er Genc

Impact of mild cognitive impairment on outcome following deep brain stimulation surgery for Parkinson's disease.

INTRODUCTION Unlike dementia, the effect of mild cognitive impairment (MCI) on outcomes after deep brain stimulation (DBS) in Parkinsons disease (PD) is less clear. We aimed to examine the effect of MCI on short- and long-term DBS outcomes. METHODS To study the effect of MCI type, cognitive domains (attention, language, visuospatial, memory, executive function), and Dementia Rating Scale (DRS) score on immediate postoperative outcomes (postoperative confusion, hospitalization days), PD patients who underwent DBS at our Center from 2006 to 2011 were analyzed. To determine cognitive predictors of intermediate (6-month) and long-term (1-year) post-operative outcomes, the changes in functional and quality-of-life (QOL) scores were analyzed in a smaller group with available preoperative health status measures. RESULTS We identified 130 patients [71% male, mean age: 63 ± 9.1, mean PD duration: 10.7 ± 5.1]. At preoperative assessment, 60% of patients had multiple-domain MCI, 21% had single-domain MCI, and 19% had normal cognition. MCI presence and type as well as DRS performance did not affect immediate outcomes. Attention impairment predicted longer postoperative hospitalization (P = 0.0015) and showed a trend towards occurrence of postoperative confusion (P = 0.089). For intermediate and long-term outcomes we identified 56 patients [73.2% male, mean age: 61.3 ± 9.6, mean PD duration: 10.6 ± 4.7]. Visuospatial impairment showed a trend towards less improvement in 6-month functional score (P = 0.0652), and 1-year QOL score (P = 0.0517). CONCLUSION The presence of MCI did not affect DBS outcomes. However, the types of impaired domains were more detrimental. Detailed cognitive testing can help stratify low- and high-risk patients based on their pattern of cognitive dysfunction.

Socioeconomic Status May Impact Functional Outcome of Deep Brain Stimulation Surgery in Parkinson's Disease

To investigate the association between socioeconomic status and deep brain stimulation (DBS) outcomes in Parkinsons disease (PD).

Predictors of Functional and Quality of Life Outcomes following Deep Brain Stimulation Surgery in Parkinson’s Disease Patients: Disease, Patient, and Surgical Factors

Objective The primary objective was to evaluate predictors of quality of life (QOL) and functional outcomes following deep brain stimulation (DBS) in Parkinsons disease (PD) patients. The secondary objective was to identify predictors of global improvement. Methods PD patients who underwent DBS at our Center from 2006 to 2011 were evaluated by chart review and email/phone survey. Postoperative UPDRS II and EQ-5D were analyzed using simple linear regression adjusting for preoperative score. For global outcomes, we utilized the Patient Global Impression of Change Scale (PGIS) and the Clinician Global Impression of Change Scale (CGIS). Results There were 130 patients in the dataset. Preoperative and postoperative UPDRS II and EQ-5D were available for 45 patients, PGIS for 67 patients, and CGIS for 116 patients. Patients with falls/postural instability had 6-month functional scores and 1-year QOL scores that were significantly worse than patients without falls/postural instability. For every 1-point increase in preoperative UPDRS III and for every 1-unit increase in body mass index (BMI), the 6-month functional scores significantly worsened. Patients with tremors, without dyskinesia, and without gait-freezing were more likely to have “much” or “very much” improved CGIS. Conclusions Presence of postural instability, high BMI, and worse baseline motor scores were the greatest predictors of poorer functional and QOL outcomes after DBS.

ASSOCIATION BETWEEN NADSYN1/DHCR7 AND CYP2R1 GENOTYPES AND PARKINSON’S DISEASE AND ITS CLINICAL FEATURES

dysfunction, however, the association between MT genetic variants and AD has not been fully explored in large datasets. Methods:The Alzheimer’s Disease Genetics Consortium (ADGC) recently genotyped 8,706 AD cases and 7,002 healthy controls of European ancestry from five cohorts using the Illumina Exome-Chip 1.0 containing 227MT single nucleotide variants (SNVs). Each cohort was analyzed separately for variants with minor allele count (MAC) 10 and call rate 0.95 (94 variants on average). In gene-based tests, only SNVs with minor allele frequency (MAF) <0.05 were considered, and genes with 2 SNVs and cumulative MAC 10 were tested. Associations with AD status were tested using single variant SCORE tests and gene-based (SKAT-O) tests in seqMeta in R package, controlling for age, sex, and principal components of ancestry. Results were combined across cohorts using meta-analysis. Bonferroni-corrected thresholds were used to determine statistical significance for single variant (a1⁄48.6310) and gene-based (a1⁄44.5310) associations. Finally, SNVs (MAF<0.05) in genes that encode subunits of the respiratory oxidative phosphorylation (OXPHOS) complexes were aggregated for testing association with AD. Results: In single variant analyses, one missense SNV in MT-ND3which encodes NADH dehydrogenase 3 involved in oxidative phosphorylation of ATP (rs2853826, Thr114Ala, MAF1⁄40.22) was significantly associated with AD risk (OR1⁄41.043; P1⁄42.50310). The most significant gene-based association finding was obtained withMT-TP (P1⁄4 7.9310), but this result did not survive correction for multiple testing. However, the hypothesis-driven test of aggregated rare variants in the OXPHOS complex was significant (P1⁄40.02, cumulative MAF1⁄40.015), which is consistent with previous reports that the expression level of OXPHOS genes is significantly lower in AD than in MCI or cognitively healthy subjects. Conclusions:We identified significant association of AD risk with one common MT SNV and the collective group of OXPHOS pathway genes. A replication study of independent cohorts from the International Genomics of Alzheimer’s Project is currently underway. Additional replication and discovery of novel rare AD-associated MT variants in datasets from the Alzheimer’s Disease Sequencing Project data are also in progress.

THE BLOOD PROFILE OF MTDNA ENCODED GENES EXPRESSION IN PARKINSON’S DISEASE PATIENTS AND HEALTHY INDIVIDUALS

0.00001), 24(s)-hydroxycholesterol (1.27, 1.03-1.57, p1⁄40.02), SAP (1.30, 1.01-1.67, p1⁄40.05), SAM (0.90, 0.83-0.98, p1⁄40.01), 5-MTHF (0.91, 0.85-0.97, p1⁄40.008), and homocysteine: (plasma 1.19, 95% CI 1.11-1.28, p< 0.00001; CSF 1.15, 95% CI 1.101.34 p1⁄40.06). Conclusions: The neurovascular hypothesis implicates glial, vascular, and neuronal changes in AD pathology. Glial involvement was suggested by highly significant elevations of glial markers YKL-40 and MCP-1. Vascular (endothelial) dysfunction is not implicated as homocysteine was significantly elevated in blood, but NOT CSF. Vascular involvement via reduced cholesterol clearance is suggested by elevation of CSF 24(s)-hydroxycholesterol levels. Additional data analysis yielded unforeseen results, such as possible dysfunction of methylation reactions in the AD brain (SAM, 5MTHF). Our meta-analysis validates glial involvement in the neurovascular hypothesis, suggest that homocysteine lowering therapies may be ineffective, and compels the investigation of further therapeutic targets.

Erratum to: GC and VDR SNPs and Vitamin D Levels in Parkinson's Disease: The Relevance to Clinical Features.

Tables 3, 4 and supplementary Table 4 of the original article contained errors in the labeling of the genotype and allele columns for the first GC SNP (rs2282679). The correct labels for the genotype columns (left to right) are ‘AA’, ‘CA’ and ‘CC’. The correct labels for the allele columns (left to right) are ‘A’ and ‘C’. The error did not affect the genotype or allele distributions, statistical analysis or results, and thus the conclusions of the study were not affected. The authors regret the inconvenience caused to the readers. ThecorrectedTables 3, 4 and supplementary Table 4 are given along with this erratum.

Goggle-like Appearance of Injured Cerebellothalamic Axons Surrounding Red Nuclei in Holmes Tremor

A 66-year-old man on rivaroxaban (Xarelto) for atrial fibrillation experienced a pontine hemorrhage. He survived the acute hospitalization and was discharged to a rehabilitation facility in a quadriparetic state. Over the 4 months following the hemorrhage, he developed a tremor, first in the lower and then in the upper extremities, which prompted his referral to the Movement Disorders clinic. On examination of visual tracking, there was no horizontal movement of the left eye and no adduction of the right eye. He had distal more than proximal, left more than right, and lower more than upper limb weakness, ranging from 3/5 in the left leg to 4/5 in the right arm, with depressed deep tendon reflexes. In the left upper extremity, he had a tremor that was present at rest, with posture, and with action. The movements met the description of Holmes tremor in the Consensus Statement of the Movement Disorder Society on Tremor. The movements lacked the jerky quality of myoclonus, the randomness of chorea, or the sustained twisting quality of dystonia, nor was there any pulling toward a null position as in dystonic tremor. There was also head tremor with activation of the left shoulder girdle and neck muscles. When he held the left arm outstretched, supporting it against gravity, and the examiner shoved the limb out of position, the limb oscillated for several cycles before settling into position again. Pointing (finger-chin-finger) was ataxic, and there were mild athetoid movements of the fingers. A similar resting tremor was present in the left lower extremity, although weakness there precluded testing postural or kinetic tremor. A postural and kinetic tremor similar to that of the left upper extremity was seen in the right upper extremity as well, but not as severe. There was no bradykinesia or rigidity. We recommended a trial of levodopa, and, if this failed, leviteracitam, but the patient died before results of this could be determined. Magnetic resonance imaging of the brain done at 1 day after the acute hemorrhage shows the pontine hemorrhage (Figure 1A). Higher cuts, at the level of the midbrain, show a striking “gogglelike” appearance of T2 hyperintensity representing anterograde axonal edema extended rostrally to midbrain (Figure 1B) where it is seen in cerebellothalamic fibers surround the red nuclei. It is well-known that mesencephalic lesions may cause a lowfrequency tremor present at rest, with posture, and with action (Holmes tremor). The term “rubral” for such tremors implies a role for the red nucleus (RN), but the critical structure may instead be cerebellar efferents, some of which synapse in the parvocellular RN, whereas others wrap around the RN en route to thalamus. The question is difficult to resolve because it would be rare for a mesencephalic lesion to affect a substantial portion of the cerebellothalamic fibers while sparing the RN. Our patient’s Holmes tremor was caused by a pontine lesion some distance away from the midbrain and is thus a “cerebellar outflow tremor.” Its remarkable feature is the magnetic resonance imaging, which shows a midbrain lesion, presumably representing edema associated with anterograde degeneration of axons damaged in the pons. To our knowledge, this is the first case in which a midbrain lesion limited to cerebellar efferents, while sparing surrounding structures, has been imaged in a case of Holmes tremor.