedical research, with higher scores indicating more favorable attitudes. The objective of this study was to describe the performance of the Research Attitudes Questionnaire over time and to examine whether Research Attitudes Questionnaire scores predict study dropout and other participant behaviors that affect trial integrity. METHODS: The Research Attitudes Questionnaire was collected at baseline and weeks 26 and 52 from each member of 119 participant/study partner dyads enrolled in a Phase 2, randomized, double-blind, placebo-controlled mild-to-moderate Alzheimer's disease clinical trial. Within-subject longitudinal analyses examined change in Research Attitudes Questionnaire scores over time in each population. Logistic regression analyses that controlled for trial arm and clustering in trial sites were used to assess whether baseline Research Attitudes Questionnaire scores predicted trial completion, study medication compliance, and enrollment in optional substudies. RESULTS: Participants and study partners endorsed statistically similar ratings on the Research Attitudes Questionnaire that were stable over time. Participants with baseline Research Attitudes Questionnaire scores above 28.5 were 4.7 (95% confidence interval = 1.01 to 21.95) times as likely to complete the trial compared to those with lower scores. Applying the same cutoff, baseline study partner Research Attitudes Questionnaire scores were similarly able to predict study completion (odds ratio = 4.2, 95% confidence interval = 1.71 to 10.32). Using a score cutoff of 27.5, higher participant Research Attitudes Questionnaire scores predicted study medication compliance (odds ratio = 5.85, 95% confidence interval = 1.34 to 25.54). No relationship was observed between Research Attitudes Questionnaire score and participation in optional substudies. CONCLUSION: This brief instrument that measures research attitudes may identify participants at risk for behaviors that cause missing data.
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Doença de Alzheimer , Pacientes Desistentes do Tratamento , Inquéritos e Questionários , Doença de Alzheimer/tratamento farmacológico , Atitude , Ensaios Clínicos Fase II como Assunto , Método Duplo-Cego , Humanos , Pacientes Desistentes do Tratamento/psicologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
This study examined the maintenance of anomia treatment effects in primary progressive aphasia (PPA). Following baseline testing, a phonological treatment and an orthographic treatment were administered over the course of six months. The treatment stimuli consisted of nouns that were consistently named correctly at baseline (Prophylaxis items) and/or nouns that were consistently named incorrectly at baseline (Remediation items). Naming accuracy was measured at baseline, and it was measured at 1 month, 8 months, and 15 months post-treatment. The change in naming accuracy from baseline to each post-treatment evaluation was calculated within each treatment condition, and within a matched untrained condition. The change in naming accuracy was then compared between the three conditions. The results of these analyses indicate that phonological and orthographic treatments are both effective in the Prophylaxis and Remediation of anomia in all three variants of PPA. For Prophylaxis items, some of the effects of each treatment can persist for as long as 15 months post-treatment. These long-term treatment effects were more robust in the orthographic treatment condition and for participants with the semantic variant of PPA.
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Anomia/reabilitação , Afasia Primária Progressiva/reabilitação , Terapia da Linguagem/métodos , Reabilitação Neurológica/métodos , Adulto , Idoso , Anomia/etiologia , Afasia Primária Progressiva/complicações , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Our recent study demonstrated that an amyloid-ß binding molecule, BTA-EG4, increases dendritic spine number via Ras-mediated signaling. To potentially optimize the potency of the BTA compounds, we synthesized and evaluated an amyloid-ß binding analog of BTA-EG4 with increased solubility in aqueous solution, BTA-EG6. We initially examined the effects of BTA-EG6 on dendritic spine formation and found that BTA-EG6-treated primary hippocampal neurons had significantly increased dendritic spine number compared to control treatment. In addition, BTA-EG6 significantly increased the surface level of AMPA receptors. Upon investigation into the molecular mechanism by which BTA-EG6 promotes dendritic spine formation, we found that BTA-EG6 may exert its effects on spinogenesis via RasGRF1-ERK signaling, with potential involvement of other spinogenesis-related proteins such as Cdc42 and CDK5. Taken together, our data suggest that BTA-EG6 boosts spine and synapse number, which may have a beneficial effect of enhancing neuronal and synaptic function in the normal healthy brain.
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Benzotiazóis/química , Benzotiazóis/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas ras/metabolismo , ras-GRF1/metabolismo , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Células Cultivadas , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/ultraestrutura , Etilenoglicol/química , Etilenoglicol/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismoRESUMO
BACKGROUND: Treatment of mild-moderate Alzheimer's disease (AD) subjects (N = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aß40 levels and activities of daily living (ADL) scores. METHODS: For this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aß42 <600 ng/ml (biomarker-confirmed AD) at baseline (N = 19 resveratrol-treated and N = 19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples. RESULTS: Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aß42 levels during the 52-week trial, but did not alter tau levels. CONCLUSIONS: Collectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders. TRIAL REGISTRATION: ClinicalTrials.gov NCT01504854.
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Imunidade Adaptativa/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Citocinas/metabolismo , Encefalite/tratamento farmacológico , Estilbenos/farmacologia , Estilbenos/uso terapêutico , Atividades Cotidianas , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Quimiocina CCL5/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Método Duplo-Cego , Encefalite/etiologia , Feminino , Fator 2 de Crescimento de Fibroblastos/líquido cefalorraquidiano , Seguimentos , Humanos , Masculino , Metaloproteinase 9 da Matriz/líquido cefalorraquidiano , Entrevista Psiquiátrica Padronizada , Fragmentos de Peptídeos/líquido cefalorraquidiano , Resveratrol , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidianoRESUMO
The tetra(ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, is a novel amyloid-binding small molecule that can penetrate the blood-brain barrier and protect cells from Aß-induced toxicity. However, the effects of Aß-targeting molecules on other cellular processes, including those that modulate synaptic plasticity, remain unknown. We report here that BTA-EG4 decreases Aß levels, alters cell surface expression of amyloid precursor protein (APP), and improves memory in wild-type mice. Interestingly, the BTA-EG4-mediated behavioral improvement is not correlated with LTP, but with increased spinogenesis. The higher dendritic spine density reflects an increase in the number of functional synapses as determined by increased miniature EPSC (mEPSC) frequency without changes in presynaptic parameters or postsynaptic mEPSC amplitude. Additionally, BTA-EG4 requires APP to regulate dendritic spine density through a Ras signaling-dependent mechanism. Thus, BTA-EG4 may provide broad therapeutic benefits for improving neuronal and cognitive function, and may have implications in neurodegenerative disease therapy.
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Compostos de Anilina/farmacologia , Benzotiazóis/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Etilenoglicóis/farmacologia , Genes ras/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/genética , Animais , Biotinilação , Células COS , Circulação Cerebrovascular/efeitos dos fármacos , Chlorocebus aethiops , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/psicologia , Ensaio de Imunoadsorção Enzimática , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Imuno-Histoquímica , Potenciação de Longa Duração/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Receptores de AMPA/efeitos dos fármacosRESUMO
Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with (11)C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, (11)C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater (11)C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. (11)C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. (11)C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater (11)C-PBR28 binding than late-onset patients, and in parietal cortex and striatum (11)C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between (11)C-PBR28 and (11)C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased (11)C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. (11)C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer's disease.
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Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Receptores de GABA/metabolismo , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Análise de Variância , Compostos de Anilina/farmacocinética , Encéfalo/patologia , Mapeamento Encefálico , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Escalas de Graduação Psiquiátrica , Pirimidinas/farmacocinética , Receptores de GABA/genética , Estatística como Assunto , Tiazóis/farmacocinéticaRESUMO
PURPOSE: We evaluated whether plasma Alzheimer's Disease (AD)-related biomarkers were associated with cancer-related cognitive decline (CRCD) among older breast cancer survivors. METHODS: We included survivors 60-90 years with primary stage 0-III breast cancers (n = 236) and frequency-matched non-cancer controls (n = 154) who passed a cognitive screen and had banked plasma specimens. Participants were assessed at baseline (pre-systemic therapy) and annually for up to 60-months. Cognition was measured using tests of attention, processing speed and executive function (APE) and learning and memory (LM); perceived cognition was measured by the FACT-Cog PCI. Baseline plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), beta-amyloid 42/40 (Aß42/40) and phosphorylated tau (p-tau181) were assayed using single molecule arrays. Mixed models tested associations between cognition and baseline AD-biomarkers, time, group (survivor vs control) and their two- and three-way interactions, controlling for age, race, WRAT4 Word Reading score, comorbidity and BMI; two-sided 0.05 p-values were considered statistically significant. RESULTS: There were no group differences in baseline AD-related biomarkers except survivors had higher baseline NfL levels than controls (p = .013). Survivors had lower adjusted longitudinal APE than controls starting from baseline and continuing over time (p = <0.002). However, baseline AD-related biomarker levels were not independently associated with adjusted cognition over time, except controls had lower APE scores with higher GFAP levels (p = .008). CONCLUSION: The results do not support a relationship between baseline AD-related biomarkers and CRCD. Further investigation is warranted to confirm the findings, test effects of longitudinal changes in AD-related biomarkers and examine other mechanisms and factors affecting cognition pre-systemic therapy.
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Several epidemiological and preclinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), reduce the risk of Alzheimer's disease (AD) and can lower ß-amyloid (Aß) production and inhibit neuroinflammation. However, follow-up clinical trials, mostly using selective cyclooxygenase (COX)-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive deficits. Recent data indicated that COX-1, classically viewed as the homeostatic isoform, is localized in microglia and is actively involved in brain injury induced by pro-inflammatory stimuli including Aß, lipopolysaccharide, and interleukins. We hypothesized that neuroinflammation is critical for disease progression and selective COX-1 inhibition, rather than COX-2 inhibition, can reduce neuroinflammation and AD pathology. Here, we show that treatment of 20-month-old triple transgenic AD (3 × Tg-AD) mice with the COX-1 selective inhibitor SC-560 improved spatial learning and memory, and reduced amyloid deposits and tau hyperphosphorylation. SC-560 also reduced glial activation and brain expression of inflammatory markers in 3 × Tg-AD mice, and switched the activated microglia phenotype promoting their phagocytic ability. The present findings are the first to demonstrate that selective COX-1 inhibition reduces neuroinflammation, neuropathology, and improves cognitive function in 3 × Tg-AD mice. Thus, selective COX-1 inhibition should be further investigated as a potential therapeutic approach for AD.
Assuntos
Doença de Alzheimer/complicações , Proteínas Amiloidogênicas/metabolismo , Inibidores de Ciclo-Oxigenase/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Pirazóis/uso terapêutico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Mutação/genética , Fagócitos/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Presenilina-1/genética , Proteínas tau/genéticaRESUMO
Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is one of the most common pathological findings associated with the clinical FTLD syndromes. However, molecular characterization with genetic sequencing and protein expression techniques are recognizing many new subtypes for FTLDs. FTLDs are diverse and new nomenclature schemes have been proposed based on the molecular defects that are being discovered ( Mackenzie et al., 2010 , Acta Neuropathologica, 119, 1). Adult polyglucosan body disease (APBD) is a very rare disorder associated with systemic neurological signs and symptoms including progressive dementia with executive dysfunction and motor neuron disease. We report the clinical course of an individual with a clinical FTLD and the as yet unreported findings of coexistent APBD with FTLD-U and transactivation response DNA-binding protein-43 (TDP-43)-positive inclusions at autopsy (or more accurately, FTLD-TDP). It is unclear if these distinct findings are coincidental in this individual, or if pathogenic pathways may intersect to promote these coexisting pathologies.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Degeneração Lobar Frontotemporal/patologia , Glucanos/metabolismo , Corpos de Inclusão/patologia , Neurônios/patologia , Atividades Cotidianas , Encéfalo/patologia , Proteínas de Ligação a DNA/genética , Evolução Fatal , Feminino , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/psicologia , Humanos , Corpos de Inclusão/genética , Corpos de Inclusão/metabolismo , Judeus , Pessoa de Meia-Idade , Exame Neurológico , Neurônios/metabolismo , Testes Neuropsicológicos , Ativação TranscricionalRESUMO
Alzheimer's Disease (AD) and related dementias are a leading cause of death globally and are predicted to increase in prevalence. Despite this expected increase in the prevalence of AD, we have yet to elucidate the causality of the neurodegeneration observed in AD and we lack effective therapeutics to combat the progressive neuronal loss. Throughout the past 30 years, several non-mutually exclusive hypotheses have arisen to explain the causative pathologies in AD: amyloid cascade, hyper-phosphorylated tau accumulation, cholinergic loss, chronic neuroinflammation, oxidative stress, and mitochondrial and cerebrovascular dysfunction. Published studies in this field have also focused on changes in neuronal extracellular matrix (ECM), which is critical to synaptic formation, function, and stability. Two of the greatest non-modifiable risk factors for development of AD (aside from autosomal dominant familial AD gene mutations) are aging and APOE status, and two of the greatest modifiable risk factors for AD and related dementias are untreated major depressive disorder (MDD) and obesity. Indeed, the risk of developing AD doubles for every 5 years after ≥ 65, and the APOE4 allele increases AD risk with the greatest risk in homozygous APOE4 carriers. In this review, we will describe mechanisms by which excess ECM accumulation may contribute to AD pathology and discuss pathological ECM alterations that occur in AD as well as conditions that increase the AD risk. We will discuss the relationship of AD risk factors to chronic central nervous system and peripheral inflammation and detail ECM changes that may follow. In addition, we will discuss recent data our lab has obtained on ECM components and effectors in APOE4/4 and APOE3/3 expressing murine brain lysates, as well as human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 expressing AD individuals. We will describe the principal molecules that function in ECM turnover as well as abnormalities in these molecular systems that have been observed in AD. Finally, we will communicate therapeutic interventions that have the potential to modulate ECM deposition and turnover in vivo.
RESUMO
Second-generation anti-amyloid monoclonal antibodies are emerging as a viable therapeutic option for individuals with prodromal and mild dementia due to Alzheimer's disease (AD). Passive immunotherapy with aducanumab (Aduhelm), lecanemab, donanemab, and gantenerumab all lower CNS amyloid (Aß) burden but come with a significant risk of amyloid-related imaging abnormality (ARIA)-the most common side effect of this class of drugs. While usually asymptomatic and detected only on brain MRI, ARIA may lead to new signs and symptoms including headache, worsening confusion, dizziness, visual disturbances, nausea, and seizures. In addition, one fatality related to ARIA-E (edema) with aducanumab and one fatality due to ARIA-H (hemorrhage) with donanemab are reported to date. ARIA-E may be associated with excessive neuroinflammation and saturation of perivascular clearance pathways, while ARIA-H may be related to vascular amyloid clearance with weakening and rupture of small blood vessels. The risk of ARIA-E is higher at treatment initiation, in ApoE4 carriers, with higher dosage, and with >4 of microhemorrhages on a baseline MRI. The risk of ARIA-H increases with age and cerebrovascular disease. Dose titration mitigates the risk of ARIA, and contraindications include individuals with >4 microhemorrhages and those prescribed anti-platelet or anti-coagulant drugs. A brain MRI is required before aducanumab is initiated, before each scheduled dose escalation, and with any new neurologic sign or symptom. Management of ARIA ranges from continued antibody treatment with monthly MRI monitoring for asymptomatic individuals to temporary or permanent suspension for symptomatic individuals or those with moderate to severe ARIA on MRI. Controlled studies regarding prevention and treatment of ARIA are lacking, but anecdotal evidence suggests that a pulse of intravenous corticosteroids may be of benefit, as well as a course of anticonvulsant for seizures.
RESUMO
Introduction: Bosutinib, a dual Abelson/Src inhibitor, was investigated in individuals with dementia with Lewy bodies (DLB). Methods: A single site, randomized, double-blind, placebo-controlled study of the effects of oral bosutinib, 100 mg once daily for 12 weeks on primary safety and pharmacokinetics and secondary biomarker outcomes. Results: Twenty-six participants were randomized and included male and female (12:1) in the bosutinib arm and all male (13) in the placebo arm. The average age was 72.9 ± 8.1 (year ± standard deviation). There were no serious adverse events and no dropouts. Bosutinib was measured in the cerebrospinal fluid (CSF) and inhibited Abelson. Bosutinib reduced CSF alpha-synuclein and dopamine catabolism. Discussion: Bosutinib is safe and well tolerated and penetrates the blood-brain barrier to inhibit Abelson and reduce CSF alpha-synuclein and dopamine catabolism, suggesting that bosutinib (100 mg) may be at or near the lowest effective dose in DLB. These results will guide adequately powered studies to determine the efficacy of a dose range of bosutinib and longer treatment in DLB. Highlights: Bosutinib is a dual Abl/Src inhibitor that penetrates the blood brain barrierBosutinib is safe and tolerated in individuals with dementia with Lewy bodiesBosutinib engages its target via inhibition of Abl and SrcBosutinib reduces CSF alpha-synuclein and attenuates breakdown of dopamineBosutinib improves activities of daily living in dementia with Lewy bodies.
RESUMO
The goal of this study was to determine the effect of X11alpha on ApoE receptor 2 (ApoEr2) trafficking and the functional significance of this interaction on cell movement in MCF 10A epithelial cells. We found that X11alpha increased surface levels of ApoEr2 by 64% compared to vector control, as determined by surface protein biotinylation. To examine the functional significance of this effect, we tested whether ApoEr2 played a novel role in cell movement in a wound-healing assay. We found that overexpression of ApoEr2 in MCF 10A cells increased cell migration velocity by 87% (P<0.01, n=4) compared to GFP control. Cotransfection of X11alpha had an additive effect on average velocity compared to ApoEr2 alone (13%; P<0.05, n=4). In addition, we tested whether ApoEr2 ligands altered the effect of ApoEr2 on cell movement. We found that treatment with concentrated medium containing the extracellular matrix protein Reelin, but not control medium, further increased the velocity of ApoEr2- but not APP-transfected cells (20%; P<0.001, n=4). Similarly, Reelin treatment increased cell velocity in the presence of ApoEr2 and X11alpha (10%; P<0.05, n=4). In the present study, we are the first to demonstrate that ApoEr2 regulates cell movement, and both X11alpha and Reelin enhance this effect.