The overnight reduction of amyloid ß 1-42 plasma levels is diminished by the extent of sleep fragmentation, sAPP-ß, and APOE ε4 in psychiatrists on call.

INTRODUCTION: In mice there might be an association between sleep deprivation and amyloid ß plasma levels. Hence, we examined whether amyloid plasma levels are associated with sleep duration or fragmentation in 17 psychiatrists on-call. METHODS: Amyloid ß (Aß)42, Aß40, and soluble amyloid precursor protein ß (sAPP-ß) plasma concentrations were measured at the beginning and end of 90 on-call nights, and analyzed using generalized linear models. RESULTS: In on-call nights, a 10.7% reduction of Aß42 was revealed overnight. Every single short sleep interruption diminished this reduction by 5.4%, as well as every pg/mL of sAPP-ß by 1.2%, each copy of APOE ε4 by 10.6%, and each year of professional experience by 3.0%. DISCUSSION: The extent of sleep fragmentation diminishes the physiological overnight reduction of Aß42 but not Aß40 plasma levels in the same direction as the enzyme for Aß42 production, the genetic risk factor for Alzheimer's disease (AD), and on-call experience. Might on-call duty and sleep fragmentation in general alter the risk for AD?

The National Institute on Aging-Alzheimer's Association research criteria for mild cognitive impairment due to Alzheimer's disease: predicting the outcome.

The National Institute on Aging-Alzheimer's Association (NIA-AA) clinical research criteria for mild cognitive impairment (MCI) due to Alzheimer's disease (AD) incorporate the use of biomarkers to classify patients according to the likelihood of the presence of AD pathology. The aim of the study was to compare the risk of progression to AD dementia between the four NIA-AA MCI subgroups using data from the AD Neuroimaging Initiative. Patients with MCI were categorised according to the NIA-AA criteria into subgroups with high, intermediate, and low likelihood of the presence of AD pathology (MCI-high, MCI-intermediate, and MCI-unlikely, respectively) or into a group of patients that only met the MCI-core clinical criteria (MCI-core). Data of follow-up visits conducted 6-60 months after baseline were used to compare the relative risk of future AD dementia between the four subgroups employing a Cox regression model. The MCI-high subgroup (N = 22) had a 2.3 times higher risk of developing AD dementia compared with the MCI-core subgroup (N = 327; P = 0.002), while there was a trend for a higher risk in the MCI-high subgroup in contrast to the MCI-intermediate subgroup (N = 31, P = 0.08). No patients in the MCI-unlikely subgroup (N = 17) progressed to AD dementia. Patients with MCI-high have a higher risk for developing AD dementia. The new NIA-AA MCI criteria represent a valuable research instrument that could be incorporated into the diagnostic process of the MCI syndrome after optimisation and refinement.

Association of the tau haplotype H2 with age at onset and functional alterations of glucose utilization in frontotemporal dementia.

OBJECTIVE: The microtubule-associated protein tau gene (MAPT) contains two extended haplotypes, H1 and H2, which have been linked with sporadic tauopathies. However, there is little evidence as to how these haplotypes may influence the clinical features of the disease. The aim of this study was to investigate the MAPT haplotypes in relation to risk for, and functional alterations of glucose metabolism in, patients with frontotemporal dementia (FTD). METHOD: The authors investigated MAPT haplotypes in 142 individuals with FTD and 292 comparison subjects. Additionally, in a subset of 41 individuals with FTD and 16 comparison subjects, the authors undertook functional [ (18)F]fluorodeoxyglucose positron emission tomography (PET) imaging. RESULTS: MAPT haplotype distribution did not differ significantly between individuals with FTD and comparison subjects. However, the H2 haplotype was clinically associated with an earlier age at onset of FTD, which presented in a dose-dependent manner. Correspondingly, PET analysis revealed functional differences in glucose utilization patterns between MAPT haplotypes, with H2 carriers having a more pronounced hypometabolism in frontal brain areas than H1 carriers, which could not be accounted for by differences in duration of illness. CONCLUSIONS: While the extended MAPT H1 and H2 haplotypes do not appear to confer risk for disease development, the H2 haplotype appears to modify age at onset and functionally shows a more severe decline of glucose utilization in frontal brain areas.

No association of TDP-43 with sporadic frontotemporal dementia.

A hyperphosphorylated, ubiquitinated form of TDP-43, known as pathologic TDP-43, was shown to be a central component of ubiquitin-positive, tau-negative and alpha-synuclein-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amytrophic lateral sclerosis (ALS). To investigate the role of the TDP-43 gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 10 single nucleotide polymorphisms covering the entire TDP-43 genomic region, including the MASP2 gene in 173 patients with sporadic FTD (including 7 patients that were diagnosed with FTD and ALS) and 184 matched controls from Germany. Although we could observe a weak trend towards a potential disease association in a few FTD/ALS patients, no significant association with sporadic FTD could be demonstrated. There is no evidence, that common variants in TDP-43 confer a strong risk to the development of sporadic FTD.

No association of chromatin-modifying protein 2B with sporadic frontotemporal dementia.

Mutations of the chromatin modifying protein 2B gene (CHMP2B) were identified, in a Danish pedigree, to cause familial frontotemporal dementia (FTD). To explore the possible genetic contribution of common CHMP2B variants in sporadic FTD, we analyzed 14 single nucleotide polymorphisms covering the entire genomic region of CHMP2B. After adjustment for multiple testing single marker and haplotype analysis revealed no significant association with sporadic FTD. Thus, we conclude that CHMP2B can be excluded as a susceptibility gene conferring risk to sporadic forms of FTD.