Bradley Hiner

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.

Frequency of Known Mutations in Early-Onset Parkinson Disease: Implication for Genetic Counseling: The Consortium on Risk for Early Onset Parkinson Disease Study

OBJECTIVE To assess the frequency and clinical characteristics of carriers of previously identified mutations in 6 genes associated with early-onset Parkinson disease (PD) and provide empirical data that can be used to inform genetic counseling. DESIGN Cross-sectional observational study. SETTING Thirteen movement disorders centers. PATIENTS Nine hundred fifty-three individuals with early-onset PD defined as age at onset (AAO) younger than 51 years. Participants included 77 and 139 individuals of Hispanic and Jewish ancestry, respectively. Intervention Mutations in SNCA, PRKN, PINK1, DJ1, LRRK2, and GBA were assessed. A validated family history interview and the Unified Parkinson Disease Rating Scale were administered. Demographic and phenotypic characteristics were compared among groups defined by mutation status. Main Outcome Measure Mutation carrier frequency stratified by AAO and ethnic background. RESULTS One hundred fifty-eight (16.6%) participants had mutations, including 64 (6.7%) PRKN, 35 (3.6%) LRRK2 G2019S, 64 (6.7%) GBA, and 1 (0.2%) DJ1. Mutation carriers were more frequent in those with an AAO of 30 years or younger compared with those with AAO between 31 and 50 years (40.6% vs 14.6%, P < .001), in individuals who reported Jewish ancestry (32.4% vs 13.7%, P < .001), and in those reporting a first-degree family history of PD (23.9% vs 15.1%, P = .01). Hispanic individuals were more likely to be PRKN carriers than non-Hispanic individuals (15.6% vs 5.9%, P = .003). The GBA L444P mutation was associated with a higher mean Unified Parkinson Disease Rating Scale III score after adjustment for covariates. CONCLUSION Individuals of Jewish or Hispanic ancestry with early-onset PD, those with AAO of 30 years or younger, and those with a history of PD in a first-degree relative may benefit from genetic counseling.

Motor Phenotype of LRRK2 G2019S Carriers in Early-Onset Parkinson Disease

OBJECTIVE To determine the motor phenotype of LRRK2 G2019S mutation carriers. LRRK2 mutation carriers were previously reported to manifest the tremor dominant motor phenotype, which has been associated with slower motor progression and less cognitive impairment compared with the postural instability and gait difficulty (PIGD) phenotype. DESIGN Cross-sectional observational study. SETTING Thirteen movement disorders centers. PARTICIPANTS Nine hundred twenty-five early-onset Parkinson disease cases defined as age at onset younger than 51 years. MAIN OUTCOME MEASURES LRRK2 mutation status and Parkinson disease motor phenotype: tremor dominant or PIGD. Demographic information, family history of Parkinson disease, and the Unified Parkinsons Disease Rating Scale score were collected on all participants. DNA samples were genotyped for LRRK2 mutations (G2019S, I2020T, R1441C, and Y1699C). Logistic regression was used to examine associations of G2019S mutation status with motor phenotype adjusting for disease duration, Ashkenazi Jewish ancestry, levodopa dose, and family history of Parkinson disease. RESULTS Thirty-four cases (3.7%) (14 previously reported) were G2019S carriers. No other mutations were found. Carriers were more likely to be Ashkenazi Jewish (55.9% vs 11.9%; P < .001) but did not significantly differ in any other demographic or disease characteristics. Carriers had a lower tremor score (P = .03) and were more likely to have a PIGD phenotype (92.3% vs 58.9%; P = .003). The association of the G2019S mutation with PIGD phenotype remained after controlling for disease duration and Ashkenazi Jewish ancestry (odds ratio, 17.7; P < .001). CONCLUSION Early-onset Parkinson disease G2019S LRRK2 carriers are more likely to manifest the PIGD phenotype, which may have implications for disease course.

Self-report of cognitive impairment and Mini-Mental State Examination performance in PRKN, LRRK2, and GBA carriers with early onset Parkinson's disease

While little is known about risk factors for cognitive impairment in early onset Parkinson disease (EOPD), postmortem studies have shown an association between dementia with Lewy bodies (DLB) and glucocerebrosidase (GBA) mutation. We compared Mini-Mental State Examination (MMSE) performance and self-reported cognitive impairment in 699 EOPD participants genotyped for mutations in parkin (PRKN), leucine-rich repeat kinase-2 (LRRK2), and GBA. Logistic regression was used to assess the association between reported cognitive impairment and MMSE score, as well as between GBA group membership and self-reported impairment and MMSE. GBA carriers reported more impairment, but MMSE performance did not differ among genetic groups. Detailed neuropsychological testing is required to explore the association between cognitive impairment and GBA mutations.

Where is the action? Action sentence processing in Parkinson's disease

According to an influential view of conceptual representation, action concepts are understood through motoric simulations, involving motor networks of the brain. A stronger version of this embodied account suggests that even figurative uses of action words (e.g., grasping the concept) are understood through motoric simulations. We investigated these claims by assessing whether Parkinsons disease (PD), a disorder affecting the motor system, is associated with selective deficits in comprehending action-related sentences. Twenty PD patients and 21 age-matched controls performed a sentence comprehension task, where sentences belonged to one of four conditions: literal action, non-idiomatic metaphoric action, idiomatic action, and abstract. The same verbs (referring to hand/arm actions) were used in the three action-related conditions. Patients, but not controls, were slower to respond to literal and idiomatic action than to abstract sentences. These results indicate that sensory-motor systems play a functional role in semantic processing, including processing of figurative action language.

Cognitive and Motor Function in Long-Duration PARKIN-Associated Parkinson Disease

IMPORTANCE Data on the long-term cognitive outcomes of patients with PARKIN-associated Parkinson disease (PD) are unknown but may be useful when counseling these patients. OBJECTIVE Among patients with early-onset PD of long duration, we assessed cognitive and motor performances, comparing homozygotes and compound heterozygotes who carry 2 PARKIN mutations with noncarriers. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of 44 participants at 17 different movement disorder centers who were in the Consortium on Risk for Early-Onset PD study with a duration of PD greater than the median duration (>14 years): 4 homozygotes and 17 compound heterozygotes (hereafter referred to as carriers) and 23 noncarriers. MAIN OUTCOMES AND MEASURES Unified Parkinson Disease Rating Scale Part III (UPDRS-III) and Clinical Dementia Rating scores and neuropsychological performance. Linear regression models were applied to assess the association between PARKIN mutation status and cognitive domain scores and UPDRS-III scores. Models were adjusted for age, education, disease duration, language, and levodopa equivalent daily dose. RESULTS Carriers had an earlier age at onset of PD (P < .001) and were younger (P = .004) at time of examination than noncarriers. They performed better than noncarriers on the Mini-Mental State Examination (P = .010) and were more likely to receive lower scores on the Clinical Dementia Rating (P = .003). In multivariate analyses, carriers performed better than noncarriers on the UPDRS-III (P = .02) and on tests of attention (P = .03), memory (P = .03), and visuospatial (P = .02) cognitive domains. CONCLUSIONS AND RELEVANCE In cross-sectional analyses, carriers demonstrated better cognitive and motor performance than did noncarriers with long disease duration, suggesting slower disease progression. A longitudinal follow-up study is required to confirm these findings.

Spectral signal space projection algorithm for frequency domain MEG and EEG denoising, whitening, and source imaging

MEG and EEG data contain additive correlated noise generated by environmental and physiological sources. To suppress this type of spatially coloured noise, source estimation is often performed with spatial whitening based on a measured or estimated noise covariance matrix. However, artifacts that span relatively small noise subspaces, such as cardiac, ocular, and muscle artifacts, are often explicitly removed by a variety of denoising methods (e.g., signal space projection) before source imaging. Here, we introduce a new approach, the spectral signal space projection (S(3)P) algorithm, in which time-frequency (TF)-specific spatial projectors are designed and applied to the noisy TF-transformed data, and whitened source estimation is performed in the TF domain. The approach can be used to derive spectral variants of all linear time domain whitened source estimation algorithms. The denoised sensor and source time series are obtained by the corresponding inverse TF-transform. The method is evaluated and compared with existing subspace projection and signal separation techniques using experimental data. Altogether, S(3)P provides an expanded framework for MEG/EEG data denoising and whitened source imaging in both the time and frequency/scale domains.

Lack of overlap in genetic risks for Alzheimer's disease and Parkinson's disease

We explored the question of genetic overlap between Alzheimers disease (AD) and Parkinsons disease (PD) because evidence suggests clinical, pathologic, and epidemiologic overlap between the two disorders. We compared the frequency of AD and PD between the first-degree relatives of probands with AD and PD and first-degree relatives of spouse control subjects. Using life-table methods, we found increased risk of AD in first-degree relatives of patients with AD and an increased risk of PD in first-degree relatives of patients with PD. The risk of PD in first-degree relatives of patients with AD was not increased, nor was the risk of AD in first-degree relatives of patients with PD increased. These data do not support the hypothesis that important genetic overlap exists between AD and PD.

Characteristic Pulvinar Sign in Pseudo-α-galactosidase Deficiency Syndrome

Pseudo-α-galactosidase deficiency (PAGD) syndrome occurs when a mutation reduces measured enzyme activity in vitro, despite normal intracellular activity. White matter lesions have been reported infrequently in PAGD syndrome.1 Importantly, to our knowledge, no report mentions characteristic pulvinar hyperintensity on T1-weighted imaging in PAGD syndrome, a highly specific sign of Fabry disease in male patients.2,3 Although atrophy of selective brain areas occurs in a few cases, to our knowledge, no article reports diffuse cortical atrophy by imaging in Fabry disease or PAGD syndrome.1,4 We report a case of a woman in her 40s with a 3-year history of a complex progressive disorder with emotional lability, cognitive decline, generalized ataxia, and autonomic dysfunction. She denied paresthesias, dysesthesias, or loss of sensation. Metabolic testing showed reduced activity of α-galactosidase (0.056 U/L; normal range, 0.074-0.457 U/L). Autonomic testing demonstrated abnormal cardiac parasympathetic function (but no orthostatic hypotension) and a patchy decrease in sweat output on the quantitative sudomotor axon reflex test as well as a markedly abnormal thermoregulatory sweat test, with near complete global anhidrosis. Repeated magnetic resonance imaging (Figure) compared with one the prior year at an outside hospital showed unchanged global diffuse brain volume loss and bilateral mineralization of the pulvinar region of thalami (manifesting as hyperintensity in the pulvinar on T1-weighted imaging). Genetic testing showed the presence of the pseudo-α-galactosidase allele. Neuropsychological testing done in view of diffuse cortical atrophy showed mild neurocognitive and memory deficits (Table), and the patient was diagnosed with mild neurocognitive disorder. Magnetic resonance imaging of the entire spine showed no spinal cord lesions. Cerebrospinal fluid analysis showed elevated protein levels (95 mg/dL) but no pleocytosis (white blood cell counts: 0/μL; polymorphonucleocytes: 7%; lymphocytes: 83%; monocytes: 9%).

Deep brain stimulator artifact in needle electromyography: Effects and distribution in paraspinal and upper limb muscle

Introduction: Deep brain stimulators (DBS) have become a more widespread treatment option for individuals with centrally mediated movement disorders. Such devices are expected to create artifact in standard needle electromyographic (EMG) recordings. Methods: Five subjects with DBS were studied with standard concentric needle electrode EMG in paraspinal and upper limb muscles. Results: All subjects showed EMG artifact directly related to, and corresponding with, the DBS unit settings. The artifact was very prominent in all paraspinal muscles, although the amplitude was less in lumbar compared with cervical levels. With a large ground electrode next to the insertion site, the artifact was sufficiently small to allow standard EMG examination of upper limb muscles. Conclusions: The DBS artifact is so prominent in paraspinal muscles that it will not allow standard EMG examination for diagnostic purposes such as radiculopathy. The artifact itself can easily be distinguished from pathological insertional and spontaneous activity. Muscle Nerve, 2013