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Rare and common GBA variants are risk factors for both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (ß: -0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0-1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease-risk associations of GBA in PD, PD dementia, and DLB.
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Enfermedad de Alzheimer , Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Humanos , Enfermedad por Cuerpos de Lewy/patología , Enfermedad de Parkinson/patología , Enfermedad de Alzheimer/patología , Sustancia Negra/patología , Ovillos Neurofibrilares/patologíaRESUMEN
BACKGROUND: Mixed pathology is common at autopsy for a number of age-associated neurodegenerative disorders; however, the frequency of comorbid pathologies in multiple system atrophy (MSA) and their clinical correlations are poorly understood. OBJECTIVE: We determined the frequency of comorbid pathologic processes in autopsy-confirmed MSA and assessed their clinical correlates. METHODS: This study included 160 neuropathologically established MSA from the Mayo Clinic brain bank. Clinical information, including age at onset or death, clinical subtype, initial symptoms, antemortem clinical diagnosis, and cognitive dysfunction was collected. We assessed comorbid pathologies including Alzheimer's disease neuropathologic change, Lewy-related pathology, argyrophilic grain disease, age-related τ astrogliopathy, transactive DNA-binding protein 43 pathology, cerebral amyloid angiopathy, and cerebrovascular small vessel disease and examined their clinical impact. RESULTS: The majority of MSA patients (62%) had no significant comorbid pathologies. There was a positive correlation between age at onset or death with the number of comorbid pathologies; however, even in the highest quartile group (average age at death 78 ± 6 years), the average number of comorbid pathologies was <2. Logistic regression analysis revealed that none of the assessed variables, including sex, age at onset, and the presence or absence of each comorbid pathology, were significantly associated with cognitive dysfunction. CONCLUSIONS: The majority of MSA patients do not have comorbid pathologies, even in advanced age, indicating that MSA is unique among neurodegenerative disorders in this regard. There was minimal clinical impact of comorbid pathologies in MSA. These findings warrant focusing on α-synuclein for the treatment strategy for MSA. © 2023 International Parkinson and Movement Disorder Society.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Atrofia de Múltiples Sistemas , Humanos , Anciano , Anciano de 80 o más Años , Atrofia de Múltiples Sistemas/complicaciones , Atrofia de Múltiples Sistemas/epidemiología , Atrofia de Múltiples Sistemas/diagnóstico , Enfermedad de Alzheimer/metabolismo , Encéfalo/patología , Comorbilidad , Disfunción Cognitiva/complicacionesRESUMEN
BACKGROUND: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2. OBJECTIVES: Our goal was to investigate the effects of genetic variants on risk and time to LID. METHODS: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID. RESULTS: We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HRfourth_quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147). CONCLUSIONS: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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PURPOSE: The aim of this study was to assess whether cancer occurs with increased frequency in multiple system atrophy (MSA). The pathological hallmark of MSA is glial cytoplasmic inclusions containing aggregated α-synuclein, and the related protein γ-synuclein correlates with invasive cancer. We investigated whether these two disorders are associated clinically. METHODS: Medical records of 320 patients with pathologically confirmed MSA seen between 1998 and 2022 were reviewed. After excluding those with insufficient medical histories, the remaining 269 and an equal number of controls matched for age and sex were queried for personal and family histories of cancer recorded on standardized questionnaires and in clinical histories. Additionally, age-adjusted rates of breast cancer were compared with US population incidence data. RESULTS: Of 269 cases in each group, 37 with MSA versus 45 of controls had a personal history of cancer. Reported cases of cancer in parents were 97 versus 104 and in siblings 31 versus 44 for MSA and controls, respectively. Of 134 female cases in each group, 14 MSA versus 10 controls had a personal history of breast cancer. The age-adjusted rate of breast cancer in MSA was 0.83%, as compared with 0.67% in controls and 2.0% in the US population. All comparisons were nonsignificant. CONCLUSION: The evidence from this retrospective cohort found no significant clinical association of MSA with breast cancer or other cancers. These results do not exclude the possibility that knowledge about synuclein pathology at the molecular level in cancer may lead to future discoveries and potential therapeutic targets for MSA.
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Neoplasias de la Mama , Atrofia de Múltiples Sistemas , Humanos , Femenino , Atrofia de Múltiples Sistemas/metabolismo , Estudios Retrospectivos , alfa-Sinucleína/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , EncéfaloRESUMEN
Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson's disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10-5) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.
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Parálisis Supranuclear Progresiva/genética , Parálisis Supranuclear Progresiva/patología , Proteínas tau/genética , Anciano , Anciano de 80 o más Años , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We report two cases from the frontotemporal lobar degeneration (FTLD) spectrum with remarkably slow progression. The first case demonstrated insidious-onset behavioral symptoms and personality changes resembling behavioral variant of frontotemporal dementia, followed a benign course over 26 years, his brain autopsy revealed the diffuse form of argyrophilic grain disease. The second case presented with slowly progressive cognitive and motor deficits, reminiscent of the corticobasal syndrome, deteriorated slowly over 22 years, his brain autopsy revealed FTLD-TDP with C9ORF72 pathology. These two cases confirm the notion of slowly progressive frontotemporal lobar degeneration caused by an underlying FTLD pathology, rather than a phenocopy.
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Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Enfermedad de Pick , Encéfalo/diagnóstico por imagen , Demencia Frontotemporal/complicaciones , Degeneración Lobar Frontotemporal/complicaciones , Humanos , SíndromeRESUMEN
PURPOSE: Investigate single nucleotide variants and short tandem repeats in 39 genes related to spinocerebellar ataxia in clinical and pathologically defined cohorts of multiple system atrophy. METHODS: Exome sequencing was conducted in 28 clinical multiple system atrophy patients to identify single nucleotide variants in spinocerebellar ataxia-related genes. Novel variants were validated in two independent disease cohorts: 86 clinically diagnosed multiple system atrophy patients and 166 pathological multiple system atrophy cases. Expanded repeat alleles in spinocerebellar ataxia genes were evaluated in 36 clinically diagnosed multiple system atrophy patients, and CAG/CAA repeats in TATA-Box Binding Protein (TBP, causative of SCA17) were screened in 216 clinical and pathological multiple system atrophy patients and 346 controls. RESULTS: No known pathogenic spinocerebellar ataxia single nucleotide variants or pathogenic range expanded repeat alleles of ATXN1, ATXN2, ATXN3, CACNA1A, AXTN7, ATXN8OS, ATXN10, PPP2R2B, and TBP were detected in any clinical multiple system atrophy patients. However, four novel variants were identified in four spinocerebellar ataxia-related genes across three multiple system atrophy patients. Additionally, four multiple system atrophy patients (1.6%) and one control (0.3%) carried an intermediate length 41 TBP CAG/CAA repeat allele (OR = 4.11, P = 0.21). There was a significant association between the occurrence of a repeat length of longer alleles (> 38 repeats) and an increased risk of multiple system atrophy (OR = 1.64, P = 0.03). CONCLUSION: Occurrence of TBP CAG/CAA repeat length of longer alleles (> 38 repeats) is significantly associated with increased multiple system atrophy risk. This discovery warrants further investigation and supports a possible genetic overlap of multiple system atrophy with SCA17.
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Atrofia de Múltiples Sistemas , Ataxias Espinocerebelosas , Ataxina-10 , Humanos , Atrofia de Múltiples Sistemas/genética , Mutación , Ataxias Espinocerebelosas/genética , Proteína de Unión a TATA-Box/genética , Expansión de Repetición de TrinucleótidoRESUMEN
INTRODUCTION: Cognitive impairment is common in Parkinson's Disease, but the impact of predictive factors on incidence and rate of cognitive decline is incompletely understood. We aimed to determine the effects of sex and APOE allele status on cognitive performance in patients with Parkinson's Disease (PD). MATERIAL AND METHODS: We conducted a retrospective analysis of 325 clinically diagnosed PD patients who underwent one or more cognitive screenings with a Mini-Mental Status Examination (MMSE) or Mattis Dementia Rating Scale (DRS-2). We used proportional odds regression models to estimate odds ratios for higher versus lower cognitive scores in association with age, sex, education, disease duration, and APOE allele status. RESULTS: Higher cognitive scores were independently associated with female sex on the MMSE (OR 2.43; 95% CI 1.14, 5.14) and DRS-2 total (OR 4.14; 95% CI 2.01, 8.53). APOE ε4 dose was associated with lower DRS-2 totals (OR 0.42; 95% CI 0.22, 0.81), but there was no evidence of association with MMSE. Higher education level was also associated with higher scores on the MMSE (OR 1.22; 95% CI 1.07, 1.38) and DRS-2 total (OR 1.31; 95% CI 1.15, 1.50). Disease duration was not associated with cognitive performance on any measure when adjusting for age. CONCLUSION: Male sex and APOE ε4, along with age and lower education level, were associated with poorer cognitive performance among a population of predominantly non-demented PD patients.
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Apolipoproteínas E , Disfunción Cognitiva , Enfermedad de Parkinson , Factores Sexuales , Apolipoproteínas E/genética , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/genética , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/genética , Estudios RetrospectivosRESUMEN
OBJECTIVE: We describe a three-phase implementation of the International Consortium for Health Outcomes Measurement Depression and Anxiety Standard Set in a Consultation-Liaison Psychiatry practice. METHODS: During the preintervention phase, we reviewed patient-reported outcome tools and engaged stakeholders and leadership. During phase 1, the standard set was converted into an electronic previsit intake assessment that was implemented in a physician champion's practice. Patients completed the intake on a tablet, and computer adaptive testing was used to reduce response burden. Physician-facing data display facilitated use during subsequent in-person visits. An electronic version of the follow-up standard set was used during follow-up visits. During phase 2, a second physician tested scalability and the intervention was disseminated department wide in phase 3. RESULTS: During phase 1, 186 intakes and 67 follow-up electronic patient-reported outcome sets were completed. Average patient age was 54 years, and 44% were male. On average, patients ranked the tool 4.4 out of 5 and spent 22 minutes completing the intake. Time-driven activity-based costing found the new process to be cost-effective. During phase 2, 386 patients completed electronic patient-reported outcome sets, with 315 follow-up visits. Patients ranked the tool as 4.0 out of 5 and spent 26 minutes completing the questions. During phase 3, 2166 patients completed intake electronic patient-reported outcome sets and 1249 follow-up visits. Patients ranked the tool 4.3 out of 5 and spent 26 minutes on it. Scores and completion time did not differ greatly between phases. CONCLUSIONS: Integration of the International Consortium for Health Outcomes Measurement Depression and Anxiety Standard Set is feasible. Future research comparing International Consortium for Health Outcomes Measurement set with other approaches and in different settings is needed.
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Atención Ambulatoria/métodos , Ansiedad/diagnóstico , Computadoras de Mano , Recolección de Datos/métodos , Depresión/diagnóstico , Medición de Resultados Informados por el Paciente , Psiquiatría , Adulto , Anciano , Alcoholismo/diagnóstico , Alcoholismo/psicología , Ansiedad/psicología , Depresión/psicología , Registros Electrónicos de Salud , Estudios de Factibilidad , Femenino , Humanos , Ciencia de la Implementación , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/psicología , Cuestionario de Salud del Paciente , Fobia Social/diagnóstico , Fobia Social/psicología , Medicina Psicosomática , Mejoramiento de la Calidad , Participación de los InteresadosRESUMEN
AIM OF THE STUDY: Multiple system atrophy (MSA) and spinocerebellar ataxia (SCA) share similar symptomatology. We describe a rare occurrence of familial MSA that proved to be SCA6 upon genetic analysis. MATERIALS AND METHODS: Eighty MSA patients were enrolled in our study; blood samples were collected and genetic screening of the familial case for known SCA loci was performed. RESULTS: A 68-year-old woman presented with recurrent and severe episodes of light-headedness, imbalance, frequent falls, neck and lower back stiffness, subjective arm and leg weakness, and numbness and tingling in both feet. One year later, her condition had declined; she experienced more falls, worsening instability, again more generalised but still subjective weakness, impaired fine motor movements, slurred speech, difficulty swallowing, episodes of choking, bladder incontinence, and constipation. Clinical suspicion included parkinsonism, MSA, and SCA. The patient was enrolled in our MSA study and was found to have 22 and 12 CAG repeats in CACNA1A. The other 79 clinical MSA patients were negative for SCA6 screening. CONCLUSIONS AND CLINICAL IMPLICATIONS: While MSA and SCA may have similar presentations during early disease stages, the presence of both conditions on the list of differential diagnoses can be a diagnostic dilemma. Further analysis will aid in developing a biomarker to distinguish between the two conditions and guide proper management.
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Atrofia de Múltiples Sistemas , Ataxias Espinocerebelosas , Anciano , Ataxia , Femenino , Pruebas Genéticas , HumanosRESUMEN
BACKGROUND: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuronal loss in the extrapyramidal system with pathologic accumulation of tau in neurons and glia. The most common clinical presentation of PSP, referred to as Richardson syndrome, is that of atypical parkinsonism with vertical gaze palsy, axial rigidity, and frequent falls. Although cognitive deficits in PSP are often ascribed to subcortical dysfunction, a subset of patients has dementia with behavioral features similar to the behavioral variant of frontotemporal dementia. In this study we aimed to identify the clinical and pathological characteristics of PSP presenting with frontotemporal dementia. METHODS: In this study, we compared clinical and pathologic characteristics of 31 patients with PSP with Richardson syndrome with 15 patients with PSP with frontotemporal dementia. For pathological analysis, we used semiquantitative methods to assess neuronal and glial lesions with tau immunohistochemistry, as well image analysis of tau burden using digital microscopic methods. RESULTS: We found greater frontal and temporal neocortical neuronal tau pathology in PSP with frontotemporal dementia compared with PSP with Richardson syndrome. White matter tau pathology was also greater in PSP with frontotemporal dementia than PSP with Richardson syndrome. Genetic and demographic factors were not associated with atypical distribution of tau pathology in PSP with frontotemporal dementia. CONCLUSIONS: The results confirm the subset of cognitive-predominant PSP mimicking frontotemporal dementia in PSP. PSP with frontotemporal dementia has distinct clinical features that differ from PSP with Richardson syndrome, as well as differences in distribution and density of tau pathology. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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Encéfalo/patología , Demencia Frontotemporal/patología , Trastornos del Movimiento/patología , Parálisis Supranuclear Progresiva/patología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/fisiopatología , Trastornos Parkinsonianos/patología , Tauopatías/patología , Proteínas tau/metabolismoRESUMEN
INTRODUCTION: The corticobasal syndrome (CBS) is associated with several neuropathologic disorders, including corticobasal degeneration and Alzheimer's disease (AD). METHOD: In this report, we studied 43 AD patients with CBS (AD-CBS) and compared them with 42 AD patients with typical amnestic syndrome (AD-AS), as well as 15 cases of corticobasal degeneration and CBS pathology. RESULTS: Unlike AD-AS, AD-CBS had prominent motor problems, including limb apraxia (90%), myoclonus (81%), and gait disorders (70%). Alien limb phenomenon was reported in 26% and cortical sensory loss in 14%. Language problems were also more frequent in AD-CBS, and memory impairment was less frequent. AD-CBS had more tau pathology in perirolandic cortices but less in superior temporal cortex than AD-AS. In addition, AD-CBS had greater neuronal loss in the substantia nigra. DISCUSSION: AD-CBS is a clinicopathological subtype of AD with an atypical distribution of Alzheimer-type tau pathology. Greater neuronal loss in the substantia nigra may contribute to Parkinsonism which is not a feature of typical AD.
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Enfermedad de Alzheimer , Corteza Cerebral/patología , Enfermedades Neurodegenerativas , Anciano , Enfermedad de Alzheimer/clasificación , Enfermedad de Alzheimer/patología , Femenino , Apraxia de la Marcha/etiología , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/patología , Trastornos Parkinsonianos , Lóbulo Temporal/patología , Proteínas tauRESUMEN
Corticobasal degeneration (CBD) is a clinically heterogeneous tauopathy, which has overlapping clinicopathologic and genetic characteristics with progressive supranuclear palsy (PSP). This study aimed to elucidate whether transactive response DNA-binding protein of 43 kDa (TDP-43) pathology contributes to clinicopathologic heterogeneity of CBD. Paraffin-embedded sections of the midbrain, pons, subthalamic nucleus, and basal forebrain from 187 autopsy-confirmed CBD cases were screened with immunohistochemistry for phospho-TDP-43. In cases with TDP-43 pathology, additional brain regions (i.e., precentral, cingulate, and superior frontal gyri, hippocampus, medulla, and cerebellum) were immunostained. Hierarchical clustering analysis was performed based on the topographical distribution and severity of TDP-43 pathology, and clinicopathologic and genetic features were compared between the clusters. TDP-43 pathology was observed in 45% of CBD cases, most frequently in midbrain tegmentum (80% of TDP-43-positive cases), followed by subthalamic nucleus (69%). TDP-43-positive CBD was divided into TDP-limited (52%) and TDP-severe (48%) by hierarchical clustering analysis. TDP-severe patients were more likely to have been diagnosed clinically as PSP compared to TDP-limited and TDP-negative patients (80 vs 32 vs 30%, P < 0.001). The presence of downward gaze palsy was the strongest factor for the antemortem diagnosis of PSP, and severe TDP-43 pathology in the midbrain tectum was strongly associated with downward gaze palsy. In addition, tau burden in the olivopontocerebellar system was significantly greater in TDP-positive than TDP-negative CBD. Genetic analyses revealed that MAPT H1/H1 genotype frequency was significantly lower in TDP-severe than in TDP-negative and TDP-limited CBD (65 vs 89 vs 91%, P < 0.001). The homozygous minor allele frequencies in GRN rs5848 and TMEM106B rs3173615 were not significantly different between the three groups. In conclusion, the present study indicates that CBD with severe TDP-43 pathology is a distinct clinicopathologic subtype of CBD, characterized by PSP-like clinical presentations, severe tau pathology in the olivopontocerebellar system, and low frequency of MAPT H1 haplotype.
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Encéfalo/metabolismo , Proteínas de Unión al ADN/metabolismo , Degeneración Nerviosa/metabolismo , Parálisis Supranuclear Progresiva/etiología , Tauopatías/complicaciones , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Degeneración Nerviosa/patología , Parálisis Supranuclear Progresiva/metabolismo , Parálisis Supranuclear Progresiva/patología , Tauopatías/metabolismo , Tauopatías/patología , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes has been associated with the unique neuropathology of MSA. We hypothesized that apolipoprotein E, which is associated with neurodegeneration, may also play a role in the pathogenesis of MSA. OBJECTIVE: This study evaluated genetic associations of Apolipoprotein E alleles with risk of MSA and α-synuclein pathology, and also examined whether apolipoprotein E isoforms differentially affect α-synuclein uptake in a oligodendrocyte cell. METHODS: One hundred sixty-eight pathologically confirmed MSA patients, 89 clinically diagnosed MSA patients, and 1,277 control subjects were genotyped for Apolipoprotein E. Human oligodendrocyte cell lines were incubated with α-synuclein and recombinant human apolipoprotein E, with internalized α-synuclein imaged by confocal microscopy and cells analyzed by flow cytometry. RESULTS: No significant association with risk of MSA or was observed for either Apolipoprotein E É2 or É4. α-Synuclein burden was also not associated with Apolipoprotein E alleles in the pathologically confirmed patients. Interestingly, in our cell assays, apolipoprotein E É4 significantly reduced α-synuclein uptake in the oligodendrocytic cell line. CONCLUSIONS: Despite differential effects of apolipoprotein E isoforms on α-synuclein uptake in a human oligodendrocytic cell, we did not observe a significant association at the Apolipoprotein E locus with risk of MSA or α-synuclein pathology. © 2018 International Parkinson and Movement Disorder Society.
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Apolipoproteínas E/genética , Atrofia de Múltiples Sistemas/genética , alfa-Sinucleína/metabolismo , Anciano , Astrocitos/metabolismo , Línea Celular Transformada , Femenino , Pruebas Genéticas , Genotipo , Humanos , MasculinoRESUMEN
BACKGROUND: Palliative care has been increasingly recognized as an important part of cancer care but remains underutilized in patients with solid cancers. There is a current gap in knowledge regarding why palliative care is underutilized nationwide. OBJECTIVE: To identify the factors associated with palliative care use among deceased patients with solid cancer tumors. METHODS: Using the 2016 National Cancer Data Base, we identified deceased patients (2004-2013) with breast, colon, lung, melanoma, and prostate cancer. Data were described as percentages. Associations between palliative care use and patient, facility, and geographic characteristics were evaluated through multivariate logistic regression. RESULTS: A total of 1 840 111 patients were analyzed; 9.6% received palliative care. Palliative care use was higher in the following patient groups: survival >24 months (17% vs 2%), male (54% vs 46%), higher Charlson-Deyo comorbidity score (16% vs 8%), treatment at designated cancer programs (74% vs 71%), lung cancer (76% vs 28%), higher grade cancer (53% vs 24%), and stage IV cancer (59% vs 13%). Patients who lived in communities with a greater percentage of high school degrees had higher odds of receiving palliative care; Central and Pacific regions of the United States had lower odds of palliative care use than the East Coast. Patients with colon, melanoma, or prostate cancer had lower odds of palliative care than patients with breast cancer, whereas those with lung cancer had higher odds. CONCLUSIONS: Palliative care use in solid cancer tumors is variable, with a preference for patients with lung cancer, younger age, known insurance status, and higher educational level.
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Neoplasias/terapia , Cuidados Paliativos/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estados UnidosRESUMEN
INTRODUCTION: We sought to assess the individual and combined contribution of limbic and neocortical α-synuclein, tau, and amyloid ß (Aß) to duration of illness in dementia with Lewy bodies (DLB). METHODS: Quantitative digital pathology of limbic and neocortical α-synuclein, tau, and Aß was assessed in 49 patients with clinically probable DLB. Regression modeling examined the unique and shared contribution of each pathology to the variance of illness duration. RESULTS: Patients with diffuse Lewy body disease had more severe pathology of each type and a shorter duration of illness than individuals with transitional Lewy body disease. The three pathologies accounted for 25% of the total variance of duration of illness, with 19% accounted for by α-synuclein alone or in combination with tau and Aß. When the diffuse Lewy body disease group was examined separately, α-synuclein deposition significantly exceeded that of tau and Aß. In this model, 20% of 24% total variance in the model for duration of illness was accounted for independently by α-synuclein. DISCUSSION: In DLB, α-synuclein is an important predictor of disease duration, both independently and synergistically with tau and Aß.
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Péptidos beta-Amiloides/metabolismo , Enfermedad por Cuerpos de Lewy/metabolismo , Sistema Límbico/metabolismo , Neocórtex/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/patología , Sistema Límbico/patología , Masculino , Neocórtex/patología , Estudios Prospectivos , Factores de TiempoRESUMEN
AIM OF THE STUDY: To report a family with a novel TRIO gene mutation associated with phenotype of cerebellar ataxia. MATERIALS AND METHODS: Seven family members of Caribbean descent were recruited through our ataxia research protocol; of the family members, the mother and all 3 children were found to be affected with severe young-onset and rapidly progressive truncal and appendicular ataxia leading to early disability. Array comparative genomic hybridization, mitochondrial DNA analysis, and whole-exome sequencing were performed on 3 of the family members (mother and 2 daughters). RESULTS: While the maternal grandmother, great uncle and great aunt were unaffected, the mother and 3 children displayed cognitive dysfunction, severe ataxia, spasticity, and speech disturbances. Age of onset ranged between 3 and 17 years, with average current disease duration of 21 years. Whole-exome sequencing showed a variant p.A1214V in exon 22 of the TRIO gene in 3 of the family members. Array comparative genomic hybridization and mitochondrial DNA analysis were normal. The same variant was later discovered in all but one family member. CONCLUSIONS AND CLINICAL IMPLICATIONS: The TRIO p.A1214V variant is associated with cerebellar ataxia in the studied family; it was present in all affected and unaffected family members. Phenotype is severe and broad. Anticipation seems to be present (based on 2 affected generations). It is warranted to screen additional familial early-onset and rapidly progressive ataxia cases for this genotype. TRIO gene mutations may well represent a novel spinocerebellar ataxia subtype.
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Ataxia Cerebelosa , Adolescente , Niño , Preescolar , Hibridación Genómica Comparativa , Humanos , Mutación , Linaje , FenotipoRESUMEN
BACKGROUND: The objectives of this study were to elucidate any potential association between α-synuclein pathology and cognitive impairment and to determine the profile of cognitive impairment in multiple system atrophy (MSA) patients. To do this, we analyzed the clinical and pathologic features in autopsy-confirmed MSA patients. METHODS: We retrospectively reviewed medical records, including neuropsychological test data, in 102 patients with autopsy-confirmed MSA in the Mayo Clinic brain bank. The burden of glial cytoplasmic inclusions and neuronal cytoplasmic inclusions were semiquantitatively scored in the limbic regions and middle frontal gyrus. We also assessed concurrent pathologies potentially causing dementia including Alzheimer's disease, hippocampal sclerosis, and cerebrovascular pathology. RESULTS: Of 102 patients, 33 (32%) were documented to have cognitive impairment. Those that received objective testing, deficits primarily in processing speed and attention/executive functions were identified, which suggests a frontal-subcortical pattern of dysfunction. Of these 33 patients with cognitive impairment, 8 patients had concurrent pathologies of dementia. MSA patients with cognitive impairment had a greater burden of neuronal cytoplasmic inclusions in the dentate gyrus than patients without cognitive impairment, both including and excluding patients with concurrent pathologies of dementia. CONCLUSIONS: The cognitive deficits observed in this study were more evident on neuropsychological assessment than with cognitive screens. Based on these findings, we recommend that clinicians consider more in-depth neuropsychological assessments if patients with MSA present with cognitive complaints. Although we did not identify the correlation between cognitive deficits and responsible neuroanatomical regions, a greater burden of neuronal cytoplasmic inclusions in the limbic regions was associated with cognitive impairment in MSA. © 2016 International Parkinson and Movement Disorder Society.
Asunto(s)
Disfunción Cognitiva , Demencia , alfa-Sinucleína/metabolismo , Anciano , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Disfunción Cognitiva/fisiopatología , Demencia/etiología , Demencia/metabolismo , Demencia/patología , Demencia/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/complicaciones , Atrofia de Múltiples Sistemas/metabolismo , Atrofia de Múltiples Sistemas/patología , Atrofia de Múltiples Sistemas/fisiopatología , Estudios RetrospectivosRESUMEN
BACKGROUND: Cognitive impairment is one of the core features of progressive supranuclear palsy. This study aimed to clarify the profile of cognitive impairment and its underlying pathology in progressive supranuclear palsy. METHODS: We retrospectively reviewed medical records to evaluate the pattern and severity of cognitive impairment in 121 autopsy-confirmed progressive supranuclear palsy patients. A subset of 37 patients underwent neuropsychological evaluation as part of their clinical workup. The burden of progressive supranuclear palsy-related tau pathology (neurofibrillary tangles/pretangles, coiled bodies, tufted astrocytes, and threads) was semiquantitatively scored in 20 vulnerable brain regions. Concurrent pathologies potentially associated with cognitive impairment, such as Alzheimer's-type pathology, were also assessed. To evaluate possible genetic risk factors for cognitive impairment, genetic analysis for APOE and MAPT was performed. RESULTS: Ninety patients (74%) had documented cognitive impairment based on neurologic evaluation. In a subgroup with neuropsychological testing (n = 37), executive functioning was the most severely impaired cognitive domain. A global cognitive impairment index (Spearman's rho, -0.49; P = 0.005) and executive functioning were negatively correlated with total tau burden (Spearman's rho, -0.51; P = 0.003), but not correlated with the Alzheimer's-type pathology. APOE É4 carriers had more severe amyloid pathology, but total tau burden and a global cognitive impairment index did not differ from APOE É4 noncarriers. CONCLUSION: Cognitive impairment in progressive supranuclear palsy, most notably executive dysfunction, is associated with severity of progressive supranuclear palsy-related tau pathology. © 2017 International Parkinson and Movement Disorder Society.