Neurology March 2009 Volume 72 Issue 12

Objective: To use a combined neurogenetic-neuroimaging approach to examine the functional consequences of preclinical dopaminergic nigrostriatal dysfunction in the human motor system. Specifically, we examined how a single heterozygous mutation in different genes associated with recessively inherited Parkinson disease alters the cortical control of sequential finger movements.Methods: Nonmanifesting individuals carrying a single heterozygous Parkin (n = 13) or PINK1 (n = 9) mutation and 23 healthy controls without these mutations were studied with functional MRI (fMRI). During fMRI, participants performed simple sequences of three thumb-to-finger opposition movements with their right dominant hand. Since heterozygous Parkin and PINK1 mutations cause a latent dopaminergic nigrostriatal dysfunction, we predicted a compensatory recruitment of those rostral premotor areas that are normally implicated in the control of complex motor sequences. We expected this overactivity to be independent of the underlying genotype.Results: Task performance was comparable for all groups. The performance of a simple motor sequence task consistently activated the rostral supplementary motor area and right rostral dorsal premotor cortex in mutation carriers but not in controls. Task-related activation of these premotor areas was similar in carriers of a Parkin or PINK1 mutation.Conclusion: Mutations in different genes linked to recessively inherited Parkinson disease are associated with an additional recruitment of rostral supplementary motor area and rostral dorsal premotor cortex during a simple motor sequence task. These premotor areas were recruited independently of the underlying genotype. The observed activation most likely reflects a "generic" compensatory mechanism to maintain motor function in the context of a mild dopaminergic deficit.(C)2009AAN Enterprises, Inc.

Objective: To investigate the relationship between CSF biomarkers and cognitive profiles in Alzheimer disease (AD).Methods: We included 177 patients with AD. Digit Span, Visual Association Test (VAT), VAT object naming, Trail Making Test (TMT), and category fluency were used to assess cognitive functions. Disease severity was assessed using Mini-Mental State Examination; functional impairment was rated by Clinical Dementia Rating. In CSF, levels of amyloid-beta 1-42 (A[beta]1-42), tau, and tau phosphorylated at threonine 181 (p-tau) were measured. K-means cluster analysis was performed with the three biomarkers to obtain three clusters. Multivariate analysis of variance for repeated measures was performed with CSF cluster as between-subjects factor, neuropsychological z scores as within-subjects variable, and age, sex, and education as covariates.Results: Cluster 1 consisted of 88 patients (49%) with relatively high levels of A[beta]1-42 and low levels of tau and p-tau. Cluster 2 contained 72 patients (41%) with relatively low levels of A[beta]1-42 and high levels of tau and p-tau. Cluster 3 was made up of 17 patients (10%) with low levels of A[beta]1-42 and very high levels of tau and p-tau. No differences between clusters on age, sex, education, APOE genotype, disease duration, functional impairment, or disease severity were found. Patients in cluster 3 performed worse on VAT, TMT-A and -B, and fluency.Conclusions: Clusters of CSF biomarker levels are related to cognitive profiles in Alzheimer disease. A subgroup of patients with extremely high CSF levels of tau and tau phosphorylated at threonine 181 shows a distinct cognitive profile with more severe impairment of memory, mental speed, and executive functions, which cannot be explained by disease severity.(C)2009AAN Enterprises, Inc.

Objective: Causes of benign positional vertigo (BPV) are mostly unknown. The aim of this study was to elucidate an association of osteoporosis with idiopathic BPV.Methods: Two hundred nine consecutive patients with a confirmed diagnosis of idiopathic BPV underwent bone mineral densitometry of anterior-posterior lumbar spine and femur. The T scores were compared with those of 202 controls without a history of dizziness. Recurrence was defined when the patients reported two or more previous episodes of positional vertigo similar to those experienced at the time of diagnosis.Results: In both women and men, the lowest T scores were decreased in patients with BPV compared with those in controls. Furthermore, the prevalences of osteopenia (-2.5 < T score < -1.0) and osteoporosis (T score <=-2.5) were higher in both women and men with BPV than in controls. Multiple logistic regression analyses adjusted for age, sex, alcohol, smoking, and hyperphosphatemia showed that only the existence of osteopenia/osteoporosis was associated with an increased risk of BPV (adjusted odds ratio of osteopenia = 2.0, 95% confidence interval 1.2-3.4, p = 0.011; adjusted odds ratio of osteoporosis = 3.1, 95% confidence interval 1.4-7.2, p = 0.007). In women aged >=45 years, the lowest T scores were also decreased in the recurrent group, compared with those in the de novo group.Conclusion: Osteopenia/osteoporosis may be associated with idiopathic benign positional vertigo (BPV). The effectiveness of measuring bone mineral densitometry and restoring normal calcium metabolism for preventing recurrences of BPV requires further validation.(C)2009AAN Enterprises, Inc.

Background: The autosomal recessive disorder Niemannn-Pick type C (NPC) presents in adulthood with psychosis or cognitive deficits associated with supranuclear gaze palsies. While saccadic innervation to the extraocular muscles is generated in the brainstem, the frontal lobes play an integral role in the initiation of volitional saccades and the suppression of unwanted reflexive saccades. No study has examined the frontally driven volitional control of saccadic eye movements in NPC.Objective: To examine self-paced and antisaccades as well as reflexive saccades in adult patients with NPC, a disorder known to affect brainstem and frontal cortical function.Methods: Three biochemically confirmed adult patients with NPC were compared with 10 matched controls on horizontal saccadic and antisaccadic measures using an infrared limbus eye tracker. Patients' cholesterol esterification and filipin staining, Mini-Mental State performance, and NPC symptom level were rated.Results: Reflexive saccade latency ranged from shorter to longer than normal, reflexive saccade gain was reduced, asymptotic peak velocity was reduced, fewer self-paced saccades were generated, and increased errors on antisaccades were made by patients compared to controls. Patients with more severe biochemical, cognitive, and symptom deficits performed most poorly on brainstem and frontal ocular motor measures. Paradoxically, less severe illness was associated with an abnormally reduced saccadic latency.Conclusions: Ocular motor measures provide an index of disease severity in Niemannn-Pick type C (NPC) and may be a useful adjunct for monitoring the illness progress and medication response. Reduced saccadic latency may result from inadequate fixation input from abnormally functioning frontal eye fields in NPC.(C)2009AAN Enterprises, Inc.

Over the past 2 decades, botulinum toxin (BT) has enjoyed phenomenal success as a safe and effective therapeutic tool for neurologic and non-neurologic conditions. Even though recent evidence-based conclusions are limited by the availability of data, clinicians' practice confidently recommends BT for many clinical conditions. Besides being effective, BT injected locally has also been considered safe, because no evidence showed that the toxin acts also at distant sites. Recent findings from basic scientific research now challenge this conviction and raise concern that the toxin may have a less localized function than previously thought. Studies in rodents show that the toxin is retrogradely transported and even transcytosed to second-order neurons in the CNS. We therefore need to reappraise whether BT injected into muscles, glands, or cutis might induce previously unconsidered central actions, and whether these actions might have clinical implications. In eliciting clinical benefits, BT's peripheral and central action probably summate. Whether BT acts centrally mainly through retrograde transport, transcytosis, or both remains unclear. Whatever the mechanism, the lack of deleterious central effects implies that while research into action mechanisms continues, physicians can safely use BT for therapy.(C)2009AAN Enterprises, Inc.