Neurology July 2012 Volume 79 Issue 3

Objective: To elucidate possible mechanisms leading to neurodegeneration in patients with glucocerebrosidase (GBA)-associated Parkinson disease (PD) using combined proton (1H) and phosphorus (31P) magnetic resonance spectroscopic imaging (MRSI) in vivo.Methods: 1H and 1H-decoupled 31P MRSI was performed in 13 patients with PD with heterozygous GBA mutations (GBA-PD) and 19 age- and sex-matched healthy controls to investigate metabolite concentrations in the mesostriatal target regions of PD pathology. NAA as marker of neuronal integrity, choline and ethanolamine containing compounds as markers of membrane phospholipid metabolism, and energy metabolites (notably high-energy phosphates) were quantified.Results: Compared to controls, NAA was significantly reduced in the putamen (p = 0.012) and in the midbrain of GBA-PD (p = 0.05). The choline concentration obtained from 1H MRSI was significantly decreased in the midbrain of GBA-PD (p = 0.010). The phospholipid degradation product glycerophosphoethalonamine was increased in the putamen of GBA-PD (p = 0.05). Changes of energy metabolism were not detected in any region of interest.Conclusion: The pattern of neurodegeneration in GBA-associated PD is more pronounced in the putamen than in the midbrain. Our MRSI findings suggest that the neurodegenerative process in GBA-PD is associated with alterations of membrane phospholipid metabolism which might be also involved in abnormal [alpha]-synuclein aggregation.GLOSSARY: ADP: adenosine diphosphateATP: adenosine triphosphateCCT: phosphocholine cytidylyltransferaseCr: creatineETS: electron transport systemGBA: glucocerebrosidaseGBA-PD: patients with Parkinson disease with heterozygous GBA mutationsGD: Gaucher diseaseGM: gray matterGPC: glycerophosphocholineGPE: glycerophosphoethalonamine1H: protonHEP: high-energy phosphateLB: Lewy bodyLEP: low-energy metaboliteMPRAGE: magnetization-prepared rapid gradient echoMRSI: magnetic resonance spectroscopic imagingMSA: multiple system atrophyNAA: N-acetyl aspartate31P: phosphorousPCho : phosphocholinePCr : phosphocreatinePD : Parkinson diseasePEth : phosphoethanolaminePi : inorganic phosphatePtdCho : phosphatidylcholinePtdSer : phosphatidylserineSPM : Statistical Parametric MappingtCho : total cholinetCr : total creatineTE : echo timeTR : repetition timeUPDRS-III : motor part of the Unified Parkinson's Disease Rating ScaleWM : white matter(C)2012 American Academy of Neurology

Objective: To investigate the particular pathology of the Arctic APP (APParc) early-onset familial Alzheimer disease (eoFAD) mutation for the first time in vivo with PET in comparison with other eoFAD mutations and sporadic Alzheimer disease (sAD).Methods: We examined 2 APParc mutation carriers together with 5 noncarrier siblings cross-sectionally with 11C-labeled Pittsburgh compound B (PiB) and 18F-fluorodeoxyglucose (FDG) PET, as well as MRI, CSF biomarkers, and neuropsychological tests. Likewise, we examined 7 patients with sAD, 1 carrier of a presenilin 1 (PSEN1) mutation, 1 carrier of the Swedish APP (APPswe) mutation, and 7 healthy controls (HCs).Results: Cortical PiB retention was very low in the APParc mutation carriers while cerebral glucose metabolism and CSF levels of A[beta]1-42, total and phosphorylated tau were clearly pathologic. This was in contrast to the PSEN1 and APPswe mutation carriers revealing high PiB retention in the cortex and the striatum in combination with abnormal glucose metabolism and CSF biomarkers, and the patients with sAD who showed typically high cortical PiB retention and pathologic CSF levels as well as decreased glucose metabolism when compared with HCs.Conclusions: The lack of fibrillar [beta]-amyloid (A[beta]) as visualized by PiB PET in APParc mutation carriers suggests, given the reduced glucose metabolism and levels of A[beta]1-42 in CSF, that other forms of A[beta] such as oligomers and protofibrils are important for the pathologic processes leading to clinical Alzheimer disease.GLOSSARY: A[beta]: [beta]-amyloidAD: Alzheimer diseaseAPParc: Arctic APPAPPswe: Swedish APP mutation carrierCAA: cerebral amyloid angiopathyeoFAD: early-onset familial Alzheimer diseaseFDG: 18F-fluorodeoxyglucoseMCI: mild cognitive impairmentMMSE: Mini-Mental State Examinationp-tau: phosphorylated tauPiB: Pittsburgh compound BsAD: sporadic Alzheimer diseaset-tau: total tauvarAD: variant AD(C)2012 American Academy of Neurology

Objective: Sporadic, genetically complex essential tremor (ET) is one of the most common movement disorders and may lead to severe impairment of the quality of life. Despite high heritability, the genetic determinants of ET are largely unknown. We performed the second genome-wide association study (GWAS) for ET to elucidate genetic risk factors of ET.Methods: Using the Affymetrix Genome-Wide SNP Array 6.0 (1000K) we conducted a two-stage GWAS in a total of 990 subjects and 1,537 control subjects from Europe to identify genetic variants associated with ET.Results: We discovered association of an intronic variant of the main glial glutamate transporter (SLC1A2) gene with ET in the first-stage sample (rs3794087, p = 6.95 x 10-5, odds ratio [OR] = 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p = 1.25 x 10-3, OR = 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087 obtained genome-wide significance (p = 3.44 x 10-10, OR = 1.59) in the combined first- and second-stage sample. Genetic fine mapping using nonsynonymous single nucleotide polymorphisms (SNPs) and SNPs in high linkage disequilibrium with rs3794087 did not reveal any SNP with a stronger association with ET than rs3794087.Conclusions: We identified SLC1A2 encoding the major glial high-affinity glutamate reuptake transporter in the brain as a potential ET susceptibility gene. Acute and chronic glutamatergic overexcitation is implied in the pathogenesis of ET. SLC1A2 is therefore a good functional candidate gene for ET.GLOSSARY: ET: essential tremorGWAS: genome-wide association studyOR: odds ratioQC: quality controlSNP: single nucleotide polymorphismTRIG: Tremor Investigation Group(C)2012 American Academy of Neurology

Objective: To determine whether interferon-[beta] (IFN-[beta]) medication use is associated with vitamin D levels and whether the two interact in exerting effects on relapse risk.Methods: In a prospective cohort of 178 persons with clinically definite multiple sclerosis (MS) living in southern Tasmania in 2002-2005, serum 25-hydroxyvitamin D [25(OH)D] was measured biannually, with assessment by questionnaire for relevant factors, including IFN-[beta] treatment.Results: Subjects reporting IFN-[beta] use had significantly higher mean 25(OH)D than persons who did not (p < 0.001). This was mediated by an interaction between personal sun exposure and IFN-[beta], with treated persons realizing nearly three times 25(OH)D per hour of sun exposure of persons not on therapy. The association between 25(OH)D and 1,25-dihydroxyvitamin D did not differ by IFN-[beta] therapy (p = 0.82). 25(OH)D was associated with a reduced relapse risk only among persons on IFN-[beta] (p < 0.001). Importantly, IFN-[beta] was only protective against relapse among persons with higher 25(OH)D (hazard ratio [HR] 0.58 [95% confidence interval (CI) 0.35-0.98]), while among 25(OH)D-insufficient persons, IFN-[beta] increased relapse risk (HR 2.01 [95% CI 1.22-3.32]).Conclusion: In this study, we found that IFN-[beta] therapy is associated with greater production of vitamin D from sun exposure, suggesting part of the therapeutic effects of IFN-[beta] on relapse in MS may be through modulation of vitamin D metabolism. These findings suggest persons being treated with IFN-[beta] should have vitamin D status monitored and maintained in the sufficiency range.Classification of evidence: This study provided Class III evidence that IFN-[beta] is associated with reduced risk of relapse, and this effect may be modified by a positive effect of IFN-[beta] on serum 25(OH)D levels.GLOSSARY: 25(OH)D: 25-hydroxyvitamin D7-DHC: 7-dehydrocholesterolBMI: body mass indexCI: confidence intervalEDSS: Expanded Disability Status ScaleHR: hazard ratioIFN-[beta]: interferon-[beta]MS: multiple sclerosisRRMS: relapsing-remitting multiple sclerosis(C)2012 American Academy of Neurology

Objective: Studies based on deseasonalized vitamin D levels suggest that vitamin D may influence the disease activity in multiple sclerosis (MS), and high doses are suggested as add-on treatment to interferon-[beta] (IFN-[beta]). Seasonal fluctuation of vitamin D varies between individuals, thus the relationship to disease activity should preferentially be studied by repeated and simultaneous vitamin D and MRI measurements from each patient.Methods: This was a cohort study comprising 88 patients with relapsing-remitting MS who were followed for 6 months with 7 MRI and 4 25-hydroxyvitamin D measurements before initiation of IFN-[beta], and for 18 months with 5 MRI and 5 25-hydroxyvitamin D measurements during IFN-[beta] treatment.Results: Prior to IFN-[beta] treatment, each 10 nmol/L increase in 25-hydroxyvitamin D was associated with 12.7% (p = 0.037) reduced odds for new T1 gadolinium-enhancing lesions, 11.7% (p = 0.044) for new T2 lesions, and 14.1% (p = 0.024) for combined unique activity. Patients with the most pronounced fluctuation in 25-hydroxyvitamin D displayed larger proportion of MRI scans with new T1 gadolinium-enhancing lesions (51% vs 23%, p = 0.004), combined unique activity (60% vs 32%, p = 0.003), and a trend for new T2 lesions (49% vs 28%, p = 0.052) at the lowest compared to the highest 25-hydroxyvitamin D level. No association between 25-hydroxyvitamin D and disease activity was detected after initiation of IFN-[beta]. HLA-DRB1*15 status did not affect the results.Conclusion: In untreated patients with MS, increasing levels of 25-hydroxyvitamin D are inversely associated with radiologic disease activity irrespective of their HLA-DRB1*15 status.GLOSSARY: 25(OH)D: 25-hydroxyvitamin DCI: confidence intervalCUA: combined unique activityEDSS: Expanded Disability Status ScaleIFN-[beta]: interferon-[beta]MS: multiple sclerosisRRMS: relapsing-remitting MS(C)2012 American Academy of Neurology

Functional (psychogenic) motor symptoms are diagnosed on the basis of positive signs of inconsistency or incongruity with known neurologic disease. These signs, such as Hoover sign or tremor entrainment, are often regarded by neurologists as 'tricks of the trade,' to 'catch the patient out, ' and certainly not to be shared with them. In this reflective article, the authors suggest that showing the patient with functional motor symptoms their physical signs, if done in the right way, is actually one of the most useful things a neurologist can do for these patients in persuading them of the accuracy of their diagnosis and the potential reversibility of their symptoms.(C)2012 American Academy of Neurology