Neurology January 2009 Volume 72 Issue 1

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with complicated pathogenesis that poses challenges with respect to diagnosis and monitoring of disease progression.Objectives: To identify a biomarker panel that elucidates ALS disease pathogenesis, distinguishes patients with ALS from neurologic disease controls, and correlates with ALS disease characteristics, and to determine the effect of HFE gene variants, a potential risk factor for sporadic ALS, on the biomarker profile.Methods: We obtained CSF samples by lumbar puncture from 41 patients with ALS and 33 neurologic disease controls. All patients were genotyped for HFE polymorphisms. We performed a multiplex cytokine and growth factor analysis and immunoassays for iron-related analytes. Classification statistics were generated using a support vector machine algorithm.Results: The groups of patients with ALS and neurologic disease controls were each associated with distinct profiles of biomarkers. Fourteen biomarkers differed between patients with ALS and the control group. The five proteins with the lowest p values differentiated patients with ALS from controls with 89.2% accuracy, 87.5% sensitivity, and 91.2% specificity. Expression of IL-8 was higher in those patients with lower levels of physical function. Expression of [beta]2-microglobulin was higher in subjects carrying an H63D HFE allele, while expression of several markers was higher in subjects carrying a C282Y HFE allele.Conclusions: A CSF inflammatory profile associated with amyotrophic lateral sclerosis (ALS) pathogenesis may distinguish patients with ALS from neurologic disease controls, and may serve as a biomarker panel to aid in the diagnosis of ALS pending further validation. Some of these biomarkers differ by HFE genotype.(C)2009AAN Enterprises, Inc.

Background: Primary lateral sclerosis (PLS) is a rare neurodegenerative disease that affects the upper motor neurons of the CNS. Juvenile-onset PLS (JPLS) is inherited in an autosomal recessive mode and is also found in sporadic cases. A consanguineous Cypriot family with three affected individuals presenting with JPLS was identified and studied.Methods: Patients were clinically evaluated and samples were taken from consenting family members. All available family members were genotyped and linkage analysis at marker loci spanning the wider region of the ALS2 gene was performed. Selected exons of the ALS2 gene were sequenced and RNA analysis was performed using available lymphoblastoid cell lines from the proband.Results: All affected individuals presented in the second year of life with progressive upper motor neuron dysfunction, affecting both bulbar and extremity muscles. Severity was variable, with two of the patients remaining ambulatory in the second and fifth decade of life while the third one was never able to walk. A novel ALS2 homozygous c.2980-2A>G mutation at the splice acceptor site of intron 17 was identified and its effect was confirmed at the RNA level.Conclusions: This novel ALS2 splice-site mutation is causing the loss of exon 18 in the transcript which results in a frameshift after exon 17. This frameshift most probably introduces a stop codon seven amino acids further down the new reading frame (p.993fsX7) and is expected to lead to a premature stop in exon 19 thus leading to a truncated protein after translation.(C)2009AAN Enterprises, Inc.

Background: Inconsistent changes of cognitive functioning have been reported in patients with Parkinson disease (PD) with deep brain stimulation (DBS) of the subthalamic nucleus (STN). To investigate the underlying pathomechanisms, we correlated alterations of cognitive test performance and changes of neuronal energy metabolism in frontal basal ganglia projection areas under bilateral STN stimulation.Methods: We conducted verbal fluency, learning, and memory tests and 18-fluorodeoxyglucose (FDG) PET in nine patients with PD with STN-DBS before and 6 months after surgery. Using coregistered MRI, postoperative changes of the normalized cerebral metabolic rates of glucose (nCMRGlc) in the dorsolateral prefrontal cortex (DLPFC), lateral orbitofrontal cortex (LOFC), ventral and dorsal cingulum (v/dACC), and in Broca area were determined and correlated with alterations of neuropsychological test results.Results: After surgery, highly variable changes of both cognitive test performance and frontal nCMRGlc values were found with significant correlations between verbal fluency and FDG uptake in the left DLPFC (Brodmann area [BA] 9, 46), left Broca area (BA 44/45), and the right dACC (BA 32). A decrease of nCMRGlc in the left OFC (BA 11/47) and dACC (BA 32) correlated with a decline of verbal learning. All patients showed reduced metabolic activity in the right anterior cingulate cortex after DBS. Baseline cognitive abilities did not predict verbal learning or fluency changes after surgery.Conclusions: These data show a significant linear relationship between changes in frontal 18-fluorodeoxyglucose PET activity and changes in cognitive outcome after deep brain stimulation of the subthalamic nucleus (STN) in advanced Parkinson disease. The best correlations were found in the left frontal lobe (dorsolateral prefrontal cortex and Broca area). Baseline performance on cognitive tests did not predict cognitive or metabolic changes after STN electrode implantation.(C)2009AAN Enterprises, Inc.

Background: Activated microglia may play a role in the pathogenesis of Alzheimer disease (AD) as they cluster around beta-amyloid (A[beta]) plaques. They are, therefore, a potential therapeutic target in both AD and its prodrome amnestic mild cognitive impairment (MCI).Objective: To characterize in vivo with 11C-(R)-PK11195 and 11C-PIB PET the distribution of microglial activation and amyloid deposition in patients with amnestic MCI.Methods: Fourteen subjects with MCI had 11C-(R)-PK11195 and 11C-PIB PET with psychometric tests.Results: Seven out of 14 (50%) patients with MCI had increased cortical 11C-PIB retention (p < 0.001) while 5 out of 13 (38%) subjects with MCI showed increased 11C-(R)-PK11195 uptake. The MCI subgroup with increased 11C-PIB retention also showed increased cortical 11C-(R)-PK11195 binding (p < 0.036) though this increase only remained significant in frontal cortex after a correction for multiple comparisons. There was no correlation between regional levels of 11C-(R)-PK11195 and 11C-PIB binding in individual patients with MCI: only three of the five MCI cases with increased 11C-(R)-PK11195 binding had increased levels of 11C-PIB retention.Conclusions: Our findings indicate that, while amyloid deposition and microglial activation can be detected in vivo in around 50% of patients with mild cognitive impairment (MCI), these pathologies can occur independently. The detection of microglial activation in patients with MCI suggests that anti-inflammatory therapies may be relevant to the prevention of AD.(C)2009AAN Enterprises, Inc.

Objective: Smoking and family history of aneurysmal subarachnoid hemorrhage (aSAH) are independent risk factors for aSAH. Using a population-based case-control study of hemorrhagic stroke, we hypothesized that having both a first-degree relative with a brain aneurysm or SAH (+FH) and current smoking interact to increase the risk of aSAH.Methods: Cases of aneurysmal SAH were prospectively recruited from all 17 hospitals in the five-county region around the University of Cincinnati. Controls were identified by random digit dialing. Controls were matched to cases of aSAH by age (+/-5 years), race, and sex. Conditional multiple logistic regression was used to identify independent risk factors. For deviation from the additive model, the interaction constant ratio test was used.Results: A total of 339 cases of aSAH were matched to 1,016 controls. Compared to current nonsmokers with no first-degree relatives with aSAH (-FH), the odds ratio (OR) for aSAH for current nonsmokers with +FH was 2.5 (95% confidence interval [CI] 0.9-6.9); for current smokers with -FH, OR = 3.1 (95% CI 2.2-4.4); and for current smokers with +FH, OR = 6.4 (95% CI 3.1-13. 2). The interaction constant ratio, which measured the deviation from the additive model, was significant: 2.19 (95% CI 0.80-5.99). The lower bound of the 95% CI >0.5 signifies a departure from the additive model.Conclusion: Evidence of a gene-environment interaction with smoking exists for aneurysmal subarachnoid hemorrhage. This finding is important to counseling family members and for screening of intracranial aneurysm (IA) as well as the design and interpretation of genetic epidemiology of IA studies.(C)2009AAN Enterprises, Inc.

When the delusional misidentification syndromes reduplicative paramnesia and Capgras syndromes result from neurologic disease, lesions are usually bifrontal and/or right hemispheric. The related disorders of confabulation and anosognosis share overlapping mechanisms and anatomic pathology. A dual mechanism is postulated for the delusional misidentification syndromes: negative effects from right hemisphere and frontal lobe dysfunction as well as positive effects from release (i.e., overactivity) of preserved left hemisphere areas. Negative effects of right hemisphere injury impair self-monitoring, ego boundaries, and attaching emotional valence and familiarity to stimuli. The unchecked left hemisphere unleashes a creative narrator from the monitoring of self, memory, and reality by the frontal and right hemisphere areas, leading to excessive and false explanations. Further, the left hemisphere's cognitive style of categorization, often into dual categories, leads it to invent a duplicate or impostor to resolve conflicting information. Delusions result from right hemisphere lesions. But it is the left hemisphere that is deluded.(C)2009AAN Enterprises, Inc.

Background: Objective evaluation of neurology resident clinical skills is required by the American Board of Psychiatry and Neurology and is important to insure improvement in clinical competency throughout their residency.Methods: In this study, neurology residents from all 3 years of training and neurology faculty independently completed a form on new clinic patients documenting their decisions on anatomic localization, diagnosis, diagnostic tests, and management.Results: Compared to the attending patient evaluation, we found significant improvement in identical scoring by year of residency training. All resident years outperformed medical students in the neurology clerkship.Conclusion: Our clinical assessment form adds one more tool to the list of currently used assessment methods to evaluate resident clinical competency.(C)2009AAN Enterprises, Inc.