This Month in Archives of Neurology

KraincArticle emphasizes that accumulation and aggregation of disease-causing proteins is a hallmark of several neurodegenerative disorders such as Parkinson, Alzheimer, and Huntington diseases. One of the main goals of research in neurodegenerative disorders has been to improve clearance of these accumulated proteins. Using the example of Huntington disease, he discusses strategies to selectively activate cellular degradation machinery to improve clearance of the mutant protein and identify therapeutic targets for the treatment of Huntington disease and related neurodegenerative disorders.

Abrahams and GeschwindArticle indicate that the autism spectrum disorders are a complex group of neuropsychiatric conditions that involve language, social communication, and mental flexibility. Here, they attempt to place recent genetic advances in a developmental and anatomical context. Recent progress in identifying autism spectrum disorder candidate genes supports the involvement of multiple brain regions including the frontal lobes, anterior temporal lobes, caudate, and cerebellum. Understanding genetic data in an anatomical context will be critical to explain how individual risk factors operate to shape phenotypic presentation in patients.

In their study van der Voort and colleaguesArticle report that anti–interferon beta–neutralizing antibodies can persist after interferon beta therapy withdrawal and are associated with overt clinical disease activity. This is made apparent by an increase in relapse rate and faster disability progression and supported by the observed need for more aggressive therapy after interferon beta therapy cessation. Editorial perspective is provided by J. T. Phillips, MD, PhD.Article

Arif et alArticle compared the effectiveness of antiepileptic drugs for use in older adults with epilepsy. Lamotrigine was the most effective antiepileptic drug, as measured by 12-month retention and seizure freedom, with levetiracetam a close second. Oxcarbazepine was consistently less effective than most other antiepileptic drugs.

Ballanger and colleaguesArticle report with this pilot study the first in vivo evidence that suggests a role for serotonin 2A receptors in mediating visual hallucinations via the ventral visual stream in Parkinson disease. This imaging study provides a rational basis for treatment studies using selective serotonin 2A receptor antagonists, which has important implications for the clinical management of visual hallucinations and psychosis in Parkinson disease.

Lemos et alArticle confirm the involvement of syntaxin 1A in migraine susceptibility regarding the single-nucleotide polymorphism rs941298. In addition, they found rs6951030 to also be associated in Portuguese patients with migraine. Sex differences need to be explored to disentangle possible sex susceptibility in syntaxin 1A.

Burns and colleaguesArticle report that loss of lean mass is accelerated in Alzheimer disease and is associated with brain atrophy and cognitive performance, perhaps as a direct or indirect consequence of Alzheimer disease pathophysiology or through shared mechanisms common to both Alzheimer disease and sarcopenia.

Carrera and colleaguesArticle determined the predictors of impaired cerebrovascular reactivity (CVR) and the value of CVR to predict delayed cerebral ischemia. They found that impaired CVR in response to carbon dioxide challenge is frequent after subarachnoid hemorrhage, particularly in patients with poor clinical grade. Progressive loss of normal CVR identifies patients at high risk of delayed cerebral ischemia, and persistently normal reactivity implies low risk.

Albin and colleaguesArticle compared assessment of regional cerebral metabolic changes with [¹¹C]dihydrotetrabenazine–positron-emission tomography (DTBZ-PET) measurement of regional cerebral blood flow (K₁) and fludeoxyglucose F18 (FDG)–PET measurement of regional cerebral glucose uptake (CMR_glc) in a clinically representative sample of subjects with mild dementia and mild cognitive impairment (MCI). They hypothesized that DTBZ-PET K₁ and FDG-PET CMR_glc provide equivalent information. They report that DTBZ-PET K₁ and FDG-PET CMR_glc provide comparable information in assessment of regional cerebral metabolic deficits in mild dementia and MCI. Measures of K₁ can assess regional cerebral metabolism deficits accurately in mild dementia and MCI; K₁ assessments of regional cerebral metabolic deficits can be combined with tracer binding results to improve utility of PET imaging in mild dementia and MCI.

Pellicano et alArticle investigated the relationship between fatigue in multiple sclerosis and regional cortical and subcortical gray matter atrophy. They report that cortical atrophy of the parietal lobe had the strongest relationship with fatigue. Given the implications of the posterior parietal cortex in motor planning and integration of information from different sources, the interpretation of their preliminary results is that dysfunctions in higher-order aspects of motor control may have a role in determining fatigue in multiple sclerosis.

Hewitt and colleaguesArticle indicate that mutations in FUS/TLS have recently been found to cosegregate with familial cases of amyotrophic lateral sclerosis (ALS). The aim of the present study was to determine the frequency of and clinicopathological phenotypes associated with FUS/TLS mutations in a large cohort of ALS cases. They find that FUS/TLS mutations represented approximately 5% of familial ALS cases screened. A FUS/TLS mutation was also identified in a single sporadic ALS case. Subsequent screening of this region in a larger cohort of sporadic ALS cases, however, did not reveal any additional mutations.

Langbaum et alArticle studied the extent to which the apolipoprotein E (APOE) ε4 allele is a susceptibility gene for late-onset Alzheimer disease (AD) in Latino individuals. Fluorodeoxyglucose positron emission tomography (FDG-PET) was used to investigate whether regional reductions in the cerebral metabolic rate for glucose previously found in cognitively healthy late-middle-aged APOE ε4 carriers extends to members of the Latino Mexican American community. They obtained support for the relationship between APOE ε4 and risk of AD in Latino individuals. It illustrates the role of PET as a presymptomatic endophenotype for the assessment of AD risk factors and supports the inclusion of Latino APOE ε4 carriers in proof-of-concept studies that use FDG-PET to evaluate promising presymptomatic treatments in cognitively healthy carriers of this common AD susceptibility gene.

Beukers et alArticle report that in SGCE mutation carriers, significant hyperresponsiveness in contralateral inferior parietal cortical areas, ipsilateral premotor and primary somatosensory cortex, and ipsilateral cerebellum were observed during the motor task compared with healthy controls. The cortical activation patterns in SGCE mutation carriers during this motor task point to disorganized sensorimotor integration in this uniform group of dystonic patients and are consistent with functional neuroimaging studies in other types of (hereditary) dystonia.

Aggarwal and colleaguesArticle review that white matter hyperintensity volume, cerebral infarcts, and total brain volume are associated with cognitive function but that few studies have examined these associations in the general population or whether they differ by race. The authors examined the association of white matter hyperintensity volume, cerebral infarcts, and total brain volume with global cognition and cognition in 5 separate domains in a biracial population sample. They report that the associations of magnetic resonance imaging measures with cognition differed according to subjects' clinical status (stronger among subjects without dementia) and were not modified by race. These associations did not affect all cognitive domains equally but were more consistent with impairments in perceptual speed.

Kertesz et alArticle describe a large, clinically defined cohort of patients with semantic dementia, highlighting important, sometimes overlooked features and comparing it with similar entities. They indicate that semantic dementia is distinguishable from other presentations of frontotemporal dementia and Alzheimer disease, not only by fluent speech and impaired comprehension without loss of episodic memory, syntax, and phonology but also by empty, garrulous speech with thematic perseverations, semantic paraphasias, and poor category fluency. Questioning the meaning of words is an important diagnostic clue not seen in other groups, and behavior change is prevalent.