Characterization of monomeric and soluble aggregated Aβ in Down's syndrome and Alzheimer's disease brains

The major characteristics of Alzheimer's disease (AD) are amyloid plaques, consisting of aggregated beta amyloid (Aβ) peptides, together with tau pathology (tangles, neuropil treads and dystrophic neurites surrounding the plaques), in the brain. Down's syndrome (DS) individuals are at increased risk to develop AD-type pathology; most DS individuals have developed substantial pathology already at the age of 40. DS individuals have an extra copy of chromosome 21, harbouring the amyloid precursor protein gene (APP). Our aim was to investigate the Aβ peptide pattern in DS and AD brains to investigate differences in their amyloid deposition and aggregation, respectively. Cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (water soluble) and formic acid (water insoluble) fractions. Immunoprecipitation (IP) was performed using a variety of antibodies targeting different Aβ species including oligomeric Aβ. Mass spectrometry was then used to evaluate the presence of Aβ species in the different patient groups. A large number of Aβ peptides were identified including Aβ1-X, 2-X, 3-X, 4-X, 5-X, 11-X, and Aβ peptides extended N terminally of the BACE1 cleavage site and ending at amino 15 in the Aβ sequence APP/Aβ(-X to 15), as well as peptides post-translationally modified by pyroglutamate formation. Most Aβ peptides had higher abundance in AD and DS compared to controls, except the APP/Aβ(-X to 15) peptides which were most abundant in DS followed by controls and AD. Furthermore, the abundancies of AβX-40 and AβX-34 were increased in DS compared with AD. Aβ1-40, Aβ1-42, and Aβ4-42 were identified as the main constitutes of protofibrils (IP'd using mAb158) and higher relative Aβ1-42 signals were obtained compared with samples IP'd with 6E10 + 4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at amino acid 42. All Aβ peptides found in AD were also present in DS indicating similar pathways of Aβ peptide production, degradation and accumulation, except for APP/Aβ(-X to 15). Likewise, the Aβ peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility that treatment with clinical benefit in sporadic AD might also be beneficial for subjects with DS

Handwriting performance in the absence of visual control in writer's cramp patients: Initial observations

BACKGROUND: The present study was aimed at investigating the writing parameters of writer's cramp patients and control subjects during handwriting of a test sentence in the absence of visual control. METHODS: Eight right-handed patients with writer's cramp and eight healthy volunteers as age-matched control subjects participated in the study. The experimental task consisted in writing a test sentence repeatedly for fifty times on a pressure-sensitive digital board. The subject did not have visual control on his handwriting. The writing performance was stored on a PC and analyzed off-line. RESULTS: During handwriting all patients developed a typical dystonic limb posture and reported an increase in muscular tension along the experimental session. The patients were significantly slower than the controls, with lower mean vertical pressure of the pen tip on the paper and they could not reach the endmost letter of the sentence in the given time window. No other handwriting parameter differences were found between the two groups. CONCLUSION: Our findings indicate that during writing in the absence of visual feedback writer's cramp patients are slower and could not reach the endmost letter of the test sentence, but their level of automatization is not impaired and writer's cramp handwriting parameters are similar to those of the controls except for even lower vertical pressure of the pen tip on the paper, which is probably due to a changed strategy in such experimental conditions

Lack of hemispheric dominance for consciousness in acute ischaemic stroke

Background: Previous reports have suggested left hemispheric dominance for maintaining consciousness, although there is controversy over this claim. Objective: To compare early impairment of level of consciousness between patients with right and left hemispheric stroke. Methods: Data from 564 patients with ischaemic stroke enrolled in the placebo arm of a trial of a putative neuroprotectant were analysed. All patients had major hemispheric stroke with cortical dysfunction, visual field deficit, and limb weakness, with symptom onset within 12 hours of enrolment. Patients were prospectively evaluated on a predefined scale (1–6; 1 = fully awake, higher scores representing greater impairment) to measure level of consciousness at multiple time points over the initial 24 hours after presentation. The National Institutes of Health (NIH) stroke scale score at presentation and infarct volume at 30 days were determined. Results: Some degree of impairment in level of consciousness was observed in 409 of the 564 patients (73%). Median maximum sedation score was 2 for both right and left hemispheric stroke (p = 0.91). Mean sedation score over 24 hours was 1.5 for both right and left stroke (p = 0.75). There was no difference between level of consciousness scores in right and left stroke at any individual time point during the 24 hour monitoring period. No association between side and impairment in level of consciousness was seen after adjustment for stroke severity and infarct volume. Conclusions: In contrast to previous reports, there was no evidence for hemispheric dominance for consciousness in the setting of a major hemispheric stroke