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1.  Influence of Single Nucleotide Polymorphisms in COMT, MAO-A and BDNF Genes on Dyskinesias and Levodopa Use in Parkinson’s Disease 
Neuro-degenerative diseases  2013;13(1):24-28.
Clinical heterogeneity in the development of levodopa-induced dyskinesias (LID) suggests endogenous factors play a significant role in determining their overall prevalence.
We hypothesised that single nucleotide polymorphisms (SNPs) in specific genes may result in a clinical phenotype conducive to an increased risk of LID.
We examined the influence of SNPs in the catechol-O-methyltransferase (COMT), monoamine oxidase A (MAO-A) and brain-derived neurotrophic factor (BDNF) genes on LID in a cohort of 285 pathologically confirmed Parkinson’s disease patients, using data from their complete disease course.
Dyskinetic patients demonstrated younger age at disease onset (60.3 vs. 66.4 years, p < 0.0001), a longer disease duration (17.0 vs. 12.0 years, p < 0.0001) and a higher maximum daily levodopa equivalent dose (LED; 926.7 vs. 617.1 mg/day, p < 0.0001) than patients without dyskinesias. No individual SNP was found to influence prevalence or time to onset of dyskinesias, including after adjustment for known risk factors. We observed that patients carrying alleles conferring both high COMT activity and increased MAO-A mRNA expression received significantly higher maximum and mean daily LEDs than those with low enzyme activity/mRNA expression (max LED: 835 ± 445 vs. 508 ± 316 mg; p = 0.0056, mean LED: 601 ± 335 vs. 398 ± 260 mg; p = 0.025).
Individual SNPs in BDNF, COMT and MAO-A genes did not influence prevalence or time to onset of dyskinesias in this cohort. The possibility that combined COMT and MAO-A genotype is a significant factor in determining an individual’s lifetime levodopa exposure warrants further investigation.
PMCID: PMC4194629  PMID: 24008922
Parkinson’s disease; Levodopa-induced dyskinesias; Catechol-O-methyltransferase; Monoamine oxidase A; Brain-derived neurotrophic factor
2.  Dynamic Magnetic Resonance Imaging of the Pharynx During Deglutition 
To utilize dynamic magnetic resonance imaging (dMRI) to visualize the pharynx and upper esophageal segment in normal, healthy controls.
A 3-T scanner with a 4-channel head coil and a dual-channel neck coil was employed to obtain hsMRI images of subjects swallowing liquids and pudding. Thirty sequential images were acquired over 3300ms for each swallow. Imaging was performed in the midsagittal and axial plane at the level of the oropharynx and pharyngoesophageal segment. Axial images were then analyzed for variables related to alterations in pharyngeal and UES area during swallowing as well as temporal measures related to these structures.
All subjects tolerated the study protocol without complaint. Changes in pharyngeal wall luminal area and temporal measurements were consistent within and between subjects. Inter- and intra-rater reliability for the measurement tool was excellent.
dMRI of the swallow sequence is both feasible and reliable and may eventually compliment currently-used diagnostic modalities as it adds substantive information.
PMCID: PMC4012293  PMID: 23577565
Deglutition; Swallowing; Dynamic MRI; Dysphagia
3.  Sensory neuropathy as part of the cerebellar ataxia neuropathy vestibular areflexia syndrome 
Neurology  2011;76(22):1903-1910.
The syndrome of cerebellar ataxia with bilateral vestibulopathy was delineated in 2004. Sensory neuropathy was mentioned in 3 of the 4 patients described. We aimed to characterize and estimate the frequency of neuropathy in this condition, and determine its typical MRI features.
Retrospective review of 18 subjects (including 4 from the original description) who met the criteria for bilateral vestibulopathy with cerebellar ataxia.
The reported age at onset range was 39–71 years, and symptom duration was 3–38 years. The syndrome was identified in one sibling pair, suggesting that this may be a late-onset recessive disorder, although the other 16 cases were apparently sporadic. All 18 had sensory neuropathy with absent sensory nerve action potentials, although this was not apparent clinically in 2, and the presence of neuropathy was not a selection criterion. In 5, the loss of pinprick sensation was virtually global, mimicking a neuronopathy. However, findings in the other 11 with clinically manifest neuropathy suggested a length-dependent neuropathy. MRI scans showed cerebellar atrophy in 16, involving anterior and dorsal vermis, and hemispheric crus I, while 2 were normal. The inferior vermis and brainstem were spared.
Sensory neuropathy is an integral component of this syndrome. It may result in severe sensory loss, which contributes significantly to the disability. The MRI changes are nonspecific, but, coupled with loss of sensory nerve action potentials, may aid diagnosis. We propose a new name for the condition: cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Neurology® 2011;76:1903–1910
PMCID: PMC3115806  PMID: 21624989
5.  Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series 
Brain  2008;131(10):2632-2646.
The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.
PMCID: PMC2570713  PMID: 18757886
P102L; sCJD; early-onset dementia; Gerstmann-Sträussler-Scheinker syndrome; prion disease

Results 1-6 (6)