Apathy in patients with Parkinson's disease following deep brain stimulation of the subthalamic nucleus.

OBJECTIVE: Apathy has been reported as a possible adverse effect of deep brain stimulation of the subthalamic nucleus (STN-DBS). We investigated the prevalence and severity of apathy in 22 patients with Parkinson's disease (PD) who underwent STN-DBS, as well as the effects of apathy on quality of life (QOL). METHODS: All patients were assessed with the Lille Apathy Rating Scale (LARS), the Apathy Scale (AS), and the Parkinson's Disease Questionnaire and were compared to a control group of 38 patients on pharmacotherapy alone. RESULTS: There were no significant differences in the prevalence or severity of apathy between patients who had undergone STN-DBS and those on pharmacotherapy alone. Significant correlations were observed between poorer QOL and degree of apathy, as measured by the LARS (p<0.001) and the AS (p=0.021). PD-related disability also correlated with both apathy ratings (p<0.001 and p=0.017, respectively). CONCLUSION: Our findings suggest that STN-DBS is not necessarily associated with apathy in the PD population; however, more severe apathy appears to be associated with a higher level of disability due to PD and worse QOL, but no other clinico-demographic characteristics.

Phenotypic insights into ADCY5-associated disease.

BACKGROUND: Adenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal-dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations. METHODS: In 5 of the 7 patients, followed over a period of 9 to 32 years, ADCY5 was sequenced by Sanger sequencing. The other 2 unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders and underwent whole-exome sequencing. RESULTS: Five patients had the previously reported p.R418W ADCY5 mutation; we also identified two novel mutations at p.R418G and p.R418Q. All patients presented with motor milestone delay, infantile-onset action-induced generalized choreoathetosis, dystonia, or myoclonus, with episodic exacerbations during drowsiness being a characteristic feature. Axial hypotonia, impaired upward saccades, and intellectual disability were variable features. The p.R418G and p.R418Q mutation patients had a milder phenotype. Six of seven patients had mild functional gain with clonazepam or clobazam. One patient had bilateral globus pallidal DBS at the age of 33 with marked reduction in dyskinesia, which resulted in mild functional improvement. CONCLUSION: We further delineate the clinical features of ADCY5 gene mutations and illustrate its wide phenotypic expression. We describe mild improvement after treatment with clonazepam, clobazam, and bilateral pallidal DBS. ADCY5-associated dyskinesia may be under-recognized, and its diagnosis has important prognostic, genetic, and therapeutic implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Theory of mind deficits in Parkinson's disease: a product of executive dysfunction?

OBJECTIVE: Patients with Parkinson's disease (PD) can perform poorly on tasks involving theory of mind (ToM): the ability to reason about mental states. We investigated whether patients' ToM deficits were independent of executive dysfunction. METHOD: Experiment 1 aimed to establish that ToM deficits were present, and 2 following experiments manipulated the working memory (WM) demands of the ToM task. RESULTS: In Experiment 1, 15 patients with PD performed significantly more poorly than controls on a false belief vignette task but not on a faux pas task. Errors were related to poor verbal fluency. In Experiment 2, 24 patients with PD made fewer errors on shorter false belief vignettes than the original FBT, and errors on the latter were related to WM impairment. In Experiment 3, the FBT was presented as a comic strip visible throughout questioning, reducing WM demands. Patients (n = 24) made memory errors but no false belief errors on the comic strip. They exhibited no verbal fluency or WM impairments, but did exhibit deficits on a black-and-white Stroop task. False belief errors were not correlated with executive performance. CONCLUSIONS: PD patients made very few ToM errors that were independent of errors on memory questions, so in this sample, ToM deficits per se appear unlikely. However, patients still made errors on ToM tasks when associated incidental WM demands were considerably reduced, highlighting the need for future investigations of ToM in PD to account for the role of more general cognitive restrictions exhibited by even some medicated, early stage patients.

Analysis of European case-control studies suggests that common inherited variation in mitochondrial DNA is not involved in susceptibility to amyotrophic lateral sclerosis.

While some cases of familial ALS can be entirely attributed to known inherited variation, the majority (∼ 90%) are sporadic, where the cause(s) are not entirely understood. Both genetic and environmental factors may contribute to susceptibility. Mitochondrial damage, a common feature of neurodegenerative disease, is observed in most patients and inherited polymorphism in the mitochondrial genome has been suggested as a contributing factor. We used an economic and efficient method to test whether such involvement is probable. We genotyped 22 mtDNA coding region SNPs and sequenced the mtDNA hypervariable region 1 to determine the position of each mitochondrial genome within the genealogy of mitochondrial haplotypes in samples of ALS patients (n = 700) and controls (n = 462) from two European populations. We compared haplotype and haplogroup distribution in cases and controls drawn from the same populations. No statistical difference was observed between cases and controls at either the haplogroup or haplotype level (p = ≥ 0.2). In conclusion, it is unlikely that common, shared genetic variants in the mitochondrial genome contribute substantially to ALS. Combining the data with other studies will allow meta-analysis to look for variants with modest effect sizes. The sequencing of complete mitochondrial genomes will be required to assess the role of rare mutations.

Deep brain stimulation of the subthalamic nucleus for advanced Parkinson disease using general anesthesia: long-term results.

OBJECT: The authors analyze long-term outcome in a substantial number of patients who underwent subthalamic nucleus (STN) deep brain stimulation (DBS) surgery under general anesthesia. METHODS: Eighty-two patients underwent bilateral placement of DBS electrodes under general anesthesia for advanced Parkinson disease; the STN was the target in all cases. All patients underwent intraoperative microelectrode recording of the STN. No intraoperative macrostimulation was performed. Unified Parkinson's Disease Rating Scale (UPDRS) data were recorded in 28 patients. Assessment of outcome was performed using the UPDRS (in 28 cases), the electrophysiological recordings (in all 82 cases), medication reduction (in 78 cases), and complications (in 82 cases). RESULTS: There was improvement in UPDRS scores across all measures following surgery. The total UPDRS score, off medication, improved from 68.78 (geometrical mean, 95% CI 61.76-76.60) preoperatively to 45.89 (geometrical mean, 95% CI 34.86-60.41) at 1 year postoperatively (p = 0.003, data available in 26 patients). Improvements were obtained in UPDRS Part II (Activities of Daily Living) off medication (p = 0.001) and also UPDRS Part III (Motor Examination) off medication (p < 0.001). Results for the on-medication and on-stimulation states also showed a statistically significant improvement for UPDRS Part III (p = 0.047). Good microelectrode recording of the STN was obtained under general anesthesia; the median first-track length was 4.0 mm, and the median number of tracks passed per patient was 3.0. The median reduction in levodopa medication was 58.1% (interquartile range 42.9%-73.3%). One patient had an intracerebral hemorrhage in the track of 1 electrode but did not require surgical evacuation. One patient had generalized convulsive seizures 24 hours postoperatively and was intubated for seizure control. Unified Parkinson's Disease Rating Scale scores were obtained in 26 patients at 1 year, 28 patients at 3 years, 17 at 5 years, and 7 at 7 years postoperatively. Up to 7 years postoperatively, there was sustained improvement in the total UPDRS score. The results in these patients showed minimal deterioration in the motor section of the UPDRS over time, up to 7 years following the operation. The authors found no evidence that the UPDRS Part II scores changed significantly over the period of 1-7 years after surgery (p = 0.671, comparison of mean scores at 1 and 7 years using generalized estimating equations). CONCLUSIONS: Long-term outcomes confirm that it is both safe and effective to perform STN DBS under general anesthesia. As part of patient choice, this option should be offered to all DBS candidates with advanced Parkinson disease to enable more of these patients to undergo this beneficial surgery.

Genetic studies of GRN and IFT74 in amyotrophic lateral sclerosis.

There is increasing evidence of a clinical, neuropathological and genetic overlap between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We conducted a case-control study using a UK dataset to test the hypothesis that polymorphisms in two FTD-related genes (GRN and FT74) are associated with increased susceptibility to ALS. We evaluated the majority of known genetic variability in IFT74 and GRN. The results revealed that the common variations in IFT74 and GRN neither constitute strong ALS risk factors nor modify the age-at-onset. However, the possibility of a modest risk effect remains to be assessed in large datasets.

Large-scale pathways-based association study in amyotrophic lateral sclerosis.

Sporadic amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, most likely results from complex genetic and environmental interactions. Although a number of association studies have been performed in an effort to find genetic components of sporadic ALS, most of them resulted in inconsistent findings due to a small number of genes investigated in relatively small sample sizes, while the replication of results was rarely attempted. Defects in retrograde axonal transport, vesicle trafficking and xenobiotic metabolism have been implicated in neurodegeneration and motor neuron death both in human disease and animal models. To assess the role of common genetic variation in these pathways in susceptibility to sporadic ALS, we performed a pathway-based candidate gene case-control association study with replication. Furthermore, we determined reliability of whole genome amplified DNA in a large-scale association study. In the first stage of the study, 1277 putative functional and tagging SNPs in 134 genes spanning 8.7 Mb were genotyped in 822 British sporadic ALS patients and 872 controls using whole genome amplified DNA. To detect variants with modest effect size and discriminate among false positive findings 19 SNPs showing a trend of association in the initial screen were genotyped in a replication sample of 580 German sporadic ALS patients and 361 controls. We did not detect strong evidence of association with any of the genes investigated in the discovery sample (lowest uncorrected P-value 0.00037, lowest permutation corrected P-value 0.353). None of the suggestive associations was replicated in a second sample, further excluding variants with moderate effect size. We conclude that common variation in the investigated pathways is unlikely to have a major effect on susceptibility to sporadic ALS. The genotyping efficiency was only slightly decreased ( approximately 1%) and genotyping quality was not affected using whole genome amplified DNA. It is reliable for large scale genotyping studies of diseases such as ALS, where DNA sample collections are limited because of low disease prevalence and short survival time.