The effect of n-3 fatty acids on heart rate variability in patients treated with chronic hemodialysis.

OBJECTIVE: The aim of the present study was to address the effect of n-3 polyunsaturated fatty acids (PUFAs) on heart rate variability (HRV) in patients treated with chronic hemodialysis. DESIGN: We performed a randomized, placebo-controlled intervention trial. SETTING: The study took place at two hospital-based dialysis centers. PATIENTS: Thirty patients with documented cardiovascular disease who were treated with hemodialysis for at least 6 months were included. INTERVENTION: Treatment consisted of 1.7 g of n-3 PUFA or a control treatment (olive oil). MAIN OUTCOME MEASURE: The outcome measure was 24-hour Holter recordings with time domain HRV measurements at baseline and after 3 months of treatment. Blood samples were obtained to assess the content of n-3 PUFA in serum phospholipids before and after treatment. RESULTS: n-3 PUFA did not significantly affect time domain parameters of HRV, compared with a control group. CONCLUSION: We conclude that treatment with n-3 PUFA does not increase HRV in patients treated with chronic hemodialysis, a result that may have been compromised by a small sample size.     

The validity of schizophrenia diagnosis in the Finnish Hospital Discharge Register: findings from a 10-year birth cohort sample

The purpose of this study was to investigate the diagnostic validity of schizophrenia in the Finnish Hospital Discharge Register (FHDR) with a large, epidemiologically representative sample using a multidiagnostic approach (DSM-III-R, DSM-IV, ICD-10), and to find additional criteria that could be used to improve the validity of schizophrenia diagnosis in future register-based research that utilizes the FHDR. The study population consisted of all individuals (n=877) who were born in Helsinki, Finland, between 1 January 1951 and 31 December 1960, and who had had at least one diagnosis of schizophrenia, schizophreniform disorder or schizoaffective disorder in the FHDR. All their available hospital case notes were collected. The total number of subjects for whom case notes were obtained was 806. We used the OPCRIT system (version 3.4) to produce diagnoses according to ICD-10, DSM-III-R and DSM-IV criteria based on the information extracted from the hospital case notes. We examined the distribution of the DSM-III-R, DSM-IV and ICD-10 diagnoses generated by the OPCRIT and calculated the proportion of individuals who received the same diagnosis in the FHDR and in the OPCRIT assessment. The proportion of subjects who received a core schizophrenia spectrum diagnosis (schizophrenia, schizoaffective disorder or schizophreniform disorder) in both the FHDR and OPCRIT assessment varied between 75% (DSM-III-R criteria) and 78% (ICD-10 criteria). Of the subjects with a narrow schizophrenia diagnosis in the FHDR, between 74% (DSM-IV) and 78% (ICD-10) received a diagnosis of schizophrenia in the reassessment depending on the diagnostic criteria applied. Eighty per cent of those who had received a core schizophrenia spectrum FHDR diagnosis after 1982 (vs. 56% of those who had received their last schizophrenia diagnosis in 1982 or before) received a DSM-IV diagnosis of core schizophrenia spectrum disorder. Of the 58 subjects in the sample who had been given at various times diagnoses of both core schizophrenia diagnosis and bipolar I diagnosis in FHDR, 43% received a core schizophrenia spectrum diagnosis according to DSM-IV criteria. The validity of the FHDR schizophrenia diagnosis is acceptable for large-scale register studies and comparable with that of other Nordic registers. Diagnostic validity can be further improved by selecting subjects who have core schizophrenia spectrum disorder as the latest diagnosis, by omitting cases diagnosed before 1982, and by excluding cases with a register diagnoses of both a core schizophrenia spectrum and bipolar I disorder.     

A survey of ABCA1 sequence variation confirms association with dementia

We and others have conducted targeted genetic association analyses of ABCA1 in relation to Alzheimer disease risk with a resultant mixture of both support and refutation, but all previous studies have been based upon only a few markers. Here, a detailed survey of genetic variation in the ABCA1 region has been performed in a total of 1,567 Swedish dementia cases (including 1,275 with Alzheimer disease) and 2,203 controls, providing evidence of association with maximum significance at marker rs2230805 (odds ratio [OR]=1.39; 95% confidence interval [CI] 1.23–1.57, p=7.7×10⁻⁸). Haplotype‐based tests confirmed association of this genomic region after excluding rs2230805, and imputation did not reveal additional markers with greater support. Significantly associating markers reside in two distinct linkage disequilibrium blocks with maxima near the promoter and in the terminal exon of a truncated ABCA1 splice form. The putative risk allele of rs2230805 was also found to be associated with reduced cerebrospinal fluid levels of β‐amyloid. The strongest evidence of association was obtained when all forms of dementia were considered together, but effect sizes were similar when only confirmed Alzheimer disease cases were assessed. Results further implicate ABCA1 in dementia, reinforcing the putative involvement of lipid transport in neurodegenerative disease. Hum Mutat 30:1–7, 2009. © 2009 Wiley‐Liss, Inc.     

A highly insoluble state of Abeta similar to that of Alzheimer's disease brain is found in Arctic APP transgenic mice

Amyloid-β (Aβ) is a major drug target in Alzheimer's disease. Here, we demonstrate that deposited Aβ is SDS insoluble in tgAPP-ArcSwe, a transgenic mouse model harboring the Arctic (E693G) and Swedish (KM670/671NL) APP mutations. Formic acid was needed to extract the majority of deposited Aβ in both tgAPP-ArcSwe and Alzheimer's disease brain, but not in a commonly used type of mouse model with the Swedish mutation alone. Interestingly, the insoluble state of Arctic Aβ was determined early on and did not gradually evolve with time. In tgAPP-ArcSwe, Aβ plaques displayed a patchy morphology with bundles of Aβ fibrils, whereas amyloid cores in tgAPP-Swe were circular with radiating fibrils. Amyloid was more densely stacked in tgAPP-ArcSwe, as demonstrated with a conformation sensitive probe. A reduced increase in plasma Aβ was observed following acute administration of an Aβ antibody in tgAPP-ArcSwe, results that might imply reduced brain to plasma Aβ efflux. TgAPP-ArcSwe, with its insoluble state of deposited Aβ, could serve as a complementary model to better predict the outcome of clinical trials.     

Longitudinal cerebrospinal fluid biomarkers over four years in mild cognitive impairment

Cerebrospinal fluid (CSF) measurements of amyloid-β42 (Aβ42), total-tau (T-tau), and phosphorylated tau (P-tau) may be used to predict future Alzheimer's disease (AD) dementia in patients with mild cognitive impairment (MCI). The precise temporal development of these biomarkers in relation to clinical progression is unclear. Earlier studies have been hampered by short follow-up. In an MCI cohort, we selected 15 patients who developed AD (MCI-AD) and 15 who remained cognitively stable during 4 years of follow-up. CSF was sampled at three serial occasions from each patient and analyzed for Aβ peptides, the soluble amyloid-β protein precursor protein fragments sAβPPα and sAβPPβ, T-tau, P-tau, and chromogranin B, which is a protein linked to regulated neuronal secretion. We also measured, for the first time in MCI patients, an extended panel of Aβ peptides by matrix-assisted-laser-desorption/ionization time-of-flight mass spectrometry (MS). Most biomarkers were surprisingly stable over the four years with coefficients of variation below or close to 10%. However, MCI-AD patients decreased in CSF AβX??? and chromogranin B concentrations, which may indicate a reduced number of functional neurons or synapses with disease progression. The MS Aβ peptide panel was more useful than any single Aβ peptide to identify MCI-AD patients already at baseline. Knowledge on these biomarkers and their trajectories may facilitate early diagnosis of AD and be useful in future clinical trials to track effects of disease modifying drugs.