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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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Enfermedad de Alzheimer , Enfermedad por Cuerpos de Lewy , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad por Cuerpos de Lewy/diagnóstico , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
Synaptic loss is the structural basis for memory impairment in Alzheimer's disease (AD). While the underlying pathological mechanism remains elusive, it is known that misfolded proteins accumulate as ß-amyloid (Aß) plaques and hyperphosphorylated Tau tangles decades before the onset of clinical disease. The loss of Pin1 facilitates the formation of these misfolded proteins in AD. Pin1 protein controls cell-cycle progression and determines the fate of proteins by the ubiquitin proteasome system. The activity of the ubiquitin proteasome system directly affects the functional and structural plasticity of the synapse. We localized Pin1 to dendritic rafts and postsynaptic density (PSD) and found the pathological loss of Pin1 within the synapses of AD brain cortical tissues. The loss of Pin1 activity may alter the ubiquitin-regulated modification of PSD proteins and decrease levels of Shank protein, resulting in aberrant synaptic structure. The loss of Pin1 activity, induced by oxidative stress, may also render neurons more susceptible to the toxicity of oligomers of Aß and to excitation, thereby inhibiting NMDA receptor-mediated synaptic plasticity and exacerbating NMDA receptor-mediated synaptic degeneration. These results suggest that loss of Pin1 activity could lead to the loss of synaptic plasticity in the development of AD.
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Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Plasticidad Neuronal , Densidad Postsináptica/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/patología , Células Cultivadas , Espinas Dendríticas/metabolismo , Espinas Dendríticas/patología , Homólogo 4 de la Proteína Discs Large/metabolismo , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Proteínas del Tejido Nervioso/metabolismo , Fosforilación , Densidad Postsináptica/patología , Receptores de N-Metil-D-Aspartato/metabolismo , Ubiquitina/metabolismo , Proteínas tau/metabolismoRESUMEN
As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article titled "Time to Redefine PD? Introductory Statement of the MDS Task Force on the Definition of Parkinson's Disease." In particular, we suggest that the 1-year rule distinguishing Parkinson's disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice and clinical and basic science research and when helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, "PD (dementia with Lewy bodies subtype)," will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development. We present arguments supporting our contentions. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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Demencia , Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Comités Consultivos , Humanos , FenotipoRESUMEN
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
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Enfermedad de Alzheimer/genética , Demencia Frontotemporal/genética , Variación Genética , Proteínas tau/genética , Anciano , Enfermedad de Alzheimer/epidemiología , Demencia Frontotemporal/epidemiología , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Persona de Mediana Edad , RiesgoRESUMEN
Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.
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Demencia Frontotemporal/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Proteínas/genética , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Alelos , Proteína C9orf72 , Estudios de Cohortes , Expansión de las Repeticiones de ADN , Proteínas de Unión al ADN/metabolismo , Femenino , Demencia Frontotemporal/complicaciones , Demencia Frontotemporal/metabolismo , Predisposición Genética a la Enfermedad , Genotipo , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Modelos Genéticos , Enfermedad de la Neurona Motora/complicaciones , Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/metabolismo , Polimorfismo de Nucleótido SimpleRESUMEN
Objective: To determine the frequency with which suspected pathogenic factors, including metals and metabolites that might contribute to Alzheimer's disease (AD), may be found in patients with cognitive impairment through commonly available blood tests. Methods: A variety of serum studies, including metals, ammonia, homocysteine, vitamin B12, folate, thyroid tests, metabolic products, and inflammatory markers, were measured in two cohorts: one meeting mild cognitive impairment (MCI) criteria and the other meeting mild-to-moderate dementia (DE) criteria. Medications these patients received were reviewed. Results: Metal abnormalities were detected in over half the subjects, including evidence of mercury, lead, and arsenic elevation as well as instances of excessive essential metals, iron (Fe), and copper. Some metal aberration was detected in 64% of the DE group and 66% of the MCI group. Females were more likely to have elevated copper, consistent with hormonal effects on copper excretion. Homocysteinemia was the most common abnormality, detected in 71% with DE and 67% with MCI, while methylmalonic acid was not elevated. Slight hyperammonemia was moderately common (38%) suggesting a hepatic factor in this subset. Findings of moderate insulin resistance were present in nearly half (44% DE, 52% MCI). Sixty of 65 (92%) had at least one abnormal biomarker and 60% had two or more. The most common drug taken by the total cohort was proton pump inhibitors at 22% DE and 38% MCI. Conclusions: This study suggests that both toxic metals and excessive vital metals such as copper and iron, as well as common metabolic and hepatic factors are detectable at both stages of MCI and DE. There appears to be a multiplicity of provocative factors leading to DE. Individualized interventions based on these parameters may be a means to reduce cognitive decline leading to DE. A more comprehensive prospective study of these environmental and metabolic factors with corrective early interventions appears warranted.
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Biomarcadores , Disfunción Cognitiva , Demencia , Humanos , Femenino , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/metabolismo , Masculino , Anciano , Biomarcadores/sangre , Demencia/sangre , Demencia/diagnóstico , Anciano de 80 o más Años , Persona de Mediana Edad , Homocisteína/sangre , Metales/sangre , Metales/metabolismo , Vitamina B 12/sangreRESUMEN
BACKGROUND AND OBJECTIVES: The clinical diagnosis of dementia with Lewy bodies (DLB) depends on identifying significant cognitive decline accompanied by core features of parkinsonism, visual hallucinations, cognitive fluctuations, and REM sleep behavior disorder (RBD). Hyposmia is one of the several supportive features. α-Synuclein seeding amplification assays (αSyn-SAAs) may enhance diagnostic accuracy by detecting pathologic αSyn seeds in CSF. In this study, we examine how different clinical features associate with CSF αSyn-SAA positivity in a large group of clinically diagnosed participants with DLB. METHODS: Cross-sectional and longitudinal CSF samples from the multicentered observational cohort study of the DLB Consortium and similar studies within the Parkinson's Disease Biomarker Program, contributed by academic medical centers in the United States, underwent αSyn-SAA testing. Participants included those clinically diagnosed with DLB and 2 control cohorts. Associations between core DLB features and olfaction with αSyn-SAA positivity were evaluated using logistic regression. RESULTS: CSF samples from 191 participants diagnosed with DLB (mean age 69.9 ± 6.8, 15% female), 50 age-matched and sex-matched clinical control participants, and 49 younger analytical control participants were analyzed. Seventy-two percent (137/191) of participants with DLB had positive αSyn-SAAs vs 4% of the control groups. Among participants with DLB, those who were αSyn-SAA-positive had lower Montreal Cognitive Assessment scores (18.8 ± 5.7 vs 21.2 ± 5.2, p = 0.01), had worse parkinsonism on the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (33.8 ± 15.1 vs 25.6 ± 16.4, p = 0.001), were more likely to report RBD (114/133 [86%] vs 33/53 [62%], p < 0.0001), and had worse hyposmia on the University of Pennsylvania Smell Identification Test (UPSIT) (94/105 [90%] below 15th percentile vs 14/44 [32%], p < 0.0001). UPSIT percentile had the highest area under the curve (0.87, 95% CI 0.81-0.94) in predicting αSyn-SAA positivity and participants scoring at or below the 15th percentile of age and sex normative values had 18.3 times higher odds (95% CI 7.52-44.6) of having a positive αSyn-SAA test. Among 82 participants with longitudinal CSF samples, 81 (99%) had the same αSyn-SAA result for initial and follow-up specimens. DISCUSSION: A substantial proportion of clinically diagnosed participants with DLB had negative αSyn-SAA results. Hyposmia was the strongest clinical predictor of αSyn-SAA positivity. Hyposmia and αSyn-SAA may have utility in improving the diagnostic assessment of individuals with potential DLB. CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that CSF αSyn-SAA distinguishes patients with clinically diagnosed DLB from normal controls.
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Enfermedad por Cuerpos de Lewy , alfa-Sinucleína , Humanos , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Enfermedad por Cuerpos de Lewy/diagnóstico , Femenino , Anciano , Masculino , alfa-Sinucleína/líquido cefalorraquídeo , Persona de Mediana Edad , Estudios Transversales , Estudios Longitudinales , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Anciano de 80 o más AñosRESUMEN
Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; P= 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31-33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.
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Degeneración Nerviosa/genética , Proteínas del Tejido Nervioso/genética , Secuencias Repetitivas de Ácidos Nucleicos/genética , Adulto , Anciano , Anciano de 80 o más Años , Ataxinas , Estudios de Cohortes , Demografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Degeneración Nerviosa/patología , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
Libon et al. (2010) provided evidence for three statistically determined clusters of patients with mild cognitive impairment (MCI): amnesic (aMCI), dysexecutive (dMCI), and mixed (mxMCI). The current study further examined dysexecutive impairment in MCI using the framework of Fuster's (1997) derailed temporal gradients, that is, declining performance on executive tests over time or test epoch. Temporal gradients were operationally defined by calculating the slope of aggregate letter fluency output across 15-s epochs and accuracy indices for initial, middle, and latter triads from the Wechsler Memory Scale-Mental Control subtest (Boston Revision). For letter fluency, slope was steeper for dMCI compared to aMCI and NC groups. Between-group Mental Control analyses for triad 1 revealed worse dMCI performance than NC participants. On triad 2, dMCI scored lower than aMCI and NCs; on triad 3, mxMCI performed worse versus NCs. Within-group Mental Control analyses yielded equal performance across all triads for aMCI and NC participants. mxMCI scored lower on triad 1 compared to triads 2 and 3. dMCI participants also performed worse on triad 1 compared to triads 2 and 3, but scored higher on triad 3 versus triad 2. These data suggest impaired temporal gradients may provide a useful heuristic for understanding dysexecutive impairment in MCI.
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Trastornos del Conocimiento/fisiopatología , Función Ejecutiva/fisiología , Anciano , Anciano de 80 o más Años , Amnesia/fisiopatología , Análisis de Varianza , Análisis por Conglomerados , Trastornos del Conocimiento/clasificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estudios Retrospectivos , Aprendizaje VerbalRESUMEN
INTRODUCTION: Prior studies have focused on the clinical efficacy of combination therapy, donepezil and memantine, for patient's diagnosed with Alzheimer's disease. As a result, it has become increasingly routine for providers to prescribe both medications for all-cause neurodegenerative disorders in variable stages of disease. However, the potential adverse drug reactions while described as mild can have serious sequelae in older adults who are already managing the side effects of polypharmacy. This study looks to explore the tolerability of switching cholinesterase inhibitors to memantine monotherapy versus adding memantine as combination therapy for all-cause neurodegenerative disorders. MATERIALS & METHODS: The study is an IRB approved retrospective chart review that includes 175 patients diagnosed with neurocognitive disorders (ICD 10 F00-F03.91 and ICD10 G30-G31.84). Only side effects reported to and recorded by a neurocognitive subspecialist at Jefferson's Memory Disorder Center from 2016 to 2019 were included. RESULTS & DISCUSSION: The odds of a patient reporting side effects on combination therapy in comparison with those patients on memantine monotherapy reporting side effects were significantly greater (ORâ¯=â¯4.33, CI 95% (1.62, 11.52), pâ¯=â¯0.003). In our patient sample, more than 80% of the patients reporting side effects qualified as polypharmacy or excessive polypharmacy (Table 2). As a result, variable polypharmacy (pâ¯=â¯0.047) was statistically significant in the in a binary logistic regression model for predicting outcomes for patients on combination therapy (Table 3). Therefore, as a patient progresses to moderate-severe stages of disease, we recommend switching CI monotherapy to memantine monotherapy as opposed to adding memantine as combination therapy for those patients on more than 10 other medications to increase tolerability. Given the limitations of a smaller sample size, variables such as severity of disease, renal and liver impairment as well as medication dosing were not significant predictors (Table 3) for those reporting side effects on combination therapy.
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Inhibidores de la Colinesterasa , Memantina , Anciano , Inhibidores de la Colinesterasa/uso terapéutico , Donepezilo , Quimioterapia Combinada , Humanos , Memantina/efectos adversos , Estudios RetrospectivosRESUMEN
Neuronal synaptic functional deficits are linked to impaired learning and memory in Alzheimer's disease (AD). We recently demonstrated that O-GlcNAc, a novel cytosolic and nuclear carbohydrate post-translational modification, is enriched at neuronal synapses and positively regulates synaptic plasticity linked to learning and memory in mice. Reduced levels of O-GlcNAc have been observed in AD, suggesting a possible link to deficits in synaptic plasticity. Using lectin enrichment and mass spectrometry, we mapped several human cortical synaptic O-GlcNAc modification sites. Overlap in patterns of O-GlcNAcation between mouse and human appears to be high, as previously mapped mouse synaptic O-GlcNAc sites in Bassoon, Piccolo, and tubulin polymerization promoting protein p25 were identified in human. Novel O-GlcNAc modification sites were identified on Mek2 and RPN13/ADRM1. Mek2 is a signaling component of the Erk 1/2 pathway involved in synaptic plasticity. RPN13 is a component of the proteasomal degradation pathway. The potential interplay of phosphorylation with mapped O-GlcNAc sites, and possible implication of those sites in synaptic plasticity in normal versus AD states is discussed. iTRAQ is a powerful differential isotopic quantitative approach in proteomics. Pulsed Q dissociation (PQD) is a recently introduced fragmentation strategy that enables detection of low mass iTRAQ reporter ions in ion trap mass spectrometry. We optimized LTQ ion trap settings for PQD-based iTRAQ quantitation and demonstrated its utility in O-GlcNAc site mapping. Using iTRAQ, abnormal synaptic expression levels of several proteins previously implicated in AD pathology were observed in addition to novel changes in synaptic specific protein expression including Synapsin II.
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Acetilglucosamina/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Proteínas/metabolismo , Proteómica/métodos , Sinapsis/química , Sinapsis/metabolismo , Secuencia de Aminoácidos , Animales , Corteza Cerebral/química , Corteza Cerebral/metabolismo , Glicosilación , Humanos , Espectrometría de Masas , Ratones , Datos de Secuencia Molecular , Plasticidad Neuronal , Mapeo Peptídico , Fosforilación , Proteínas/química , Proteínas/genética , Alineación de SecuenciaRESUMEN
Using cluster analysis Libon et al. (2010) found three verbal serial list-learning profiles involving delay memory test performance in patients with mild cognitive impairment (MCI). Amnesic MCI (aMCI) patients presented with low scores on delay free recall and recognition tests; mixed MCI (mxMCI) patients scored higher on recognition compared to delay free recall tests; and dysexecutive MCI (dMCI) patients generated relatively intact scores on both delay test conditions. The aim of the current research was to further characterize memory impairment in MCI by examining forgetting/savings, interference from a competing word list, intrusion errors/perseverations, intrusion word frequency, and recognition foils in these three statistically determined MCI groups compared to normal control (NC) participants. The aMCI patients exhibited little savings, generated more highly prototypic intrusion errors, and displayed indiscriminate responding to delayed recognition foils. The mxMCI patients exhibited higher saving scores, fewer and less prototypic intrusion errors, and selectively endorsed recognition foils from the interference list. dMCI patients also selectively endorsed recognition foils from the interference list but performed similarly compared to NC participants. These data suggest the existence of distinct memory impairments in MCI and caution against the routine use of a single memory test score to operationally define MCI.
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Atención/fisiología , Trastornos del Conocimiento/complicaciones , Trastornos de la Memoria/etiología , Aprendizaje Verbal/fisiología , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Señales (Psicología) , Humanos , Trastornos de la Memoria/diagnóstico , Recuerdo Mental/fisiología , Escala del Estado Mental , Persona de Mediana Edad , Pruebas Neuropsicológicas , Reconocimiento en PsicologíaRESUMEN
The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.
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Esclerosis Amiotrófica Lateral/genética , Proteínas de Unión al ADN/genética , Mutación Missense , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Esclerosis Amiotrófica Lateral/metabolismo , Línea Celular Tumoral , Estudios de Cohortes , Análisis Mutacional de ADN , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , LinajeRESUMEN
This study examined the characteristics, activities, challenges, and perceived burden of high-risk family caregivers of persons diagnosed with Alzheimer's disease. A descriptive design was used. A convenience sample of 121 family caregivers participated in the interview. High-risk family caregivers with poor health and one medical condition were compared with low-risk family caregivers. Caregivers with low income, depressive symptoms, and high care demands are more likely to be in the high-risk group. Health care providers need to screen family caregivers for depression and monitor those with high care demands.
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Enfermedad de Alzheimer/enfermería , Cuidadores/psicología , Depresión/prevención & control , Promoción de la Salud , Evaluación en Enfermería , Estrés Psicológico/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Philadelphia , Medición de Riesgo , Factores SocioeconómicosRESUMEN
A group of 94 nondemented patients self-referred to an outpatient memory clinic for memory difficulties were studied to determine the incidence of single versus multi-domain mild cognitive impairment (MCI) using Petersen criteria. Fifty-five community dwelling normal controls (NC) participants without memory complaints also were recruited. Tests assessing executive control, naming/lexical retrieval, and declarative memory were administered. Thirty-four patients exhibited single-domain MCI, 43 patients presented with multi-domain MCI. When the entire MCI sample (n = 77) was subjected to a cluster analysis, 14 patients were classified with amnesic MCI, 21 patients with dysexecutive MCI, and 42 patients were classified into a mixed/multi-domain MCI group involving low scores on tests of letter fluency, "animal" fluency, and delayed recognition discriminability. Analyses comparing the three cluster-derived MCI groups versus a NC group confirmed the presence of memory and dysexecutive impairment for the amnesic and dysexecutive MCI groups. The mixed MCI group produced lower scores on tests of letter fluency compared with the amnesic MCI and NC groups and lower scores on tests of naming and memory compared with the NC group. In summary, multi-domain MCI is quite common. These data suggest that MCI is a highly nuanced and complex clinical entity.
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Trastornos del Conocimiento/clasificación , Trastornos del Conocimiento/fisiopatología , Pruebas Neuropsicológicas , Anciano , Anciano de 80 o más Años , Amnesia/fisiopatología , Evaluación de la Discapacidad , Función Ejecutiva/fisiología , Femenino , Evaluación Geriátrica , Humanos , Masculino , Memoria/fisiología , Persona de Mediana Edad , Solución de Problemas/fisiología , Escalas de Valoración Psiquiátrica , Encuestas y CuestionariosRESUMEN
Lewy body dementia (LBD) is a common cause of dementia but to date, little is known about caregiver burden. The Lewy Body Dementia Association (www.LBDA.org) conducted a web-based survey of 962 caregivers (mean age 56 y; 88% women). The most common initial symptoms were cognitive (48%), motor (39%), or both (13%). Caregivers expressed concerns about fear of future (77%), feeling stressed (54%), loss of social life (52%), and uncertainty about what to do next (50%). Caregivers reported moderate-to-severe burden; 80% felt the people around them did not understand their burden and 54% reported feelings of isolation with spousal caregivers reporting more burden than nonspousal caregivers. Only 29% hired in-home assistance, whereas less than 40% used respite or adult day care, geriatric case managers, or attended a support group meeting. Lack of service utilization occurred despite two-thirds of caregivers reporting medical crises requiring emergency services, psychiatric care, or law enforcement. Caregivers reported preferences for web-based information, directories of LBD expert providers, information on LBD research, and location of local support groups. These findings highlight significant unmet needs for LBD caregivers and provide targets for intervention to reduce caregiver burden. Community resources such as the Lewy Body Dementia Association may serve this end, while also providing practical information and support for caregivers.
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Cuidadores/psicología , Costo de Enfermedad , Enfermedad por Cuerpos de Lewy , Femenino , Necesidades y Demandas de Servicios de Salud , Humanos , Masculino , Persona de Mediana Edad , Apoyo SocialRESUMEN
Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson's disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features, are limited with only two drugs (cholinesterase inhibitors) currently approved by regulatory agencies for dementia in LBD. Clinical trials represent a top research priority, but there are many challenges in the development and implementation of trials in LBD. To address these issues and advance the field of clinical trials in the LBDs, the Lewy Body Dementia Association formed an Industry Advisory Council (LBDA IAC), in addition to its Research Center of Excellence program. The LBDA IAC comprises a diverse and collaborative group of experts from academic medical centers, pharmaceutical industries, and the patient advocacy foundation. The inaugural LBDA IAC meeting, held in June 2019, aimed to bring together this group, along with representatives from regulatory agencies, to address the topic of optimizing the landscape of LBD clinical trials. This review highlights the formation of the LBDA IAC, current state of LBD clinical trials, and challenges and opportunities in the field regarding trial design, study populations, diagnostic criteria, and biomarker utilization. Current gaps include a lack of standardized clinical assessment tools and evidence-based management strategies for LBD as well as difficulty and controversy in diagnosing LBD. Challenges in LBD clinical trials include the heterogeneity of LBD pathology and symptomatology, limited understanding of the trajectory of LBD cognitive and core features, absence of LBD-specific outcome measures, and lack of established standardized biologic, imaging, or genetic biomarkers that may inform study design. Demands of study participation (e.g., travel, duration, and frequency of study visits) may also pose challenges and impact trial enrollment, retention, and outcomes. There are opportunities to improve the landscape of LBD clinical trials by harmonizing clinical assessments and biomarkers across cohorts and research studies, developing and validating outcome measures in LBD, engaging the patient community to assess research needs and priorities, and incorporating biomarker and genotype profiling in study design.
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Enfermedad de Alzheimer , Enfermedad por Cuerpos de Lewy , Inhibidores de la Colinesterasa , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico , Enfermedad por Cuerpos de Lewy/tratamiento farmacológicoRESUMEN
Importance: Evidence shows that sleep dysfunction and ß-amyloid (Aß) deposition work synergistically to impair brain function in individuals with normal cognition, increasing the risk of developing dementia later in life. However, whether Aß continues to play an integral role in sleep dysfunction after the onset of cognitive decline in individuals with dementia is unclear. Objective: To determine whether Aß deposition in the brain is associated with subjective measures of sleep quality and cognition in elderly individuals with cognitive disorders. Design, Setting, and Participants: A nested survey study was conducted at the Cognitive Disorders and Comprehensive Alzheimer Disease Center of Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. Participants included patients aged 65 years and older with cognitive disorders verified by neuropsychological testing. Eligible participants were identified from a referral center-based sample of patients who underwent fluorine 18-labeled florbetaben positron emission tomography imaging at Thomas Jefferson University Hospital as part of the multicenter Imaging Dementia-Evidence for Amyloid Scanning study. Data collection and analysis occurred between November 2018 and March 2019. Main Outcomes and Measures: Sleep quality was measured via responses to sleep questionnaires, Aß deposition was measured via fluorine 18-labeled florbetaben positron emission tomography, and cognition was measured via Mini-Mental State Examination (MMSE) performance. Results: Of the 67 eligible participants, 52 (77.6%) gave informed consent to participate in the study. Of the 52 enrolled participants (mean [SD] age, 76.6 [7.4] years), 27 (51.9%) were women. Daytime sleepiness was associated with Aß deposition in the brainstem (B = 0.0063; 95% CI, 0.001 to 0.012; P = .02), but not MMSE performance (B = -0.01; 95% CI, -0.39 to 0.37; P = .96). The number of nocturnal awakenings was associated with Aß deposition in the precuneus (B = 0.11; 95% CI, 0.06 to 0.17; P < .001) and poor MMSE performance (B = -2.13; 95% CI, -3.13 to -1.13; P < .001). Mediation analysis demonstrated an indirect association between Aß deposition and poor MMSE performance that relied on nocturnal awakenings as an intermediary (B = -3.99; 95% CI, -7.88 to -0.83; P = .01). Conclusions and Relevance: Nighttime sleep disruption may mediate the association between Aß and cognitive impairment, suggesting that there is an underlying sleep-dependent mechanism that links Aß burden in the brain to cognitive decline. Further elucidation of this mechanism may improve understanding of disease processes associated with Aß accumulation.
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Péptidos beta-Amiloides/metabolismo , Trastornos del Conocimiento/metabolismo , Trastornos del Sueño-Vigilia/metabolismo , Anciano , Anciano de 80 o más Años , Cognición , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/psicología , Femenino , Humanos , Masculino , Neuroimagen , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Sueño , Trastornos del Sueño-Vigilia/complicaciones , Trastornos del Sueño-Vigilia/diagnóstico por imagen , Trastornos del Sueño-Vigilia/psicología , Somnolencia , Encuestas y CuestionariosRESUMEN
Introduction: ß-Amyloid protein (Aß) putatively plays a seminal role in synaptic loss in Alzheimer's disease (AD). While there is no consensus regarding the synaptic-relevant species of Aß, it is known that Aß oligomers (AßOs) are noticeably increased in the early stages of AD, localizing at or within the synapse. In cell and animal models, AßOs have been shown to attach to synapses and instigate synapse dysfunction and deterioration. To establish the pathological mechanism of synaptic loss in AD, it will be important to identify the synaptic targets to which AßOs attach. Methods: An unbiased approach using far western ligand blots has identified three synaptic proteins to which AßOs specifically attach. These proteins (p100, p140, and p260) were subsequently enriched by detergent extraction, ultracentrifugation, and CHT-HPLC column separation, and sequenced by LC-MS/MS. P100, p140, and p260 were identified. These levels of AßOs targets in human AD and aging frontal cortexes were analyzed by quantitative proteomics and western-blot. The polyclonal antibody to AßOs was developed and used to block the toxicity of AßOs. The data were analyzed with one-way analysis of variance. Results: AßOs binding proteins p100, p140, and p260 were identified as Na/K-ATPase, synGap, and Shank3, respectively. α3-Na/K-ATPase, synGap, and Shank3 proteins showed loss in the postsynaptic density (PSD) of human AD frontal cortex. In short term experiments, oligomers of Aß inhibited Na/K-ATPase at the synapse. Na/K-ATPase activity was restored by an antibody specific for soluble forms of Aß. α3-Na/K-ATPase protein and synaptic ß-amyloid peptides were pulled down from human AD synapses by co-immunoprecipitation. Results suggest synaptic dysfunction in early stages of AD may stem from inhibition of Na/K-ATPase activity by Aß oligomers, while later stages could hypothetically result from disrupted synapse structure involving the PSD proteins synGap and Shank3. Conclusion: We identified three AßO binding proteins as α3-Na/K-ATPase, synGap, and Shank3. Soluble Aß oligomers appear capable of attacking neurons via specific extracellular as well as intracellular synaptic proteins. Impact on these proteins hypothetically could lead to synaptic dysfunction and loss, and could serve as novel therapeutic targets for AD treatment by antibodies or other agents.
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The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator's meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics.