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1.
Mov Disord Clin Pract ; 10(8): 1217-1218, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37635770
2.
Mov Disord Clin Pract ; 10(1): 9-16, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36704075

ABSTRACT

Background: Idiopathic normal pressure hydrocephalus (iNPH) is characterized by the classic clinical triad of gait, cognitive, and urinary dysfunction, albeit incomplete in a relevant proportion of patients. The clinical findings and evolution of these symptoms have been variably defined in the literature. Objectives: To evaluate how the phenomenology has been defined, assessed, and reported, we performed a critical review of the existing literature discussing the phenomenology of iNPH. The review also identified the instrumental tests most frequently used and the evolution of clinical and radiologic findings. Methods: The review was divided into 3 sections based on gait, cognitive, and urinary dysfunction. Each section performed a literature search using the terms "idiopathic normal pressure hydrocephalus" (iNPH), with additional search terms used by each section separately. The number of articles screened, duplicates, those meeting the inclusion criteria, and the number of articles excluded were recorded. Findings were subsequently tallied and analyzed. Results: A total of 1716 articles with the aforementioned search criteria were identified by the 3 groups. A total of 81 full-text articles were reviewed after the elimination of duplicates, articles that did not discuss phenomenological findings or instrumental testing of participants with iNPH prior to surgery, and articles with fewer than 10 participants. Conclusions: "Wide-based gait" was the most common gait dysfunction identified. Cognitive testing varied significantly across articles, and ultimately a specific cognitive profile was not identified. Urodynamic testing found detrusor overactivity and "overactive bladder" as the most common symptom of urinary dysfunction.

3.
Mov Disord ; 37(10): 2110-2121, 2022 10.
Article in English | MEDLINE | ID: mdl-35997131

ABSTRACT

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.


Subject(s)
Multiple System Atrophy , Olivopontocerebellar Atrophies , Striatonigral Degeneration , Autoantibodies , Autopsy , Genome-Wide Association Study , Humans , Multiple System Atrophy/genetics , Multiple System Atrophy/pathology , Nerve Tissue Proteins/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , alpha-Synuclein/metabolism
4.
Parkinsonism Relat Disord ; 89: 155-161, 2021 08.
Article in English | MEDLINE | ID: mdl-34303202

ABSTRACT

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.


Subject(s)
Multiple System Atrophy/diagnosis , Multiple System Atrophy/pathology , Symptom Assessment/statistics & numerical data , Aged , Autopsy , Biological Specimen Banks , Brain/pathology , Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/etiology , Diagnosis, Differential , Female , Florida , Humans , Male , Multiple System Atrophy/etiology , Parkinson Disease/diagnosis , Parkinson Disease/etiology , Parkinsonian Disorders/diagnosis , Parkinsonian Disorders/etiology , REM Sleep Behavior Disorder/diagnosis , REM Sleep Behavior Disorder/etiology , Retrospective Studies , Sensitivity and Specificity , Supranuclear Palsy, Progressive/diagnosis , Supranuclear Palsy, Progressive/etiology , Symptom Assessment/methods
5.
Parkinsonism Relat Disord ; 89: 151-154, 2021 08.
Article in English | MEDLINE | ID: mdl-34303201

ABSTRACT

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.


Subject(s)
Ataxin-3/urine , Machado-Joseph Disease/urine , Peptides/urine , Repressor Proteins/urine , Adult , Case-Control Studies , Female , Humans , Male
8.
Sci Transl Med ; 12(566)2020 10 21.
Article in English | MEDLINE | ID: mdl-33087504

ABSTRACT

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.


Subject(s)
Machado-Joseph Disease , Alleles , Ataxin-3/genetics , Humans , Machado-Joseph Disease/genetics , Neurons , Repressor Proteins/genetics
9.
Ann Clin Transl Neurol ; 7(9): 1557-1563, 2020 09.
Article in English | MEDLINE | ID: mdl-32767721

ABSTRACT

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.


Subject(s)
Parkinson Disease/genetics , Parkinson Disease/physiopathology , tau Proteins/genetics , Adult , Age of Onset , Aged , Aged, 80 and over , Female , Genetic Association Studies , Haplotypes , Humans , Male , Middle Aged , Retrospective Studies
10.
Mov Disord Clin Pract ; 7(5): 489-499, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32626792

ABSTRACT

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.

11.
Neurol Neurochir Pol ; 54(4): 350-355, 2020.
Article in English | MEDLINE | ID: mdl-32687595

ABSTRACT

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.


Subject(s)
Multiple System Atrophy , Spinocerebellar Ataxias , Aged , Ataxia , Female , Genetic Testing , Humans
12.
Neurology ; 95(2): e155-e165, 2020 07 14.
Article in English | MEDLINE | ID: mdl-32561678

ABSTRACT

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.


Subject(s)
Lewy Body Disease/metabolism , alpha-Synuclein/metabolism , tau Proteins/metabolism , Age of Onset , Aged , Aged, 80 and over , Attention , Cognition , Disease Progression , Female , Humans , Lewy Body Disease/classification , Lewy Body Disease/psychology , Male , Memory , Middle Aged , Neocortex/pathology , Neurofibrillary Tangles/pathology , Psychomotor Performance , Sensitivity and Specificity
13.
Clin Auton Res ; 30(4): 317-323, 2020 08.
Article in English | MEDLINE | ID: mdl-32435874

ABSTRACT

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.


Subject(s)
Epidemics , Hyperhidrosis , Sweating Sickness , Autonomic Nervous System , England , Humans
14.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Article in English | MEDLINE | ID: mdl-31872862

ABSTRACT

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.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Mutation, Missense , Obesity/genetics , Repressor Proteins/genetics , Adult , Amino Acid Substitution/genetics , Genetic Association Studies , Glutamic Acid/genetics , Humans , Male , Middle Aged , Obesity/complications , Obesity/diagnosis , Prader-Willi Syndrome/complications , Prader-Willi Syndrome/genetics , Valine/genetics
15.
J Voice ; 34(6): 940-944, 2020 Nov.
Article in English | MEDLINE | ID: mdl-31324432

ABSTRACT

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.


Subject(s)
Dystonia , Multiple System Atrophy , Vocal Cord Paralysis , Female , Humans , Laryngeal Muscles , Male , Multiple System Atrophy/complications , Multiple System Atrophy/diagnosis , Vocal Cord Paralysis/diagnosis , Vocal Cords/diagnostic imaging
16.
Neurology ; 93(14): e1339-e1347, 2019 10 01.
Article in English | MEDLINE | ID: mdl-31484717

ABSTRACT

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.


Subject(s)
Hypotension, Orthostatic/diagnosis , Hypotension, Orthostatic/physiopathology , Supranuclear Palsy, Progressive/diagnosis , Supranuclear Palsy, Progressive/physiopathology , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Retrospective Studies
17.
Alzheimers Dement ; 15(9): 1218-1228, 2019 09.
Article in English | MEDLINE | ID: mdl-31399334

ABSTRACT

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.


Subject(s)
Alzheimer Disease , Cerebral Cortex/pathology , Neurodegenerative Diseases , Aged , Alzheimer Disease/classification , Alzheimer Disease/pathology , Female , Gait Apraxia/etiology , Humans , Male , Middle Aged , Neurodegenerative Diseases/diagnostic imaging , Neurodegenerative Diseases/pathology , Parkinsonian Disorders , Temporal Lobe/pathology , tau Proteins
18.
JAMA Neurol ; 76(6): 710-717, 2019 06 01.
Article in English | MEDLINE | ID: mdl-30882841

ABSTRACT

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.


Subject(s)
Supranuclear Palsy, Progressive/epidemiology , Supranuclear Palsy, Progressive/genetics , Supranuclear Palsy, Progressive/pathology , tau Proteins/genetics , Aged , Aged, 80 and over , Case-Control Studies , Female , Haplotypes , Humans , Male , Middle Aged , Risk , Severity of Illness Index , tau Proteins/metabolism
19.
Mov Disord ; 34(8): 1144-1153, 2019 08.
Article in English | MEDLINE | ID: mdl-30726566

ABSTRACT

BACKGROUND: In 2017, the International Parkinson and Movement Disorder Society put forward new clinical criteria for the diagnosis of PSP, recognizing diverse PSP phenotypes. In this study, we compared the sensitivity and specificity of the new criteria with the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria at different times. METHODS: Patients with clinical parkinsonism, clinical and/or neuropathological diagnosis of PSP, were identified from the Society for Progressive Supranuclear Palsy brain bank. All patients had neuropathologic diagnoses and detailed clinical examination performed by a neurologist at 1 of the 3 Mayo Clinic sites, in Florida, Arizona, and Minnesota. Clinical symptoms and signs were abstracted retrospectively in a blinded fashion and used to determine whether patients met either diagnostic criterion. Patients were divided into early and late disease stage groups using a 3-year cutoff. RESULTS: A total of 129 patients were included, of whom 66 had PSP pathology (51%). The remainder had other neurodegenerative diseases. The overall sensitivity of the International Parkinson and Movement Disorder Society criteria was 87.9%, compared with 45.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria, whereas the specificity of the International Parkinson and Movement Disorder Society probable PSP criteria was 85.7%, compared with 90.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy. Individual patients were noted to have features of multiple PSP phenotypes. CONCLUSION: The International Parkinson and Movement Disorder Society criteria recognize several phenotypes of progressive supranuclear palsy and hence have higher sensitivity than the previous criteria. © 2019 International Parkinson and Movement Disorder Society.


Subject(s)
Brain/pathology , Cognitive Dysfunction/physiopathology , Parkinsonian Disorders/physiopathology , Postural Balance/physiology , Sensation Disorders/physiopathology , Supranuclear Palsy, Progressive/diagnosis , Biological Specimen Banks , Female , Frontotemporal Lobar Degeneration/diagnosis , Humans , Lewy Body Disease/diagnosis , Male , Multiple System Atrophy/diagnosis , Sensitivity and Specificity , Supranuclear Palsy, Progressive/pathology , Supranuclear Palsy, Progressive/physiopathology , Tauopathies/diagnosis
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