Panel of Genetic Variations as a Potential Non-invasive Biomarker for Early Diagnosis of Alzheimer's Disease

Alzheimer's disease (AD) is the most prevalent form of dementia. Biomarkers such as levels of amyloid beta (Aβ) in cerebrospinal fluid and ApoE genotyping were suggested for the diagnosis of AD, however, the result is either non-conclusive or with invasive procedure. Genome-wide association studies (GWASs) for AD suggested single nucleotide polymorphisms (SNPs) in many genes are associated with the risk of AD, but each only contributed with small effect to the disease. By incorporating a panel of established genetic susceptibility factors, the risk of an individual in getting AD could be better estimated. Further research will be required to reveal if adding to the current well-developed clinical diagnosis protocol, the accuracy and specificity of diagnosis of AD would be greatly improved and if this might also be beneficial in identifying pre-symptomatic AD patients for early diagnosis and intervention of the disease

The transporter-like protein inebriated mediates hyperosmotic stimuli through intracellular signaling

We cloned the inebriated homologue MasIne from Manduca sexta and expressed it in Xenopus laevis oocytes. MasIne is homologous to neurotransmitter transporters but no transport was observed with a number of putative substrates. Oocytes expressing MasIne respond to hyperosmotic stimulation by releasing intracellular Ca(2+), as revealed by activation of the endogenous Ca(2+)-activated Cl(-) current. This Ca(2+) release requires the N-terminal 108 amino acid residues of MasIne and occurs via the inositol trisphosphate pathway. Fusion of the N terminus to the rat gamma-aminobutyric acid transporter (rGAT1) also renders rGAT1 responsive to hyperosmotic stimulation. Immunohistochemical analyses show that MasIne and Drosophila Ine have similar tissue distribution patterns, suggesting functional identity. Inebriated is expressed in tissues and cells actively involved in K(+) transport, which suggests that it may have a role in ion transport, particularly of K(+). We propose that stimulation of MasIne releases intracellular Ca(2+) in native tissues, activating Ca(2+)-dependent K(+) channels, and leading to K(+) transport

Proteolytic processing of human prorenin in renal and non-renal tissues

Proteolytic processing of human prorenin in renal and non-renal tissues. Previous studies have demonstrated that the mouse proprotein convertase PC1 (mPC1) accurately cleaves human prorenin to generate active renin and that this processing event appears to require co-packaging in secretory granules. In the current study, we have tested human PC1 (hPC1; also called PC3) for its ability to activate human prorenin. Our results suggest that while hPC1 is capable of carrying out the specific cleavage of human prorenin, it does so at a reduced efficiency as compared to mPC1. This difference is due to sequences in the carboxy-terminus of PC1 as demonstrated by the activity of hybrid hPC1/mPC1 molecules. These studies demonstrate that PC1 cleavage of prorenin can occur in humans and identify a functionally important region in the hPC1 protein for this interaction. Moreover, the localization of PC1 in human tissues suggests that it may participate in the generation of active renin in the adrenal medulla and possibly in certain adrenal tumors

Validation of multi-stage telephone-based identification of cognitive impairment and dementia

BACKGROUND: Many types of research on dementia and cognitive impairment require large sample sizes. Detailed in-person assessment using batteries of neuropyschologic testing is expensive. This study evaluates whether a brief telephone cognitive assessment strategy can reliably classify cognitive status when compared to an in-person "gold-standard" clinical assessment. METHODS: The gold standard assessment of cognitive status was conducted at the University of Southern California Alzheimer Disease Research Center (USC ADRC). It involved an examination of patients with a memory complaint by a neurologist or psychiatrist specializing in cognitive disorders and administration of a battery of neuropsychologic tests. The method being evaluated was a multi-staged assessment using the Telephone Interview of Cognitive Status-modified (TICSm) with patients and the Telephone Dementia Questionnaire (TDQ) with a proxy. Elderly male and female patients who had received the gold standard in-person assessment were asked to also undergo the telephone assessment. The unweighted kappa statistic was calculated to compare the gold standard and the multistage telephone assessment methods. Sensitivity for classification with dementia and specificity for classification as normal were also calculated. RESULTS: Of 50 patients who underwent the gold standard assessment and were referred for telephone assessment, 38 (76%) completed the TICS. The mean age was 78.1 years and 26 (68%) were female. When comparing the gold standard assessment and the telephone method for classifying subjects as having dementia or no dementia, the sensitivity of the telephone method was 0.83 (95% confidence interval 0.36, 1.00), the specificity was 1.00 (95% confidence interval 0.89,1.00). Kappa was 0.89 (95% confidence interval 0.69, 1.000). Considering a gold-standard assessment of age-associated memory impairment as cognitive impairment, the sensitivity of the telephone approach is 0.38 (95% confidence interval 0.09, 0.76) specificity 0.96 (CI 0.45, 0.89) and kappa 0.61 (CI 0.37, 0.85). CONCLUSION: Use of a telephone interview to identify people with dementia or cognitive impairment is a promising and relatively inexpensive strategy for identifying potential participants in intervention and clinical research studies and for classifying subjects in epidemiologic studies

Relationship between cortical thickness and neuropsychological performance in normal older adults and those with mild cognitive impairment

Mild cognitive impairment (MCI) has been extensively investigated in recent decades to identify groups with a high risk of dementia and to establish effective prevention methods during this period. Neuropsychological performance and cortical thickness are two important biomarkers used to predict progression from MCI to dementia. This study compares the cortical thickness and neuropsychological performance in people with MCI and cognitively healthy older adults. We further focus on the relationship between cortical thickness and neuropsychological performance in these two groups. Forty-nine participants with MCI and 40 cognitively healthy older adults were recruited. Cortical thickness was analysed with semiautomatic software, Freesurfer. The analysis reveals that the cortical thickness in the left caudal anterior cingulate (p=0.041), lateral occipital (p=0.009) and right superior temporal (p=0.047) areas were significantly thinner in the MCI group after adjustment for age and education. Almost all neuropsychological test results (with the exception of forward digit span) were significantly correlated to cortical thickness in the MCI group after adjustment for age, gender and education. In contrast, only the score on the Category Verbal Fluency Test and the forward digit span were found to have significant inverse correlations to cortical thickness in the control group of cognitively healthy older adults. The study results suggest that cortical thinning in the temporal region reflects the global change in cognition in subjects with MCI and may be useful to predict progression of MCI to Alzheimer's disease. The different pattern in the correlation of cortical thickness to the neuropsychological performance of patients with MCI from the healthy control subjects may be explained by the hypothesis of MCI as a disconnection syndrome

Would transcranial direct current stimulation (tDCS) enhance the effects of working memory training in older adults with mild neurocognitive disorder due to Alzheimer’s disease: study protocol for a randomized controlled trial

© 2015 Cheng et al. Background: There has been longstanding interesting in cognitive training for older adults with cognitive impairment. In this study, we will investigate the effects of working memory training, and explore augmentation strategies that could possibly consolidate the effects in older adults with mild neurocognitive disorder. Transcranial direct current stimulation (tDCS) has been demonstrated to affect the neuronal excitability and reported to enhance memory performance. As tDCS may also modulate cognitive function through changes in neuroplastic response, it would be adopted as an augmentation strategy for working memory training in the present study. Methods/Design: This is a 4-week intervention double-blind randomized controlled trial (RCT) of tDCS. Chinese older adults (aged 60 to 90 years) with mild neurocognitive disorder due to Alzheimer 's disease (DSM-5 criteria) would be randomized into a 4-week intervention of either tDCS-working memory (DCS-WM), tDCS-control cognitive training (DCS-CC), and sham tDCS-working memory (WM-CD) groups. The primary outcome would be working memory test - the n-back task performance and the Chinese version of the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog). Secondary outcomes would be test performance of specific cognitive domains and mood. Intention-to-treat analysis would be carried out. Changes of efficacy indicators with time and intervention would be tested with mixed effect models. Discussion: This study adopts the theory of neuroplasticity to evaluate the potential cognitive benefits of non-invasive electrical brain stimulation, working memory training and dual stimulation in older adults at risk of cognitive decline. It would also examine the tolerability, program adherence and adverse effects of this novel intervention. Information would be helpful for further research of dementia prevention studies. Trial registration: ChiCTR-TRC- 14005036Date of registration: 31 July 2014.published_or_final_versio

Dementia and risk of visual impairment in Chinese older adults

We had previously identified visual impairment increasing risk of incident dementia. While a bi-directional vision-cognition association has subsequently been proposed, no study has specifically examined the longitudinal association between dementia and incidence of clinically defined visual impairment. In this territory-wide community cohort study of 10,806 visually unimpaired older adults, we examined their visual acuity annually for 6 years and tested if dementia at baseline was independently associated with higher risk of incident visual impairment (LogMAR ≥ 0.50 in the better eye despite best correction, which is equivalent to moderate visual impairment according to the World Health Organization definition). By the end of Year 6, a total of 3151 (29.2%) participants developed visual impairment. However, we did not find baseline dementia associating with higher risk of incident visual impairment, after controlling for baseline visual acuity, cataract, glaucoma, diabetes, hypertension, hypercholesterolemia, heart diseases, stroke, Parkinson's disease, depression, hearing and physical impairments, physical, intellectual and social activities, diet, smoking, age, sex, educational level, and socioeconomic status. Among different covariables, baseline visual acuity appears to be more important than dementia in contributing to the development of visual impairment. Our present findings highlight the need for re-evaluating whether dementia is indeed a risk factor for visual impairment