Genetic landscape of recessive diseases in the Vietnamese population from large-scale clinical exome sequencing.

Accurate profiling of population-specific recessive diseases is essential for the design of cost-effective carrier screening programs. However, minority populations and ethnic groups, including Vietnamese, are still underrepresented in existing genetic studies. Here, we reported the first comprehensive study of recessive diseases in the Vietnamese population. Clinical exome sequencing data of 4503 disease-associated genes obtained from a cohort of 985 Vietnamese individuals was analyzed to identify pathogenic variants, associated diseases and their carrier frequencies in the population. A total of 118 recessive diseases associated with 164 pathogenic or likely pathogenic variants were identified, among which 28 diseases had carrier frequencies of at least 1% (1 in 100 individuals). Three diseases were prevalent in the Vietnamese population with carrier frequencies of 2-12 times higher than in the world populations, including beta-thalassemia (1 in 23), citrin deficiency (1 in 31), and phenylketonuria (1 in 40). Seven novel pathogenic and two likely pathogenic variants associated with nine recessive diseases were discovered. The comprehensive profile of recessive diseases identified in this study enables the design of cost-effective carrier screening programs specific to the Vietnamese population.

Functionalization of epoxy-based monoliths for ion exchange chromatography of proteins.

Macroporous epoxy-based monoliths prepared by emulsion polymerization have been modified for use in ion exchange chromatography (IEC) of proteins. Strong anion exchange functionality was established by iodomethane quaternization of tertiary amine present on the monolith surface as a part of the polymer backbone. The modification pathway to cation exchange materials was via incorporation of glycidyl methacrylate (GMA) brushes which were coated using atom transfer radical polymerization (ATRP). Strong (SO(3)(-)) and weak (COO(-)) cation exchange groups were thereafter introduced onto the GMA-grafted monoliths by reactions with sodium hydrogen sulfite and iminodiacetic acid, respectively. Grafting was confirmed by XPS, gravimetric measurement, and chromatographic behavior of the modified materials toward model proteins. In incubation experiments the proteins were recovered quantitatively with no obvious signs of unfolding after contact with the stationary phase for >2 h. Chromatographic assessments on the functionalized columns as well as problems associated with flow-through modification by ATRP are discussed.

Preparation and characterization of sizable macroporous epoxy resin-based monolithic supports for flow-through systems.

This paper presents further results from our efforts to prepare sizable macroporous monolithic materials from epoxy resins and polyamines by emulsion polymerization. For their uses as supports in flow systems, the study aimed at developing materials possessing maximum fluid permeability, high mechanical stability, and a controlled porosity and surface area. Characterization of the materials has been carried out using different techniques, focusing on morphological and mechanical features, and on the surface chemistry. Morphology and porosity were studied with SEM, nitrogen adsorption/desorption, mercury intrusion porosimetry (MIP), and (2)H NMR cryoporosimetry. The chemical composition of the bulk structures and their surfaces was studied by means of bulk elemental analysis and X-ray photoelectron spectroscopy, and potentiometric titration was used to assess the relative amounts of amines and epoxy groups. Essentially, the morphological features were a high fluid permeability, but rather low specific surface area. Convective flow was facilitated by large, interconnected, and evenly spaced macropores which were formed by nonporous skeletons of the connected-rod type. Despite the interfacial nature of the polymerization, the bulk and the surface of the fully cured materials showed similar elemental compositions. All materials were found to have a high surface density of hydroxyl groups, which facilitates functionalization reactions.

Estimating parameters and hidden variables in non-linear state-space models based on ODEs for biological networks inference.

MOTIVATION: Statistical inference of biological networks such as gene regulatory networks, signaling pathways and metabolic networks can contribute to build a picture of complex interactions that take place in the cell. However, biological systems considered as dynamical, non-linear and generally partially observed processes may be difficult to estimate even if the structure of interactions is given. RESULTS: Using the same approach as Sitz et al. proposed in another context, we derive non-linear state-space models from ODEs describing biological networks. In this framework, we apply Unscented Kalman Filtering (UKF) to the estimation of both parameters and hidden variables of non-linear state-space models. We instantiate the method on a transcriptional regulatory model based on Hill kinetics and a signaling pathway model based on mass action kinetics. We successfully use synthetic data and experimental data to test our approach. CONCLUSION: This approach covers a large set of biological networks models and gives rise to simple and fast estimation algorithms. Moreover, the Bayesian tool used here directly provides uncertainty estimates on parameters and hidden states. Let us also emphasize that it can be coupled with structure inference methods used in Graphical Probabilistic Models. AVAILABILITY: Matlab code available on demand.

MRI identifies MCI subtypes: vascular versus neurodegenerative.

As life expectancy increases worldwide, pandemics of cognitive impairment and dementia are emerging as major public health problems. Mild cognitive impairment (MCI), prodromal for dementia, is a descriptive term used for those clinical states showing early and subtle cognitive decline among the elderly, preceding the dementias. Psychometric screening combining Mini-Mental Status (MMSE) and Cognitive Capacity Screening (CCSE) Examinations, when combined now called CMC with C standing for Combined, M for MMSE, and C for CCSE, confirms diagnosis of MCI. Individuals identified with MCI are at increased risk for dementia of Alzheimer's type (DAT), vascular dementia (VAD) and other rare neurodegenerative dementias, including Lewy body dementia (LBD), fronto-temporal dementia (FTD) and Parkinson's disease dementia (PDD). Depending on different clinical compositions of cohorts studied, and MCI criteria used, between 19% and 50% of MCI progress to dementia within 3-5 years, two thirds to Alzheimer's (DAT) and one third to vascular types (VAD) in the United States. Not all Parkinsonians become demented, but PDD develops in 20-30%, however, PDD subjects were excluded from the present study, as were LBD and FTD. The incidence of MCI in those over age 70, with confirmed cognitive declines when tested 2 years later, is around 23%, but some spontaneously improve.

Is mild cognitive impairment prodromal for vascular dementia like Alzheimer's disease?

BACKGROUND AND PURPOSE: Individuals with mild cognitive impairment (MCI) are at increased risk of Alzheimer's disease (AD) and probably other forms of dementia. Some subtypes of vascular dementia (VaD) may possess minor neuropathological changes of AD that may contribute to cognitive impairments. It was posited that MCI, identified by criteria described here, might present as a prodrome for VaD and AD. METHODS: Serial Mini-Mental State Examination was administered at 3- to 6-month intervals, and neuroimaging was performed annually. Subtle cognitive dysfunctions were weighted and measured according to MCI criteria defined here. Subjects identified with MCI were then followed up for an additional 3.88+/-3.01 years. Diagnoses of VaD and AD were made according to established criteria. RESULTS: During 3.72+/-2.94 years of follow-up of the original normative subjects, 73 of 291 (25.1%) developed MCI. Of the 27 subjects who developed VaD, 15 (55.6%) had prodromal MCI. Of these, two thirds were subclassified as having small-vessel dementia. The remaining 12 patients with VaD (44.4%) were diagnosed directly from a cognitively normal status without preceding MCI. These were predominantly multi-infarct or strategic-infarct dementia (66.7%). An additional 35 MCI subjects (47.9%) developed AD. Both VaD and AD diagnosed after MCI prodromes manifested similar spectral domains of cognitive impairments, which included memory, during their MCI stages. CONCLUSIONS: In some VaD subtypes, particularly those caused by subcortical microvascular disease, dementia may be preceded by MCI, which has similar domains of cognitive impairment and a similar progressive course that may mimic AD.

Donepezil treatment of vascular dementia.

Cholinergic deficits are clinicopathological hallmarks of Alzheimer's disease (DAT) and during the past decade have been the sole target for clinically effective treatments. By contrast, vascular dementia subtypes (VaD) are heterogeneous clinical syndromes, and therapeutic approaches have been directed toward control of vascular risk factors. Little attention has been paid to cholinergic deficits as a mechanism contributing to cognitive impairments in VaD as a potential target for treatment. The purpose of the study was to determine whether there are therapeutic benefits from long-term treatment with cholinesterase inhibitors among VaD patients. Ten VaD patients were diagnosed according to DSM-III-R and NINDS-AIREN criteria and classified into subtypes by neuroimaging. All were treated with titrated doses of donepezil for a mean interval of 15 months. At baseline and follow-up clinic visits, patients underwent medical and neurological examinations, as well as neuropsychological testing including Mini-Mental Status Examinations (MMSE) and Cognitive Capacity Screening Examinations (CCSE). Cognitive statuses of 10 treated patients were then compared before and after treatment. Net changes were expressed as annual MMSE score changes (DeltaMMSE/year) and annual CCSE score changes (DeltaCCSE/year). Of the 10 treated VaD patients, cognitive improvements were found when comparisons were made before and after treatment. Ten treated patients also showed greater cognitive improvements, while untreated patients showed continued cognitive decline. This study suggests that cholinergic deficits in VaD are due to neuronal ischemic damage with loss of acetylcholine and that treatment of VaD with cholinesterase inhibitors is a rational therapy.

Cross-cultural comparison of mild cognitive impairment between China and USA.

Individuals with mild cognitive impairment (MCI) are at increased risk for dementia of Alzheimer's type (DAT), vascular dementia (VaD), Lewy Body (LBD) and Fronto-temporal dementias (FTD). Risk factors and conversion rates of MCI to dementia have not been thoroughly investigated in developing countries. Chinese and English versions of Mini-Mental State Examination were administered serially among well-matched subjects from two clinics located in Xi'an, China and Houston, USA. Subtle cognitive impairments were weighed according to MCI criteria as defined previously. Subjects with MCI were followed for an additional 3 years after their identification. Diagnoses of VaD and DAT were made according to established criteria. During screening period, 73 American and 65 Chinese individuals were identified with MCI. After 3 years of MCI follow-up, of the 73 American MCI subjects, 35 (47.9%) developed DAT and 15 (20.5%) developed VaD. Of the 65 Chinese MCI subjects, 12 (18.5%) developed DAT and 19 (29.2%) developed VaD. According to Kaplan-Meier analysis, Chinese MCI subjects, despite their lower educational level, are 1.7 times less likely to progress to DAT and 2.3 times more likely to progress to VaD than American subjects within 3 years of MCI being identified (p<0.01). Data suggest that progression rates of MCI vary considerably among subjects from two countries. American MCI subjects are more prone to DAT, while Chinese subjects are more prone to VaD. Differences in genetic factors, cultures, educational levels, and preventive treatments of vascular risk factors are proposed as responsible for this uneven geographic distribution for different types of dementia.

Longitudinal analysis of abnormal domains comprising mild cognitive impairment (MCI) during aging.

Research directed towards early diagnosis and therapy of dementia demands rapid identification of prodromal mild cognitive impairment (MCI). A longitudinal study was designed to clarify whether different domains of cognitive impairment, tested by Mini-Mental State Examination (MMSE), help predict dementia. After 3.74+/-2.94 years of follow-up among 291 cognitively normative volunteers, 73 developed MCI. During the next 3.88+/-3.01 years of MCI follow-up, 47.9% of MCI developed dementia of Alzheimer's type (DAT), 20.5% of MCI developed vascular dementia (VaD) and 31.5% maintained persistent MCI at the time of data analysis. Total MMSE and subtest scores analyzed at MCI onset showed significant differences for serial seven subtest scores between DAT and persistent MCI (P<0.05). Rates of change in subtests of orientation and memory and total MMSE scores predicted DAT (P<0.01). Decreasing orientation and total MMSE scores predicted VaD conversion rates of MCI to DAT at 2 years were 20.06% among single-domain MCI versus 41.7% for multi-domain MCI (P<0.05). Subjects with MCI often have impaired cognitive domains other than memory and show rapid deterioration, which predicts DAT. VaD sometimes mimics DAT with subtle cognitive impairment appearing before onset of dementia.

Screening for mild cognitive impairment (MCI) utilizing combined mini-mental-cognitive capacity examinations for identifying dementia prodromes.

OBJECTIVE: To test correctness of results when combining Mini-Mental State Examination (MMSE) and Cognitive Capacity Screening Examination (CCSE) for identifying mild cognitive impairment (MCI) among non-demented elderly subjects at risk for developing dementia. METHODS: A retrospective study was conducted among consecutively referred volunteers with memory complaints to a research out-patient clinic. Two cognitive screening tests (MMSE and CCSE) were performed according to established protocol. Resulting combined screening test (termed by acronym as CMC) combined the non-overlapping test items derived from both MMSE and CCSE. Conversion to dementia at follow-up served as the 'gold-standard' for evaluating correctness of CMC for identifying MCI. RESULTS: Of 351 subjects completing cognitive assessments and meeting requirements for study protocol, 84 (23.9%) developed dementia of different types within 3-6 years (3.89 +/- 2.17) of follow-up. Among these, 47 met criteria for probable Alzheimer disease (AD), 22 for probable vascular dementia (VaD), 12 for mixed AD/VaD and three for probable frontotemporal dementia. When final diagnosis of AD was used as the 'gold standard' for testing correctness of MCI identified by cognitive screening tests, sensitivities of MMSE, CCSE and CMC for identifying MCI were relatively 61.0%, 74.3% and 83.1% with minimum specificity set at 80%. When diagnosis of all types of dementia was used as the standard for testing predictive correctness of MCI, CCSE emerged as an optimal MCI screening test. CONCLUSION: Combining the CCSE and MMSE screening tests resulted in higher sensitivity than was achieved by MMSE alone and maintained specificity at comparable levels for identifying MCI. The results confirmed that CMC has optimal correctness and utility as a brief cognitive test for screening MCI as a prodrome for dementia among non-demented elderly populations.

Adapting mini-mental state examination for dementia screening among illiterate or minimally educated elderly Chinese.

BACKGROUND: Illiteracy is prevalent among current elderly Chinese. There are few brief cognitive tests in Chinese designed to screen those possibly demented for more detailed evaluation in a clinical setting. OBJECTIVES: The present study adapted the Mini-Mental State Examination (MMSE) for screening dementia among illiterate or less educated elderly Chinese. METHODS: Literacy-dependent items of the MMSE were modified or substituted by equivalent items that are not literacy-dependment. Some items were modified to provide socio-cultural compatibility. After developing it, the Chinese adapted MMSE (CAMSE) was administered to 370 elderly outpatients from Xijing hospitals located in Xi'an, China, 93 of whom were found to be demented and 277 non-demented. Sensitivities and specificities for detecting dementia were evaluated by adjusting for different CAMSE cut-off points. The optimal cut-off points of 22 for literates and 20 for illiterates yielded a sensitivity of 83.87% and a specificity of 84.48%. Corresponding positive predictive value (PPV) was 0.65, and negative predictive value (NPV) was 0.94. The impact of literacy on CAMSE and individual test items was also evaluated. Illiterate subjects got a higher CAMSE total score than literate subjects (p < 0.05). Only one out of 12 test items, serial sevens, was negatively influenced by illiteracy (p < 0.01). After an interval of 4-6 weeks, 32 randomly selected subjects were retested with CAMSE. The test-retest reliability for total scores was 0.75 (p < 0.01). CONCLUSIONS: Results suggest that in the socio-cultural context for Chinese, irrespective of their literacy skills, CAMSE proved feasible for use in clinical settings for dementia screening.