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INTRODUCTION: Remote screening for cognitive impairment associated with Alzheimer's disease (AD) has grown in importance with the expected rise in prevalence of AD in an aging population and with new potential treatment options. METHODS: The Telephone Interview for Cognitive Status (TICS) and new telephone adaptation of the Montreal Cognitive Assessment (T-MoCA) were administered to participants independently classified through in-person clinical evaluation as cognitively normal (CN; n = 167), mild cognitive impairment (MCI; n = 25), or dementia (n = 23). Cerebrospinal fluid AD biomarkers were measured (n = 79). RESULTS: TICS and T-MoCA were highly correlated (r = 0.787; P < 0.001): groups differed on both (CNAsunto(s)
Enfermedad de Alzheimer
, Disfunción Cognitiva
, Humanos
, Anciano
, Enfermedad de Alzheimer/epidemiología
, Péptidos beta-Amiloides
, Pruebas Neuropsicológicas
, Disfunción Cognitiva/epidemiología
, Pruebas de Estado Mental y Demencia
, Teléfono
, Cognición
, Biomarcadores
RESUMEN
INTRODUCTION: Empathy relies on fronto-cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress. METHODS: Four hundred thirty-one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non-carrier controls were enrolled. In sub-samples, we investigated empathy measured by the informant-based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51). RESULTS: Empathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p < 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p < 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy. DISCUSSION: Loss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials.
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Empatía , Demencia Frontotemporal , Humanos , Demencia Frontotemporal/diagnóstico , Pruebas Neuropsicológicas , Atrofia , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND/AIMS: Differences in cognition between frontotemporal dementia (FTD) and Alzheimer disease (AD) are well described in clinical cohorts, but have rarely been confirmed in studies with pathologic verification. For emerging therapeutics to succeed, determining underlying pathology early in the disease course is increasingly important. Neuropsychological evaluation is an important component of the diagnostic workup for AD and FTD. Patients with FTD are thought to have greater deficits in language and executive function while patients with AD are more likely to have deficits in memory. OBJECTIVES: To determine if performance on initial cognitive testing can reliably distinguish between patients with frontotemporal lobar degeneration (FTLD) and AD neuropathology. In addition, are there other factors of the neuropsychological assessment that can be used to enhance the accuracy of underlying pathology? METHODS: Using a logistic regression we retrospectively compared neurocognitive performance on initial evaluation of 106 patients with pathologically verified FTLD (pvFTLD), with 558 pathologically verified AD (pvAD) patients from the National Alzheimer's Coordinating Center using data from the Uniform Data Set (UDS) and the neuropathology data set. RESULTS: As expected, pvFTLD patients were younger, demonstrated better memory performance, and had more neuropsychiatric symptoms than pvAD patients. Other results were less predictable: pvFTLD patients performed better on one test of executive function (trail making test part B) but worse on another (digit span backward). Performance on language testing did not strongly distinguish the 2 groups. To determine what factors led to a misdiagnosis of AD in patients with FTLD, we further analyzed a small group of pvFTLD patients. These patients demonstrated older age and lower Neuropsychiatric Inventory Questionnaire counts compared with accurately diagnosed cases. CONCLUSIONS: Other than memory, numerical scores of neurocognitive performance on the UDS are of limited value in differentiating FTLD from AD at the initial visit. These results highlight the difficulty of obtaining an accurate early diagnosis of FTLD and argue for adding supplemental tests to those included in the UDS to assess cognition in FTD and AD patients.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Bases de Datos Factuales/normas , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/psicología , Pruebas Neuropsicológicas/normas , Anciano , Anciano de 80 o más Años , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is pathologically heterogeneous. With emerging therapeutics, determining underlying pathology during life is increasingly important. Neuropsychiatric symptoms are prevalent and diagnostic in bvFTD. METHODS: We assessed the neuropsychiatric profile of patients with clinically diagnosed bvFTD as a function of pathology at autopsy. Patients with a clinical diagnosis of bvFTD at the initial visit were selected from the National Alzheimer's Coordinating Center (NACC) database. Neuropsychiatric symptoms endorsed on the Neuropsychiatric Inventory Questionnaire (NPI-Q) were analyzed. RESULTS: Of 149 patients with clinically diagnosed bvFTD, pathology was primarily Alzheimer's disease (AD) in 20.5%. These patients differed from those with underlying frontotemporal lobar degeneration: patients with AD pathology (plaques and tangles) were more likely to have hallucinations, delusions, or agitation. Patients were further differentiated into tau-positive (30% of cases, including Pick's disease, FTD and parkinsonism with tau-positive or argyrophilic inclusions, and other tauopathies) or tau-negative cases (70% of cases, including bvFTD tau-negative ubiquitin-positive inclusions). These patients also differed in some of the neuropsychiatric symptoms seen. Tau-negative cases were more likely to demonstrate depression, delusions, and changes in appetite and eating. CONCLUSIONS: These preliminary findings contribute to our increasing ability to predict, using simple clinical tools, the neuropathological underpinnings of bvFTD during life.
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Demencia Frontotemporal/psicología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Apetito , Biomarcadores , Bases de Datos Factuales , Conducta Alimentaria , Femenino , Demencia Frontotemporal/metabolismo , Humanos , Estudios Longitudinales , Masculino , Trastornos Mentales/etiología , Trastornos Mentales/psicología , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Pruebas Neuropsicológicas , Placa Amiloide/patología , Factores Socioeconómicos , Encuestas y Cuestionarios , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. OBJECTIVE: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. METHODS: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. CONCLUSION: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.
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Enfermedad de Alzheimer , Tiamina , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Tiamina/análogos & derivados , Tiamina/uso terapéutico , Tiamina/administración & dosificación , Tiamina/efectos adversos , Método Doble Ciego , Masculino , Femenino , Anciano , Persona de Mediana Edad , Resultado del Tratamiento , Profármacos/efectos adversos , Profármacos/uso terapéutico , Profármacos/administración & dosificación , Profármacos/farmacocinéticaRESUMEN
Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.
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BACKGROUND: The uncompetitive NMDA antagonist, memantine (MEM), enhances prepulse inhibition of startle (PPI) across species. MEM is used to treat Alzheimer's disease (AD); conceivably, its acute impact on PPI might be used to predict a patient's sensitivity to MEM's therapeutic effects. OBJECTIVE: To begin to test this possibility, we studied MEM effects on PPI and related measures in AD patients. METHODS: 18 carefully screened individuals with AD (mean ageâ=â72.8 y; M:F=9â:â9) completed double-blind order-balanced testing with MEM (placebo versus 20âmg), assessing acoustic startle magnitude, habituation, PPI, and latency. RESULTS: Fifteen out of 18 participants exhibited reliable startle responses. MEM did not significantly impact startle magnitude or habituation. Compared to placebo responses, PPI was significantly increased after MEM (pâ<â0.04; dâ=â0.40); this comparison reached a large effect size for the 60âms interval (dâ=â0.62), where maximal MEM effects on PPI were previously detected. Prepulses reduced peak startle latency ("latency facilitation") and this effect was amplified after MEM (pâ=â0.03; dâ=â0.41; for 60âms intervals, dâ=â0.69). No effects of MEM were detected on cognition, nor were MEM effects on startle associated with cognitive or clinical measures. CONCLUSION: MEM enhances prepulse effects on startle magnitude and latency in AD; these changes in PPI and latency facilitation with MEM suggest that these measures can be used to detect an AD patient's neural sensitivity to acute MEM challenge. Studies in progress will determine whether such a "biomarker" measured at the outset on treatment can predict sensitivity to MEM's therapeutic effects.
Asunto(s)
Enfermedad de Alzheimer , Memantina , Anciano , Humanos , Estimulación Acústica , Enfermedad de Alzheimer/tratamiento farmacológico , Cognición , Memantina/farmacología , Memantina/uso terapéutico , Reflejo de Sobresalto/fisiología , Masculino , Femenino , Método Doble CiegoRESUMEN
Neuronal intranuclear inclusion disease (NIID), a neurodegenerative disease previously thought to be rare, is increasingly recognized despite heterogeneous clinical presentations. NIID is pathologically characterized by ubiquitin and p-62 positive intranuclear eosinophilic inclusions that affect multiple organ systems, including the brain, skin, and other tissues. Although the diagnosis of NIID is challenging due to phenotypic heterogeneity, a greater understanding of the clinical and imaging presentations can improve accurate and early diagnosis. Here, we present three cases of pathologically proven adult-onset NIID, all presenting with episodes of acute encephalopathy with protracted workups and lengthy time between symptom onset and diagnosis. Case 1 highlights challenges in the diagnosis of NIID when MRI does not reveal classic abnormalities and provides a striking example of hyperperfusion in the setting of acute encephalopathy, as well as unique pathology with neuronal central chromatolysis, which has not been previously described. Case 2 highlights the progression of MRI findings associated with multiple NIID-related encephalopathic episodes over an extended time period, as well as the utility of skin biopsy for antemortem diagnosis.
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BACKGROUND AND OBJECTIVE: Patients with earlier age at onset of sporadic Alzheimer disease (AD) are more likely than those with later onset to present with atypical clinical and cognitive features. We sought to determine whether this age-related clinical and cognitive heterogeneity is mediated by different topographic distributions of tau-aggregate neurofibrillary tangles (NFTs) or by variable amounts of concomitant non-AD neuropathology. METHODS: The relative distribution of NFT density in hippocampus and midfrontal neocortex was calculated, and α-synuclein, TAR DNA binding protein 43 (TDP-43), and microvascular copathologies were staged, in patients with severe AD and age at onset of 51-60 (n = 40), 61-70 (n = 41), and >70 (n = 40) years. Regression, mediation, and mixed effects models examined relationships of pathologic findings with clinical features and longitudinal cognitive decline. RESULTS: Patients with later age at onset of AD were less likely to present with nonmemory complaints (odds ratio [OR] 0.46 per decade, 95% confidence interval [CI] 0.22-0.88), psychiatric symptoms (ß = -0.66, 95% CI -1.15 to -0.17), and functional impairment (ß = -1.25, 95% CI -2.34 to -0.16). TDP-43 (OR 2.00, 95% CI 1.23-3.35) and microvascular copathology (OR 2.02, 95% CI 1.24-3.40) were more common in later onset AD, and α-synuclein copathology was not related to age at onset. NFT density in midfrontal cortex (ß = -0.51, 95% CI -0.72 to -0.31) and midfrontal/hippocampal NFT ratio (ß = -0.18, 95% CI -0.26 to -0.10) were lower in those with later age at onset. Executive function (ß = 0.48, 95% CI 0.09-0.90) and visuospatial cognitive deficits (ß = 0.97, 95% CI 0.46-1.46) were less impaired in patients with later age at onset. Mediation analyses showed that the effect of age at onset on severity of executive function deficits was mediated by midfrontal/hippocampal NFT ratio (ß = 0.21, 95% CI 0.08-0.38) and not by concomitant non-AD pathologies. Midfrontal/hippocampal NFT ratio also mediated an association between earlier age at onset and faster decline on tests of global cognition, executive function, and visuospatial abilities. DISCUSSION: Worse executive dysfunction and faster cognitive decline in people with sporadic AD with earlier rather than later age at onset is mediated by greater relative midfrontal neocortical to hippocampal NFT burden and not by concomitant non-AD neuropathology.
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Enfermedad de Alzheimer , Neocórtex , Edad de Inicio , Enfermedad de Alzheimer/patología , Autopsia , Humanos , Neocórtex/patología , Ovillos Neurofibrilares/patología , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Studies of cumulative anticholinergic drug burden on cognitive function and impairment are emerging, yet few for Hispanics/Latinos. OBJECTIVE: To examine associations between anticholinergic use and neurocognitive performance outcomes among diverse Hispanics/Latinos. METHODS: This prospective cohort study included diverse Hispanic/Latino participants, enrolled in the Study of Latinos-Investigation of Neurocognitive, from New York, Chicago, Miami, and San Diego (nâ=â6,249). Survey linear regression examined associations between anticholinergic use (measured during baseline [Visit 1] and average 7-year follow up [Visit 2]) with global cognition, episodic learning, memory, phonemic fluency, processing speed, executive functioning, and average 7-year change. RESULTS: Anticholinergic use was associated with lower cognitive global cognition (ß=â-0.21; 95% CI [-0.36; -0.05]), learning (ß=â-0.27; 95% CI [-0.47; -0.07]), memory (ß=â-0.22; 95% CI [-0.41; -0.03]), and executive functioning (ß=â-0.22; 95% CI [-0.40; -0.03]) scores, particularly among those who took anticholinergics at both visits. Anticholinergic use was associated with faster decline in global cognition, learning, and verbal fluency (ß: -0.28 [95% CI: -0.55, -0.01]; ß: -0.28 [95% CI: -0.55, -0.01]; ß: -0.25, [95% CI -0.47, -0.04], respectively). Sex modified associations between anticholinergic use with global cognition, learning, and executive functioning (F3â=â3.59, F3â=â2.84, F3â=â3.88, respectively). CONCLUSION: Anticholinergic use was associated with lower neurocognitive performance, especially among those who used anticholinergics at both visits, among a study population of diverse Hispanics/Latinos. Findings will support evidence-based decisions regarding anticholinergic prescriptions and efforts to minimize cognitive impact.
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Envejecimiento , Hispánicos o Latinos , Envejecimiento/psicología , Antagonistas Colinérgicos/efectos adversos , Cognición , Humanos , Pruebas Neuropsicológicas , Estudios ProspectivosRESUMEN
Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.
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Demencia Frontotemporal , Enfermedad de Pick , Estudios Transversales , Demencia Frontotemporal/diagnóstico , Humanos , Filamentos Intermedios , Proteínas de Neurofilamentos/genética , SíndromeRESUMEN
OBJECTIVE: To review the different pharmacological approaches to the cognitive, functional, and behavioural manifestations of Alzheimer disease (AD). METHODS: We searched and critically analyzed the most recent relevant literature on pharmacological treatment of AD. RESULTS: The current pharmacological approach to AD treatment is based on vascular prevention and symptomatic therapy with cholinesterase inhibitors (ChEIs) and memantine, an N-methyl-d-aspartic acid antagonist. Clinical trials of 6- to 12-month duration have shown statistically significant benefits with ChEIs and memantine on cognitive, global, functional, and behavioural outcome measures. In general, these benefits are modest. However, they are dose-dependent and reproducible across studies. Most importantly, these benefits are symptomatic as they do not alter disease course. According to the third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, these agents are considered standard treatment options in AD. We will discuss practical issues related to current pharmacological management, such as setting realistic expectations, management of side effects, switching ChEIs, and the decision to discontinue treatment. The results of clinical trials studying potentially disease-modifying approaches in AD will also be reviewed. Unfortunately, although there remains much promise and enthusiasm, none of these agents has shown consistent benefits, and none are available for use in clinical practice. CONCLUSION: Pharmacological options are presently available for the symptomatic treatment of AD. These treatments provide mild but sustained benefits. Before disease-modifying approaches become available, optimizing the use of the available treatment options is crucial.
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Enfermedad de Alzheimer/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Inhibidores de la Colinesterasa/uso terapéutico , Progresión de la Enfermedad , Donepezilo , Galantamina/uso terapéutico , Humanos , Indanos/uso terapéutico , Memantina/uso terapéutico , Pruebas Neuropsicológicas , Piperidinas/uso terapéuticoRESUMEN
OBJECTIVE: To identify predictors of Alzheimer's disease (AD) versus frontotemporal lobar degeneration pathology in primary progressive aphasia (PPA), and determine whether the AD pathology is atypically distributed to fit the aphasic phenotype. METHODS: Neuropsychological and neuropathological analyses of 23 consecutive PPA autopsies. All had qualitative determination of neurofibrillary tangle (NFT) density. Additional quantitation was done in four of the PPA/AD cases and four AD cases with the typical amnestic dementia of the Alzheimer type. RESULTS: The sample contained mostly logopenic, agrammatic, and mixed forms of PPA. All six agrammatics had frontotemporal lobar degeneration (five of six with tauopathy). Seven of the 11 logopenics had AD. In logopenics, lower memory scores increased the probability of AD, but there were exceptions. The PPA/AD group showed predominance of entorhinal NFT typical of the amnestic dementia of the Alzheimer type. In the small subgroup examined quantitatively, neocortical NFTs were more numerous in the left hemisphere of PPA/AD. However, the asymmetry was low and inconsistent. Neuritic plaques did not display consistent asymmetry. Apolipoprotein E4, a major risk factor for typical AD, did not predict AD pathology in PPA. INTERPRETATION: Subtyping PPA helps to predict AD versus frontotemporal lobar degeneration pathology at the group level. However, our results and the literature also indicate that no clinical predictor is completely reliable in individual patients. The inconsistent concordance of NFT distribution with the asymmetric atrophy and the nonamnestic phenotype also raises the possibility that the AD markers encountered at autopsy in PPA may not always reflect the nature of the initiating neurodegenerative process.
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Enfermedad de Alzheimer/patología , Afasia Progresiva Primaria/patología , Encéfalo/patología , Demencia/patología , Neuronas/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/fisiopatología , Afasia Progresiva Primaria/etiología , Afasia Progresiva Primaria/fisiopatología , Atrofia/etiología , Atrofia/patología , Atrofia/fisiopatología , Biomarcadores , Encéfalo/fisiopatología , Demencia/complicaciones , Demencia/fisiopatología , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Degeneración Nerviosa/etiología , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Ovillos Neurofibrilares/patología , FenotipoRESUMEN
Alzheimer's disease (AD) dementia refers to a particular onset and course of cognitive and functional decline associated with age together with a particular neuropathology. It was first described by Alois Alzheimer in 1906 about a patient whom he first encountered in 1901. Modern clinical diagnostic criteria have been developed, and criteria have also been proposed to recognize preclinical (or presymptomatic) stages of the disease with the use of biomarkers. The primary neuropathology was described by Alzheimer, and in the mid-1980s subsequently evolved into a more specific neuropathologic definition that recognizes the comorbid neuropathologies that frequently contribute to clinical dementia. Alzheimer's disease is now the most common form of neurodegenerative dementia in the United States with a disproportionate disease burden in minority populations. Deficits in the ability to encode and store new memories characterizes the initial stages of the disease. Subsequent progressive changes in cognition and behavior accompany the later stages. Changes in amyloid precursor protein (APP) cleavage and production of the APP fragment beta-amyloid (Aß) along with hyperphosphorylated tau protein aggregation coalesce to cause reduction in synaptic strength, synaptic loss, and neurodegeneration. Metabolic, vascular, and inflammatory changes, as well as comorbid pathologies are key components of the disease process. Symptomatic treatment offers a modest, clinically measurable effect in cognition, but disease-modifying therapies are desperately needed.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/terapia , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Biomarkers are being used increasingly to support the diagnosis of dementia with Lewy bodies (DLB). Novel biomarkers that increase diagnostic specificity of DLB are needed. We assessed previously known FDG-PET occipital cortex hypometabolism, and cingulate island sign biomarkers of DLB against a novel amygdala signature. METHODS: Retrospective analysis of 49 patients evaluated at one tertiary memory clinic. All had a FDG-PET brain scan performed as part of their diagnostic work up evaluating three common neurodegenerative etiologies: Alzheimer dementia (AD), Frontotemporal dementia (FTD) and DLB. A consensus diagnosis of dementia was made based on accepted clinical criteria for AD, FTD and DLB. FDG-PET regional metabolism was delineated by automatic segmentation as well as manual tracing of amygdala and posterior cingulate volumes of interest. Mean normalized values calculated for regional FDG-PET signatures of DLB: occipital cortex hypometabolism and preservation of posterior cingulate and amygdala metabolism relative to whole brain metabolism were evaluated. RESULTS: Significant overlap between DLB and AD patients (occipital, parietal, temporal and frontal hypometabolism) and between DLB and FTD (frontal hypometabolism and the posterior cingulate sign) were identified. Right amygdala (pâ¯=â¯0.028) and right posterior cingulate (pâ¯=â¯0.035) mean normalized regional metabolism levels were preserved in DLB compared to AD. Among subjects at less advanced stages of dementia (MoCA>10), relative preservation of regional metabolism was notable across both left (pâ¯=â¯0.006) and right (pâ¯=â¯0.020) amygdala. CONCLUSION: Relative preservation of amygdala metabolism could complement previously described FDG-PET findings in earlier stages of DLB.
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Enfermedad de Alzheimer/metabolismo , Amígdala del Cerebelo/metabolismo , Demencia Frontotemporal/metabolismo , Giro del Cíngulo/metabolismo , Enfermedad por Cuerpos de Lewy/metabolismo , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Amígdala del Cerebelo/diagnóstico por imagen , Femenino , Fluorodesoxiglucosa F18 , Demencia Frontotemporal/diagnóstico por imagen , Giro del Cíngulo/diagnóstico por imagen , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Radiofármacos , Estudios RetrospectivosRESUMEN
Chronic traumatic encephalopathy (CTE) is associated with pathological changes, yet detecting these changes during life has proven elusive. Positron emission tomography (PET) offers the potential for identifying such pathology. Few studies have been completed to date and their approaches and results have been diverse. It was the objective of this review to systematically examine relevant research using ligands for PET that bind to identified pathology in CTE. We focused on identification of patterns of binding and addressing gaps in knowledge of PET imaging for CTE. A comprehensive literature search was conducted. Data used were published on or before May 22, 2017. As the extant literature is limited, any peer-reviewed article assessing military, contact sports athletes, or professional fighters was considered for inclusion. The main outcomes were regional binding to brain regions identified through control comparisons or through clinical metrics (e.g., standardized uptake volume ratios). A total of 1207 papers were identified for review, of which six met inclusion criteria. Meta-analyses were planned but were deemed inappropriate given the small number of studies identified. Methodological concerns in these initial papers included small sample sizes, lack of a control comparison, use of nonstandard statistical procedures to quantify data, and interpretation of potentially off-target binding areas. Across studies, the hippocampi, amygdalae, and midbrain had reasonably consistent increased uptake. Evidence for increased uptake in cortical regions was less consistent. The evidence suggests that the field of PET imaging in those at risk for CTE remains nascent. As the field evolves to include more stringent studies, ligands for PET may prove an important tool in identifying CTE in vivo.
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Neuropatías Amiloides/diagnóstico por imagen , Péptidos beta-Amiloides/metabolismo , Encefalopatía Traumática Crónica/diagnóstico por imagen , Inflamación/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Tauopatías/diagnóstico por imagen , Proteínas tau/metabolismo , Encéfalo/diagnóstico por imagen , Encefalopatía Traumática Crónica/complicaciones , Traumatismos Craneocerebrales/diagnóstico por imagen , Medicina Basada en la Evidencia , Humanos , Inflamación/etiologíaRESUMEN
The Montreal Cognitive Assessment (MoCA) has become widely used as a brief test of cognitive function in patients with neurological disease. More convenient application of the MoCA might increase its use and enhance its utility. An electronic version of the MoCA has recently been developed. To establish validity of the electronic version (eMoCA), discrepancy scores, concordance correlation coefficients (CCC), and root mean squared differences (RMSD) were calculated between each administration method in a sample of 43 new adult patients presenting with primary memory complaints. The CCC was 0.84 and the RMSD was 2.27, with 76% of the sample having a difference score within 2 points. Overall, this study establishes adequate convergent validity between the MoCA and eMoCA among an adult population presenting with memory concerns.
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Diagnóstico por Computador , Trastornos de la Memoria/diagnóstico , Pruebas de Estado Mental y Demencia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
This article critically considers current diagnostic criteria for dementia and reports recommendations approved by at least 80% of experts attending the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD3). There was consensus that many of the features proposed as essential to a diagnosis of dementia in the 1980s no longer are relevant (for example, the requirements for memory impairment, electroencephalogram and cerebrospinal fluid studies, age-specific exclusions). In addition, other syndromes such as frontotemporal dementia have been recognized and need to inform new dementia criteria. It is also recognized that a diagnosis of depression need not exclude a dementia diagnosis. Other proposals, such as neuropathology should be considered as additional evidence and not as a gold standard or that some people with dementia have prolonged plateaus so that progressive decline need not be a criterion for Alzheimer's disease (AD), were more controversial and did not receive similar support. Given the evidence of the last three decades, there is merit in reconsidering the criteria by which dementia and AD are diagnosed.
RESUMEN
BACKGROUND: Patients with frontotemporal dementia (FTD) typically have initial deficits in language or changes in personality, while the defining characteristic of Alzheimer's disease (AD) is memory impairment. Neuropsychological findings in the two diseases tend to differ, but can be confounded by verbal impairment in FTD impacting performance on memory tests in these patients. METHODS: Twenty-seven patients with FTD and 102 patients with AD underwent a neuropsychological assessment before diagnosis. By utilizing analogous versions of a verbal and nonverbal memory test, we demonstrated differences in these two modalities between AD and FTD. DISCUSSION: Better differentiation between AD and FTD is found in a nonverbal memory test, possibly because it eliminates the confounding variable of language deficits found in patients with FTD. These results highlight the importance of nonverbal learning tests with multiple learning trials in diagnostic testing.