Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations

Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) are major genetic causes of early-onset Alzheimer's disease (EOAD). Clinical heterogeneity is frequently observed in patients with PSEN1 and PSEN2 mutations. Using whole exome sequencing, we screened a Dutch cohort of 68 patients with EOAD for rare variants in Mendelian Alzheimer's disease, frontotemporal dementia, and prion disease genes. We identified 3 PSEN1 and 2 PSEN2 variants. Three variants, 1 in PSEN1 (p.H21Profs*2) and both PSEN2 (p.A415S and p.M174I), were novel and absent in control exomes. These novel variants can be classified as probable pathogenic, except for PSEN1 (p.H21Profs*2) in which the pathogenicity is uncertain. The initial clinical symptoms between mutation carriers varied from behavioral problems to memory impairment. Our findings extend the mutation spectrum of EOAD and underline the clinical heterogeneity among PSEN1 and PSEN2 mutation carriers. Screening for Alzheimer's disease–causing genes is indicated in presenile dementia with an overlapping clinical diagnosis

Are white matter lesions directly associated with cognitive impairment in patients with lacunar infarcts?

Forty-four patients (mean age 66, SD 8 years) with either clinical evidence of a focal lacunar syndrome (n = 36) or with disorders of memory or gait (n = 8) in the presence of a lacunar infarct on CT were studied for cognitive functioning and for the presence of white matter lesions on MRI. MR images were assessed by a neurologist and a neuroradiologist blinded to the clinical data. Thirty-six patients had one or more lacunar infarcts on CT or MRI (in the thalamus in 5, in the caudate nucleus in 3 and in the internal capsule or corona radiata in the remaining patients). Twelve patients had multiple infarcts. Severe lesions of the white matted were found in 13 patients, mild to moderate lesions in 20 patients. Scores on Digit Span, Digit Symbol and delayed recall of the 15-Words test were significantly lower in the group with severe lesions, whilst there was a trend in the same direction for the Cognitive part of the Cambridge Examination of Mental Disorders in the Elderly, the Trailmaking B, Stroop colour interference test and the delayed visual reproduction of the Wechsler Memory Scale. These findings suggest that diffuse lesions of the white matter are an independent factor in the pathogenesis of intellectual dysfunction, also in patients with lacunar infarcts, but a truly independent analysis is difficult because the most severe involvement of the white matter tended to be associated with the largest number of lacunar infarcts

Qualitative Assessment of Verbal Fluency Performance in Frontotemporal Dementia

Background/Aims: Verbal fluency is impaired in patients with frontotemporal dementia (FTD) and primary progressive aphasia (PPA). This study explored qualitative differences in verbal fluency (clustering of words, switching between strategies) between FTD and PPA variants. Methods: Twenty-nine patients with behavioral variant FTD (bvFTD) and 50 with PPA (13 nonfluent/agrammatic, 14 semantic, and 23 logopenic) performed a semantic and letter fluency task. Clustering (number of multiword strings) and switching (number of transitions between clustered and nonclustered words) were recorded by two independent raters. Between-group differences, associations with memory, language, and executive functioning, and longitudinal change (subsample) in clustering and switching were examined. Results: Interrater reliability was high (median 0.98). PPA patients generated (a) smaller (number of) clusters on semantic and letter fluency than bvFTD patients (p < 0.05). Semantic variant patients used more switches than nonfluent/agrammatic or logopenic variant patients (p < 0.05). Clustering in semantic fluency was significantly associated with memory and language (range standardized regression coefficients 0.24-0.38). Switching in letter fluency was associated with executive functioning (0.32-0.35). Conclusion: Clustering and switching in verbal fluency differed between patients with subtypes of FTD and PPA. Qualitative aspects of verbal fluency provide additional information on verbal ability and executive control which can be used for clinically diagnostic purposes

18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers

Tau positron emission tomography ligands provide the novel possibility to image tau pathology in vivo. However, little is known about how in vivo brain uptake of tau positron emission tomography ligands relates to tau aggregates observed post-mortem. We performed tau positron emission tomography imaging with 18F-AV-1451 in three patients harbouring a p.R406W mutation in the MAPT gene, encoding tau. This mutation results in 3- and 4-repeat tau aggregates similar to those in Alzheimer's disease, and many of the mutation carriers initially suffer from memory impairment and temporal lobe atrophy. Two patients with short disease duration and isolated memory impairment exhibited 18F-AV-1451 uptake mainly in the hippocampus and adjacent temporal lobe regions, correlating with glucose hypometabolism in corresponding regions. One patient died after 26 years of disease duration with dementia and behavioural deficits. Pre-mortem, there was 18F-AV-1451 uptake in the temporal and frontal lobes, as well as in the basal ganglia, which strongly correlated with the regional extent and amount of tau pathology in post-mortem brain sections. Amyloid-β (18F-flutemetamol) positron emission tomography scans were negative in all cases, as were stainings of brain sections for amyloid. This provides strong evidence that 18F-AV-1451 positron emission tomography can be used to accurately quantify in vivo the regional distribution of hyperphosphorylated tau protein

Product costing and activity-based costing/management in Bacalhôa Vinhos de Portugal

The present Work Project introduces a case study addressing the adoption of an ABC/M system in a winemaking company. The system was implemented in only one area of the company, and its adoption allows the company to perform ABM analysis resorting to the ABC information. A mixed approach is used to cost the products: both traditional and ABC systems are used although in different areas of the company. ABC/M implementation was perceived as ‘successful’ despite not following recommendations prescribed in literature

Reproductive period and risk of dementia in postmenopausal women

CONTEXT: Exogenous estrogen use may lower risk of dementia in postmenopausal women. A relationship between long-term exposure to endogenous estrogens and incident dementia has been hypothesized but not studied. OBJECTIVE: To determine whether a longer reproductive period, as an indicator of longer exposure to endogenous estrogens, is associated with lower risk of dementia and Alzheimer disease (AD) in women who have natural menopause. DESIGN AND SETTING: The Rotterdam Study, a population-based prospective cohort study conducted in the Netherlands. PARTICIPANTS: A total of 3601 women aged 55 years or older who did not have dementia at baseline (1990-1993) and had information on age at menarche

Vascular risk factors, atherosclerosis, cerebral white matter lesions and cerebral perfusion in a population-based study

We studied risk factors for cerebral vascular disease (blood pressure and hypertension, factor VIIc, factor VIIIc, fibrinogen), indicators of atherosclerosis (intima-media thickness and plaques in the carotid artery) and cerebral white matter lesions in relation to regional cerebral blood flow (rCBF) in 60 persons (aged 65-85 years) recruited from a population-based study. rCBF was assessed with single-photon emission tomography using technetium-99m d,l-hexamethylpropylene amine oxime (99mTc-HMPAO). Statistical analysis was performed with multiple linear regression with adjustment for age, sex and ventricle-to-brain ratio. A significant positive association was found between systolic and diastolic blood pressure and temporo-parietal rCBF. In analysis with quartiles of the distribution, we found a threshold effect for the relation of low diastolic blood pressure (≤ 60 mmHg) and low temporo-parietal rCBF. Levels of plasma fibrinogen were inversely related to parietal rCBF, with a threshold effect of high fibrinogen levels (> 3.2 g/l) and low rCBF. Increased atherosclerosis was related to low rCBF in all cortical regions, but these associations were not significant. No consistent relation was observed between severity of cerebral white matter lesions and rCBF. Our results may have implications for blood pressure control in the elderly population

Cleaved TMEM106B forms amyloid aggregates in central and peripheral nervous systems

Filaments made of residues 120-254 of transmembrane protein 106B (TMEM106B) form in an age-dependent manner and can be extracted from the brains of neurologically normal individuals and those of subjects with a variety of neurodegenerative diseases. TMEM106B filament formation requires cleavage at residue 120 of the 274 amino acid protein; at present, it is not known if residues 255-274 form the fuzzy coat of TMEM106B filaments. Here we show that a second cleavage appears likely, based on staining with an antibody raised against residues 263-274 of TMEM106B. We also show that besides the brain TMEM106B inclusions form in dorsal root ganglia and spinal cord, where they were mostly found in non-neuronal cells. We confirm that in the brain, inclusions were most abundant in astrocytes. No inclusions were detected in heart, liver, spleen or hilar lymph nodes. Based on their staining with luminescent conjugated oligothiophenes, we confirm that TMEM106B inclusions are amyloids. By in situ immunoelectron microscopy, TMEM106B assemblies were often found in structures resembling endosomes and lysosomes.</p