Parkinson's Disease Subtypes Research Articles

Clinicopathologic discrepancies in a population-based incidence study of parkinsonism in olmsted county: 1991-2010.

The purpose of this study was to examine the discrepancies between the clinical diagnosis of parkinsonism and neuropathological findings in a population-based cohort with parkinsonian disorders. The specific clinical diagnosis of parkinsonism is challenging, and definite confirmation requires neuropathological evaluation. Currently, autopsies are seldom performed, and most brain autopsies represent atypical or diagnostically unresolved cases. We used a defined population-based incidence cohort with clinical parkinsonism (n = 669) from the Rochester Epidemiology Project in Olmsted County, Minnesota, 1991-2010. We reviewed reports of all patients who underwent neuropathologic examination at autopsy (n = 60; 9%) and applied consensus pathologic guidelines for neurodegenerative disease diagnosis. Among the 60 patients examined pathologically, the median time from the last recorded clinical diagnosis to death was 7 years (range from 2 to 17 years). Clinical-pathological concordance was found in 52 cases (86.7%), whereas 8 (13.3%) had a clinical-pathological discrepancy. Four patients with a clinical diagnosis of idiopathic Parkinson's disease had no pathological evidence of Lewy bodies or α-synucleinopathy; of these, pathological diagnoses were Alzheimer's disease (2 cases), progressive supranuclear palsy (1 case), and vascular parkinsonism (1 case). Two patients with clinical diagnoses of "dementia with Lewy bodies" and one patient with an "unspecified parkinsonism" had a pathological diagnosis of Alzheimer's disease without concomitant α-synuclein lesions. One patient with clinically diagnosed "progressive supranuclear palsy" had indeterminate pathological findings without α-synuclein or Aβ- or tau-immunoreactive lesions at autopsy. Overall, the clinical diagnoses of parkinsonian subtypes had good concordance with pathological confirmation (86.7%). However, clinical-pathological discrepancies were documented in 13.3%. © 2017 International Parkinson and Movement Disorder Society.

Global, Yet Incomplete Overview of Cohort Studies in Parkinson's disease.

Parkinson's disease (PD) is characterized by heterogeneity and multifactorial longitudinal changes. To identify PD subtypes and factors influencing the disease course, multiple cohort studies have been designed globally. Knowledge about existing cohorts is pivotal to foster collaboration, which may help to advance the understanding of PD. To raise the awareness about PD cohorts and potential global collaboration opportunities. Observational cohort studies in clinical PD were identified by a European working group (JPND BioLoC-PD) and through literature search. Using a structured survey investigators of 44 cohorts provided basic information on cohorts and assessments performed. For the 44 cohorts (32% on early/de-novo PD), 14.666 participants (cohorts' median: 138; range: 23-3.090), a median 1.5-year follow-up interval (0.5-4 years) and a median (planned) observational period of 5 years (1-20 years) were indicated. All studies have assessed motor functions often using rating scales (UPDRS-III; 93% of studies) and less frequently quantitative gait/balance (25%) or fine motor assessments (27%). Cognitive (100%), neuropsychiatric (91%), daily living (78%), sleep (70%), sensory (63%), and gastrointestinal/autonomic (55%) assessments were common and often comparable. Neuroimaging data (82%) and biomaterial (69%) have been collected in many studies. Surprisingly, possible disease modifiers, such as sport/physical activity (11%), have rarely been assessed. Existing data of PD cohorts provide vast collaboration opportunities. We propose to establish a comprehensive, up-to-date, open-access internet platform with easy-to-use search tools of PD cohort descriptions and potentially available data. Bringing researchers together to enable collaborative joint, meta- and replication analyses is timely and necessary to advance PD research ultimately required for an understanding of PD that can be translated into more effective therapies.

Rapid eye movement sleep behaviour disorder and striatal dopamine depletion in patients with Parkinson's disease.

Rapid eye movement sleep behaviour disorder (RBD) is related to striatal dopamine depletion. This study was performed to confirm whether clinically probable RBD (cpRBD) in patients with Parkinson's disease (PD) is associated with a specific pattern of striatal dopamine depletion. A prospective survey was conducted using the RBD Screening Questionnaire (RBDSQ) in 122 patients with PD who had undergone dopamine transporter (DAT) positron emission tomography scan. Patients with cpRBD (RBDSQ ≥ 7) exhibited greater motor deficits, predominantly in the less-affected side and axial symptoms, and were prescribed higher levodopa-equivalent doses at follow-up than those without cpRBD (RBDSQ ≤ 4), despite their similar disease and treatment durations. Compared to patients without cpRBD, those with cpRBD showed lower DAT activities in the putamen, particularly in the less-affected side in all putaminal subregions, and a tendency to be lower in the ventral striatum. In addition, greater motor deficits in patients with cpRBD than in those without cpRBD remained significant after controlling for DAT binding in the putamen and other confounding variables. These results demonstrated that the presence of RBD in patients with PD is associated with different patterns of both motor deficit distribution and striatal DAT depletion, suggesting that the presence of RBD represents a distinct PD subtype with a malignant motor parkinsonism.

Motor subtype changes in early Parkinson's disease

IntroductionDistinct motor subtypes of Parkinson's disease (PD) have been described through both clinical observation and through data-driven approaches. However, the extent to which motor subtypes change during disease progression remains unknown. Our objective was to determine motor subtypes of PD using an unsupervised clustering methodology and evaluate subtype changes with disease duration. MethodsThe Parkinson's Progression Markers Initiative database of 423 newly diagnosed PD patients was utilized to retrospectively identify unique motor subtypes through a data-driven, hierarchical correlational clustering approach. For each patient, we assigned a subtype to each motor assessment at each follow-up visit (time points) and by using published criteria. We examined changes in PD subtype with disease duration using both qualitative and quantitative methods. ResultsFive distinct motor subtypes were identified based on the motor assessment items and these included: Tremor Dominant (TD), Axial Dominant, Appendicular Dominant, Rigidity Dominant, and Postural and Instability Gait Disorder Dominant. About half of the patients had consistent subtypes at all time points. Most patients met criteria for TD subtype soon after diagnosis. For patients with inconsistent subtypes, there was an overall trend to shift away from a TD phenotype with disease duration, as shown by chi-squared test, p < 0.001, and linear regression analysis, p < 0.05. ConclusionThese results strongly suggest that classification of motor subtypes in PD can shift with increasing disease duration. Shifting subtypes is a factor that should be accounted for in clinical practice or in clinical trials.

Transcranial sonography image characteristics in different Parkinson's disease subtypes.

Recently, Parkinson's disease (PD) has been classified into three subtypes: postural instability gait difficulty (PIGD), tremor dominate (TD), and indeterminate PD. Transcranial sonography (TCS) is considered to be an important tool to diagnose PD. However, it is uncertain that whether there are differences in TCS image characteristics in different PD subtypes, so 373 idiopathic PD (188 PIGD, 108 TD, 77 indeterminate PD) were registered and received TCS in our investigation; also, the association between clinical characteristics and TCS results in different PD subtypes was analyzed. In accordance with several previous studies, we detected substantia nigra (SN) by TCS in 85.4% of patients with idiopathic PD; we concluded that PIGD patients had more serious disease than TD and indeterminate PD group (p<0.05). They always had larger SN hyperechogenicity areas on TCS (p<0.05), and we found that there was no correlation between SN hyperechogenicity and disease duration or severity (p>0.05). Similarly, abnormal brainstem raphe signal was also more often in PIGD group than in TD and indeterminate PD group (p<0.05), which might imply that PIGD group was vulnerable to suffer from depression in the future.

Validity and reliability of a pilot scale for assessment of multiple system atrophy symptoms

BackgroundMultiple system atrophy (MSA) is a rare progressive neurodegenerative disorder for which brief yet sensitive scale is required in order for use in clinical trials and general screening. We previously compared several scales for the assessment of MSA symptoms and devised an eight-item pilot scale with large standardized response mean [handwriting, finger taps, transfers, standing with feet together, turning trunk, turning 360°, gait, body sway]. The aim of the present study is to investigate the validity and reliability of a simple pilot scale for assessment of multiple system atrophy symptoms.MethodsThirty-two patients with MSA (15 male/17 female; 20 cerebellar subtype [MSA-C]/12 parkinsonian subtype [MSA-P]) were prospectively registered between January 1, 2014 and February 28, 2015. Patients were evaluated by two independent raters using the Unified MSA Rating Scale (UMSARS), Scale for Assessment and Rating of Ataxia (SARA), and the pilot scale. Correlations between UMSARS, SARA, pilot scale scores, intraclass correlation coefficients (ICCs), and Cronbach’s alpha coefficients were calculated.ResultsPilot scale scores significantly correlated with scores for UMSARS Parts I, II, and IV as well as with SARA scores. Intra-rater and inter-rater ICCs and Cronbach’s alpha coefficients remained high (> 0.94) for all measures.ConclusionThe results of the present study indicate the validity and reliability of the eight-item pilot scale, particularly for the assessment of symptoms in patients with early state multiple system atrophy.

Association of Autonomic Dysfunction With Disease Progression and Survival in Parkinson Disease

Evidence suggests that development of autonomic dysfunction (AutD) may negatively affect disease course and survival in patients with synucleinopathies. However, the few available studies on Parkinson disease (PD) have conflicting results, comprise a small number of patients, have short follow-up periods, and lack pathologic confirmation of the diagnosis. To examine the association of time of onset of AutD with disease progression and survival in PD. This retrospective review of clinical data from 100 consecutive patients with an autopsy-confirmed diagnosis of PD from the archives of the Queen Square Brain Bank in London, United Kingdom, from January 1, 2006, to June 3, 2016, included patients with PD regularly seen by hospital specialists (neurologists or geriatricians) in the United Kingdom throughout their disease until death. Patients with dementia before or within 1 year after onset of motor symptoms, monogenic forms of PD, comorbidities that affect autonomic function, a coexisting neuropathologic diagnosis, or insufficient clinical information were excluded. Survival and time from diagnosis to specific disease milestones were calculated to assess disease progression. Autonomic dysfunction was defined as autonomic failure at autonomic function testing or 2 of the following symptoms: urinary symptoms, constipation, upper gastrointestinal tract dysfunction, orthostatic hypotension, sweating abnormalities, or erectile dysfunction. Multivariable Cox proportional hazards regression models on the risk of a disease milestone and death were used. A total of 100 patients (60 [60.0%] male; mean [SD] age at diagnosis, 63.9 [10.3] years; mean [SD] disease duration, 14.6 [7.7] years) were studied. Autonomic dysfunction developed in 85 patients (mean [SD] time from diagnosis, 6.7 [7.7] years) and was associated with older age at diagnosis, male sex, poor initial levodopa treatment response, and postural instability and gait difficulty motor PD subtype in linear regression analysis, but staging of α-synuclein pathologic changes was unrelated. Earlier AutD increased the risk of reaching the first milestone (hazard ratio, 0.86; 95% CI, 0.83-0.89; P < .001) and shortened survival (hazard ratio, 0.92; 95% CI, 0.88-0.96; P < .001). Older age at diagnosis and poorer levodopa treatment response were the other factors associated with shorter survival in adjusted multivariate analysis. Earlier AutD is associated with a more rapid development of disease milestones and shorter survival in patients with PD.

Clinical criteria for subtyping Parkinson's disease: biomarkers and longitudinal progression.

Parkinson's disease varies widely in clinical manifestations, course of progression and biomarker profiles from person to person. Identification of distinct Parkinson's disease subtypes is of great priority to illuminate underlying pathophysiology, predict progression and develop more efficient personalized care approaches. There is currently no clear way to define and divide subtypes in Parkinson's disease. Using data from the Parkinson's Progression Markers Initiative, we aimed to identify distinct subgroups via cluster analysis of a comprehensive dataset at baseline (i.e. cross-sectionally) consisting of clinical characteristics, neuroimaging, biospecimen and genetic information, then to develop criteria to assign patients to a Parkinson's disease subtype. Four hundred and twenty-one individuals with de novo early Parkinson's disease were included from this prospective longitudinal multicentre cohort. Hierarchical cluster analysis was performed using data on demographic and genetic information, motor symptoms and signs, neuropsychological testing and other non-motor manifestations. The key classifiers in cluster analysis were a motor summary score and three non-motor features (cognitive impairment, rapid eye movement sleep behaviour disorder and dysautonomia). We then defined three distinct subtypes of Parkinson's disease patients: 223 patients were classified as 'mild motor-predominant' (defined as composite motor and all three non-motor scores below the 75th percentile), 52 as 'diffuse malignant' (composite motor score plus either ≥1/3 non-motor score >75th percentile, or all three non-motor scores >75th percentile) and 146 as 'intermediate'. On biomarkers, people with diffuse malignant Parkinson's disease had the lowest level of cerebrospinal fluid amyloid-β (329.0 ± 96.7 pg/ml, P = 0.006) and amyloid-β/total-tau ratio (8.2 ± 3.0, P = 0.032). Data from deformation-based magnetic resonance imaging morphometry demonstrated a Parkinson's disease-specific brain network had more atrophy in the diffuse malignant subtype, with the mild motor-predominant subtype having the least atrophy. Although disease duration at initial visit and follow-up time were similar between subtypes, patients with diffuse malignant Parkinson's disease progressed faster in overall prognosis (global composite outcome), with greater decline in cognition and in dopamine functional neuroimaging after an average of 2.7 years. In conclusion, we introduce new clinical criteria for subtyping Parkinson's disease based on a comprehensive list of clinical manifestations and biomarkers. This clinical subtyping can now be applied to individual patients for use in clinical practice using baseline clinical information. Even though all participants had a recent diagnosis of Parkinson's disease, patients with the diffuse malignant subtype already demonstrated a more profound dopaminergic deficit, increased atrophy in Parkinson's disease brain networks, a more Alzheimer's disease-like cerebrospinal fluid profile and faster progression of motor and cognitive deficits.

Intrinsic functional connectivity alterations in progressive supranuclear palsy: Differential effects in frontal cortex, motor, and midbrain networks.

The topography of functional network changes in progressive supranuclear palsy can be mapped by intrinsic functional connectivity MRI. The objective of this study was to study functional connectivity and its clinical and behavioral correlates in dedicated networks comprising the cognition-related default mode and the motor and midbrain functional networks in patients with PSP. Whole-brain-based "resting-state" functional MRI and high-resolution T1-weighted magnetic resonance imaging data together with neuropsychological and video-oculographic data from 34 PSP patients (22 with Richardson subtype and 12 with parkinsonian subtype) and 35 matched healthy controls were subjected to network-based functional connectivity and voxel-based morphometry analysis. After correction for global patterns of brain atrophy, the group comparison between PSP patients and controls revealed significantly decreased functional connectivity (P < 0.05, corrected) in the prefrontal cortex, which was significantly correlated with cognitive performance (P = 0.006). Of note, midbrain network connectivity in PSP patients showed increased connectivity with the thalamus, on the one hand, whereas, on the other hand, lower functional connectivity within the midbrain was significantly correlated with vertical gaze impairment, as quantified by video-oculography (P = 0.004). PSP Richardson subtype showed significantly increased functional motor network connectivity with the medial prefrontal gyrus. PSP-associated neurodegeneration was attributed to both decreased and increased functional connectivity. Decreasing functional connectivity was associated with worse behavioral performance (ie, dementia severity and gaze palsy), whereas the pattern of increased functional connectivity may be a potential adaptive mechanism. © 2017 International Parkinson and Movement Disorder Society.

Comparison of Clinical Features Among Parkinson Disease Subtypes (P6.014)

Comparison of Clinical Features Among Parkinson Disease Subtypes (P6.014)

Lower levels of uric acid and striatal dopamine in non-tremor dominant Parkinson's disease subtype.

Parkinson’s disease (PD) patients who present with tremor and maintain a predominance of tremor have a better prognosis. Similarly, PD patients with high levels of uric acid (UA), a natural neuroprotectant, have also a better disease course. Our aim was to investigate whether PD motor subtypes differ in their levels of UA, and if these differences correlate with the degree of dopamine transporter (DAT) availability. We included 75 PD patients from whom we collected information about their motor symptoms, DAT imaging and UA concentration levels. Based on the predominance of their motor symptoms, patients were classified into postural instability and gait disorder (PIGD, n = 36), intermediate (I, n = 22), and tremor-dominant (TD, n = 17) subtypes. The levels of UA and striatal DAT were compared across subtypes and the correlation between these two measures was also explored. We found that PIGD patients had lower levels of UA (3.7 vs 4.5 vs 5.3 mg/dL; P<0.001) and striatal DAT than patients with an intermediate or TD phenotype. Furthermore, UA levels significantly correlated with the levels of striatal DAT. We also observed that some PIGD (25%) and I (45%) patients had a predominance of tremor at disease onset. We speculate that UA might be involved in the maintenance of the less damaging TD phenotype and thus also in the conversion from TD to PIGD. Low levels of this natural antioxidant could lead to a major neuronal damage and therefore influence the conversion to a more severe motor phenotype.

Effects of progressive resistance exercise in akinetic-rigid Parkinson's disease patients: a randomized controlled trial.

Progressive resistance exercise (PRE) can have a positive effect in individuals with Parkinson's disease (PD). However, the effect of PRE may vary with the clinical subtype of PD. To date, no study has assessed the effects of PRE in the different subtypes of PD. The aim of the present study was to assess the effects of PRE in PD patients with akinesia and rigidity (AR-subtype). A randomized controlled trial was conducted. Outpatients clinics of the Bierzo Parkinson Association (Ponferrada, Spain) and the Asturias Parkinson Association (Oviedo, Spain). Twenty-eight patients with AR-subtype PD were randomized into an Experimental Group (EG, N.=13) and Control Group (CG, N.=15). Static posturography (Centre of Pressure -CoP- parameters), gait (the Ten-Meter Walk Test [TMWT]), freezing of gait (the Freezing of Gait Questionnaire [FOG-Q]), the motor portion of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and patient-perceived quality of life (the 39-item Parkinson's disease Questionnaire [PDQ39]), were assessed at pre-test, post-test, and re-test. Ratings of perceived exertion (RPE) (Borg >6-20 Scale) were recorded at the end of each PRE training session. The EG displayed significant ameliorations in Length (CoP parameters) from pre- to post-test (P=0.048), in speed of fast rhythm walking (TMWT) from pre- to post-test (P=0.000), and from pre- to re-test (P=0.027), and in the PDQ39 Score from pre- to post-test (P=0.024). No significant differences were detected in Area or Speed (CoP parameters), speed of preferred rhythm walking (TMWT), FOG-Q scores, or the motor portion of the MDS-UPDRS scores. The EG reported a mean RPE of 9.95 (between "very light" and "fairly light") for the whole training program. These findings provide support for the use of PRE training in the rehabilitation of individuals with AR-subtype PD, as it can improve static posturography, gait, and quality of life. Furthermore, RPE scores showed that individuals with AR-subtype PD consider that PRE training require only light efforts. The PRE training can be a helpful and fruitful rehabilitation tool for AR-subtype PD patients.

Personalized Medicine and Nonmotor Symptoms in Parkinson's Disease.

Parkinson's disease (PD) is a multineurotransmitter dysfunction related disorder resulting in a range of motor and nonmotor symptoms. Phenotypic heterogeneity is pronounced in PD and nonmotor symptoms dominant subtypes have been described. These endophenotypes may be underpinned by considerable nondopaminergic dysfunction; however, conventional treatment of PD continues to be mostly reliant on dopamine replacement strategy or manipulation of brain dopaminergic pathways. Consequently, treatment of many nondopaminergic nonmotor and some motor symptoms remains a key unmet need. It is also recognized that treatment strategies for PD are influenced by a number of nondrug-related issues. These include factors such as age, personality, and preferences for treatment, cultural beliefs, lifestyle, pharmacoeconomics, pharmacogenetics as well as comorbidity. Therefore, the success of clinical therapy will rest on how much these factors are considered to develop a truly holistic treatment plan. Personalized medicine is the modern way of delivering this holistic strategy for treatment of PD. Personalized medicine thus encompasses several strands of treatment. From the pharmaceutical point of view, it should involve dopaminergic and nondopaminergic strategies. In addition, there are substrategies involving precision and tailored medicine to suit the needs and requirements of individual patients. Precision medicine would be relevant for patients who may be at risk of developing the clinical syndrome of Parkinson's as identified by specific gene mutations. Precision medicine in this scenario will attempt to be preventive. Tailored medicine would address the "single multifactorial" complex nature of PD and address symptoms as well subtype-specific strategies. Personalized medicine is now practiced for other conditions such as oncology as well as diabetes. In this chapter, we discuss the rationale and the need to develop strategies for personalized medicine for PD.

Nonmotor Parkinson's and Future Directions.

Nonmotor symptoms (NMS) of Parkinson's disease (PD) are integral to the condition largely regarded as a motor syndrome. A range of NMS underpin the prodromal stage of Parkinson's and are present with variable frequency, range, and nature across the whole journey of a patient with Parkinson's from the onset of the motor disease to palliative stage. These symptoms also are key determinants of quality of life of the patient as well as the carer. Despite this, recognition management and focused treatment of NMS of PD remain poor. Future would, therefore, need to focus on better definition and management of NMS of PD. This would include development of robust animal models of specific NMS such as cognitive, sleep, and autonomic dysfunctions as well as pain to understand the mechanistic pathways of these symptoms. In turn this will lead to better drug development using a bench to bedside model. Nonmotor clinical subtypes of PD have also been described and, in future, proper biomarkers will consolidate these findings in addition to defining the natural history of the subtypes. Revised versions of established scales and questionnaires will enable the adoption of good clinical practice with recognition of these subtypes in clinic. This will enhance the delivery of true subtype-specific therapies. Drug development should also include nondopaminergic and cell replacement restorative therapies with a nonmotor focus. An additional key area of future research would be the formalizing of true personalized medicine for PD. Personalized medicine pathways should concentrate on the role of exercise, complementary medicine as well as age, body weight, ethnicity on various NMS of PD. Genetics and pharmacogenetic developments in PD will add to the precision of the individualized approach.

The New Diagnostic Criteria for Parkinson's Disease.

This chapter summarizes the advances in diagnosis of Parkinson's disease (PD) that were encapsulated in new International Parkinson Disease and Movement Disorders Society diagnostic criteria for PD. Numerous changes in our understanding of PD have occurred, including our understanding of the nonmotor profile of disease, the recognition of PD as a synucleinopathy, identification of genetic causes, novel hypotheses about spread of disease, etc. These have been reflected in a new definition of PD, which includes a clinicogenetic subtype of PD, removes dementia with Lewy Bodies as an exclusion criterion against PD, and recognizes multiple stages of early disease. The Clinical Diagnostic Criteria for PD reflect these changes and offer a new standardized diagnostic method for use in clinical research and even clinical practice. The criteria for prodromal PD use a method not seen in previous diagnostic criteria; they rely upon published studies of PD predictors to calculate the probability that any individual will develop PD. The field of PD is constantly advancing, and our methods of diagnosis need to advance with it; one hopes for a future filled with constant revisions and updates in our diagnostic methodology.

The Epidemiology of Nonmotor Symptoms in Parkinson's Disease (Cohort and Other Studies).

Nonmotor symptoms (NMS) of Parkinson's disease (PD) were recognized by James Parkinson himself and are now considered to be an integral part of PD. While clinical assessment had focused on prevalence and severity of individual NMS such as dementia and depression, work in the last decade has concentrated on global or holistic assessment of NMS using validated tools such as the NMS questionnaire and NMS scale. These studies from cohorts of varying sizes have allowed comparison of NMS across different disease stages, duration, age, and ethnicity in PD. The data also allow exploration of the concept of the nonlinear relationship of NMS to disease duration of PD and motor stages as well as nonmotor subtypes of PD. In this chapter, these aspects of epidemiological studies of NMS in PD cohorts are described.

Re-emergent tremor in Parkinson's disease

IntroductionRe-emergent tremor (RET) is a postural tremor that appears after a variable delay in patients with Parkinson's disease (PD). The aim of the present study was to evaluate the occurrence and the clinical characteristics of RET in a population of patients with PD. MethodsWe consecutively assessed 210 patients with PD. We collected the patients' demographic and clinical data. RET was clinically characterized in terms of latency, severity and body side affected. We also investigated a possible relationship with motor and non-motor symptoms and differences in the clinical features in patients with and without RET. ResultsRET was present in 42/210 patients. The mean latency of RET was 9.20 ± 6.8 seconds. Mean severity was 2.4 ± 1.9. RET was unilateral in 21 patients. Patients with RET had less severe speech, posture and gait disorders and upper limb and global bradykinesia than patients without RET. Similar findings were observed when we compared patients with RET with patients with tremor at rest associated with action tremor, patients with isolated action tremor and patients with no tremor. By contrast, patients with RET tremor did not clinically differ from those with isolated tremor at rest. ConclusionOur results suggest that patients with RET and patients with isolated tremor at rest represent the same clinical subtype, whereas patients with action tremor (whether isolated or associated with tremor at rest) might belong to a distinct subtype that is clinically worse. Patients with RET represents a benign subtype of PD, even within the tremor-dominant phenotype.

Clinical subtypes and genetic heterogeneity: of lumping and splitting in Parkinson disease.

Recent studies on clinical, genetic and pathological heterogeneity of Parkinson disease have renewed the old debate whether we should think of Parkinson disease as one disease with variations, or as a group of independent diseases that happen to present with similar phenotypes. Here, we provide an overview of where the debate is coming from, and how recent findings in clinical subtyping, genetics and clinico-pathological correlation have shaped this controversy over the last few years. New and innovative clinical diagnostic criteria for Parkinson disease have been proposed and await validation. Studies using functional imaging or wearable biosensors, as well as biomarker studies, provide new support for the validity of the traditional clinical subtypes of Parkinson disease (tremor-dominant versus akinetic-rigid or postural instability/gait difficulty). A recent cluster analysis (as unbiased data-driven approach to subtyping) included a wide spectrum of nonmotor variables, and showed correlation of the proposed subtypes with disease progression in a longitudinal analysis. New genetic factors contributing to Parkinson disease susceptibility continue to be identified, including rare mutations causing monogenetic disease, common variants with small effect size and risk factors (like mutations in the gene for glucocerebrosidase) that fall in between the two other categories. Recent studies show some limited correlation between genetic factors and clinical heterogeneity. Despite some variations in patterns of pathology, Lewy bodies are still the hallmark of Parkinson disease, including the vast majority of genetic subgroups. Evidence of clinical, genetic and pathological heterogeneity of Parkinson disease continues to emerge, but clearly defined subtypes that hold up in more than one of these domains remain elusive. For research to identify such subtypes, splitting is likely the way forward; until then, for clinical practice, lumping remains the more pragmatic approach.

Relationship between the plasma levels of neurodegenerative proteins and motor subtypes of Parkinson's disease.

The aim of our study is to examine the plasma levels of the four kinds of neurodegenerative proteins in plasma: α-syn, T-tau, P-tau181, and Aβ-42 in Parkinson's disease (PD) and to evaluate the relationship between their plasma levels and PD motor subtypes. 84 patients with PD were enrolled in our study, and finally, 73 of them were classified into the tremor-dominant subtype (TD) and the postural instability gait difficulty subtype (PIGD). Their motor performance was evaluated by a series of clinical assessments: Freezing of Gait Questionnaire (FOGQ), Timed Up and Go (TUGs), Tinetti balance, and Tinetti gait. Plasma levels of these proteins were measured by enzyme-linked immunosorbent assay (ELISA). The plasma level of α-syn was significantly higher in PD patients when compared to controls (p=0.004), and significantly higher in the PIGD group when compared to the TD group (p=0.03). While the plasma level of Aβ-42 was significantly lower in PD patients than in controls (p=0.002), and significantly lower in the PIGD group than in the TD group (p=0.05). In PD patients, the plasma level of α-syn (r=-0.355, p<0.001) was significantly related to the severity of Tenitti Gait score, even after performing multiple linear regression (p=0.002). While the plasma level of Aβ-42 (r=-0.261, p<0.05) was significantly associated with the severity of PIGD score and remained correlate when performed multiple linear regression (p=0.005). The patients with PIGD subtype are characterized with a lower level of plasma Aβ-42 and a higher plasma level of α-syn, which may be used as biomarkers for diagnosis and progression of the subtypes of PD.

Advance in diagnosis and therapy of multiple system atrophy

Multiple system atrophy(MSA) is an fatal neurological degenerative disease featured by parkinsonian symptoms, cerebellar symptoms and autonomic failure.It can be divided into the parkinsonian subtype if parkinsonism is the main feature and the cerebellar subtype if cerebellar features main.With its various clinical manifestations, especially in the early disease, it is easy to be misdiagnosed due to lack of obvious specificity.Now, the clinical manifestations, diagnosis and principles of therapy of multiple system atrophy were reviewed. Key words: Multiple system atrophy; Clinical manifestation; Diagnosis; Principle of therapy