A distinctive interaction between memory and chronic daytime somnolence in asymptomatic APOE e4 homozygotes

STUDY OBJECTIVES: To correlate memory measures with a trait measure of chronic daytime somnolence in cognitively normal individuals with different gene doses of the apolipoprotein E (APOE) e4 allele, a common Alzheimer's disease susceptibility gene. DESIGN: Cross-sectional, exploratory study of cognitive abilities in APOE e4 homozygotes (HMZ) (n=42), heterozygotes (HTZ), (n=42) and noncarriers (NC) (n=42) who are matched for age, gender, educational level, and family history of dementia. SETTING: Tertiary care academic medical center. PARTICIPANTS: Cognitively normal residents of Maricopa County, Arizona who are 30-70 years of age, genotyped for APOE, and have no history of a sleep disorder INTERVENTIONS: N/A. MEASUREMENTS: Epworth Sleepiness Scale (ESS) and a battery of neuropsychological tests RESULTS: Age, education, gender, and insomnia complaints did not significantly differ among groups. Despite normal baseline memory scores, memory declined with increasing ESS on all eight memory measures in the HMZ, two of eight in the HTZ, and one of eight in the NC. Differences between HMZ and NC on the slope of memory decline with increasing ESS reached statistical significance on two verbal memory measures, AVLT Long-Term Memory (p=0.048) and Percent Delayed Recall (p=0.035). CONCLUSIONS: Chronic daytime somnolence is associated with a distinctive decline in verbal memory in cognitively normal APOE e4 HMZ, a group at particularly high risk of Alzheimer's disease. Additional studies are needed to confirm these exploratory findings and to determine the effects of acute somnolence on cognition in these genetic subgroups.     

Testing normal older people three or four times at 1- to 2-year intervals: defining normal variance

Normative data were presented that defined the upper and lower standards for deciding if cognitive abilities show reliable change over 2 or more testing occasions when retesting occurs at 1- to 2-year intervals. The Mayo Cognitive Factor Scores (MCFS; G. E. Smith et al., 1994) were analyzed because they permit the quantitation of overall functioning in 5 clinically important cognitive domains: established verbal knowledge, nonverbal reasoning, attention and concentration, new learning, and delayed memory. To the authors' knowledge, this is the first report of both group-level and individual-level data analyses derived from a respectably sized sample of normal persons who have been tested 3 or more times at clinically common test-retest intervals.     

苍白球脑桥黑质变性家族11例成员的快动眼睡眠行为障碍缺失

背景：快动眼睡眠行为障碍（RBD）是一种表现为梦境行为的深眠状态。RBD多导睡眠图的电生理基础是无张力减低的快动眼睡眠。尽管尚不清楚累及何种特殊的网络，但RBD可能缘自脑干的神经元网络功能紊乱。RBD通常与散发的突触核蛋白病相联系，但很少与散发的tau病相关。无张力减低的快动眼睡眠与任何家族性tau病的RBD之间可能存在的联系尚无报道。目的：描述1个家族性tau病家族的临床睡眠和多导睡眠图特征。方法：对苍白球脑桥黑质变性家族中的11例成员进行标准多导睡眠图检查，而不考虑任何睡眠相关疾病。结果：对6例受累和5例从家系上而言有患病风险的家族成员进行研究，11例受试者均无梦境行为病史。11例家族成员中9例的多导睡眠图表现为充足的快动眼睡眠，所有受试者均缺失无张力减低的快动眼睡眠电生理特征和RBD的行为表现。4例受累受试者的神经病理检查显示3例受试者表现为显著的黑质变性以及蓝斑、脑桥神经核和被盖部、延髓被盖部的轻度变性改变。结论：上述试验结果与黑质变性是RBD主要原因的观点相反，该家族缺乏RBD的病史、电生理学和行为表现，进一步为RBD在散发性和家族性tau病中罕见的观点提供了证据。与tau病相比，RBD相关突触核蛋白病发病率的不同提示，突触核蛋白病与tau病之间脑干环路的选择性损害存在差异。     

Diagnostic Utility of Letter Fluency,Category Fluency,and Fluency Difference Scores in Alzheimer's Disease

Word generation tasks, specifically letter fluency and category fluency, are a standard part of most test protocols used by clinical neuropsychologists to measure aspects of language and executive retrieval functions. Given the reliance on these measures as clinical tools, it is important to understand the diagnostic implications of patients' performances. In Alzheimer's disease (AD), category fluency has generally been found to be disproportionately impaired, whereas letter fluency is usually more mildly impaired. It has been proposed that this performance pattern occurs because access to temporal-lobe semantic stores is necessary for category fluency but not letter fluency. In this study, the diagnostic utility of category fluency, letter fluency, and difference scores (letter fluency minus category fluency) in AD were examined. Forty AD patients and 221 normal control subjects took category fluency and letter fluency tests. Traditional t -test comparisons revealed that the groups differed significantly on the two test tasks and in terms of mean difference scores. However, using sensitivity and specificity to calculate predictive values, only category fluency and letter fluency (but not difference scores) were useful in predicting AD in individuals. Furthermore, category fluency was superior to letter fluency in this regard. Likelihood ratio tables are provided for use in calculating the odds of AD for specific category fluency and letter fluency scores generated by individual patients.     

ApoE and Quality of Life in Nonagenarians

ObjectivesApoE ε4 is associated with adverse health conditions that negatively impact the quality of life (QOL). The relationship between ApoE ε4 and QOL has not been explored in the oldest old. Our study aimed to examine ApoE in the oldest old and explore its association with QOL.DesignCross-sectional cohort study.SettingA medium sized community in Olmsted County, Minnesota.ParticipantsIndividuals aged 90 to 99 years, living independently or in long term care environments.MeasurementsWe collected demographic information and measured cognitive function (Short Test of Mental Status, Mini-Mental State Examination, Mattis Dementia Rating Scale), QOL (Linear Analogue Self Assessment), and ApoE distribution. Subjects were classified as cognitively normal, mild cognitive impairment, dementia, or dementia with stroke and/or parkinsonism (DEMSP). Regression model was used to assess the predictors of QOL.ResultsA total of 121 subjects (45 cognitively normal, 13 with mild cognitive impairment, 34 with dementia, 29 DEMSP) aged 90–99 years, 106 (87.6 %) females, were included. Frequency of ApoE ε3 allele was highest (194 [80.2%]: ε2/3 18, ε3/3 77, ε3/4 22) followed by ApoE ε4 (25 [10.3%]: ε2/4 3, ε3/4 22) and ApoE ε2 (23 [9.5%; ε2/2 1, ε2/3 18, ε2/4 3). None of the subjects carried ApoE ε4/4 genotype. QOL was similar between ApoE ε4 carrier and noncarriers. Physical well-being, emotional well-being, intellectual well-being, social connectedness, and coping ability were positively associated with QOL, whereas male sex, DEMSP, pain frequency, and pain severity were negatively associated.ConclusionsThe most common ApoE in the oldest old was ε3/3 genotype and ε3 allele. No association was found between ApoE ε4 and QOL. However, those with high physical, emotional and intellectual well being, social connectedness, and coping ability had the highest overall QOL.     

Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS

The nuclear protein fused in sarcoma (FUS) is found in cytoplasmic inclusions in a subset of patients with the neurodegenerative disorder frontotemporal lobar degeneration (FTLD-FUS). FUS contains a methylated arginine–glycine–glycine domain that is required for transport into the nucleus. Recent findings have shown that this domain is hypomethylated in patients with FTLD-FUS. To determine whether the cause of hypomethylation is the result of mutations in protein N-arginine methyltransferases (PRMTs), we selected 3 candidate genes (PRMT1, PRMT3, and PRMT8) and performed complete sequencing analysis and real-time polymerase chain reaction mRNA expression analysis in 20 FTLD-FUS cases. No mutations or statistically significant changes in expression were observed in our patient samples, suggesting that defects in PRMTs are not the cause of FTLD-FUS.     

Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration

In order to determine the frequency of microtubule-associated protein tau gene (MAPT) mutations and rare variants in CBD, we performed a systematic sequence analysis of MAPT coding and 3′ untranslated region (3′UTR) in a large cohort of autopsy-confirmed CBD patients (N = 109). This identified a novel MAPT mutation in exon 13, p.N410H, in a case that is neuropathologically indistinguishable from sporadic CBD. On immunoblot, the p.N410H mutation carrier had the same insoluble tau profile as seen in CBD. Additionally, tau expression analysis in brain tissue found a significant increase in the 4R/3R tau mRNA ratio (P = 0.04), indicating that p.N410H disrupts tau isoform homeostasis. Biochemically, recombinant tau protein with p.N410H showed a marked increase in tau filament formation compared to wild-type tau (P < 0.001), had a 19.2 % decrease in rate of microtubule assembly (P < 0.05), and a 10.3 % reduction in the extent of total microtubule polymerization (P < 0.01). Sequence analysis of the complete MAPT 3′UTR in autopsy-confirmed CBD cases further identified two rare variants with nominally significant association with CBD. An ATC nucleotide insertion (“MAPTv8”) was found in 4.6 % of CBD patients compared to 1.2 % of controls (P = 0.031, OR = 3.71), and rs186977284 in 4.6 % CBD patients, but only 0.9 % of controls (P = 0.04, OR = 3.58). Rs186977284 was also present in 2.7 % of a large cohort of autopsy-confirmed PSP patients (N = 566) and only 0.9 % of an additional control series (P = 0.034, OR = 3.08), extending the association to PSP. Our findings show that mutations in MAPT can cause CBD and MAPT non-coding variants may increase the risk of complex 4R tauopathies.     

The alien limb phenomenon

Alien limb phenomenon refers to involuntary motor activity of a limb in conjunction with the feeling of estrangement from that limb. Alien limb serves as a diagnostic feature of corticobasal syndrome. Our objective was to determine the differential diagnoses of alien limb and to determine the features in a large group of patients with the alien limb with different underlying etiologies. We searched the Mayo Clinic Medical Records Linkage system to identify patients with the diagnosis of alien limb seen between January 1, 1996, and July 11, 2011. One hundred and fifty patients with alien limb were identified. Twenty-two were followed in the Alzheimer’s Disease Research Center. Etiologies of alien limb included corticobasal syndrome (n = 108), stroke (n = 14), Creutzfeldt Jakob disease (n = 9), hereditary diffuse leukoencephalopathy with spheroids (n = 5), tumor (n = 4), progressive multifocal leukoencephalopathy(n = 2), demyelinating disease (n = 2), progressive dementia not otherwise specified (n = 2), posterior reversible encephalopathy syndrome (n = 1), corpus callosotomy (n = 1), intracerebral hemorrhage (n = 1) and thalamic dementia (n = 1). Ten of 14 cerebrovascular cases were right hemisphere in origin. All cases involved the parietal lobe. Of the 44 patients with corticobasal syndrome from the Alzheimer’s Disease Research Center cohort, 22 had alien limb, and 73 % had the alien limb affecting the left extremities. Left sided corticobasal syndrome was significantly associated with the presence of alien limb (p = 0.004). These findings support the notion that the alien limb phenomenon is partially related to damage underlying the parietal cortex, especially right parietal, disconnecting it from other cortical areas.