Capgras Syndrome in Advanced Parkinson's Disease.

Psychosis is common in Parkinson's disease (PD), especially in advanced disease, and can lead to a number of psychotic symptoms, including delusions. One uncommon delusion is Capgras syndrome (CS). The authors report on three PD patients with a history of deep brain stimulation (DBS) who developed this delusion. The anatomic targets in these three patients were the subthalamic nuclei in two patients and the globus pallidus interna in one patient. The length of time between surgery and development of CS varied but was greater than 6 months. Additionally, all three patients showed evidence of impaired cognition prior to development of CS. Therefore, due to the length of time between DBS and CS in all three cases and the fact that one patient developed CS months after DBS explanation, DBS does not appear to be associated with CS. Given the distressing nature of this condition, patients with advanced PD who undergo DBS should be regularly screened for symptoms of psychosis with awareness of CS as a potential form.

Relationship of age of onset and family history in Parkinson disease.

BACKGROUND: The aim of this study was to determine whether age of onset of Parkinson disease (PD) is associated with differences in PD risk and PD age of onset in parents and siblings. METHODS: Clinical and detailed family history data were available for 1,114 PD probands. RESULTS: Proband age of onset was not associated with differences in PD prevalence or PD age of onset in parents. Proband age of PD onset <50, compared with ≥ 50 years, was associated with significantly greater risk of PD in siblings (hazard ratio: 2.4; P=0.002; 95% confidence interval: 1.4, 4.1), and proband age of onset was significantly correlated with sibling age of onset (Somer's D=0.20; P=0.018). CONCLUSIONS: Proband age of PD onset is not associated with differences in parental PD risk. Siblings of PD patients with onset before age 50 are at increased risk of PD and are more likely to have early-onset disease.

Mortality in levodopa-treated Parkinson's disease.

Parkinson's disease (PD) is associated with increased mortality despite many advances in treatment. Following the introduction of levodopa in the late 1960's, many studies reported improved or normalized mortality rates in PD. Despite the remarkable symptomatic benefits provided by levodopa, multiple recent studies have demonstrated that PD patients continue to die at a rate in excess of their peers. We undertook this retrospective study of 211 deceased PD patients to determine the factors associated with mortality in levodopa-treated PD. Our findings confirm that PD is associated with increased mortality in both men and women. Unlike the majority of other mortality studies, we found that women have a greater reduction in lifespan compared to men. We also found that patients with early onset PD (onset at the age of 50 or before) have reduced survival relative to PD patients with later ages of onset. A final important finding is that survival is equal in PD patients treated with levodopa early (within 2 years or less of PD onset) versus later.

The risky business of dopamine agonists in Parkinson disease and impulse control disorders.

Risk-taking behavior is characterized by pursuit of reward in spite of potential negative consequences. Dopamine neurotransmission along the mesocorticolimbic pathway is a potential modulator of risk behavior. In patients with Parkinson's disease (PD), impulse control disorder (ICD) can result from dopaminergic medication use, particularly dopamine agonists (DAA). Behaviors associated with ICD include hypersexuality as well as compulsive gambling, shopping, and eating, and these behaviors are potentially linked to alterations to risk processing. Using the Balloon Analogue Risk Task, we assessed the role of agonist therapy on risk-taking behavior in PD patients with (n = 22) and without (n = 19) active ICD symptoms. Patients performed the task both "on" and "off" DAA. DAA increased risk-taking in PD patients with active ICD symptoms, but it did not affect risk behavior of PD controls. DAA dose was also important in explaining risk behavior. Both groups similarly reduced their risk-taking in high compared to low risk conditions and following the occurrence of a negative consequence, suggesting that ICD patients do not necessarily differ in their abilities to process and adjust to some aspects of negative consequences. Our findings suggest dopaminergic augmentation of risk-taking behavior as a potential contributing mechanism for the emergence of ICD in PD patients.

Handedness and motor symptom asymmetry in Parkinson's disease.

BACKGROUND: The objective of this study was to confirm whether an association between handedness and the side of symptom onset exists and to evaluate the impact of this association on specific clinical characteristics of Parkinson's disease (PD). METHODS: 1173 PD patients were identified from a clinical database. Patients with asymmetrical onset (n=1015) were divided into those with dominant-side onset and those with non-dominant-side onset, and the clinical characteristics of the two subgroups were compared. RESULTS: In our PD sample, 86.5% of patients presented asymmetrically. There was a significant association between handedness and the side of the initial symptom; that is, the dominant side was affected first in the majority of both left- and right-handed patients. Compared with patients with non-dominant side onset, more patients with dominant-side onset presented with bradykinesia, while fewer patients presented with gait difficulty. Patients with dominant-side onset were diagnosed and began dopaminergic medication after a longer symptom duration than patients with non-dominant-side onset. The only difference in Unified Parkinson Disease Rating Scale scores between the two groups was in a subscore addressing dominant-hand tasks. CONCLUSIONS: An association exists between the dominant hand and the side of the initial motor symptom in PD. Whether the initial symptom occurs on the dominant or non-dominant side has implications for the reported first symptom, the time to diagnosis and the time to dopaminergic treatment initiation. The side of disease onset does not affect the severity of disease, as measured by the Unified Parkinson Disease Rating Scale.

UPDRS activity of daily living score as a marker of Parkinson's disease progression.

The activities of daily living (ADL) subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) captures the impact of Parkinson's disease (PD) on daily function and may be less affected than other subsections by variability associated with drug cycle and motor fluctuations. We examined UPDRS mentation, ADL and motor subscores in 888 patients with idiopathic PD. Multiple linear regression analyses determined the association between disease duration and UPDRS subscores as a function of medication status at examination and in a subset of patients with multiple examinations. Independent of medication status and across cross-sectional and longitudinal analyses, ADL subscores showed a stronger and more stable association with disease duration than other UPDRS subscores after adjusting for age of disease onset. The association between disease duration and the motor subscore depended on medication status. The strong association between ADL subscore and disease duration in PD suggests that this measure may serve as a better marker of disease progression than signs and symptoms assessed in other UPDRS sections.

The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study.

BACKGROUND: We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD. METHODS: A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample. RESULTS: Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families. CONCLUSION: Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

Huntington CAG repeat size does not modify onset age in familial Parkinson's disease: the GenePD study.

The ATP/ADP ratio reflects mitochondrial function and has been reported to be influenced by the size of the Huntington disease gene (HD) repeat. Impaired mitochondrial function has long been implicated in the pathogenesis of Parkinson's disease (PD), and therefore, we evaluated the relationship of the HD CAG repeat size to PD onset age in a large sample of familial PD cases. PD affected siblings (n = 495), with known onset ages from 248 families, were genotyped for the HD CAG repeat. Genotyping failed in 11 cases leaving 484 for analysis, including 35 LRRK2 carriers. All cases had HD CAG repeats (range, 15-34) below the clinical range for HD, although 5.2% of the sample (n = 25) had repeats in the intermediate range (the intermediate range lower limit = 27; upper limit = 35 repeats), suggesting that the prevalence of intermediate allele carriers in the general population is significant. No relation between the HD CAG repeat size and the age at onset for PD was found in this sample of familial PD.

Validity, sensitivity and specificity of the mentation, behavior and mood subscale of the UPDRS.

OBJECTIVE: The unified Parkinson's disease rating scale (UPDRS) is the most widely used tool to rate the severity and the stage of Parkinson's disease (PD). However, the mentation, behavior and mood (MBM) subscale of the UPDRS has received little investigation regarding its validity and sensitivity. Three items of this subscale were compared to criterion tests to examine validity, sensitivity and specificity. METHODS: Ninety-seven patients with idiopathic PD were assessed on the UPDRS. Scores on three items of the MBM subscale, intellectual impairment, thought disorder and depression, were compared to criterion tests, the telephone interview for cognition status (TICS), psychiatric assessment for psychosis and the geriatric depression scale (GDS). Non-parametric tests of association were performed to examine concurrent validity of the MBM items. The sensitivities, specificities and optimal cutoff scores for each MBM item were estimated by receiver operating characteristic (ROC) curve analysis. RESULTS: The MBM items demonstrated low to moderate correlation with the criterion tests, and the sensitivity and specificity were not strong. Even using a score of 7.0 on the items of the MBM demonstrated a sensitivity/specificity of only 0.19/0.48 for intellectual impairment, 0.60/0.72 for thought disorder and 0.61/0.87 for depression. Using a more appropriate cutoff of 2.0 revealed sensitivities of 0.01, 0.38 and 0.13 respectively. DISCUSSION: The MBM subscale items of intellectual impairment, thought disorder and depression are not appropriate for screening or diagnostic purposes. Tools such as the TICS and the GDS should be considered instead.

G2019S mutation in the leucine-rich repeat kinase 2 gene is not associated with multiple system atrophy.

Multiple system atrophy (MSA) is characterized clinically by Parkinsonism, cerebellar dysfunction, and autonomic impairment. Multiple mutations in the LRRK2 gene are associated with parkinsonian disorders, and the most common one, the G2019S mutation, has been found in approximately 1% of sporadic cases of Parkinsonism. In a well-characterized cohort of 136 subjects with probable MSA and 110 neurologically evaluated control subjects, none carried the G2019S mutation. We conclude that the G2019S mutation in the LRRK2 gene is unlikely to be associated with MSA.

Preliminary FMRI evidence of visual system dysfunction in Parkinson's disease patients with visual hallucinations.

Using functional magnetic resonance imaging (fMRI), the authors examined visual cortex function in Parkinson's disease patients who did and did not experience visual hallucinations. Patients with visual hallucinations demonstrated increased activation in the visual association cortex and deficits in the primary visual cortex, suggesting that visual hallucinations are associated with an abnormality of visual-cortex function.

Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the GenePD study.

BACKGROUND: The PARK2 gene at 6q26 encodes parkin, whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD). OBJECTIVE: To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members. DESIGN: Clinical and genetic study. SETTING: Twenty collaborative clinical sites. PATIENTS: Patients with familial PD collected in the GenePD study. Studied families were selected for (1) affected sibling pairs sharing 2 alleles identical by state at PARK2 (D6S305) or (2) 1 or more family members with onset age younger than 54 years, regardless of D6S305 status. At least 1 member from each of 183 families underwent comprehensive screening for deletion/insertion variants and point mutations in PARK2. MAIN OUTCOME MEASURES: Mutations in the parkin gene were screened by means of single-stranded conformation polymorphism and sequencing in all 12 coding exons and flanking intronic sequences for point mutations and duplex quantitative polymerase chain reaction in all exons for rearrangement, duplication, and deletion. RESULTS: Mutations were found in 23 families (12.6% of those screened). Among the mutation-positive families, 10 (43%) contained compound heterozygotes; 3 (13%), homozygotes; and 10 (43%), heterozygotes. The onset age in patients with parkin gene mutations ranged from 20 to 76 years. Patients with 1 parkin mutation had an 11.7-year age at onset than did patients with none (P = .04), and patients with 2 or more parkin mutations had a 13.2-year decrease in age at onset compared with patients with 1 mutation (P = .04). CONCLUSIONS: These data indicate that parkin mutations are not rare in multiply affected sibships, and that heterozygous mutation carrier status in PARK2 significantly influences age at onset of PD.

Depression is associated with impairment of ADL, not motor function in Parkinson disease.

Depression was diagnosed in 15% of 100 consecutive patients with Parkinson disease (PD). Depression was associated with lower cognition, history of depression, and a higher Unified Parkinson's Disease Rating Scale score. The latter was due to differences in the activities of daily living (ADL) subscale (17 +/- 7 vs 12 +/- 6; p = 0.004) rather than the motor subscale (30 +/- 13 vs 26 +/- 13; p = 0.27). These results suggest that ADL impairment may in part be due to depression. Patients with PD with poor function should be closely evaluated for depression.