Faculty Bibliography

OBJECTIVE: Multiple system atrophy (MSA), the most common of the atypical parkinsonian disorders, is characterized by the presence of an abnormal spatial covariance pattern in resting state metabolic brain images from patients with this disease. Nonetheless, the potential utility of this pattern as a MSA biomarker is contingent upon its specificity for this disorder and its relationship to clinical disability in individual patients. METHODS: We used [(18)F]fluorodeoxyglucose PET to study 33 patients with MSA, 20 age- and severity-matched patients with idiopathic Parkinson disease (PD), and 15 healthy volunteers. For each subject, we computed the expression of the previously characterized metabolic covariance patterns for MSA and PD (termed MSARP and PDRP, respectively) on a prospective single-case basis. The resulting network values for the individual patients were correlated with clinical motor ratings and disease duration. RESULTS: In the MSA group, disease-related pattern (MSARP) values were elevated relative to the control and PD groups (p < 0.001 for both comparisons). In this group, MSARP values correlated with clinical ratings of motor disability (r = 0.57, p = 0.0008) and with disease duration (r = -0.376, p = 0.03). By contrast, MSARP expression in the PD group did not differ from control values (p = 1.0). In this group, motor ratings correlated with PDRP (r = 0.60, p = 0.006) but not with MSARP values (p = 0.88). CONCLUSIONS: MSA is associated with elevated expression of a specific disease-related metabolic pattern. Moreover, differences in the expression of this pattern in patients with MSA correlate with clinical disability. The findings suggest that the MSARP may be a useful biomarker in trials of new therapies for this disorder.

OBJECTIVE: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. METHODS: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. RESULTS: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. CONCLUSIONS: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.

OBJECTIVE: Genome-wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility. METHODS: A 2-stage design was used. First, individual level genotypic data from 5 recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 single-nucleotide polymorphisms (SNPs) were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls). RESULTS: Genome-wide significance was reached for SNPs in SNCA (rs356165; G: odds ratio [OR]=1.37; p=9.3x10(-21)), MAPT (rs242559; C: OR=0.78; p=1.5x10(-10)), GAK/DGKQ (rs11248051; T: OR=1.35; p=8.2x10(-9)/rs11248060; T: OR=1.35; p=2.0x10(-9)), and the human leukocyte antigen (HLA) region (rs3129882; A: OR=0.83; p=1.2x10(-8)), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K; OR=1.71; p=5x10(-8) Combined Sample) (N370; OR=3.08; p=7x10(-5) Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5x10(-5) Discovery Sample; p=1.52x10(-7) Replication sample; p=2x10(-10) Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes. INTERPRETATION: We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA.

BACKGROUND: Essential tremor (ET) is among the most misdiagnosed neurological diseases, and overdiagnosis is especially common. As many as 30-50% of supposed 'ET' cases have other diagnoses, with dystonia prominent among these. Therefore, the recognition of differences in tremor phenomenology has potential diagnostic value for practising clinicians. There is an anecdotal sense that head tremor in ET is positional rather than resting, a feature which could aid in the diagnosis, yet no published data exist. METHODS: In this cross-sectional study of ET and spasmodic torticollis (ST) patients (3:1 matching) who had head tremor while upright, the prevalence of supine (ie, resting) head tremor was compared. RESULTS: There were 60 ET cases and 19 ST cases with head tremor while seated. When supine, head tremor persisted in only 5/60 (8.3%) ET versus 13/19 (68.4%) ST cases (p<0.001), indicating that essential head tremor is more likely to resolve in the supine position than is the head tremor of ST. Supine head tremor, when present in ET, did not seem to preferentially occur in patients with more severe disease (p>0.05). CONCLUSIONS: These results indicate that there is some validity to the anecdotal sense that head tremor in ET is a postural tremor that dissipates when a patient lies down; by contrast, in ST, head tremor more often persists. In a clinical context, these results have potential implications in diagnostically ambiguous patients with head tremor. Physicians should consider asking their tremor patients to lie down to assess whether head tremor resolves.

Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) is an episodic movement disorder with autosomal-dominant inheritance and high penetrance, but the causative genetic mutation is unknown. We have now identified four truncating mutations involving the gene PRRT2 in the vast majority (24/25) of well-characterized families with PKD/IC. PRRT2 truncating mutations were also detected in 28 of 78 additional families. PRRT2 encodes a proline-rich transmembrane protein of unknown function that has been reported to interact with the t-SNARE, SNAP25. PRRT2 localizes to axons but not to dendritic processes in primary neuronal culture, and mutants associated with PKD/IC lead to dramatically reduced PRRT2 levels, leading ultimately to neuronal hyperexcitability that manifests in vivo as PKD/IC.

BACKGROUND: Careful characterization of the phenotype and genotype of Huntington disease (HD) can foster better understanding of the condition. METHODS: We conducted a cohort study in the United States, Canada, and Australia of members of families affected by HD. We collected demographic and clinical data, conducted the Unified Huntington's Disease Rating Scale and Mini-Mental State Examination, and determined Huntingtin trinucleotide CAG repeat length. We report primarily on cross-sectional baseline data from this recently completed prospective, longitudinal, observational study. RESULTS: As of December 31, 2009, 2,318 individuals enrolled; of these, 1,985 (85.6%) were classified into six analysis groups. Three groups had expanded CAG alleles (36 repeats or more): individuals with clinically diagnosed HD [n = 930], and clinically unaffected first-degree relatives who had previously pursued [n = 248] or not pursued [n = 112] predictive DNA testing. Three groups lacked expanded alleles: first-degree relatives who had previously pursued [n = 41] or not pursued [n = 224] genetic testing, and spouses and caregivers [n = 430]. Baseline mean performance differed across groups in all motor, behavioral, cognitive, and functional measures (p<0.001). Clinically unaffected individuals with expanded alleles weighed less (76.0 vs. 79.6 kg; p = 0.01) and had lower cognitive scores (28.5 vs. 29.1 on the Mini Mental State Examination; p = 0.008) than individuals without expanded alleles. The frequency of "high normal" repeat lengths (27 to 35) was 2.5% and repeat lengths associated with reduced penetrance (36 to 39) was 2.7%. CONCLUSION: Baseline analysis of COHORT study participants revealed differences that emerge prior to clinical diagnosis. Longitudinal investigation of this cohort will further characterize the natural history of HD and genetic and biological modifiers. TRIAL REGISTRATION: Clinicaltrials.gov NCT00313495.

BACKGROUND: Mutations in parkin are a known genetic risk factor for early onset Parkinson's disease (EOPD) but their role in non-motor manifestations is not well established. Genetic factors for depression are similarly not well characterized. We investigate the role of parkin mutations in depression among those with EOPD and their relatives. METHODS: We collected psychiatric information using the Patient Health Questionnaire and Beck Depression Inventory II on 328 genotyped individuals including 88 probands with early onset PD (41 with parkin mutations, 47 without) and 240 first and second-degree relatives without PD. RESULTS: Genotype was not associated with depression risk among probands. Among unaffected relatives of EOPD cases, only compound heterozygotes (n = 4), and not heterozygotes, had significantly increased risk of depressed mood (OR = 14.1; 95% CI 1.2-163.4), moderate to severe depression (OR = 17.8; 95% CI 1.0-332.0), depression (score >/= 15) on the Beck Depression Inventory II (BDI-II) (OR = 51.9; 95% CI 4.1-657.4), and BDI-II total depression score (beta = 8.4; 95% CI 2.4-11.3) compared to those without parkin mutations. CONCLUSIONS: Relatives of EOPD cases with compound heterozygous mutations and without diagnosed PD may have a higher risk of depression compared to relatives without parkin mutations. These findings support evidence of a genetic contribution to depression and may extend the phenotypic spectrum of parkin mutations to include non-motor manifestations that precede the development of PD.