Movement Disorders Emergencies Part 1: Hypokinetic Disorders
Robottom and colleaguesArticle have reviewed the literature regarding movement disorder emergencies and divided them into hypokinetic (part 1) and hyperkinetic (part 2) presentations. In part 1, drug-induced syndromes, including neuroleptic malignant syndrome, parkinsonism hyperpyrexia syndrome, and serotonin syndrome, are discussed. Emergency complications related to the management of Parkinson disease, including falling, motor fluctuations, and psychiatric issues, are also reviewed.
Statin Use Following Intracerebral Hemorrhage
Westover et alArticle address the following clinical question: Given a history of prior intracerebral hemorrhage (ICH), should statin therapy be avoided? They investigated how statin use affects this outcome measure while varying a range of clinical parameters, including hemorrhage location (deep vs lobar), ischemic cardiac and cerebrovascular risks, and magnitude of ICH risk associated with statins. In a carefully designed study and analysis, they conclude that avoiding statins should be considered for patients with a history of ICH, particularly those cases with a lobar location. Editorial perspective is provided by Larry B. Goldstein, MD Article.
Association of TMEM106B Gene Polymorphism With Age at Onset in Granulin Mutation Carriers and Plasma Granulin Protein Levels
Cruchaga and colleaguesArticle note a recent genome-wide association study for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP) that identified rs1990622 (TMEM106B) as a risk factor for FTLD-TDP. They tested whether rs1990622 (TMEM106B) is associated with age at onset (AAO) in granulin (GRN) mutation carriers and with plasma GRN levels in mutation carriers and healthy, elderly individuals. They report that the risk allele of rs1990622 was associated with a mean decrease of the AAO of 13 years (P = 9.9 × 10−7) and with lower plasma GRN levels in both healthy older adults (P = 4 × 10−4) and GRN mutation carriers (P = .0027). Their results also suggest that genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN.
Resequencing of 29 Candidate Genes in Patients With Familial and Sporadic Amyotrophic Lateral Sclerosis
Daoud et alArticle identify novel disease-causing genes for amyotrophic lateral sclerosis (ALS). They carried out a systematic mutation screening of the entire coding regions of 29 candidate genes encoding critically important proteins for proper differentiation and development of corticospinal motor neurons in 190 patients with familial and sporadic ALS. They identified several novel promising genes for ALS such as LUM and CRYM. Finally, they also highlighted the analytical challenges of large-scale sequencing screens to detect disease-causing variants.
Large Proportion of Amyotropic Lateral Sclerosis Cases in Sardinia Due to a Single Founder Mutation of the TARDBP Gene
Chiò and colleaguesArticle performed an extensive screen for mutations of amyotrophic lateral sclerosis (ALS)–related genes in a consecutive cohort of Sardinian patients. A total of 135 Sardinian patients with ALS underwent mutational analysis for SOD1, FUS, and TARDBP, and a total of 156 healthy control subjects of Sardinian origin were age- and sex-matched to these 135 patients. They found that the TARDBP p.A382T missense mutation accounts for approximately one-third of all ALS cases in this island population. These patients share a large risk haplotype across the TARDBP locus, indicating that they have a common ancestor.
Test-Retest Reliability of Memory Task Functional Magnetic Resonance Imaging in Alzheimer Disease Clinical Trials
Atri et alArticle examine the feasibility and test-retest reliability of encoding-task functional magnetic resonance imaging (fMRI) in mild Alzheimer disease (AD). Encoding-task fMRI was successfully implemented in a single-site, 24-week, AD randomized controlled trial. Week 0 to 12 whole-brain t maps were stable, and test-retest reliability of hippocampal fMRI measures ranged from moderate to substantial.
Telephone-Based Identification of Mild Cognitive Impairment and Dementia in a Multicultural Cohort
Manly and colleaguesArticle note that telephone-based interviews can be used for screening and to obtain key study outcomes when participants in longitudinal studies die or cannot be seen in person, but must be validated among ethnically and educationally diverse people. Their sample consisted of 377 (30.5% non-Hispanic white, 34.7% non-Hispanic black, and 33.7% Caribbean Hispanic) older adults. The validation standard was diagnosis of dementia and mild cognitive impairment based on in-person evaluation. The Telephone Interview for Cognitive Status (TICS) and the Dementia Questionnaire (DQ) were administered within the same assessment wave. The TICS has high diagnostic validity for identification of dementia among ethnically diverse older adults, especially when supported by the DQ and prior visit data. However, telephone interview data were unable to reliably distinguish mild cognitive impairment from normal cognition.
Cerebral Folate Deficiency Syndromes in Childhood
Pérez-Dueñas et alArticle postulate that cerebral folate deficiency (CFD) may be amenable to therapeutic supplementation. Diverse metabolic pathways and unrelated processes can lead to cerebrospinal fluid 5-methyltetrahydrofolate (5-MTHF) depletion, the hallmark of CFD. They set out to study the spectrum and frequency of disorders associated with CFD by measuring cerebrospinal fluid 5-MTHF, biogenic amines, and pterins in 134 individuals free of neurometabolic disease and in 584 patients with several diseases of the central nervous system. Direct sequencing of the FOLR1 transporter gene was also performed in some patients. They report that, of the 2 main forms of CFD identified, mild to moderate 5-MTHF deficiency was most commonly associated with disorders bearing no primary relation to folate metabolism, whereas profound 5-MTHF depletion was associated with specific mitochondrial disorders, metabolic and transporter defects, or cerebral degenerations. The results suggest that 5-MTHF can serve either as the hallmark of inborn disorders of folate transport and metabolism or, more frequently, as an indicator of neurologic dysfunction.
The APOE Gene Locus in Frontotemporal Dementia and Primary Progressive Aphasia
Seripa and colleaguesArticle investigate the role of the apolipoprotein E (APOE) locus in frontotemporal dementia (FTD) and primary progressive aphasia (PPA). They report on genotype analysis of the 3 single-nucleotide polymorphisms rs449647, rs769446, and rs405509 in the promoter region of the APOE gene and of the 2 single-nucleotide polymorphisms rs429358 and rs7412 forming the common APOE polymorphism. Although the physiological role of APOE in FTD and PPA needs further investigations, their results suggest an involvement of the APOE locus in the genetics of FTD and PPA.
Mild Cognitive Impairment, Dementia, and Their Subtypes in Oldest Old Women
Yaffe et alArticle determine the prevalence of mild cognitive impairment, dementia, and subtypes in oldest old women. In this large sample of oldest old women, 41.0% had clinically adjudicated cognitive impairment. Subtypes of dementia and mild cognitive impairment were similar to those in younger populations. Their results suggest that women in the fastest growing demographic, the oldest old, should be carefully screened for cognitive disorders, especially high-risk groups.
SCA15 Due to Large ITPR1 Deletions in a Cohort of 333 White Families With Dominant Ataxia
Marelli and colleaguesArticle determine the frequency and the phenotypical spectrum of spinocerebellar ataxia (SCA) type 15. In the index cases of 333 families with autosomal dominant cerebellar ataxia negative for CAG repeat expansions in coding exons (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17 and dentatorubral-pallidoluysian atrophy), they searched for heterozygous rearrangements in ITPR1. In this series, ITPR1 deletions were rare and accounted for approximately 1% of all autosomal dominant cerebellar ataxias. The SCA15 phenotype mostly consists of a slowly progressive isolated cerebellar ataxia with variable age at onset; an additional pyramidal syndrome and problems in executive functions may be present in a minority of patients.
Longitudinal Patterns of β-Amyloid Deposition in Nondemented Older Adults
Sojkova et alArticle investigate whether longitudinal changes in β-amyloid (Aβ) deposition can be detected in vivo in older adults without dementia (hereafter referred to as nondemented). The amount of fibrillar Aβ detected by carbon 11–labeled Pittsburgh Compound B positron emission tomography ([11C]PiB-PET) increases over time even in nondemented older adults. Individuals with higher initial [11C]PiB retention have greater rates of Aβ deposition, providing evidence of differential rates of Aβ deposition. Moreover, regional vulnerabilities to Aβ deposition allow for more targeted investigation of early Aβ changes.