Pathological findings in a patient with alpha-synuclein p.A53T and familial Parkinson's disease

The present report documents a patient harboring an alpha-synuclein p.A53T variant from a family presenting with autosomal dominant inheritance, including four patients clinically diagnosed with Parkinson's disease (PD) and two with dementia. The alpha-synuclein p.A53T variant is linked to young- or middle-aged onset parkinsonism and cognitive decline. Our patient had a different haplotype from that of a patient with a p.A53T variant from an Italian family. The proband presented at 42 years of age with progressive parkinsonism and good response to levodopa in the early stages of the disease. At 46 years of age, he developed delusions and cognitive decline. Brain magnetic resonance imaging showed bilateral atrophic changes in the hippocampus and temporal lobes. He died of pneumonia at the age of 52 years. Neuropathological examination revealed severe neuronal loss in the substantia nigra, locus coeruleus, and dorsal nucleus of the vagus nerve, as well as widespread Lewy pathology including Lewy bodies and neurites, corresponding to Braak stage 6, and diffuse neocortical-type PD. There was mild appearance of tau pathology and glial cytoplasmic inclusion, in the absence of TDP-43 pathology. Alpha-synuclein p.A53T characteristically cause the Lewy body pathology and the symptoms, that resembled those of the reported patients with p.A53T.     

Genetic characterization of Parkinson's disease patients in Ecuador and Colombia

To help address the scarcity of studies on the genetics of Parkinson's disease (PD) in Latin America, we screened 426 Ecuadorians with PD and 80 Colombians (PD = 55, Control = 26) for mutations within several PD-related genes. Among Colombians, we identified several variants within PARKIN and PINK1 genes.     

Early Onset Parkinson's disease due to DJ1 mutations: An Indian study

IntroductionEarly Onset Parkinson's Disease (EOPD) is genetically heterogeneous. PARK2 mutations are the commonest cause of autosomal recessive EOPD followed by PINK1.DJ1 mutations is rare and there is scarce literature on its phenotype and long term outcome.ObjectivesWe undertook a retrospective study to determine the prevalence of DJ1 mutation(s) in an Indian population and describe the clinical features and long term outcome of EOPD patients with these mutations.MethodsOne hundred EOPD patients and 114 controls were evaluated. All the seven coding exons of DJ1 gene were screened for novel and reported mutations by PCR- Sanger sequencing.ResultsA novel homozygous missense mutation (c.313 A > T, p. Ile105Phe) in exon 5 was seen in one patient and four unrelated patients had a homozygous missense single nucleotide variant rs71653619 (c.293 G > A, p.Arg98Gln). The clinical phenotype comprised of asymmetrical onset, slowly progressive Parkinsonism with levodopa induced motor restlessness in a patient with the novel mutation (c.313 A > T, p. Ile105Phe) while subjects with c.293 G > A, p.Arg98Gln had early onset levodopa responsive symmetrical Parkinsonism.ConclusionDJ1 mutations account for ∼5% of EOPD patients from the Indian population. This study further adds to the clinical spectrum of EOPD with DJ1 mutations.     

Impairments of speed and amplitude of movement in Parkinson's disease: A pilot study

Bradykinesia, characterized by slowness and decreased amplitude of movement, is often considered the most important deficit in Parkinson's disease (PD). The current clinical rating of bradykinesia in PD, based on the motor subscale of the Unified Parkinson's disease Rating Scale (UPDRS‐III), does not individually weigh the impairments in speed and amplitude of rapid alternating movements. We sought to categorize movement in PD to determine whether speed and amplitude have different relationships to current measures of motor impairment and disability. Categories of speed and amplitude (normal, slow/low, and very‐slow/very‐low) were ascertained using an electromagnetic tracking device. Amplitude was disproportionally more affected than speed in the “off” state. UPDRS‐III and the Schwab & England disability scale were worst in patients with very impaired amplitude and best in patients with normal amplitude. A similarly graded relationship was not found for categories of speed impairment. The examiner clinical global impression of change mirrored “off” state amplitude but not speed categories. Levodopa, however, normalized speed to a greater extent than amplitude. Our observations suggest that amplitude and speed impairments may be associated with different functional aspects in PD and deserve separate clinical assessment. © 2009 Movement Disorder Society     

Rate of clinical progression in Parkinson's disease. A prospective study.

Few prospective data on the clinical progression of Parkinson's disease (PD) in patient groups outside treatment trials in selected patients are available, and controversy exists on the rate of clinical disease progression with advancing disease. In this study, we investigated the rate of clinical progression of PD in a clinic-based sample of 145 patients over 1 year and in a community-based sample of 124 patients over 4 years. Depending on the sample and clinical scale used, mean deterioration of motor and disability scores ranged from 2.4 to 7.4% of the maximum possible score per year, and standard deviations indicated that there was considerable variability of progression rates between individuals. The progression of motor scores decreased with follow-up over 4 years and significantly decreased in more advanced disease stages. Deterioration of disability scores did not differ between disease stages; this may reflect the increasing rate of disease complications, which contribute to increasing disability in addition to motor impairment alone, in more advanced disease. Thus, motor fluctuations, hallucinations, depression, memory problems, and bladder symptoms were all reported more often at follow-up in the community-based sample (all P < 0.01), and dyskinesias, motor fluctuations, falls, and hallucinations were more common and cognitive and depression scores worse in higher disease stages in the clinic-based sample (all P < 0.001). We conclude that progression of motor scores in PD decreases with advancing disease in PD. However, disability continues to deteriorate with advancing disease and with the development of disease complications that are likely to be related to additional extrastriatal pathology.     

Cognitive profile of Parkinson's disease patients: a comparative study between early-onset and late-onset Parkinson's disease

Aim: To investigate the influence of onset age on the occurrence and progression of cognitive dysfunction using neuropsychological tests and the electrophysiological component P300 in both early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD) patients. Methods: A cohort of 76 EOPD patients and 166 LOPD patients was recruited for this study. Demographic information and clinical features, including age, disease duration, education level, family history, the Unified Parkinson's Disease Rating Scale, the Hoehn and Yahr stage, and depression scores were documented for each patient. The Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA), Wechsler Adult Intelligence Scale – Revised, Chinese version (WAIS-RC) and Wechsler Memory Scale – Revised, Chinese version (WMS-RC) were used. In addition, P300 was also examined to assess cognitive function. Results: Although EOPD patients had longer disease duration, their cognitive dysfunction progressed more slowly. The MoCA tests revealed that EOPD patients had higher scores in visuospatial function, attention, delayed recall, and orientation than the LOPD patients. The difference between the two groups on the WMS-RC test did not reach significance, whereas the scores in executive function, visuospatial function and attention as measured on the WAIS-RC test were significantly lower in the LOPD group. In addition, P300 latencies were markedly delayed and P300 amplitudes were reduced in the LOPD group. Conclusions: The current findings demonstrated that cognitive dysfunction progressed more slowly in the EOPD group. Although the LOPD patients exhibited shorter disease durations, their cognitive abilities, including executive function, visuospatial function and attention, may have been impaired.     

Atypical clinical presentation of pathologically proven Parkinson's disease: The role of Parkinson's disease related metabolic pattern

Regional changes in brain metabolism upgraded with measurements of specific metabolic brain patterns and automated diagnostic algorithms can help to differentiate among neurodegenerative parkinsonisms, but with few reports on pathological confirmation. Here we describe a parkinsonian patient with atypical presentation and ¹⁸F-FDG-PET imaging consistent with idiopathic Parkinson's disease. The latter was confirmed at the pathohistological examination.     

Parkinson's disease in Ireland: clinical presentation and genetic heterogeneity in patients with parkin mutations.

Early-onset autosomal recessive parkinsonism is associated with parkin gene mutations. Different parkin mutations occur in many ethnic backgrounds; however, the phenotype may vary. We studied 102 young-onset (age at onset <60 years) Parkinson's disease (PD) patients. From 102 patients, 40 with early-onset PD (<45 years at symptomatic onset) were selected for clinical assessment and parkin gene molecular analysis for duplications/deletions and point mutations. We identified parkin mutations in 7 of 40 early-onset patients; including novel compound heterozygotes and potential splice site changes. The mean age at onset in the 7 parkin mutation-positive patients was 33 +/- 9 years (age range, 18-42 years), marginally lower than that of the 33 parkin-negative early-onset patients, 38 +/- 7 years (age range, 17-45 years). A family history of PD was present in 4 of 7 patients with parkin mutations, compared with 6 of 33 early-onset parkin-negative patients. Overall, parkin mutations were found in 4 of 10 patients with a positive family history and 3 of 30 patients without a family history of PD. Patients with parkin mutations had more dystonia, dyskinesia, and sleep benefit compared with parkin-negative patients. We subsequently identified a single point mutation among the 62 young-onset (age at onset 45 to <60 years). Mutations in the parkin gene may account for approximately 17% of early-onset (age at onset <45 years) parkinsonism in Ireland, in agreement with previous European studies.     

A prospective study of depression in French patients with Parkinson's disease. The Depar study

To investigate the prevalence and symptomatology of depression in Parkinson's disease (PD), we have studied 506 unselected patients attending the neurology services in French general hospitals during a 5 month period defined for prospective inclusion. 246 patients (48.6%) were suspected of depression according to different methods of evaluation and 168 (33.2%) were defined as definite or probable depression. According to the Montgomery and Asberg scale, 46 cases (9%) had a severity score suggestive of major depression. As a function of the cut-off score defined for severity, these patients represented from 23.2 to 43.7% of the depressive population with PD. There was no significant difference between depressed and non depressed PD patients as a function of the patient's current age or age at onset of PD. A significantly higher rate of depression was found among women with PD. A past history of depression was a risk factor for mood disorder after onset of PD. The severely depressed patients had a significantly longer duration of PD and a higher score of cognitive impairment than mildly or moderately depressed and non depressed patients with PD. Depressed patients had a significantly more advanced stage of disability than non-depressed patients with PD.     

Genetic analysis of TRIM family genes for early-onset Parkinson's disease in Chinese population

IntroductionAmounting evidence has suggested the Tripartite Motif (TRIM) family proteins as related to Parkinson's disease (PD). However, many of the risk genes were still awaiting further explorations, and their genetic role in PD has not been investigated yet.MethodsHere, we aimed to systematically evaluate the genetic associations of TRIMs with PD in a large Chinese early-onset PD (EOPD, age at onset < 50 years) cohort. We identified rare variants (minor allele frequency < 0.01) in 743 unrelated EOPD patients using whole exome sequencing, and evaluated the association between rare variants and EOPD at allele and gene levels.ResultsTotally 123 rare variants were identified in 13 TRIM protein family members, including TRIM3, TRIM6, TRIM8, TRIM9, TRIM10, TRIM11, TRIM17, TRIM24, TRIM27, TRIM28, TRIM34, TRIM40 and TRIM41. At the allele level, three variants were nominally associated with PD, namely p.R65H in TRIM10, p.P467S in TRIM11, and p.I425V in TRIM24. Gene-based burden analysis showed a clear enrichment of rare variants of TRIM24 in EOPD.ConclusionThese results demonstrate TRIM24 as a potential risk gene for PD, provide a better understanding for the genetic involvement of TRIM protein family members in EOPD and broaden the current mutation spectrum of PD.     

A review of disease progression models of Parkinson's disease and applications in clinical trials

Quantitative disease progression models for neurodegenerative disorders are gaining recognition as important tools for drug development and evaluation. In Parkinson's disease (PD), several models have described longitudinal changes in the Unified Parkinson's Disease Rating Scale (UPDRS), one of the most utilized outcome measures for PD trials assessing disease progression. We conducted a literature review to examine the methods and applications of quantitative disease progression modeling for PD using a combination of key words including “Parkinson disease,” “progression,” and “model.” For this review, we focused on models of PD progression quantifying changes in the total UPDRS scores against time. Four different models reporting equations and parameters have been published using linear and nonlinear functions. The reasons for constructing disease progression models of PD thus far have been to quantify disease trajectories of PD patients in active and inactive treatment arms of clinical trials, to quantify and discern symptomatic and disease‐modifying treatment effects, and to demonstrate how model‐based methods may be used to design clinical trials. The historical lack of efficiency of PD clinical trials begs for model‐based simulations in planning for studies that result in more informative conclusions, particularly around disease modification. © 2016 International Parkinson and Movement Disorder Society     

EIF4G1 gene mutations are not a common cause of Parkinson's disease in the Japanese population

Pathogenic mutations in the EIF4G1 gene were recently reported as a cause of autosomal dominant parkinsonism. To assess the frequency of EIF4G1 mutations in the Japanese population we sequenced the entire gene coding region (31 exons) in 95 patients with an apparent autosomal dominant inherited form of Parkinson's disease. We detected three novel point mutations located in a poly-glutamic acid repeat within exon 10. These variants were screened through 224 Parkinson's disease cases and 374 normal controls from the Japanese population. We detected the poly-glutamic acid deletion in exon 10 in two additional patients with sporadic Parkinson's disease. Although the EIF4G1 variants identified in the present study were not observed in control subjects, co-segregation analyses and population-based screening data suggest they are not pathogenic. In conclusion, we did not identify novel or previously reported pathogenic mutations (including the p.A502V and p.R1205H mutants) within EIF4G1 in the Japanese population, thus future studies are warranted to elucidate the role of this gene in Parkinson's disease.     

A validation study of depressive syndromes in Parkinson's disease

The validity, sensitivity, and specificity of depressive symptoms for the diagnosis of major depression, minor depression, dysthymic disorder, and subsyndromal depression in Parkinson's disease (PD) were examined. A consecutive series of 173 patients with PD attending a Movement Disorders Clinic underwent a comprehensive psychiatric and neurological assessment. The symptoms of loss of interest/pleasure, changes in appetite or weight, changes in sleep, low energy, worthlessness or inappropriate guilt, psychomotor retardation/agitation, concentration deficits, and suicide ideation were all significantly associated with the presence of the DSM‐IV depressed mood criterion for major depression. The symptoms of changes in appetite, changes in sleep, low energy, low self‐esteem, poor concentration, and hopelessness were all significantly associated with the presence of the DSM‐IV criterion of sad mood for dysthymic disorder. Thirty percent of our sample met DSM‐IV diagnostic criteria for major depression, 20% met diagnostic criteria for dysthymic disorder, 10% met diagnostic criteria for minor depression, and 8% met clinical criteria for subsyndromal depression. Patients with either major or minor depression had significantly more severe deficits in activities of daily living, more severe cognitive impairments, and more severe Parkinsonism than patients with either dysthymic disorder or no depression. This study provides validation to the DSM‐IV diagnostic criteria for major depression and dysthymic disorder for use in PD. The categories of minor and subsyndromal depression may need further validation. © 2007 Movement Disorder Society     

The relevance of clinical subtypes for disease course,family history and epidemiological variables in Parkinson's disease

Clinical outcome and relevance of genetic and epidemiological factors were evaluated in 161 patients with idiopathic Parkinson's disease (PD) with regard to onset symptoms [tremor (T) vs non-tremor (NT)], to clinical classification into tremor-dominant (TD), alkineto-rigid (AR), and equivalent (EQ) subtypes, and to disease onset before the 45th year of age (EO) and after age 69 (LO). Patients were investigated by questionnaire-based personal interview and clinical examination. Allegedly symptomatic first-degree relatives were examined personally or had sufficient medical documentation to allow neurological diagnosis. Disease course was more favorable in T than in NT, in TD than in AR or EQ, and in EO compared with LO. Among EO and LO patients, clinical subtypes TD, AR and EQ were not differently distributed. Frequency of first-degree relatives with PD or essential tremor and any epidemiological variable tested were not elicited differently between TD, AR and EQ patients, with the exception that TD reported more frequent premorbid travelling. EO patients reported higher frequencies of premorbid head trauma and rural living than LO patients. The more favorable disease prognosis of patients with predominant tremor at presentation and of patients with early disease onset is corroborated. Clinical subgroups do not differ in genetic and epidemiological factors.     

帕金森病患者双眼竞争的研究

目的采用双眼竞争范式,探讨帕金森病(PD)患者的双眼竞争交替速率及其可能的神经机制。方法选取临床确诊的原发性PD患者32例(PD组)以及与其人口学资料相匹配的健康对照者32例(HC组)作为研究对象,采用双眼竞争范式进行双眼竞争交替速率的检查。结果 PD组双眼竞争交替速率[(0.24±0.07) Hz]较健康对照组[(0.35±0.11) Hz]显著减慢,且二者差异有统计学意义(t=-4.653,P=0.000)。结论 PD患者双眼竞争交替速率较健康对照组显著减慢,推测因其额叶-基底节的神经通路损伤从而削弱了知觉的交替变化而影响了双眼竞争交替速率。     

A familial form of parkinsonism,dementia, and motor neuron disease: A longitudinal study

ObjectiveTo describe the clinical, positron emission tomography (PET), pathological, and genetic findings of a large kindred with progressive neurodegenerative phenotypes in which the proband had autopsy-confirmed corticobasal degeneration (CBD).MethodsFive family members, including the proband, were examined neurologically. Clinical information from the other family members was collected by questionnaires. Three individuals underwent PET with ¹¹C-dihydrotetrabenazine and ¹⁸F-fludeoxyglucose. The proband was examined post-mortem. Genetic studies were performed.ResultsThe pedigree contains 64 individuals, including 8 affected patients. The inheritance is likely autosomal dominant with reduced penetrance. The proband developed progressive speech and language difficulties at the age of 64 years. Upon examination at the age of 68 years, she showed non-fluent aphasia, word-finding difficulties, circumlocution, frontal release signs, and right-sided bradykinesia, rigidity, and pyramidal signs. She died 5 years after disease onset. The neuropathology was consistent with CBD, including many cortical and subcortical astrocytic plaques. Other family members had progressive neurodegenerative phenotypes – two were diagnosed with parkinsonism and behavioral problems, two with parkinsonism alone, one with amyotrophic lateral sclerosis alone, one with dementia, and one with progressive gait and speech problems. PET on three potentially affected individuals showed no significant pathology. Genetic sequencing of DNA from the proband excluded mutations in known neurodegenerative-related genes including MAPT, PGRN, LRRK2, and C9ORF72.ConclusionsFamilies with such complex phenotypes rarely occur. They are usually associated with MAPT mutations; however, in this family, MAPT mutations have been excluded, implicating another causative gene or genes. Further genetic studies on this family may eventually disclose the etiology.     

Alpha‐synuclein and familial Parkinson's disease

Whole gene duplications and triplications of alpha‐synuclein (SNCA) can cause Parkinson's disease (PD), and variation in the promoter region (Rep1) and 3' region of SNCA has been reported to increase disease susceptibility. Within our cohort, one affected individual from each of 92 multiplex PD families showing the greatest evidence of linkage to the region around SNCA was screened for dosage alterations and sequence changes; no dosage or non‐synonymous sequence changes were found. In addition, 737 individuals (from 450 multiplex PD families) that met strict diagnostic criteria for PD and did not harbor a known causative mutation, as well as 359 neurologically normal controls, were genotyped for the Rep1 polymorphism and four SNPs in the 3′ region of SNCA. The four SNPs were in high LD (r² > 0.95) and were analyzed as a haplotype. The effects of the Rep1 genotype and the 3′ haplotype were evaluated using regression models employing only one individual per family. Cases had a 3% higher frequency of the Rep1 263 bp allele compared with controls (OR = 1.54; empirical P‐value = 0.02). There was an inverse linear relationship between the number of 263 bp alleles and age of onset (empirical P‐value = 0.0004). The 3′ haplotype was also associated with disease (OR = 1.29; empirical P‐value = 0.01), but not age of onset (P = 0.40). These data suggest that dosage and sequence changes are a rare cause of PD, but variation in the promoter and 3′ region of SNCA convey an increased risk for PD. © 2009 Movement Disorder Society