Importance It is increasingly evident that Parkinson disease (PD) is not a single entity but rather a heterogeneous neurodegenerative disorder. Objective To evaluate available evidence, based on findings from clinical, imaging, genetic and pathologic studies, supporting the differentiation of PD into subtypes. Evidence Review We performed a systematic review of articles cited in PubMed between 1980 and 2013 using the following search terms: Parkinson disease, parkinsonism, tremor, postural instability and gait difficulty, and Parkinson disease subtypes . The final reference list was generated on the basis of originality and relevance to the broad scope of this review. Findings Several subtypes, such as tremor-dominant PD and postural instability gait difficulty form of PD, have been found to cluster together. Other subtypes also have been identified, but validation by subtype-specific biomarkers is still lacking. Conclusions and Relevance Several PD subtypes have been identified, but the pathogenic mechanisms underlying the observed clinicopathologic heterogeneity in PD are still not well understood. Further research into subtype-specific diagnostic and prognostic biomarkers may provide insights into mechanisms of neurodegeneration and improve epidemiologic and therapeutic clinical trial designs.

Parkinson Disease Subtypes

This article-the first of a five-part series-discusses possible causes, symptoms, diagnosis, and goals for treatment of Parkinson's disease. Identifying diseases that have similar presentations is an important component of the diagnostic process.

Parkinson's Disease and Its Management: Part 1: Disease Entity, Risk Factors, Pathophysiology, Clinical Presentation, and Diagnosis.

Summary Movement disorders, which include disorders such as Parkinson's disease, dystonia, Tourette's syndrome, restless legs syndrome, and akathisia, have traditionally been considered to be disorders of impaired motor control resulting predominantly from dysfunction of the basal ganglia This notion has been revised largely because of increasing recognition of associated behavioural, psychiatric, autonomic, and other non-motor symptoms The sensory aspects of movement disorders include intrinsic sensory abnormalities and the effects of external sensory input on the underlying motor abnormality The basal ganglia, cerebellum, thalamus, and their connections, coupled with altered sensory input, seem to play a key part in abnormal sensorimotor integration However, more investigation into the phenomenology and physiological basis of sensory abnormalities, and about the role of the basal ganglia, cerebellum, and related structures in somatosensory processing, and its effect on motor control, is needed

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Sensory aspects of movement disorders.

Genetics of Parkinson's disease.

Objective: To explore clinical phenotype and characteristics of Parkinson disease (PD) at different ages at onset in recently diagnosed patients with untreated PD. Methods: We have analyzed baseline data from the Parkinson9s Progression Markers Initiative database. Four hundred twenty-two patients with a diagnosis of PD confirmed by DaTSCAN imaging were divided into 4 groups according to age at onset (onset younger than 50 years, 50–59 years, 60–69 years, and 70 years or older) and investigated for differences in side, type and localization of symptoms, occurrence/severity of motor and nonmotor features, nigrostriatal function, and CSF biomarkers. Results: Older age at onset was associated with a more severe motor and nonmotor phenotype, a greater dopaminergic dysfunction on DaTSCAN, and reduction of CSF α-synuclein and total tau. The most common presentation was the combination of 2 or 3 motor symptoms (bradykinesia, resting tremor, and rigidity) with rigidity being more common in the young-onset group. In about 80% of the patients with localized onset, the arm was the most affected part of the body, with no difference across subgroups. Conclusions: Although the presentation of PD symptoms is similar across age subgroups, the severity of motor and nonmotor features, the impairment of striatal binding, and the levels of CSF biomarkers increase with age at onset. The variability of imaging and nonimaging biomarkers in patients with PD at different ages could hamper the results of future clinical trials.

Age at onset and Parkinson disease phenotype

Approximately 3.6% of patients with Parkinson's disease develop symptoms before age 45. Early-onset Parkinson's disease (EOPD) patients have a higher familial recurrence risk than late-onset patients, and 3 main recessive EOPD genes have been described. We aimed to establish the prevalence of mutations in these genes in a UK cohort and in previous studies. We screened 136 EOPD probands from a high-ascertainment regional and community-based prevalence study for pathogenic mutations in PARK2 (parkin), PINK1, PARK7 (DJ-1), and exon 41 of LRRK2. We also carried out a systematic review, calculating the proportion of cases with pathogenic mutations in previously reported studies. We identified 5 patients with pathogenic PARK2, 1 patient with PINK1, and 1 with LRRK2 mutations. The rate of mutations overall was 5.1%. Mutations were more common in patients with age at onset (AAO) 5800 unique cases. Overall, the weighted mean proportion of cases with PARK2 (parkin), PINK1, and PARK7 (DJ-1) mutations was 8.6%, 3.7%, and 0.4%, respectively. PINK1 mutations were more common in Asian subjects. The overall frequency of mutations in known EOPD genes was lower than previously estimated. Our study shows an increased likelihood of mutations in patients with lower AAO, family history, or parental consanguinity.

Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease

Background: Parkinson's disease (PD) is heterogeneous and age at onset may define variation in clinical phenotype. Most previous studies have used various age cut-offs and have been based on clinical case series. Methods: We have studied the association between clinical features and age of onset in 358 community-based and regional patients with PD. Results: Tremor at presentation is twice as common in those with onset over 64 years as compared to those with onset under 45 (early onset PD - EOPD) and becomes more common with increasing age at onset (p values for trend ≤ 0.004). Dystonia affects 60% of those with EOPD, shows a curvilinear relationship with age at onset (cubic versus linear p=0.01) with highest risk in patients whose disease began before 48 years. In this study age at onset was a strong predictor of the development of dyskinesias, with younger age associated with a higher risk of dyskinesias. Following multivariable analysis, allowing for possibly confounding factors (disease duration, L-DOPA dosage, L-DOPA treatment duration) younger age at onset, (less than 55 years) predicted the development of L-DOPA induced dyskinesia (odds ratio <45 years 2.1, 95% CI 1.0, 4.8; odds ratio < 55 years 3.8, 95% CI 1.8, 8.0). Only 2/70 (2.9%) EOPD patients carried pathogenic parkin or PINK1 mutations and the clinical differences between early and late onset disease were not explained by the presence of mutations in these genes. Discussion: This study highlights the clinical differences between early and late onset PD, which have important implications for diagnosis and management.

The motor phenotype of Parkinson's disease in relation to age at onset

The impact of Parkinson's disease on quality of life may vary depending on age at onset. We investigated the effect of age at onset on quality of life in a large Parkinson's disease population (n = 426) using a disease-specific rating scale (PDQ-39) and with careful adjustment for confounding and intermediary factors. We also explored the relationship between depression and excessive daytime sleepiness by age at onset and compared this with the general population. We found that a younger age at onset was significantly associated with worse overall quality of life scores (odds ratio, 2.66; 95% confidence interval, 1.39–5.09; P = .003), but this was attenuated by adjustment for depression as an intermediary factor (odds ratio, 1.86; 95% confidence interval, 0.84–4.11; P = .13). Younger onset was also a risk factor for poor emotional well-being independent of depression status. Risk of depression and excessive daytime sleepiness were elevated in patients with Parkinson's disease compared with controls (odds ratio, 2.99; 95% confidence interval, 1.93–4.65; P < .001; and odds ratio, 3.84; 95% confidence interval, 2.56–5.75; P < .001, respectively), with similar findings seen in both early- and late-onset groups. Our study highlights the need for accurate diagnosis and treatment of depression in younger-onset patients in order to improve quality of life.

M. Duleeka W Knipe

Papers

Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease

The motor phenotype of Parkinson's disease in relation to age at onset

Quality of life in young‐ compared with late‐onset Parkinson's disease