Fu-Rong Sun

The clinical and pathological phenotypes of frontotemporal dementia with C9ORF72 mutations

An expanded hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72), on chromosome 9p21, has recently been identified as a major cause of familial frontotemporal dementia (FTD). The neuropathology and clinical characteristics associated with C9ORF72 mutations are heterogeneous with the unknown pathomechanism. These cases were reported with a series of neuropathology, including TDP-43 pathology, ubiquilin (UBQLN) pathology, p62 pathology, microglial pathology, RNA-binding protein pathology and pathology associated with dipeptide-repeat (DPR) proteins. TDP-43 positive neuropathology was important in FTD patients with the mutations. Nevertheless, the majority of reports agree with a special pattern of neuropathology with p62 positive, TDP-43-negative inclusions being a consistent feature. Although subjects with the C9ORF72 mutations more frequently present with earlier onset age, earlier death, a shortened survival and a positive family history, most of the subjects present with typical clinical features of FTD. All these findings support that the C9ORF72 mutations become important newly recognized causes of FTD, providing a more detailed characterization of the associated clinical and pathological features. The following review summarizes the pathological development of FTD associated with C9ORF72, the clinical and pathological features of this cohort, some pathological mechanism hypotheses, and describes their phenotypic range and overlap with other neurodegenerative diseases.

GWAS-Linked Loci and Neuroimaging Measures in Alzheimer's Disease.

Recently, 19 susceptibility loci for Alzheimer’s disease (AD) had been identified through AD genome-wide association studies (GWAS) meta-analysis. However, how they influence the pathogenesis of AD still remains largely unknown. We studied those loci with six MRI measures, abnormal glucose metabolism, and β-amyloid (Aβ) deposition on neuroimaging in a large cohort from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in order to provide clues of the mechanisms through which these genetic variants might be acting. As a result, single nucleotide polymorphisms (SNPs) at rs983392 within MS4A6A and rs11218343 within SOLR1 were both associated with the percentage of increase in the volume of left inferior temporal regions in the follow-up study. Meanwhile, rs11218343 at SORL1 and rs6733839 at BIN1 was associated with rate of volume change of left parahippocampal and right inferior parietal, respectively. Moreover, rs6656401 at CR1 and rs983392 at MS4A6A were both associated with smaller volume of right middle temporal at baseline. However, in addition to the APOE locus, we did not detect any influence on glucose metabolism and Aβ deposition. APOE ε4 allele was associated with almost all measures. Altogether, five loci (rs6656401 at CR1, rs983392within MS4A6A, rs11218343 at SORL1, rs6733839 at BIN1, and APOE ε4) have been detected to be associated with one or a few established AD-related neuroimaging measures.

Single nucleotide polymorphism rs7294919 on chromosome 12q24.22 is associated with late-onset Alzheimer's disease in Han Chinese

Recently, two large genome-wide association studies (GWASs) have identified several variants at 12q14 and 12q24 which are associated with hippocampal volume, one of the most important biological markers of Alzheimers disease (AD). The strongest association was reported for the rs7294919 polymorphism on chromosome 12q24.22. In order to explore whether rs7294919 polymorphism was also associated with late-onset AD (LOAD) risk, we recruited 1132 LOAD patients and 1159 sex- and age-matched healthy controls in the study. The results showed that rs7294919 polymorphism was significantly associated with LOAD (genotype P<0.01, allele P=0.02). After stratification by APOE, significant difference was only observed in non-APOE ɛ4 carriers (P=0.01). Logistic regression demonstrated that the C allele at rs7294919 was a risk factor for LOAD in dominant and recessive models after adjusting for age, gender and the APOE ɛ4 carrier status. In conclusion, our study demonstrates an association of rs7294919 polymorphism locus on chromosome 12q24.22 with risk for LOAD in Han Chinese.

Association of HLA-DRB1 polymorphism with Alzheimer’s disease: a replication and meta-analysis

Genome-wide association studies (GWAS) have identified one single-nucleotide polymorphism (SNP) rs9271192 within HLA-DRB1 as a risk factor for Alzheimers disease (AD) in Caucasians. The effect of rs9271192 on AD needed to be verified in other ethnic cohorts. In order to evaluate the association between HLA-DRB1 rs9271192 polymorphism and late-onset AD (LOAD) in the Northern Han Chinese population, we recruited 982 LOAD patients and 1344 sex- and age-matched healthy controls. The results showed that HLA-DRB1 rs9271192 was associated with LOAD (genotype P = 0.015, allele P = 0.04). The results of logistic regression revealed the C allele homozygosity strongly increased the risk of LOAD under a recessive model in the total sample (P = 0.004, OR =2.069, 95% CI = 1.262–3.434). When these data were stratified by apolipoprotein E (APOE) ε4 status, the observed association was confined to APOE ε4 non-carriers (additive model: P=0.048, OR =1.191, 95% CI =1.001–1.417; recessive model: P < 0.001, OR = 2.601, 95% CI =1.519–4.566). Furthermore, meta-analysis after sensitive analysis confirmed that rs9271192 within HLA-DRB1 increased the risk of LOAD (OR = 1.12, 95% CI = 1.08–1.15). To summarize, the C allele in HLA-DRB1 rs9271192 may be an independent risk factor for LOAD.

Impacts of CD33 Genetic Variations on the Atrophy Rates of Hippocampus and Parahippocampal Gyrus in Normal Aging and Mild Cognitive Impairment.

The cluster of differentiation 33 (CD33) has been proved as a susceptibility locus associated with late-onset Alzheimer’s disease (LOAD) based on recent genetic studies. Numerous studies have shown that multiple neuroimaging measures are potent predictors of AD risk and progression, and these measures are also affected by genetic variations in AD. Figuring out the association between CD33 genetic variations and AD-related brain atrophy may shed light on the underlying mechanisms of CD33-related AD pathogenesis. Thus, we investigated the influence of CD33 genotypes on AD-related brain atrophy to clarify the possible means by which CD33 impacts AD. A total of 48 individuals with probable AD, 483 mild cognitive impairment, and 281 cognitively normal controls were recruited from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. We investigated the influence of CD33 SNPs on hippocampal volume, parahippocampal gyrus volume, posterior cingulate volume, middle temporal volume, hippocampus CA1 subregion volume, and entorhinal cortex thickness. We found that brain regions significantly affected by CD33 genetic variations were restricted to hippocampal and parahippocampal gyrus in hybrid population, which were further validated in subpopulation (MCI and NC) analysis. These findings reaffirm the importance of the hippocampal and parahippocampal gyrus in AD pathogenesis, and present evidences for the CD33 variations influence on the atrophy of specific AD-related brain structures. Our findings raise the possibility that CD33 polymorphisms contribute to the AD risk by altering the neuronal degeneration of hippocampal and parahippocampal gyrus.

Effects of HLA-DRB1/DQB1 Genetic Variants on Neuroimaging in Healthy, Mild Cognitive Impairment, and Alzheimer's Disease Cohorts

Alzheimer’s disease (AD) is the most common form of dementia and exhibits a considerable level of heritability. Previous association studies gave evidence for the associations of HLA-DRB1/DQB1 alleles with AD. However, how and when the gene variants in HLA-DRB1/DQB1 function in AD pathogenesis has yet to be determined. Here, we firstly investigated the association of gene variants in HLA-DRB1/DQB1 alleles and AD related brain structure on magnetic resonance imaging (MRI) in a large sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We selected hippocampus, subregion, parahippocampus, posterior cingulate, precuneus, middle temporal, entorhinal cortex, and amygdala as regions of interest (ROIs). Twelve SNPs in HLA-DRB1/DQB1 were identified in the dataset following quality control measures. In the total group hybrid population analysis, our study (rs35445101, rs1130399, and rs28746809) were associated with the smaller baseline volume of the left posterior cingulate and rs2854275 was associated with the larger baseline volume of the left posterior cingulate. Furthermore, we detected the above four associations in mild cognitive impairment (MCI) sub-group analysis, and two risk loci (rs35445101 and rs1130399) were also the smaller baseline volume of the left posterior cingulate in (NC) sub-group analysis. Our study suggested that HLA-DRB1/DQB1 gene variants appeared to modulate the alteration of the left posterior cingulate volume, hence modulating the susceptibility of AD.

MS4A6A genotypes are associated with the atrophy rates of Alzheimer’s disease related brain structures

Membrane-spanning 4-domains, subfamily A, member 6A (MS4A6A) has been identified as susceptibility loci of Alzheimers disease (AD) by several recent genome-wide association studies (GWAS), whereas little is known about the potential roles of these variants in the brain structure and function of AD. In this study, we included a total of 812 individuals from the Alzheimers disease Neuroimaging Initiative (ADNI) database. Using multiple linear regression models, we found MS4A6A genotypes were strongly related to atrophy rate of left middle temporal (rs610932: Pc = 0.017, rs7232: Pc = 0.022), precuneus (rs610932: Pc = 0.015) and entorhinal (rs610932, Pc = 0.022) on MRI in the entire group. In the subgroup analysis, MS4A6A SNPs were significantly accerlated the percentage of volume loss of middle temporal, precuneus and entorhinal, especially in the MCI subgroup. These findings reveal that MS4A6A genotypes affect AD specific brain structures which supported the possible role of MS4A6A polymorphisms in influencing AD-related neuroimaging phenotypes.

HLA-A2 Alleles Mediate Alzheimer's Disease by Altering Hippocampal Volume.

HLA-A is a locus of the major histocompatibility complex situated on chromosome 6p21.3. HLA-A has been shown to be associated with susceptibility to Alzheimer’s disease (AD). In this study, we firstly investigated the association of gene variants in HLA-A and brain structures on MRI in a large sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to explore the effects of HLA-A on AD pathogenesis. We selected the hippocampus, parahippocampus, posterior cingulate, precuneus, middle temporal, entorhinal cortex, and amygdala as regions of interest (ROIs). In hybrid population analysis, our results showed a marginally significant association between rs9260168 and the atrophy of the left parahippocampus (P = 0.007, Pc = 0.054), rs3823342 and the atrophy of the left parahippocampus (P = 0.014, Pc = 0.054), rs76475517, which only exists in Caucasians with HLA-A23 or HLA-A24 alleles, and the atrophy of the right amygdala (P = 0.010, Pc = 0.085) at baseline. In particular, the haplotype (TGACAAGG), as a surrogate marker of HLA-A2, was founded to be positively associated with the atrophy of the right hippocampus (P = 0.047) at baseline. Furthermore, we detected the above four associations in mild cognitive impairment (MCI) subpopulation analysis. Our study provided preliminary evidences supporting HLA-A2 in Caucasians contribute to the risk of AD by modulating the alteration of hippocampal volume and HLA-A gene variants appear to play a role in altering AD-related brain structures on MRI.

Association of Frontotemporal Dementia GWAS Loci with Late-Onset Alzheimer’s Disease in a Northern Han Chinese Population

BACKGROUND Both Alzheimers disease (AD) and frontotemporal dementia (FTD) are a class of neurodegenerative diseases. Strong similarities in cerebrospinal fluid biomarker, imaging markers, and disease progression profiles suggest that some or most of the pathophysiology is shared between AD and FTD. A recent large genome-wide association study reported several single nucleotide polymorphisms (SNPs) at the RAB38, RAB38/CTSC, HLA-DRA/HLA-DRB5, and BTNL2 in association with FTD. OBJECTIVE To explore whether these SNPs are associated with AD risk. METHODS We conducted a case-control study to investigate the association of FTD-associated loci in 2338 Han Chinese subjects. RESULTS We observed significant differences in genotype distributions of rs302668 (pc = 0.025), rs9268877 (pc = 0.025), rs9268856 (p <  0.001), and rs1980493 (pc = 0.045) between cases and controls. The SNPs rs16913634 for RAB38/CTSC was unrelated to LOAD risk (p = 0.088). CONCLUSION The SNPs rs302668 in RAB38, rs9268877 and rs9268856 polymorphism in HLA-DRA/HLA-DRB5, and rs1980493 polymorphism in BTNL2 might play a role in the susceptibility to late-onset AD in the Han Chinese population.

Association study of the PLXNA4 gene with the risk of Alzheimer’s disease

BACKGROUND The Plexin-A 4 (PLXNA4) gene has recently been recognized as a functional candidate gene of late-onset Alzheimers disease (LOAD). The single nucleotide polymorphism (SNP) rs13232207 of PLXNA4 gene has been reported to be associated with Alzheimers disease (AD) in Japanese cohorts. We sought to clarify whether this novel locus gains the same effect in northern Han Chinese. METHODS To investigate the relationship between SNP rs13232207 and AD sufferers, a case-control study of unrelated individuals was conducted with a total sample size of 2,318 subjects (978 cases and 1,340 age and gender matched healthy controls) in a Northern Han Chinese population. SPSS 22.0 was applied for the statistical process. RESULTS No significant difference in polymorphic distribution of rs13232207 was observed on LOAD risk independently under dominant (P=0.057), additive (P=0.233) or recessive model (P=0.392). In terms of interaction with apolipoprotein E (APOE), there is also no positive interaction in dominant (P=0.438), additive (P=0.055) or recessive model (P=0.095). CONCLUSIONS Replication of association between the PLXNA4 rs13232207 and AD in a Han ethnic group indicates that this link is not the result of chance.