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BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Atrofia de Múltiples Sistemas , Atrofias Olivopontocerebelosas , Degeneración Estriatonigral , Autoanticuerpos , Autopsia , Estudio de Asociación del Genoma Completo , Humanos , Atrofia de Múltiples Sistemas/genética , Atrofia de Múltiples Sistemas/patología , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
BACKGROUND: Multiple system atrophy (MSA) presents with various combinations of autonomic dysfunction, parkinsonism, and cerebellar ataxia. Although clinical diagnostic criteria have been widely used, the sensitivity and specificity are suboptimal. This study aims to provide evidence supporting the revision of the current diagnostic criteria for MSA. METHODS: Medical records of 171 patients with autopsy-confirmed MSA in the Mayo Clinic brain bank were reviewed with regard to their clinical features and diagnoses. Pathologic features, including concomitant pathologies (i.e., Alzheimer-related and Lewy-related pathologies), were also assessed. RESULTS: The cohort included 133 MSA-parkinsonian type, 36 MSA-cerebellar type, and 2 unclassified MSA patients who did not show significant motor symptoms. Twenty-three patients (13%) were not clinically diagnosed with MSA, but instead with progressive supranuclear palsy, Parkinson's disease (PD), PD with dementia (PDD), or dementia with Lewy bodies (DLB). Three patients with PDD and DLB also had concomitant Lewy body pathology. Six patients had late-onset MSA, with an age of onset greater than 75 years. Erectile dysfunction was frequent in male patients (60/63; 95%) in all age ranges. REM sleep behavior disorder (RBD) was present in 82 patients (48%) and was the initial symptom in 13 patients. Cognitive impairment was present in 60 patients (35%), but was an initial symptom in only two patients. CONCLUSIONS: Our findings support the conclusion that late-onset presentation should not exclude MSA. The findings of this large autopsy-based cohort provides valuable insights for improving clinical criteria for MSA.
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Atrofia de Múltiples Sistemas/diagnóstico , Atrofia de Múltiples Sistemas/patología , Evaluación de Síntomas/estadística & datos numéricos , Anciano , Autopsia , Bancos de Muestras Biológicas , Encéfalo/patología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Diagnóstico Diferencial , Femenino , Florida , Humanos , Masculino , Atrofia de Múltiples Sistemas/etiología , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/etiología , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/etiología , Trastorno de la Conducta del Sueño REM/diagnóstico , Trastorno de la Conducta del Sueño REM/etiología , Estudios Retrospectivos , Sensibilidad y Especificidad , Parálisis Supranuclear Progresiva/diagnóstico , Parálisis Supranuclear Progresiva/etiología , Evaluación de Síntomas/métodosRESUMEN
INTRODUCTION: Accumulation of polyglutamine (polyQ) ataxin-3 (ATXN3) contributes to the pathobiology of spinocerebellar ataxia type 3 (SCA3). Recently, we showed that polyQ ATXN3 is elevated in the plasma and cerebrospinal fluid (CSF) of SCA3 patients, and has the potential to serve as a biological marker for this disease [1]. Based on these findings, we investigated whether polyQ ATXN3 can also be detected in urine samples from SCA3 patients. METHODS: We analyzed urine samples from 30 SCA3 subjects (including one pre-symptomatic subject), 35 subjects with other forms of ataxia, and 37 healthy controls. To quantify polyQ ATXN3 protein levels, we used our previously developed immunoassay. RESULTS: PolyQ ATXN3 can be detected in the urine of SCA3 patients, but not in urine samples from healthy controls or other forms of ataxia. There was a significant statistical association between polyQ ATXN3 levels in urine samples and those in plasma. Further, the levels of polyQ ATXN3 urine associated with an earlier age of SCA3 disease onset. CONCLUSION: As clinical trials for SCA3 advance, urine polyQ ATXN3 protein has potential to be a useful, non-invasive and inexpensive biomarker for SCA3.
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Ataxina-3/orina , Enfermedad de Machado-Joseph/orina , Péptidos/orina , Proteínas Represoras/orina , Adulto , Estudios de Casos y Controles , Femenino , Humanos , MasculinoRESUMEN
Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.
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Enfermedad de Machado-Joseph , Alelos , Ataxina-3/genética , Humanos , Enfermedad de Machado-Joseph/genética , Neuronas , Proteínas Represoras/genéticaRESUMEN
We present a case in which a movement disorder neurologist developed two different hyperkinetic movements due to corticospinal tract hyperexcitability, which resolved completely with surgical removal of an epidural spinal canal tumor. The first-hand description of these movements creates a unique opportunity for enhanced insight into these complex movement phenomena.
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Neoplasias Epidurales/complicaciones , Hipercinesia/etiología , Linfoma de Células B Grandes Difuso/complicaciones , Mioclonía/etiología , Espasmo/etiología , Compresión de la Médula Espinal/etiología , Descompresión Quirúrgica , Neoplasias Epidurales/diagnóstico por imagen , Neoplasias Epidurales/patología , Neoplasias Epidurales/cirugía , Humanos , Hipercinesia/fisiopatología , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/cirugía , Masculino , Persona de Mediana Edad , Mioclonía/fisiopatología , Procedimientos Neuroquirúrgicos , Reflejo Anormal , Reflejo de Sobresalto , Espasmo/fisiopatología , Compresión de la Médula Espinal/diagnóstico por imagen , Compresión de la Médula Espinal/fisiopatología , Compresión de la Médula Espinal/cirugía , Vértebras TorácicasRESUMEN
OBJECTIVE: To determine whether distinct microtubule-associated protein tau MAPT H1 subhaplotypes are associated with clinical and demographic features in Parkinson's disease. METHODS: A retrospective cohort study included 855 unrelated Caucasian patients with Parkinson's disease who were seen by Movement Disorder specialists at the Mayo Clinic Florida between 1998 and 2016. The primary outcome measures were specific demographic and clinical features of Parkinson's disease, including age at onset, disease progression, survival, motor signs, dementia, dystonia, dyskinesia, autonomic dysfunction, impulse control disorder, psychiatric features, REM sleep behavior disorder, restless legs syndrome, and Parkinson's disease subtype. Specific clinical features were measured at the initial visit and most recent visit. These outcomes were assessed for association with MAPT H1 subhaplotypes, which were defined by six haplotype tagging variants. RESULTS: Median onset age was 64 years (range: 22-94 years); 548 (64%) of patients were male. Significant associations (P < 0.0029) were observed between MAPT H1b and orthostatic hypotension (OR = 1.72, P = 0.001); between H1j and rest tremor (OR = 0.15; P < 0.001) as well as REM sleep behavior disorder (OR = 3.87, P < 0.001); between H1r and bradykinesia (OR = 0.11; P < 0.001); and between H1v and restless legs syndrome (OR = 4.02, P = 0.002). INTERPRETATION: Four MAPT H1 subhaplotypes, but not the H2 haplotype, were significantly associated with specific clinical features in Parkinson's disease. MAPT haplotypic structure may explain some of the phenotypic variability in disease. Replication of our findings will be critical to fully resolve the Parkinson's disease risk association signal at Chr17q21.
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Enfermedad de Parkinson/genética , Enfermedad de Parkinson/fisiopatología , Proteínas tau/genética , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Asociación Genética , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Many different movement disorders have similar "jerk-like" phenomenology and can be misconstrued as myoclonus. Different types of myoclonus also share similar phenomenological characteristics that can be difficult to distinguish solely based on clinical exam. However, they have distinctive physiologic characteristics that can help refine categorization of jerk-like movements. OBJECTIVES: In this review, we briefly summarize the clinical, physiologic, and pathophysiologic characteristics of different types of myoclonus. The methodology and technical considerations for the electrophysiologic assessment of jerk-like movements are reviewed. A simplistic pragmatic approach for the classification of myoclonus and other jerk-like movements based on objective electrophysiologic characteristics is proposed. CONCLUSIONS: Clinical neurophysiology is an underutilized tool in the diagnosis and treatment of movement disorders. Various jerk-like movements have distinguishing physiologic characteristics, differentiated in the milliseconds range, which is beyond human capacity. We argue that the categorization of movement disorders as myoclonus can be refined based on objective physiology that can have important prognostic and therapeutic implications.
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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
OBJECTIVE: To determine whether Lewy body disease subgroups have different clinical profiles. METHODS: Participants had dementia, autopsy-confirmed transitional or diffuse Lewy body disease (TLBD or DLBD) (n = 244), or Alzheimer disease (AD) (n = 210), and were seen at least twice (mean follow-up 6.2 ± 3.8 years). TLBD and DLBD groups were partitioned based on the presence or absence of neocortical neurofibrillary tangles using Braak staging. Four Lewy body disease subgroups and AD were compared on clinical features, dementia trajectory, and onset latency of probable dementia with Lewy bodies (DLB) or a DLB syndrome defined as probable DLB or dementia with one core feature of parkinsonism or probable REM sleep behavior disorder. RESULTS: In TLBD and DLBD without neocortical tangles, diagnostic sensitivity was strong for probable DLB (87% TLBD, 96% DLBD) and the DLB syndrome (97% TLBD, 98% DLBD) with median latencies <1 year from cognitive onset, and worse baseline attention-visual processing but better memory-naming scores than AD. In DLBD with neocortical tangles, diagnostic sensitivity was 70% for probable DLB and 77% for the DLB syndrome with respective median latencies of 3.7 years and 2.7 years from cognitive onset, each associated with tangle distribution. This group had worse baseline attention-visual processing than AD, but comparable memory-naming impairment. TLBD with neocortical tangles had 48% diagnostic sensitivity for probable DLB and 52% for the DLB syndrome, with median latencies >6 years from cognitive onset, and were cognitively similar to AD. Dementia trajectory was slowest for TLBD without neocortical tangles, and fastest for DLBD with neocortical tangles. CONCLUSIONS: The phenotypic expression of DLB was associated with the distribution of α-synuclein and tau pathology.
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Enfermedad por Cuerpos de Lewy/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Edad de Inicio , Anciano , Anciano de 80 o más Años , Atención , Cognición , Progresión de la Enfermedad , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/clasificación , Enfermedad por Cuerpos de Lewy/psicología , Masculino , Memoria , Persona de Mediana Edad , Neocórtex/patología , Ovillos Neurofibrilares/patología , Desempeño Psicomotor , Sensibilidad y EspecificidadRESUMEN
Renaissance England witnessed a series of brief epidemics of a rapid and often fatal illness, the predominant feature of which was a disturbance of the autonomic nervous system. Profuse sweating was both an emblematic and ominous sign of this Sudor Anglicus. Its story is medically fascinating as well as historically noteworthy. Possible sites of pathological involvement include the hypothalamus, serotonergic neurons in the brainstem or spinal cord, autonomic ganglia, peripheral sympathetic nerves, neuroeffector junctions, or eccrine glands. Of candidate etiologic agents, a virus is most likely, given the seasonal variation, geographic clustering, and pattern of spread of the epidemics. Hantaviruses, enteroviruses, influenza, and others provide clinical comparisons, but a definitive match with known viruses has remained elusive.
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Epidemias , Hiperhidrosis , Enfermedad del Sudor , Sistema Nervioso Autónomo , Inglaterra , HumanosRESUMEN
CONTEXT: Single-minded homologue 1 (SIM1) is a transcription factor with several physiological and developmental functions. Haploinsufficiency of SIM1 is associated with early-onset obesity with or without Prader-Willi-like (PWL) features and may exhibit incomplete penetrance. CASE DESCRIPTION: Next-generation sequencing was performed for 2 male patients with obesity, including 1 man presenting with intellectual disability (ID), body mass index (BMI) of 47.4, and impulse-control disorder, and the other man with early obesity (BMI of 36); sequencing revealed a missense variant in SIM1 (c.2144G>T; p.G715V) in both individuals. Previous studies have identified several disease-associated variants that fall near the p.G715V variant within the C-terminal domain of SIM1. We examined p.G715V variant stability and activity in a doxycycline-inducible stable cell line transfected with an artificial reporter construct and either ARNT or ARNT2 as a partner protein. CONCLUSIONS: Functional testing of the p.G715V variant revealed a significant reduction in SIM1-mediated transcriptional activity. We also generated the first ab initio hybrid protein model for full-length SIM1 to show the predicted spatial relationship between p.G715V and other previously described variants in this region and identified a putative mutation hotspot within the C-terminus. Significant clinical heterogeneity has been observed in patients with SIM1 variants, particularly with regards to the PWL phenotype. In the patient with ID, a second variant of uncertain significance in CHD2 was identified that may contribute to his ID and behavioral disturbances, emphasizing the role of additional genetic modifiers.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Mutación Missense , Obesidad/genética , Proteínas Represoras/genética , Adulto , Sustitución de Aminoácidos/genética , Estudios de Asociación Genética , Ácido Glutámico/genética , Humanos , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/diagnóstico , Síndrome de Prader-Willi/complicaciones , Síndrome de Prader-Willi/genética , Valina/genéticaRESUMEN
Multiple system atrophy (MSA) is a neurodegenerative disease characterized by a cerebellar syndrome, autonomic dysfunction, and extrapyramidal signs. Extrapyramidal signs may manifest as parkinsonism as well as dystonia, which is the involuntary contraction of a muscle(s) resulting in an abnormal posture. MSA belongs to a family of diseases known as α-synucleinopathies which are associated with dream enactment reflecting REM sleep behavior disorder (RBD). In patients with MSA, dystonia or paresis may involve the laryngeal muscles resulting in vocal fold hypomobility. We identified four individuals presenting with vocal complaints and subsequently diagnosed with vocal fold "paralysis." Within one year, each patient developed neurologic symptoms and upon evaluation by a movement disorders specialist was diagnosed with probable MSA. Our findings highlight the importance of screening by otolaryngologists when patients are diagnosed with vocal fold hypomobility. Specifically, patients should be assessed for RBD by questioning others if he/she acts out their dreams. The presence of RBD raises clinical suspicion for a synucleinopathy such as MSA. Untreated patients with MSA experiencing nocturnal stridor and breathing disorders have an increased risk for sudden death. Therefore, early evaluation by a movement disorders specialist to promptly diagnose MSA may have a substantial effect on morbidity and mortality in this high-risk patient population.
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Distonía , Atrofia de Múltiples Sistemas , Parálisis de los Pliegues Vocales , Femenino , Humanos , Músculos Laríngeos , Masculino , Atrofia de Múltiples Sistemas/complicaciones , Atrofia de Múltiples Sistemas/diagnóstico , Parálisis de los Pliegues Vocales/diagnóstico , Pliegues Vocales/diagnóstico por imagenRESUMEN
OBJECTIVE: To evaluate the pattern and severity of autonomic dysfunction in autopsy-confirmed progressive supranuclear palsy (PSP) compared to α-synuclein pathology. METHODS: Autopsy-confirmed cases of 14 patients with PSP, 18 with multiple system atrophy (MSA), and 24 with Lewy body disease (LBD) with antemortem autonomic testing were reviewed retrospectively. All patients underwent comprehensive clinical evaluations by a movement disorder specialist, formal autonomic testing, and postmortem examinations at Mayo Clinic. RESULTS: The absence of orthostatic hypotension (OH) was the strongest autonomic parameter that distinguished PSP from α-synucleinopathies (0% vs 69%, p < 0.0001). Tests of adrenergic failure, which distinguish neurogenic OH, also differentiated PSP from other groups. These included the pressure recovery time (p = 0.0008), adrenergic impairment score (p = 0.001), and magnitude of change of systolic (p = 0.0002) and diastolic (p = 0.0001) blood pressures (BPs) during upright tilt. In addition, REM sleep behavior disorder was seen less frequently (p = 0.006) in PSP (33%) compared to MSA (87%) and LBD (90%). Antemortem clinical diagnostic accuracy for these phenotypically variable disorders was 57% for PSP and 83% for α-synucleinopathies. CONCLUSION: Our results suggest that the cardiovascular adrenergic system, which sustains BP during standing, is relatively unaffected, if not spared, in PSP. These findings increase our understanding of the clinical signature of PSP and have the potential to improve diagnostic accuracy in atypical parkinsonisms by distinguishing PSP from the α-synucleinopathies.
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Hipotensión Ortostática/diagnóstico , Hipotensión Ortostática/fisiopatología , Parálisis Supranuclear Progresiva/diagnóstico , Parálisis Supranuclear Progresiva/fisiopatología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Importance: The association between the microtubule-associated protein tau (MAPT) H1 haplotype and the risk of progressive supranuclear palsy (PSP) has been well documented. However, the specific H1 subhaplotypes that drive the association have not been evaluated in large studies, nor have they been studied in relation to neuropathologic severity of disease. Objective: To comprehensively evaluate the associations of MAPT haplotypes with the risk of PSP and the severity of tau pathology using a large series of neuropathologically confirmed PSP cases. Design, Setting, and Participants: A case-control study was used to investigate the associations between MAPT haplotypes and the risk of PSP, and a case series was conducted for examination of associations of MAPT haplotypes with the severity of tau pathology. All 802 neuropathologically confirmed PSP cases were obtained from a neurodegenerative disorders brain bank between January 1, 1998, and December 31, 2013, and 1312 clinical controls were obtained from the neurology department of the Mayo Clinic. Statistical analysis was performed from February 17 to December 12, 2018. Main Outcomes and Measures: Presence of PSP in case-control analysis and semiquantitative tau pathology scores for neurofibrillary tangles, neuropil threads, tufted astrocytes, and oligodendroglial coiled bodies in PSP cases. Results: For 802 patients with PSP (376 women and 426 men), the median age at death was 75 years (range, 52-98 years). For 1312 controls (701 women and 611 men), the median age at blood collection was 69 years (range, 45-92 years). After adjustment for multiple testing, known associations with risk of PSP were observed for the H2 and H1c haplotypes. Novel associations with PSP were observed for 3 H1 subhaplotypes, including H1d (odds ratio, 1.86; 95% CI, 1.43-2.42; P = 2 × 10-6), H1g (odds ratio, 3.64; 95% CI, 2.04-6.50; P = 2 × 10-6), and H1o (odds ratio, 2.60; 95% CI, 1.63-4.16; P = 2 × 10-5). Although not significant after multiple testing adjustment, 3 of these PSP risk haplotypes (H2, H1c, and H1d) were also nominally associated with measures of severity of tau pathology in PSP cases. Nominally significant associations with severity of tau pathology were also noted for the H1e and H1q haplotypes. Conclusions and Relevance: This study has identified novel associations with risk of PSP for 3 MAPT H1 subhaplotypes. In addition, potential weaker associations between several haplotypes (including several PSP risk haplotypes) and severity of tau pathology were observed. These findings expand the current understanding of the role of MAPT haplotypic variation in susceptibility to and neuropathologic severity of PSP.
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Parálisis Supranuclear Progresiva/epidemiología , Parálisis Supranuclear Progresiva/genética , Parálisis Supranuclear Progresiva/patología , Proteínas tau/genética , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Riesgo , Índice de Severidad de la Enfermedad , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Rare coding variants ABI3_rs616338-T and PLCG2_rs72824905-G were identified as risk or protective factors, respectively, for Alzheimer's disease (AD). METHODS: We tested the association of these variants with five neurodegenerative diseases in Caucasian case-control cohorts: 2742 AD, 231 progressive supranuclear palsy (PSP), 838 Parkinson's disease (PD), 306 dementia with Lewy bodies (DLB) and 150 multiple system atrophy (MSA) vs. 3351 controls; and in an African-American AD case-control cohort (181 AD, 331 controls). 1479 AD and 1491 controls were non-overlapping with a prior report. RESULTS: Using Fisher's exact test, there was significant association of both ABI3_rs616338-T (OR = 1.41, p = 0.044) and PLCG2_rs72824905-G (OR = 0.56, p = 0.008) with AD. These OR estimates were maintained in the non-overlapping replication AD-control analysis, albeit at reduced significance (ABI3_rs616338-T OR = 1.44, p = 0.12; PLCG2_rs72824905-G OR = 0.66, p = 0.19). None of the other cohorts showed significant associations that were concordant with those for AD, although the DLB cohort had suggestive findings (Fisher's test: ABI3_rs616338-T OR = 1.79, p = 0.097; PLCG2_rs72824905-G OR = 0.32, p = 0.124). PLCG2_rs72824905-G showed suggestive association with pathologically-confirmed MSA (OR = 2.39, p = 0.050) and PSP (OR = 1.97, p = 0.061), although in the opposite direction of that for AD. We assessed RNA sequencing data from 238 temporal cortex (TCX) and 224 cerebellum (CER) samples from AD, PSP and control patients and identified co-expression networks, enriched in microglial genes and immune response GO terms, and which harbor PLCG2 and/or ABI3. These networks had higher expression in AD, but not in PSP TCX, compared to controls. This expression association did not survive adjustment for brain cell type population changes. CONCLUSIONS: We validated the associations previously reported with ABI3_rs616338-T and PLCG2_rs72824905-G in a Caucasian AD case-control cohort, and observed a similar direction of effect in DLB. Conversely, PLCG2_rs72824905-G showed suggestive associations with PSP and MSA in the opposite direction. We identified microglial gene-enriched co-expression networks with significantly higher levels in AD TCX, but not in PSP, a primary tauopathy. This co-expression network association appears to be driven by microglial cell population changes in a brain region affected by AD pathology. Although these findings require replication in larger cohorts, they suggest distinct effects of the microglial genes, ABI3 and PLCG2 in neurodegenerative diseases that harbor significant vs. low/no amyloid ß pathology.
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Proteínas Adaptadoras Transductoras de Señales/genética , Mutación Missense , Enfermedades Neurodegenerativas/genética , Fosfolipasa C gamma/genética , Negro o Afroamericano/genética , Anciano , Anciano de 80 o más Años , Encéfalo/metabolismo , Femenino , Humanos , Masculino , Microglía/metabolismo , Factores de Riesgo , Población Blanca/genéticaAsunto(s)
Trastornos Neurológicos de la Marcha , Enfermedad de Parkinson , Señales (Psicología) , Marcha , Humanos , ZapatosRESUMEN
OBJECTIVE: The triggering receptor expressed on myeloid cells 2 (TREM2) p.R47H substitution (rs75932628) is a risk factor for Alzheimer disease (AD) but has not been well studied in relation to the risk of multiple system atrophy (MSA); the aim of this study was to evaluate the association between the TREM2 p.R47H variant and the risk of MSA. METHODS: A total of 168 patients with pathologically confirmed MSA, 89 patients with clinically diagnosed MSA, and 1,695 controls were included. TREM2 p.R47H was genotyped and assessed for association with MSA. Positive results in the Taqman genotyping assay were confirmed by Sanger sequencing. The primary comparison involved patients with pathologically confirmed MSA and controls due to the definitive MSA diagnosis in the pathologically confirmed series. RESULTS: We identified TREM2 p.R47H in 3 patients with pathologically confirmed MSA (1.79%), 1 patient with clinically diagnosed MSA (1.12%), and 7 controls (0.41%). Minimal AD pathology was observed for the pathologically confirmed MSA p.R47H carriers. For the primary comparison of patients with pathologically confirmed MSA and controls, risk of disease was significantly higher for p.R47H carriers (odds ratio [OR]: 4.39, p = 0.033). When supplementing the 168 pathologically confirmed patients with the 89 clinically diagnosed and examining the combined MSA series, the association with TREM2 p.R47H remained significant (OR: 3.81, p = 0.034). CONCLUSIONS: Our preliminary results suggest that the TREM2 p.R47H substitution may be a risk factor for MSA, implying a link to neuroinflammatory processes, especially microglial activation. Validation of this finding will be important, given our relatively small sample size; meta-analytic approaches will be needed to better define the role of this variant in MSA.