Elan D. Louis

The association of incident dementia with mortality in PD.

Objective: To evaluate the association of incident dementia with mortality in a cohort of patients with idiopathic PD who were nondemented at baseline evaluation, controlling for extrapyramidal sign (EPS) severity at each study visit. Background: The development of dementia has been associated with reduced survival in PD. Because EPS severity is associated with both dementia and mortality in PD, the association of dementia with mortality may be confounded by disease severity. Methods: A cohort of patients with PD was followed annually with neurologic and neuropsychological evaluations. The association of incident dementia and the total Unified PD Rating Scale (UPDRS) motor score with mortality in PD was examined using Cox proportional hazards models with time-dependent covariates. All analyses were adjusted for age at baseline, sex, years of education, ethnicity, and duration of PD. Results: Of 180 PD patients, 41 (22.8%) died during a mean follow-up period of 3.9 ± 2.2 years. Among those who died during the study period, 48.8% (20 of 41) became demented during follow-up, as compared to 23.0% (32 of 139) of those who remained alive. Both incident dementia (RR: 2.2, 95% CI: 1.1 to 4.5, p = 0.04) and the total UPDRS motor score at each study visit (RR: 1.04, 95% CI: 1.02 to 1.07, p = 0.001) were associated with mortality in PD when included in the same Cox model. Conclusions: Incident dementia has an independent effect on mortality when controlling for EPS severity. The development of dementia is associated with a twofold increased mortality risk in PD.

Motor impairment in PD Relationship to incident dementia and age

Objective: To analyze the relationship of specific motor impairment in idiopathic PD to incident dementia. Background: The total Unified PD Rating Scale (UPDRS) motor score at baseline has been associated with an increased risk of developing dementia in PD. Methods: A cohort of 214 nondemented community-dwelling patients with PD was followed annually with neurologic and neuropsychological evaluations. The association of baseline motor impairment with incident dementia was analyzed using Cox proportional hazards models. Facial expression, tremor, rigidity, and bradykinesia were analyzed as part of subscore A (indicative of dopaminergic deficiency); speech and axial impairment were analyzed as part of subscore B (indicative of predominantly nondopaminergic deficiency). The correlation between the six motor domains and age was also analyzed. Results: Of 173 patients followed for at least 1 year, 50 became demented according to the Diagnostic and Statistical Manual of Mental Disorders, revised 3rd edition (DSM III-R) criteria (mean follow-up, 3.6 ± 2.2 years). When both subscores A and B were entered into the Cox model, subscore B was associated with incident dementia (relative risk = 1.19; 95% CI, 1.09 to 1.30; p = 0.0001), in addition to gender, age, and education, whereas subscore A was not (relative risk = 1.03; 95% CI, 0.99 to 1.07; p = 0.19). Of the six motor domains, speech and bradykinesia were associated with incident dementia (p < 0.05), and axial impairment approached significance (p = 0.06). Only axial impairment was correlated with age (correlation coefficient = 0.32; p < 0.001). Conclusion: The findings suggest that motor impairment mediated predominantly by nondopaminergic systems is associated with incident dementia in PD. Axial impairment may be the result of a combined effect of the disease and the aging process.

Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease

Objective: To evaluate the frequency of glucocerebrosidase (GBA) mutations in cases and controls enrolled in the Genetic Epidemiology of Parkinson’s Disease (GEPD) study. Methods: We sequenced all exons of the GBA gene in 278 Parkinson disease (PD) cases and 179 controls enrolled in GEPD, with a wide range of age at onset (AAO), and that included a subset of 178 Jewish cases and 85 Jewish controls. Cases and controls were recruited without knowledge of family history of PD, and cases were oversampled in the AAO < 50 years category. Results: 13.7% of PD cases (38/278) carried GBA mutations, compared with 4.5% of controls (8/179) (odds ratio [OR] 3.4, 95% CI 1.5 to 7.4). The frequency of GBA mutations was 22.2% in 90 cases with AAO ≤ 50 years, compared with 9.7% in 185 cases with AAO > 50 years (OR 2.7, 95% CI 1.3 to 5.3). Adjusting for age at the time of evaluation, sex, family history of PD, and Jewish ancestry, GBA carriers had a 1.7-year-earlier AAO of PD (95% CI 0.5 to 3.3, p < 0.04) than noncarriers. The average AAO of PD was 2.5 years earlier in carriers with an AAO ≤ 50 years compared with noncarriers (95% CI 0.6 to 4.5, p < 0.01) and this was not seen in the AAO > 50 years group. The frequency of GBA mutations was higher in a subset of 178 cases that reported four Jewish grandparents (16.9%) than in cases who did not report Jewish ancestry (8.0%) (p < 0.01). Nine different GBA mutations were identified in PD cases, including 84insGG, E326K, T369M, N370S, D409H, R496H, L444P, RecNciI, and a novel mutation, P175P. Conclusions: This study suggests that the Glucocerebrosidase gene may be a susceptibility gene for Parkinson disease and that Glucocerebrosidase mutations may modify age at onset. GLOSSARY: AAO = age at onset; cDNA = complementary DNA; GBA = glucocerebrosidase; GD = Gaucher disease; GEPD = Genetic Epidemiology of Parkinson’s Disease; MMSE = Mini-Mental State Examination; NA = not applicable; DLB = dementia with Lewy bodies; OR = odds ratio; PD = Parkinson disease; SNP = single nucleotide polymorphism; UPDRS = Unified Parkinson’s Disease Rating Scale.

Frequency of LRRK2 mutations in early-and late-onset Parkinson disease

Objective: To evaluate the frequency of leucine-rich repeat kinase gene (LRRK2) mutations and single nucleotide polymorphisms (SNPs) in early-onset Parkinson disease (EOPD) and late-onset Parkinson disease (LOPD). Methods: We genotyped five previously reported LRRK2 mutations (G2019S, L1114L, I1122V, R1441C, and Y1699C) and 17 coding SNPs for haplotype analysis in 504 cases with PD and 314 controls enrolled in the Genetic Epidemiology of PD Study. Cases and controls were recruited without knowledge of family history of PD and cases were oversampled in the ≤50 age at onset (AAO) category. Results: The LRRK2 G2019S mutation was present in 28 cases with PD (5.6%) and two controls (0.6%) (χ2 = 13.25; p < 0.01; odds ratio 9.18, 95% CI: 2.17 to 38.8). The mutations L1114L, I1122V, R1441C, and Y1699C were not identified. The frequency of the LRRK2 G2019S mutation was 4.9% in 245 cases with AAO ≤50 years vs 6.2% in 259 cases with AAO >50 (p = 0.56). All cases with PD with the G2019S mutation shared the same disease-associated haplotype. The frequency of the LRRK2 G2019S mutation was higher in the subset of 181 cases reporting four Jewish grandparents (9.9%) than in other cases (3.1%) (p < 0.01). Age-specific penetrance to age 80 was 24% and was similar in Jewish and non-Jewish cases. Conclusions: The G2019S mutation is a risk factor in both early- and late-onset Parkinson disease and confirms the previous report of a greater frequency of the G2019S mutation in Jewish than in non-Jewish cases with Parkinson disease.

Cognitive performance of GBA mutation carriers with early-onset PD The CORE-PD study

Objective: To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD). Methods: We administered a neuropsychological battery and the University of Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age- and PD duration–matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment [MCI], dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed. Results: Demographics, UPSIT, and Unified Parkinsons Disease Rating Scale–III performance did not differ between GBA carriers and noncarriers. GBA mutation carriers performed more poorly than noncarriers on the Mini-Mental State Examination (p = 0.035), and on the memory (p = 0.017) and visuospatial (p = 0.028) domains. The most prominent differences were observed in nonverbal memory performance (p < 0.001). Carriers were more likely to receive scores of 0.5 or higher on the CDR (p < 0.001), and a clinical diagnosis of either MCI or dementia (p = 0.004). Conclusion: GBA mutation status may be an independent risk factor for cognitive impairment in patients with PD.

Spectrum of gait impairments in presymptomatic and symptomatic Huntington's disease.

The purpose of this study was to quantify gait impairments in presymptomatic and symptomatic Huntingtons disease (HD) subjects, and examine sensitivity of gait measures. Our sample (n = 65) included presymptomatic mutation carriers (PMC) (n = 15), symptomatic HD subjects (SHD) (n = 30) and healthy controls (n = 20). Participants were requested to walk at their preferred speed on a computerized walkway that recorded spatiotemporal variables. We administered the Unified HD Rating Scale (UHDRS) for PMC and SHD. PMC demonstrated decreased gait velocity (P < 0.01), stride length (P < 0.008), and increased time in double support (P < 0.001); and demonstrated higher variability in stride length (P < 0.01) and step time (P < 0.004) compared with controls. These impairments worsened with increasing disease severity for SHD. Gait impairments were correlated with predicted years to onset in PMC (velocity = −0.65; cadence = −0.70, step time = 0.71) and demonstrated high sensitivity and specificity in distinguishing between controls and mutation carriers. In contrast, UHDRS scores did not reveal impairments in gait and balance. Gait bradykinesia and dynamic balance impairments begin in the presymptomatic stage of HD and continue to worsen in the symptomatic stages. Gait measures are sensitive in differentiating between mutation positive and negative individuals even when impairments were not detected by clinical neurological examination.

Accuracy of family history data on Parkinson’s disease

Background: Genetic studies of PD frequently rely on family history interviews (FHI), yet the accuracy of data obtained in this way is unclear. Objective: To assess the interinformant reliability and validity of family history information on PD in first-degree relatives of PD cases and controls. Methods: A structured FHI was administered to nondemented PD cases and controls and to a second informant (self-report, sibling or child of the subject) for each relative. Interinformant agreement was assessed on four algorithm-derived diagnostic categories of PD: definite, definite or probable, definite, probable or possible (“conservative diagnosis”); or definite, probable, possible, or uncertain (“liberal diagnosis”). The sensitivity and specificity of each diagnostic category were assessed, using as the gold standard diagnoses based on either in-person examination or medical record review. Results: Five hundred thirty-six families containing 2,225 first-degree relatives were included in the interinformant reliability study. Agreement between informants was excellent for definite or probable PD for all three pairwise comparisons: proband vs self-report (κ = 0.92), proband vs sibling of subject (κ = 0.80), and proband vs child of subject (κ = 0.87). Agreement was also good to excellent for the conservative diagnosis (κ = 0.66, 0.49, and 0.79). In the validity analysis (141 individuals in 96 families), the conservative diagnosis provided the best combination of sensitivity (95.5%) and specificity (96.2%) for the proband’s family history report. No difference was apparent across categories defined by case or control status, relationship to the proband, or gender or age at onset of the proband. However, specificity was lower for deceased relatives than for living relatives. Conclusion: The FHI can be used to obtain reliable and valid family history information on PD in first-degree relatives when a conservative diagnostic algorithm is applied.

A single-blind, open-label trial of sodium oxybate for myoclonus and essential tremor

The authors performed an open-label, rater-blinded, add-on study of sodium oxybate in 20 patients with ethanol-responsive myoclonus or essential tremor. Blinded ratings of videotaped examinations showed improvements in myoclonus at rest, stimulus-sensitive myoclonus, action myoclonus, functional performance, and postural and kinetic tremor. Tolerability was acceptable, and more than half of the patients chose to continue treatment after the trial. Double-blind placebo-controlled studies in these disorders are warranted.

Risk of action tremor in relatives of tremor-dominant and postural instability gait disorder PD

Background: Action tremor may be more prevalent in relatives of patients with Parkinson’s disease (PD) than in relatives of control subjects. This tremor could represent mild PD or essential tremor. An estimate of the risk of this condition in families of patients with PD is important when studying the genetics of PD. Objectives: To determine the risk of action tremor in first-degree relatives of probands with tremor-dominant PD (TD-PD) and postural instability gait disorder PD (PIGD-PD) compared with first-degree relatives of control probands. Methods: PD and control probands participated in a familial aggregation study of PD. The presence of action tremor in their relatives was ascertained from reports of one or more informants. Relatives who met diagnostic criteria for PD were excluded. Cox proportional hazards models adjusting for gender, education, race, and vital status (dead vs alive) of the relatives were used to assess the relative risk (RR) of action tremor in first-degree relatives of PD probands vs first-degree relatives of control probands. Results: There were 487 PD probands, 409 control probands, and 5,563 relatives. The risk of action tremor was higher in the relatives of TD-PD probands than in the relatives of control probands (RR = 2.14; 95% CI = 1.53 to 2.98) but not in the relatives of PIGD-PD probands compared with the relatives of control probands (RR = 1.81; 95% CI = 0.66 to 5.02). Conclusion: The risk of action tremor was increased in the relatives of PD probands, particularly when they had TD-PD. Whether the tremor in these relatives represents essential tremor or an isolated manifestation of PD requires further investigation.

Postural and Intention Tremors: A Detailed Clinical Study of Essential Tremor vs. Parkinson’s Disease

Background: An estimated 30–50% of essential tremor (ET) diagnoses are incorrect, and the true diagnosis in those patients is often Parkinson’s disease (PD) or other tremor disorders. There are general statements about the tremor in these ET and PD, but published data on the more subtle characteristics of tremor are surprisingly limited. Postural tremor may occur in both disorders, adding to the difficulty. There are several anecdotal impressions regarding specific features of postural tremor in ET vs. PD, including joint distribution (e.g., phalanges, metacarpal-phalangeal joints, wrist), tremor directionality (e.g., flexion-extension vs. pronation-supination), and presence of intention tremor. However, there is little data to support these impressions. Methods: In this cross-sectional study, 100 patients (ET, 50 PD) underwent detailed videotaped neurological examinations. Arm tremor was rated by a movement disorder neurologist who assessed severity and directionality across multiple joints. Results: During sustained arm extension, ET patients exhibited more wrist than metacarpal-phalangeal and phalangeal joint tremor than did PD patients (pu2009<u20090.001), and more wrist flexion-extension tremor than wrist pronation-supination tremor (pu2009<u20090.001). During the finger-nose-finger maneuver, intention tremor was present in approximately one in four (28%) ET patients vs. virtually none (4%) of the Parkinson’s patients (pu2009<u20090.001). Conclusions: We evaluated the location, severity, and directionality of postural tremor in ET and PD, and the presence of intention tremor, observing several clinical differences. We hope that detailed phenomenological data on tremor in ET and PD will help practicing physicians delineate the two diseases.