Nonmotor Symptoms in Genetic Parkinson Disease

Kasten, Meike; Kertelge, L.; Brüggemann, Norbert; Vegt, Joyce van der; Schmidt, Alexander; Tadić, Vera; Buhmann, Carsten; Steinlechner, Susanne; Behrens, María Isabel; Ramı́rez, Alfredo; Binkofski, Ferdinand; Siebner, Hartwig R.; Raspe, Heiner; Hagenah, Johann; Lencer, Rebekka; Klein, Christine

doi:10.1001/archneurol.67.6.670

Cited by 59 publications

(50 citation statements)

References 27 publications

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“…Sex differences in other genes associated with PD have been examined in a small study of LRRK2, parkin, AT-P13A2, and PINK1 mutations (n 5 27) in the context of nonmotor signs and found that 48% were men. 31 However, in a larger study of GBA and parkin that included heterozygote carriers, 32 the sex distribution was similar to idiopathic PD.…”

Section: Resultsmentioning

confidence: 92%

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

et al. 2015

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Objective: Estimates of the penetrance of LRRK2 G2019S vary widely (24%-100%), reflective of differences in ascertainment, age, sex, ethnic group, and genetic and environmental modifiers. Methods:The kin-cohort method was used to predict penetrance in 2,270 relatives of 474 Ashkenazi Jewish (AJ) Parkinson disease (PD) probands in the Michael J. Fox LRRK2 AJ Consortium in New York and Tel Aviv, Israel. Patients with PD were genotyped for the LRRK2 G2019S mutation and at least 7 founder GBA mutations. GBA mutation carriers were excluded. A validated family history interview, including age at onset of PD and current age or age at death for each first-degree relative, was administered. Neurologic examination and LRRK2 genotype of relatives were included when available.Results: Risk of PD in relatives predicted to carry an LRRK2 G2019S mutation was 0.26 (95% confidence interval [CI] 0.18-0.36) to age 80 years, and was almost 3-fold higher than in relatives predicted to be noncarriers (hazard ratio [HR] 2.89, 95% CI 1.73-4.55, p , 0.001). The risk among predicted G2019S carrier male relatives (0.22, 95% CI 0.10-0.37) was similar to predicted carrier female relatives (0.29, 95% CI 0.18-0.40; HR male to female: 0.74, 95% CI 0.27-1.63, p 5 0.44). In contrast, predicted noncarrier male relatives had a higher risk (0.15, 95% CI 0.11-0.20) than predicted noncarrier female relatives (0.07, 95% CI 0.04-0.10; HR male to female: 2.40, 95% CI 1.50-4.15, p , 0.001). Conclusion:Penetrance of LRRK2 G2019S in AJ is only 26% and lower than reported in other ethnic groups. Further study of the genetic and environmental risk factors that influence G2019S penetrance is warranted. Neurology ® 2015;85:89-95 GLOSSARY AJ 5 Ashkenazi Jewish; CI 5 confidence interval; FHI 5 family history interview; GBA 5 glucocerebrosidase; HR 5 hazard ratio; PD 5 Parkinson disease.

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Section: Resultsmentioning

confidence: 92%

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

et al. 2015

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“…All of the therapeutic approaches outlined above aim at treating the dopaminergic motor symptoms of PD, which remain the current focus of therapy development. However, it is clear that PD pathology extends far beyond the dopaminergic nigrostriatal system, and that nonmotor symptoms such as cognitive impairment, dementia, depression, psychosis, and autonomic dysfunction significantly contribute to the complex battery of deficits PD patients face, even at early stages of the disease (Chaudhuri et al, 2006(Chaudhuri et al, , 2011Chaudhuri and Schapira, 2009;Kasten et al, 2010;Lim and Lang, 2010;Poewe, 2010;Wood et al, 2010;Bassetti, 2011) (Table 3). Because most of these symptoms do not respond to, but are often exacerbated by, the traditional dopamine replacement therapy and STN DBS, the development of pharmacotherapy that could alleviate these nonmotor symptoms, while being effective in reducing parkinsonian motor signs, represents one of the most important challenges both basic and clinical PD scientists may face in the years to come.…”

Section: /1989mentioning

confidence: 99%

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

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The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

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“…In prior studies covering the EU-5 nations, reported rates of hallucinations and delusions among patients with PD ranged from 10-45% in France, [34][35][36] 13-29% in Germany, 37,38 11-32% in Italy, [39][40][41] 15-42% in Spain 42,43 and 13-55% in the UK. 17,[44][45][46] These broad reported ranges highlight the difficulty of carrying out cross-study comparisons.…”

Section: Disruptiveness and Comorbidity Ratesmentioning

confidence: 99%

Parkinson’s Disease Psychosis – Prevalence Patterns Across the EU-5

Cook¹,

Suresh²,

Lou³

et al. 2017

European Neurological Review

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Parkinson's disease psychosis (PDP) is a clinical condition that affects patients diagnosed with Parkinson's disease (PD) and has a spectrum of neuropsychiatric symptoms distinct from the hallmark motor symptoms. Although prior studies have reported on the prevalence of PDP in select European nations, variations in study design complicate study-to-study comparisons. In this study, we surveyed 1,667 medical practitioners across France, Germany, Italy, Spain, and the UK (collectively, the EU-5) to estimate the prevalence of PDP or symptoms of psychosis among patients with PD. Analysis of the survey data suggest approximately 29% of the general PD population in the EU-5 exhibit signs of PDP. Among the PD population, country-specific rates of PDP are estimated at 30% in France, 27% in Germany, 34% in Italy, 30% in Spain and 21% in the UK. These rates appear in line with those reported in prior country-specific studies. Results from the subset of 437 neurologists who proceeded to take the full survey suggest the symptoms of PDP are disruptive to patients or their respective caregivers in approximately 53% of cases. These results provide a resource that enables cross-country comparison of PDP rates across these major European nations.

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Nonmotor Symptoms in Genetic Parkinson Disease

Cited by 59 publications

References 27 publications

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Parkinson’s Disease Psychosis – Prevalence Patterns Across the EU-5

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