Juebin Huang

Common variants at 12q14 and 12q24 are associated with hippocampal volume

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimers disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10−7. In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10−11) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10−11). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10−7) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10−7); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.

Diffusion Tensor Imaging of Normal Appearing White Matter and Its Correlation with Cognitive Functioning in Mild Cognitive Impairment and Alzheimer's Disease

Abstract:  Diffusion tensor imaging (DTI) was used to examine the microstructural integrity of normal appearing white matter (NAWM) in subjects with mild cognitive impairment (MCI) and Alzheimers disease (AD). Significant frontal, temporal, and parietal white matter diffusion tensor changes were demonstrated in MCI and AD compared with normal controls. These changes were correlated with cognitive functioning, and are consistent with a hypothesized loss of axonal processes in affected regions.

MRI confirms mild cognitive impairments prodromal for Alzheimer's, vascular and Parkinson-Lewy body dementias.

OBJECTIVES MRI assessments were correlated with serial Combined Mini-Mental Cognitive Capacity Screening Examinations (CMC). Vascular-MCI (VMCI), Neurodegenerative MCI (NMCI) and Parkinson-Lewy body MCI (PLB-MCI) were compared during conversions to dementia. Mild cognitive impairments (MCI) are identifiable prodromes for all dementia subtypes. MRI abnormalities are characterized among MCI subjects prodromal for dementia of Alzheimers disease (DAT), vascular dementia (VaD) and Parkinson-Lewy body dementia (PLBD). METHODS Aging volunteers (n=166) were recruited from ongoing longitudinal studies of aging, stroke, cerebrovascular disease and dementia. Cognitively normal (CN, n=52), MCIs of neurodegenerative (N-MCI, n=30), vascular (V-MCI, n=35) and Parkinson-Lewy Body (PLB-MCI, n=8) subtypes, plus converted DAT (n=19), VaD (n=17) and PLBD (n=5) were all diagnosed according to established protocol recommendations. Cerebral MRI abnormalities were likewise intercorrelated utilizing quantitative volumetric measurements. RESULTS V-MCI and converted VaD showed extensive leukoaraiosis with more lacunar infarcts than subjects with N-MCI or PLB-MCI. N-MCI, prodromal for DAT, showed medial temporal atrophy, greater enlargement of temporal horns, and fewer vascular lesions. PLB-MCI, prodromal for PLBD, displayed third ventricular enlargement greater than N-MCI and V-MCI, with similar but less severe atrophy of medial temporal lobe than N-MCI and fewer vascular lesions than V-MCI. Cognitive Impairments due to PLB with vascular features (V-PLB-CI) showed more lacunar and microvascular lesions involving both white matter and basal ganglia with greater frontal horn enlargement. CONCLUSIONS This study confirms different MCI subtypes prior to conversion to different dementias listed, recognizable by specific MRI abnormalities.

Prevalence of Parkinson's disease and related disorders in the elderly population of greater Beijing, China.

A lower prevalence of Parkinsons disease (PD) has been reported for Chinese populations, but it is unclear whether this observation reflects a lower disease risk or is an artifact of case finding. We ascertained the prevalence of PD in elderly residents of an area that was a composite of 27 urban and rural communities of Greater Beijing, China. A team of university neurologists went door‐to‐door throughout the study area, examining 5,743 residents (at age 55 years or older) and made preliminary determinations of which residents had PD or other types of parkinsonism. Final determinations were made after follow‐up and reevaluation of those persons who were either deemed to have parkinsonism or were suspected of having the condition (n = 144; median follow‐up = 40 months). Based on stringent diagnostic criteria, 110 persons were identified to have parkinsonism, of whom 64 (58%) had PD. The prevalence of PD increased with advancing age and was about 1% overall and for each gender. In rural communities, 22 persons had PD, but 20 persons (91%) were first diagnosed for this condition by the study neurologists. The prevalence figures obtained in this study are similar to some of the highest prevalence figures reported in the West.

Progression of Mild Cognitive Impairment to Alzheimers or Vascular Dementia Versus Normative Aging Among Elderly Chinese

To compare differences in evolutionary progressions from Mild Cognitive Impairment (MCI) to dementia of Alzheimers type (DAT) or to vascular dementia (VaD) versus normal aging, subjects identified as MCI or as cognitively normal (CN) during standard cognitive evaluations among a large epidemiological study designed to determine prevalence and incidence of dementia and its major subtypes in Beijing, China were re-examined after an interval of approximately 3 years, repeating the same investigation protocol as at baseline. MCI subjects meeting criteria for dementia and the two major subtypes, DAT and VaD were identified at follow-up evaluation. Annual conversion rates for combined dementias and for major subtypes of DAT and VaD, from MCI, were compared with conversion rates among CN subjects. Relative risks for conversion from MCI to major subtypes of dementia were also compared with CN subjects by Cox regression models. 175 MCI and 400 CN subjects were identified at baseline. Among 121 MCI subjects available at follow-up, 51 were diagnosed with dementia (29 with DAT, 18 with VaD and 4 with other dementias), compared with 14(10 DAT, 3 VaD and 1 other type dementia) diagnosed as dementia among 281 CN subjects available at follow-up. Annual conversion rates calculated from MCI to all dementias, compared with conversion rates from CNs, were 14.1% versus 1.6%. Specifically for DAT, annual conversion rates were 8.0% versus 1.1% and for VaD were 5.0% versus 0.3%. Relative risks for developing all dementias, DAT and VaD among MCI subjects were 9, 6 and 5 times greater than among CN subjects. Conversion rates among MCI subjects to dementia, and major subtypes, for elderly Chinese residents of Beijing were comparable with results reported among similar studies worldwide. Risks of developing dementia, and major subtypes, among MCI subjects in Beijing were significantly higher than among normal subjects. Identification of MCI among elderly populations provides the possibilities for dementia prevention and treatment within prodromal stages.

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 Alzheimers type (DAT), vascular dementia (VAD) and other rare neurodegenerative dementias, including Lewy body dementia (LBD), fronto-temporal dementia (FTD) and Parkinsons 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 Alzheimers (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.

Midlife and late-life vascular risk factors and white matter microstructural integrity: The atherosclerosis risk in communities neurocognitive study

Background Diffusion tensor imaging measures of white matter (WM) microstructural integrity appear to provide earlier indication of WM injury than WM hyperintensities; however, risk factors for poor WM microstructural integrity have not been established. Our study quantifies the association between vascular risk factors in midlife and late life with measures of late‐life WM microstructural integrity. Methods and Results We used data from 1851 participants in ARIC (Atherosclerosis Risk in Communities Study) who completed 3‐T magnetic resonance imaging, including diffusion tensor imaging, as part of the ARIC Neurocognitive Study (ARIC‐NCS). We quantified the association among lipids, glucose, and blood pressure from the baseline ARIC visit (1987–1989, ages 44–65, midlife) and visit 5 of ARIC (2011–2013, ages 67–90, late life, concurrent with ARIC‐NCS) with regional and overall WM mean diffusivity and fractional anisotropy obtained at ARIC visit 5 for ARIC participants. We also considered whether these associations were independent of or modified by WM hyperintensity volumes. We found that elevated blood pressure in midlife and late life and elevated glucose in midlife, but not late life, were associated with worse late‐life WM microstructural integrity. These associations were independent of the degree of WM hyperintensity, and the association between glucose and WM microstructural integrity appeared stronger for those with the least WM hyperintensity. There was little support for an adverse association between lipids and WM microstructural integrity. Conclusions Hypertension in both midlife and late life and elevated glucose in midlife are related to worse WM microstructural integrity in late life.

Mortality of Dementia and Its Major Subtypes in Urban and Rural Communities of Beijing

OBJECTIVE To identify the mortality and epidemiological pattern of dementia and its various major subtypes among urban and rural senior residents in Beijing. METHODS Based on Beijings dementia prevalence survey among residents aged 55 years and above in 1997, respondents were selected by stratified multiple-stage cluster sampling and 12 urban communities and 17 rural village communities were randomly sampled then follow-up in 2001. COX regression was used to analyze relative risks controlling confounding factors on deaths of dementia cases. RESULTS The mortality of dement patients in the 55-64 age-group was 0.82/100 person-year. The age-standardized mortality of dement cases was 0.90/100 person-year. The mortality in the 65 and above age-group was 1.44/100 person-year, and the age-standardized mortality was 1.56/100 person-year. Among AD cases, the above two mortalities were 0.35/100 and 0.42/100 person-year respectively, and among VaD cases, 0.34/100 and 0.36/100 person-year respectively. For both AD and VaD cases, their mortality increased with age. Region, gender and age were more significant to survival of AD cases. CONCLUSION One major subtype of dementia, AD, among elderly urban and rural residents in Beijing, has a different mortality and epidemiological pattern from VaD.

Association Between Midlife Risk Factors and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study

Importance The incidence of epilepsy is higher in older age than at any other period of life. Stroke, dementia, and hypertension are associated with late-onset epilepsy; however, the role of other vascular and lifestyle factors remains unclear. Objective To identify midlife vascular and lifestyle risk factors for late-onset epilepsy. Design, Setting, and Participants The Atherosclerosis Risk in Communities (ARIC) study is a prospective cohort study of 15 792 participants followed up since 1987 to 1989 with in-person visits, telephone calls, and surveillance of hospitalizations (10 974 invited without completing enrollment). The ARIC is a multicenter study with participants selected from 4 US communities. This study included 10 420 black or white participants from ARIC with at least 2 years of Medicare fee-for-service coverage and without missing baseline data. Data were analyzed betweeen April 2017 and May 2018. Exposures Demographic, vascular, lifestyle, and other possible epilepsy risk factors measured at baseline (age 45-64 years) were evaluated in multivariable survival models including demographics, vascular risk factors, and lifestyle risk factors. Main Outcomes and Measures Time to development of late-onset epilepsy (2 or more International Classification of Diseases, Ninth Revision codes for epilepsy or seizures starting at 60 years or older in any claim [hospitalization or outpatient Medicare through 2013]), with first code for seizures after at least 2 years without code for seizures. Results Of the 10 420 total participants (5878 women [56.4%] and 2794 black participants [26.8%]; median age 55 years at first visit), 596 participants developed late-onset epilepsy (3.33 per 1000 person-years). The incidence was higher in black than in white participants (4.71; 95% CI, 4.12-5.40 vs 2.88; 95% CI, 2.60-3.18 per 1000 person-years). In multivariable analysis, baseline hypertension (hazard ratio [HR], 1.30; 95% CI, 1.09-1.55), diabetes (HR, 1.45; 95% CI, 1.17-1.80), smoking (HR, 1.09; 95% CI, 1.01-1.17), apolipoprotein E &egr;4 genotype (1 allele HR, 1.22; 95% CI, 1.02-1.45; 2 alleles HR, 1.95; 95% CI, 1.35-2.81), and incident stroke (HR, 3.38; 95% CI, 2.78-4.10) and dementia (HR, 2.56; 95% CI, 2.11-3.12) were associated with an increased risk of late-onset epilepsy, while higher levels of physical activity (HR, 0.90; 95% CI, 0.83-0.98) and moderate alcohol intake (HR, 0.72; 95% CI, 0.57-0.90) were associated with a lower risk. Results were similar after censoring individuals with stroke or dementia. Conclusions and Relevance Potentially modifiable risk factors in midlife and the APOE &egr;4 genotype were positively associated with risk of developing late-onset epilepsy. Although stroke and dementia were both associated with late-onset epilepsy, vascular and lifestyle risk factors were significant even in the absence of stroke or dementia.

Early Cognitive Predictors of Vascular Dementia: A Population-based Longitudinal Study in Chinese Elderly

Background and Objectve: Mild cognitive impairment (MCI) as pre-dementia syndrome has not been thouroughly studied in underdeveloped regions with cultural and social-economic backgrounds different from Western countries. This study was designed to characterize cognitive profiles of MCI prodromal for vascular dementia (VaD) among an elderly Chinese population. Methods: Subjects identified with MCI in a large epidemiological study of dementia and major subtypes in Beijing, China, were re-examined three years later, by repeating the baseline psychometric protocol. Baseline versus follow-up psychometric performance was compared among two outcome groups: 1) MCI converting to VaD (MCI-VaD) and 2) MCI-Non-converters. Results: 121 of 175 subjects identified as MCI at baseline were available for follow-up, with 18 diagnosed VaD, 70 didn’t convert to any dementias. At baseline, MCI-VaD displayed extensive impairments in attention, naming and verbal fluency. At the time of dementia diagnosed, multiple cognitive domains declined significantly. Conclusions: The present study provided additional evidence for the existence of prodromal VaD in an elderly Chinese population. The distinctive cognitive patterns of prodromal VaD allowed for an early intervention and improved control of vascular risk factors, which were less well controlled for than in developed countries.