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Because disease-associated microglia (DAM) and disease-associated astrocytes (DAA) are involved in the pathophysiology of Alzheimer's disease (AD), we systematically identified molecular networks between DAM and DAA to uncover novel therapeutic targets for AD. Specifically, we develop a network-based methodology that leverages single-cell/nucleus RNA sequencing data from both transgenic mouse models and AD patient brains, as well as drug-target network, metabolite-enzyme associations, the human protein-protein interactome, and large-scale longitudinal patient data. Through this approach, we find both common and unique gene network regulators between DAM (i.e., PAK1, MAPK14, and CSF1R) and DAA (i.e., NFKB1, FOS, and JUN) that are significantly enriched by neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1). We identify shared immune pathways between DAM and DAA, including Th17 cell differentiation and chemokine signaling. Last, integrative metabolite-enzyme network analyses suggest that fatty acids and amino acids may trigger molecular alterations in DAM and DAA. Combining network-based prediction and retrospective case-control observations with 7.2 million individuals, we identify that usage of fluticasone (an approved glucocorticoid receptor agonist) is significantly associated with a reduced incidence of AD (hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.83-0.89, P < 1.0 × 10-8). Propensity score-stratified cohort studies reveal that usage of mometasone (a stronger glucocorticoid receptor agonist) is significantly associated with a decreased risk of AD (HR = 0.74, 95% CI 0.68-0.81, P < 1.0 × 10-8) compared to fluticasone after adjusting age, gender, and disease comorbidities. In summary, we present a network-based, multimodal methodology for single-cell/nucleus genomics-informed drug discovery and have identified fluticasone and mometasone as potential treatments in AD.
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Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Animais , Astrócitos/metabolismo , Análise de Dados , Reposicionamento de Medicamentos , Humanos , Camundongos , Microglia/metabolismo , Estudos Retrospectivos , Análise de Sequência de RNARESUMO
INTRODUCTION: Cerebral amyloid angiopathy (CAA) is characterized by amyloid ß (Aß) deposition in brain vessels, leading to hemorrhagic phenomena and cognitive impairment. Magnetic resonance imaging (MRI)-based criteria allow a diagnosis of probable CAA in vivo, but such a diagnosis cannot predict the eventual development of CAA. METHODS: We conducted a retrospective cohort study of 464 patients with cognitive disorders whose data were included in a brain health biobank. De-identified parameters including sex, age, cognitive score, APOE status, and cerebrospinal fluid (CSF) levels of Aß 1-40, Aß 1-42, phosphorylated tau, and total tau were assessed in those with and without CAA. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined. RESULTS: CAA was present in 53 of 464 (11.5%) patients. P-tau level was significantly higher in those with CAA (115 vs. 84.3 pg/mL p = 0.038). In univariate analyses, the risk of developing CAA was higher with increased age (OR, 1.036; 95% CI: 1.008, 1.064; p = 0.011) and decreased CSF level of Aß 1-40 (OR, 0.685; 95% CI: 0.534, 0.878; p = 0.003). In multivariate analyses, the risk of CAA remained higher with a decreased CSF level of Aß 1-40 (OR, 0.681; 95% CI: 0.531, 0.874; p = 0.003). CONCLUSION: These findings suggest that Aß 1-40 levels in the CSF might be a useful molecular biomarker of CAA in patients with dementia.
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Alzheimer's disease (AD) has been linked to multiple immune system-related genetic variants. Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. In addition, soluble TREM2 (sTREM2) isoform is elevated in cerebrospinal fluid in the early stages of AD and is associated with slower cognitive decline in a disease stage-dependent manner. Multiple studies have reported an altered peripheral immune response in AD. However, less is known about the relationship between peripheral sTREM2 and an altered peripheral immune response in AD. The objective of this study was to explore the relationship between human plasma sTREM2 and inflammatory activity in AD. The hypothesis of this exploratory study was that sTREM2-related inflammatory activity differs by AD stage. We observed different patterns of inflammatory activity across AD stages that implicate early-stage alterations in peripheral sTREM2-related inflammatory activity in AD. Notably, fractalkine showed a significant relationship with sTREM2 across different analyses in the control groups that was lost in later AD-related stages with high levels in mild cognitive impairment. Although multiple other inflammatory factors either differed significantly between groups or were significantly correlated with sTREM2 within specific groups, three inflammatory factors (fibroblast growth factor-2, GM-CSF, and IL-1ß) are notable because they exhibited both lower levels in AD, compared with mild cognitive impairment, and a change in the relationship with sTREM2. This evidence provides important support to the hypothesis that sTREM2-related inflammatory activity alterations are AD stage specific and provides critical information for therapeutic strategies focused on the immune response.
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Doença de Alzheimer , Doença de Alzheimer/genética , Biomarcadores , HumanosRESUMO
INTRODUCTION: Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage. METHODS: We conducted a retrospective neuropathology-confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n = 1175; Lewy body pathology [LBP], n = 316; and mixed AD and LBP [AD-LBP], n = 893). We used logistic regression to evaluate age, sex, education, APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk. RESULTS: APOE ε4 increased CAA risk in all three groups, while younger age and higher NFT stages increased risk in AD and AD-LBP. In AD-LBP, male sex and lower education were additional risk factors. The odds of APOE ε4 carrier homozygosity related to CAA was higher in LBP (25.69) and AD-LBP (9.50) than AD (3.17). DISCUSSION: AD and LBPs modify risk factors for CAA and should be considered in reviewing the risk of CAA. HIGHLIGHTS: Lewy body pathology modifies risk factors for cerebral amyloid angiopathy (CAA) when present along with Alzheimer's disease (AD) neuropathology. In the context of anti-amyloid monoclonal therapies and their associated risks for hemorrhage, the risk of underlying CAA in mixed dementia with Lewy body pathology needs to be considered.
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Doença de Alzheimer , Angiopatia Amiloide Cerebral , Masculino , Humanos , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Corpos de Lewy/patologia , Estudos Retrospectivos , Angiopatia Amiloide Cerebral/epidemiologia , Angiopatia Amiloide Cerebral/patologia , Amiloide , Fatores de Risco , Hemorragia , Placa Amiloide/patologiaRESUMO
INTRODUCTION: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood. METHODS: To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort. RESULTS: We identified sex-specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female-specific elevation in glycerophosphorylcholine and N-acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)-17 signaling, C-type lectin receptor, interferon signaling, and Toll-like receptor pathways. We pinpointed distinct microglia-specific immunometabolism endophenotypes (i.e., lipid- and amino acid-specific IL-10 and IL-17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate-mediated immunometabolism. DISCUSSION: Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD. HIGHLIGHTS: Sex-specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin-10 pathway activity. Female AD subjects showed a shift in glutamate-mediated cell-cell communications between excitatory neurons to microglia and astrocyte.
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Doença de Alzheimer , Humanos , Masculino , Feminino , Doença de Alzheimer/patologia , Microglia/metabolismo , Endofenótipos , Caracteres Sexuais , Glutamatos/genética , Glutamatos/metabolismoRESUMO
INTRODUCTION: The National Institute on Aging - Alzheimer's Association (NIA-AA) ATN research framework proposes to use biomarkers for amyloid (A), tau (T), and neurodegeneration (N) to stage individuals with AD pathological features and track changes longitudinally. The overall aim was to utilize this framework to characterize pre-mortem ATN status longitudinally in a clinically diagnosed cohort of dementia with Lewy bodies (DLB) and to correlate it with the post mortem diagnosis. METHODS: The cohort was subtyped by cerebrospinal fluid (CSF) ATN category. A subcohort had longitudinal data, and a subgroup was neuropathologically evaluated. RESULTS: We observed a significant difference in Aß42/40 after 12 months in the A+T- group. Post mortem neuropathologic analyses indicated that most of the p-Tau 181 positive (T+) cases also had a high Braak stage. DISCUSSION: This suggests that DLB patients who are A+ but T- may need to be monitored to determine whether they remain A+ or ever progress to T positivity. HIGHLIGHTS: Some A+T- DLB subjects transition from A+ to negative after 12-months. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Monitoring of the A+T- sub-type of DLB may be necessary.
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Doença de Alzheimer , Doença por Corpos de Lewy , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidianoRESUMO
Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor. HIGHLIGHTS: A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.
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Doença por Corpos de Lewy , Humanos , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/terapiaRESUMO
An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.
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Doença de Alzheimer , Esclerose Lateral Amiotrófica , Demência Frontotemporal , Humanos , Doença de Alzheimer/patologia , Demência Frontotemporal/patologia , Esclerose Lateral Amiotrófica/patologia , Proteínas de Ligação a DNA/genéticaRESUMO
INTRODUCTION: The relationship between initial cognitive symptoms and subsequent rate of clinical decline is important in clinical care and the design of dementia clinical trials. METHODS: This retrospective longitudinal, autopsy-confirmed, cohort study among 2426 participants in the National Alzheimer's Coordinating Center database included Alzheimer's disease (AD) pathology, n = 1187; Lewy body pathology (LBP), n = 331; and mixed pathology (AD-LBP), n = 904. The predominant initial cognitive symptom was assessed clinically. Linear mixed models evaluated the longitudinal outcome of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. RESULTS: Non-amnestic initial symptoms had a faster rate of decline than amnestic symptoms in all three groups. Language symptoms had a faster rate of decline in all three groups. Executive symptoms had a faster rate of decline than amnestic in AD and AD-LBP. There was a similar trend for visuospatial symptoms in AD-LBP. DISCUSSION: Initial cognitive symptoms, despite varied underlying pathology, are a predictor of longitudinal functional outcomes among dementias. HIGHLIGHTS: Initial non-amnestic symptoms had a faster rate of longitudinal cognitive and functional decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores than amnestic symptoms among Alzheimer's disease, Lewy body pathology, and mixed neuropathology. Given the relative size of CDR-SB changes in Alzheimer's disease clinical trials, clarifying the nature of initial symptoms could be an important variable in ensuring appropriately designed clinical trials.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/patologia , Estudos de Coortes , Estudos Retrospectivos , Testes Neuropsicológicos , Progressão da Doença , Disfunção Cognitiva/diagnósticoRESUMO
INTRODUCTION: African Americans (AAs) and European Americans (EAs) differ in Alzheimer's disease (AD) prevalence, risk factors, and symptomatic presentation and AAs are less likely to enroll in AD clinical trials. METHODS: We conducted race-conscious pharmacoepidemiologic studies of 5.62 million older individuals (age ≥60) to investigate the association of telmisartan exposure and AD outcome using Cox analysis, Kaplan-Meier analysis, and log-rank test. We performed Mendelian randomization (MR) analysis of large ethnically diverse genetic data to test likely causal relationships between telmisartan's target and AD. RESULTS: We identified that moderate/high telmisartan exposure was significantly associated with a reduced incidence of AD in the AAs compared to low/no telmisartan exposure (hazard ratio [HR] = 0.77, 95% CI: 0.65-0.91, p-value = 0.0022), but not in the non-Hispanic EAs (HR = 0.97, 95% CI: 0.89-1.05, p-value = 0.4110). Sensitivity and sex-/age-stratified patient subgroup analyses identified that telmisartan's medication possession ratio (MPR) and average hypertension daily dosage were significantly associated with a stronger reduction in the incidence of both AD and dementia in AAs. Using MR analysis from large genome-wide association studies (GWAS) (over 2 million individuals) across AD, hypertension, and diabetes, we further identified AA-specific beneficial effects of telmisartan for AD. DISCUSSION: Randomized controlled trials with ethnically diverse patient cohorts are warranted to establish causality and therapeutic outcomes of telmisartan and AD. HIGHLIGHTS: Telmisartan is associated with lower risk of Alzheimer's disease (AD) in African Americans (AAs). Telmisartan is the only angiotensin II receptor blockers having PPAR-γ agonistic properties with beneficial anti-diabetic and renal function effects, which mitigate AD risk in AAs. Mendelian randomization (MR) analysis demonstrates the specificity of telmisartan's protective mechanism to AAs.
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Doença de Alzheimer , Diabetes Mellitus , Hipertensão , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/epidemiologia , Negro ou Afro-Americano/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Telmisartan/uso terapêutico , Pessoa de Meia-IdadeRESUMO
Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA-binding protein 43 (TDP-43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co-pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co-pathologies in DLB and their cross-sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease-specific and disease-nonspecific biomarkers and how co-pathologies can impact these biomarkers. We propose a framework for integrating multi-modal biomarker fingerprints and step-wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co-pathologies.
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Doença por Corpos de Lewy , Humanos , Doença de Alzheimer/patologia , Biomarcadores , Ensaios Clínicos como Assunto , Estudos Transversais , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/patologia , Transtornos Parkinsonianos/etiologia , Transtorno do Comportamento do Sono REM/etiologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismoRESUMO
BACKGROUND: Hippocampal and amygdala subfields variably affect cognitive impairment in neurodegenerative diseases. Subfields of these regions can be well segmented using modern neuroimaging tools but their role in neurodegenerative disease is under active investigation. In this study, we identified hippocampal and amygdala subregions predictive of cognitive performance and motor symptoms severity measured by MoCA (Montreal Cognitive Assessment) and MDS-UPDRS III, respectively, in patients with dementia with Lewy Bodies (DLB). METHOD: We selected all participants with probable DLB (N = 48, mean age = 71±7 years, 15% female) enrolled in the Dementia with Lewy Bodies Consortium (DLBC) as of July 2022, with concurrent measures of 3D T1 MRI sequence, MoCA, and MDS-UPDRS III scores. We performed cortical reconstruction and volumetric segmentation of hippocampal subfields and nuclei of the amygdala using FreeSurfer (v 7.2). We used combat harmonization to account for site and scanner differences. We trained and applied a bootstrapped, bidirectional stepwise regression model of 29 predictor variables comprised of sub-fields and mean cortical thickness against MoCA and MDS-UPDRS III, respectively, with an 80-20 train-test split ratio, and 5000 repetitions, corrected for age and sex. RESULT: Subfield segmentation is shown in Figure 1A. The best fitting model for MoCA included mean cortical thickness, parasubiculum, hippocampal and amygdala transition area, corticoamygdaloid transition area, and CA3 body (Figure 1B, adjusted R2 = 0.51). The best fitting model for MDS-UPDRS III included the cortical nucleus of the amygdala and CA1 body (Figure 1C, adjusted R2 = 0.22). This model was considered a poor fit. We considered MoCA for further analysis and closely predicted scores in our 20% partitioned test sample (Figure 2A, R2 = 0.38). CONCLUSION: We report model-based selection of hippocampal and amygdala subfields to predict MoCA scores in DLB. Atrophy in these regions has been associated with global cognitive deficit in mild cognitive impairment and Alzheimer disease cohorts. The model fit for MDS-UPDRS III scores was poor, providing evidence that these brain regions do not serve a role in motor control.
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Tonsila do Cerebelo , Hipocampo , Doença por Corpos de Lewy , Imageamento por Ressonância Magnética , Humanos , Feminino , Idoso , Masculino , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/diagnóstico por imagem , Doença por Corpos de Lewy/patologia , Doença por Corpos de Lewy/diagnóstico por imagem , Hipocampo/patologia , Hipocampo/diagnóstico por imagem , Disfunção Cognitiva/patologia , Testes de Estado Mental e Demência/estatística & dados numéricos , Neuroimagem/métodosRESUMO
Individuals with Down syndrome (DS) develop Alzheimer's disease (AD)-related neuropathology, characterized by amyloid plaques with amyloid ß (Aß) and neurofibrillary tangles with tau accumulation. Peripheral inflammation and the innate immune response are elevated in DS. Triggering receptor expressed in myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. Soluble TREM2 (sTREM2), a soluble cleavage product of TREM2, is elevated in AD cerebrospinal fluid and positively correlates with cognitive decline. There is relatively little information about TREM2 in DS. Our objective was to examine the relationship between sTREM2 and inflammatory markers in young adults with DS, prior to the development of dementia symptoms. Because TREM2 plays a role in the innate immune response and has been associated with dementia, the hypothesis of this exploratory study was that young adults with DS predementia (n = 15, mean age = 29.5 y) would exhibit a different relationship between sTREM2 and inflammatory markers in plasma, compared with neurotypical, age-matched controls (n = 16, mean age = 29.6 y). Indeed, young adults with DS had significantly elevated plasma sTREM2 and inflammatory markers. Additionally, in young adults with DS, sTREM2 correlated positively with 24 of the measured cytokines, whereas there were no significant correlations in the control group. Hierarchical clustering of sTREM2 and cytokine concentrations also differed between the groups, supporting the hypothesis that its function is altered in people with DS predementia. This preliminary report of human plasma provides a basis for future studies investigating the relationship between TREM2 and the broader immune response predementia.
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Síndrome de Down/imunologia , Mediadores da Inflamação/imunologia , Glicoproteínas de Membrana/imunologia , Receptores Imunológicos/imunologia , Adulto , Biomarcadores/sangue , Citocinas/sangue , Citocinas/imunologia , Síndrome de Down/sangue , Feminino , Humanos , Mediadores da Inflamação/sangue , Masculino , Glicoproteínas de Membrana/sangue , Receptores Imunológicos/sangueRESUMO
INTRODUCTION: Mid-life dietary patterns are associated with Alzheimer's disease (AD) risk, although few controlled trials have been conducted. METHODS: Eighty-seven participants (age range: 45 to 65) with normal cognition (NC, n = 56) or mild cognitive impairment (MCI, n = 31) received isocaloric diets high or low in saturated fat, glycemic index, and sodium (Western-like/West-diet vs. Mediterranean-like/Med-diet) for 4 weeks. Diet effects on cerebrospinal fluid (CSF) biomarkers, cognition, and cerebral perfusion were assessed to determine whether responses differed by cognitive status. RESULTS: CSF amyloid beta (Aß)42/40 ratios increased following the Med-diet, and decreased after West-diet for NC adults, whereas the MCI group showed the reverse pattern. For the MCI group, the West-diet reduced and the Med-diet increased total tau (t-tau), whereas CSF Aß42 /t-tau ratios increased following the West-diet and decreased following the Med-diet. For NC participants, the Med-diet increased and the West-diet decreased cerebral perfusion. DISCUSSION: Diet response during middle age may highlight early pathophysiological processes that increase AD risk.
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Doença de Alzheimer , Disfunção Cognitiva , Dieta Mediterrânea , Dieta Ocidental , Adulto , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Circulação Cerebrovascular , Cognição/fisiologia , Disfunção Cognitiva/líquido cefalorraquidiano , Humanos , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
BACKGROUND: Dementia with Lewy body (DLB) diagnostic criteria define "indicative" and "supportive" biomarkers, but clinical practice patterns are unknown. METHODS: An anonymous survey querying clinical use of diagnostic tests/biomarkers was sent to 38 center of excellence investigators. The survey included "indicative" biomarkers (dopamine transporter scan, myocardial scintigraphy, polysomnography), "supportive" biomarkers [magnetic resonance imaging (MRI)], positron emission tomography, or single-photon emission computed tomography perfusion/metabolism scans, quantitative electroencephalography), and other diagnostic tests (neuropsychological testing, cerebrospinal fluid analysis, genetics). Responses were analyzed descriptively. RESULTS: Of the 22 respondents (58%), all reported the capability to perform neuropsychological testing, MRI, polysomnography, dopamine transporter scans, positron emission tomography/single-photon emission computed tomography scans, and cerebrospinal fluid analysis; 96% could order genetic testing. Neuropsychological testing and MRI were the most commonly ordered tests. Diagnostic testing beyond MRI and neuropsychological testing was most helpful in the context of "possible" DLB and mild cognitive impairment and to assist with differential diagnosis. Myocardial scintigraphy and electroencephalograpy use were rare. CONCLUSIONS AND RELEVANCE: Neuropsychological testing and MRI remain the most widely used diagnostic tests by DLB specialists. Other tests-particularly indicative biomarkers-are used only selectively. Research is needed to validate existing potential DLB biomarkers, develop new biomarkers, and investigate mechanisms to improve DLB diagnosis.
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Biomarcadores , Diagnóstico Diferencial , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Doença por Corpos de Lewy/diagnóstico , Idoso , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Disfunção Cognitiva/diagnóstico , Eletroencefalografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Inquéritos e Questionários , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Following two decades of more than 400 clinical trials centered on the "one drug, one target, one disease" paradigm, there is still no effective disease-modifying therapy for Alzheimer's disease (AD). The inherent complexity of AD may challenge this reductionist strategy. Recent observations and advances in network medicine further indicate that AD likely shares common underlying mechanisms and intermediate pathophenotypes, or endophenotypes, with other diseases. In this review, we consider AD pathobiology, disease comorbidity, pleiotropy, and therapeutic development, and construct relevant endophenotype networks to guide future therapeutic development. Specifically, we discuss six main endophenotype hypotheses in AD: amyloidosis, tauopathy, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and lysosomal dysfunction. We further consider how this endophenotype network framework can provide advances in computational and experimental strategies for drug-repurposing and identification of new candidate therapeutic strategies for patients suffering from or at risk for AD. We highlight new opportunities for endophenotype-informed, drug discovery in AD, by exploiting multi-omics data. Integration of genomics, transcriptomics, radiomics, pharmacogenomics, and interactomics (protein-protein interactions) are essential for successful drug discovery. We describe experimental technologies for AD drug discovery including human induced pluripotent stem cells, transgenic mouse/rat models, and population-based retrospective case-control studies that may be integrated with multi-omics in a network medicine methodology. In summary, endophenotype-based network medicine methodologies will promote AD therapeutic development that will optimize the usefulness of available data and support deep phenotyping of the patient heterogeneity for personalized medicine in AD.
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Doença de Alzheimer , Células-Tronco Pluripotentes Induzidas , Doença de Alzheimer/tratamento farmacológico , Animais , Reposicionamento de Medicamentos , Endofenótipos , Humanos , Camundongos , Ratos , Estudos RetrospectivosRESUMO
INTRODUCTION: Clinical differentiation between Alzheimer's disease (AD) and AD with Lewy body disease (LBD) is relatively imprecise. The current study examined pathologically confirmed group differences in neuropsychological functioning, and the classification ability of specific tests. METHODS: Fifty-one participants with postmortem diagnoses of AD (n = 34) and AD plus LBD (n = 17) were drawn from the Predictors Study. One-way analyses of variance (ANOVAs) and χ2 analyses examined group differences in neuropsychological performance. Binary logistic regressions examined predictive utility of specific tests for pathological diagnosis. RESULTS: Individuals with AD had better visuoconstruction (P = .006), phonemic fluency (P = .08), and processing speed than AD plus LBD (P = .013). No differences were found in memory, naming, semantic fluency, or set-switching. Processing speed and visuoconstruction predicted pathologic group (P = .03). DISCUSSION: Processing speed and visuoconstruction predicted postmortem diagnosis of AD versus AD plus LBD. Current results offer guidance in the selection and interpretation of neuropsychological tests to be used in the differential diagnosis of early dementia.
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Doença de Alzheimer/diagnóstico , Doença por Corpos de Lewy/diagnóstico , Testes Neuropsicológicos , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Clinicians and researchers commonly use global cognitive assessments to screen for impairment. Currently there are no published studies directly comparing the sensitivity and specificity of the Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 in PD. The objective of this study was to identify the relative sensitivity and specificity of the Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 in PD. METHODS: The Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 were administered to training and validation cohorts. Cutoff scores were determined within the training cohort (n = 85) to optimize sensitivity and specificity for cognitive impairment and were applied to an independent validation cohort (n = 521). RESULTS: The Montreal Cognitive Assessment was consistently sensitive across training and validation cohorts (90.0% and 80.3%, respectively), whereas the Mattis Dementia Rating Scale-2 was not (87.5% and 60.3%, respectively). In individual domains, the Montreal Cognitive Assessment remained sensitive to memory and visuospatial impairments (91.9% and 87.8%, respectively), whereas the Mattis Dementia Rating Scale-2 was sensitive to executive impairments (86.2%). CONCLUSION: The Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 demonstrated individual strengths. Future work should focus on developing domain-specific cognitive screening tools for PD. © 2018 International Parkinson and Movement Disorder Society.
Assuntos
Transtornos Cognitivos/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Testes de Estado Mental e Demência , Doença de Parkinson/fisiopatologia , Idoso , Cognição/fisiologia , Transtornos Cognitivos/diagnóstico , Disfunção Cognitiva/diagnóstico , Demência/diagnóstico , Demência/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/diagnóstico , Sensibilidade e EspecificidadeRESUMO
The apolipoprotein E (APOE) ε4 allele is the major genetic risk factor for Alzheimer's disease (AD). Multiple regulatory elements, spanning the extended TOMM40-APOE-APOC2 region, regulate gene expression at this locus. Regulatory element DNA methylation changes occur under different environmental conditions, such as disease. Our group and others have described an APOE CpG island as hypomethylated in AD, compared to cognitively normal controls. However, little is known about methylation of the larger TOMM40-APOE-APOC2 region. The hypothesis of this investigation was that regulatory element methylation levels of the larger TOMM40-APOE-APOC2 region are associated with AD. The aim was to determine whether DNA methylation of the TOMM40-APOE-APOC2 region differs in AD compared to cognitively normal controls in post-mortem brain and peripheral blood. DNA was extracted from human brain (n = 12) and peripheral blood (n = 67). A methylation array was used for this analysis. Percent methylation within the TOMM40-APOE-APOC2 region was evaluated for differences according to tissue type, disease state, AD-related biomarkers, and gene expression. Results from this exploratory analysis suggest that regulatory element methylation levels within the larger TOMM40-APOE-APOC2 gene region correlate with AD-related biomarkers and TOMM40 or APOE gene expression in AD.
Assuntos
Doença de Alzheimer/genética , Apolipoproteína C-II/genética , Apolipoproteínas E/genética , Metilação de DNA , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas de Membrana Transportadoras/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Biomarcadores , Biópsia , Estudos de Casos e Controles , Cerebelo/metabolismo , Cerebelo/patologia , Ilhas de CpG , Feminino , Expressão Gênica , Loci Gênicos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Especificidade de Órgãos/genética , Regiões Promotoras GenéticasRESUMO
OBJECTIVE: Dementia with Lewy bodies (DLB) is frequently misdiagnosed for Alzheimer dementia (AD), especially in its earlier stages. We characterized color vision impairment (CVI) in patients with DLB versus patients with AD to determine its usefulness in improving accuracy of early diagnosis. METHODS: We retrospectively reviewed charts of patients with AD, DLB, and patients with mild cognitive impairment suspected to be in the prodromal phase of DLB (pro-DLB) or prodromal phase of AD (pro-AD). All patients underwent an online 15-hue color vision arrangement test. RESULTS: Fifty-two patients were included in this study with a median age of 77 years, of which 44% were female. No significant differences in gender, age, or Montreal Cognitive Assessment existed among patients with AD (n = 15), pro-AD (n = 5), pro-DLB (n = 8), and DLB (n = 24). Of the 52 patients, 4 (2 AD, 1 DLB, and 1 pro-AD) had CVI history from a young age and were excluded from final analyses. New-onset CVI prevalence differed significantly based on diagnosis: patients with pro-AD (20%), patients with AD (15%), patients with pro-DLB (38%), and patients with DLB (78%, P < .001). In a stepwise multivariate logistic regression analysis to determine factors associated with CVI, "diagnosis type" as a binary variable (DLB or pro-DLB vs AD or pro-AD) was the only variable retained in the model (odds ratio = 9.8 [95% CI: 2.3-42.1], P < .001). CONCLUSIONS: Color vision impairment in patients with DLB showed a prevalence similar to the core features of DLB (â¼80%) and can be supportive to a diagnosis of DLB versus AD. Pending prospective confirmation of our findings, simple online color vision testing could be incorporated into multivariate diagnostic tools to possibly improve accuracy of early diagnosis of DLB.