中老年人群脂联素基因多态性与脑白质病变的关系

目的 探讨在中老年人群中脂联素基因多态性与脑白质病变(WML)之间的关系。方法 纳入2012年6月—2013年1月第三军医大学大坪医院神经内科811例中老年(≥50岁)住院患者的临床资料、血液学指标等进行横断面研究。根据头颅MRI检查结果及Fazekas评分标准诊断WML并分组:诊断为WML者419例纳入观察组,非WML者392例纳入对照组。采用连接酶链反应对患者基因进行分型。应用多因素logistic回归分析脂联素基因多态性与WML关系。结果 与对照组比,观察组平均年龄更大,冠心病、既往卒中史、高血压和糖尿病的比例更高,血浆TC、高密度脂蛋白胆固醇(HDL-C)和载脂蛋白A-Ⅰ浓度较低,空腹血糖浓度较高(P值均<0.05)。rs7649121的AA、AT、TT基因型、等位基因A、T频率在两组间的分布差异有统计学意义(P<0.01)。调整了年龄、性别、既往卒中史、冠心病、高血压、糖尿病和HDL-C后,相对AA基因型,AT基因型和TT基因型仍是WML的独立危险因素;在显性模型中,AT/TT基因型患WML的风险是AA基因型的1.73倍。结论在中国中老年人群中首次发现,脂联素基因的rs7649121位点与WML有关,T等位基因是WML发生的易感基因。     

HFE H63D, C282Y and AGTR1 A1166C polymorphisms and brain white matter lesions in the aging brain

Incidental white matter lesions (WML) are a common neuroradiological finding in elderly people and have been linked to dementia and depression. Various mechanisms including hypoxia and increased production of reactive oxygen species (ROS) are implicated in the etiology of WML. The hemochromatosis (HFE) gene p.H63D and p.C282Y polymorphisms have been linked to dysregulation of iron metabolism and increased levels of ROS, whereas Angiotensin II receptor 1 (AGTR1) c.1166A → C polymorphism is known as a vascular risk factor. These genetic polymorphisms were characterized in brains donated to the UK MRC Cognitive Function and Ageing Study (CFAS) to assess their potential role in the risk for development of age-related WML. The study cohort comprised 258 brain donated to CFAS. WML severity was assessed in the postmortem brain donations using magnetic resonance imaging (MRI) scans and scored using the Scheltens' scale. Polymerase chain reaction (PCR) amplification of extracted DNA followed by restriction enzyme digestion was used to genotype the samples. Genotypes were validated using direct sequencing in a smaller sample. The results show that HFE p.H63D polymorphism is not associated with WML severity in the whole cohort. However, there is a significant association of the D allele with severity of WML in noncarriers of the APOE ε4 allele. No association is demonstrated between the HFE p.C282Y nor the AGTR1 c.1166A → C polymorphisms and WML severity. The HFE gene appears to be a genetic risk factor for severe aging WML independently of the APOE ε4 genotype. This would support the role of iron-related oxidative stress, in addition to previously studied factors, e.g., hypoxia as potential risk factors for developing prominent aging WML.     

Apolipoprotein E epsilon4 influences on episodic recall and brain structures in aging pilots

The apolipoprotein (APOE) epsilon4 allele is associated with cognitive deficits and hippocampal atrophy in nondemented middle-aged and older adults. It is not known to what extent this genetic risk factor for Alzheimer's disease (AD) impacts performance in late middle-aged and older workers in cognitively demanding occupations. This cross-sectional analysis examines brain-cognitive-genetic relationships in actively flying general aviation pilots, half of whom are APOE epsilon4 carriers. Fifty pilots were studied with structural MRI and memory tasks. Average visual paired associate memory recall performance was lower in APOE epsilon4 carriers than non-carriers. Memory performance correlated positively with hippocampal volume, but no structural differences were found in hippocampal or frontal volumes with respect to APOE epsilon4 allele. These results were evident in healthy professionals without any presenting memory problems and without selection for a family history of AD. These findings point to basic memory testing as a sensitive tool for detecting APOE epsilon4-related influences on memory in aging workers.     

Brain atrophy and cognition: Interaction with cerebrovascular pathology?

We examined the interaction of brain atrophy and white matter lesions (WML) with cognitive functioning in 605 patients (mean age, 58 ± 10; 76% men) with atherosclerotic disease from the Second Manifestations of ARTerial disease-MR substudy (SMART-MR study). Automated brain segmentation was used to quantify volumes of brain tissue, cerebrospinal fluid, and WML on MRI. Total brain, ventricular, and cortical gray matter volume were divided by intracranial volume (ICV). Neuropsychological tests assessing executive functioning and memory performance were performed and composite scores were calculated. We observed that smaller total brain volume, larger ventricular volume, and smaller cortical gray matter volume (all as % of ICV) were associated with worse executive performance and that this association became stronger with presence of brain infarcts or severe WML volume (P-values for interaction <0.05). No interaction between measures of brain volume and cerebrovascular pathology on memory performance was observed. Our findings suggest that patients with cerebrovascular pathology on MRI may be more vulnerable to impairment in executive functioning related to global as well as focal brain atrophy.     

Coupling phenomena during asynchronous submaximal two-hand,multi-finger force production tasks in humans

Since a deletion/insertion polymorphism in the promoter region of the apolipoprotein C-I (APOC1) gene has been reported to be associated with late-onset Alzheimer's disease (LOAD), we examined the hypothesis in a Korean population with 120 LOAD cases and 132 age-matched controls. The frequency of APOC1 insertion allele (H2) was significantly increased in LOAD than in controls, giving an odds ratio of 3.3 (95% CI 2.0-5.5, P<0.0001). Logistic regression analysis revealed that the interaction model between APOE epsilon4 and APOC1 H2 yielded larger odds ratio than other models including either APOE epsilon4 or APOC1 H2 alone. In addition, the association between APOC1 H2 and LOAD remained significant after adjustment of the effect of APOE epsilon4 (P=0.036). These results support previous observations that the APOC1 might be an additional susceptibility gene for LOAD.     

HFE H63D,C282Y and AGTR1 A1166C Polymorphisms and Brain White Matter Lesions in the Aging Brain

Abstract: Incidental white matter lesions (WML) are a common neuroradiological finding in elderly people and have been linked to dementia and depression. Various mechanisms including hypoxia and increased production of reactive oxygen species (ROS) are implicated in the etiology of WML. The hemochromatosis (HFE) gene p.H63D and p.C282Y polymorphisms have been linked to dysregulation of iron metabolism and increased levels of ROS, whereas Angiotensin II receptor 1 (AGTR1) c.1166A → C polymorphism is known as a vascular risk factor. These genetic polymorphisms were characterized in brains donated to the UK MRC Cognitive Function and Ageing Study (CFAS) to assess their potential role in the risk for development of age-related WML. The study cohort comprised 258 brain donated to CFAS. WML severity was assessed in the postmortem brain donations using magnetic resonance imaging (MRI) scans and scored using the Scheltens’ scale. Polymerase chain reaction (PCR) amplification of extracted DNA followed by restriction enzyme digestion was used to genotype the samples. Genotypes were validated using direct sequencing in a smaller sample. The results show that HFE p.H63D polymorphism is not associated with WML severity in the whole cohort. However, there is a significant association of the D allele with severity of WML in noncarriers of the APOE ε4 allele. No association is demonstrated between the HFE p.C282Y nor the AGTR1 c.1166A → C polymorphisms and WML severity. The HFE gene appears to be a genetic risk factor for severe aging WML independently of the APOE ε4 genotype. This would support the role of iron-related oxidative stress, in addition to previously studied factors, e.g., hypoxia as potential risk factors for developing prominent aging WML.     

Activation of gonadotropin-releasing hormone receptors induces a long-term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus

Besides apolipoprotein E (APOE) polymorphism, whose association with Alzheimer's disease (AD) has been confirmed in most of the numerous population samples studied, other markers have been investigated. In most cases the association firstly described was not confirmed in subsequent works. Since it is important to examine these associations in as many populations as possible, we investigated APOE, APOC1, APOC2, alpha-1 antichymotrypsin (ACT) and presenilin-1 (PS-1) polymorphisms in a series of elderly patients with late-onset sporadic AD from Northern Italy and in a sex and age-matched control group. We could not confirm the significantly higher frequency of the ACT*A allele among carriers of APOE e*4 allele described elsewhere, although a similar trend was observed. The APOC2 and the PS-1 distributions were similar between patients and controls. However, we observed a significant difference in the genotype and allele frequencies of APOE and APOC1: patients had higher e*4 and C1*2 allele frequencies. This finding confirms the important role for APOE in AD occurrence. In addition, APOC1 seems to be an interesting marker because, though in strict linkage disequilibrium with APOE, it seems to play an independent role in AD risk. In contrast to previously reported data, plasma apoE concentrations were similar in patients and in controls. An interaction between APOE and APOC1 polymorphisms and apoE levels was observed in patients: subjects carrying the APOE E3/E2 or the APOC1 2-2 genotype have higher apoE concentrations than those who do not.     

Association between APOC3 polymorphisms and non-alcoholic fatty liver disease risk: a meta-analysis

Background and AimThe apolipoprotein C3 (APOC3) polymorphism has been reported to predispose to non-alcoholic fatty liver disease (NAFLD). However, the results remain inconclusive. This meta-analysis aimed to provide insights into the association between APOC3 polymorphisms and NAFLD risk.MethodsStudies with terms “NALFD” and “APOC3” were retrieved from PubMed, Web of Science, CNKI and Wanfang databases up to August 1, 2019. Pooled odds ratio (OR) and 95% confidence interval (95% CI) for the association of APOC3 polymorphisms and NAFLD risk were calculated using fixed and random-effects models.ResultsA total of twelve studies from eleven articles were included. Of them, eight studies (1750 cases and 2181 controls) reported the strong association of variant rs2854116 with NAFLD and six studies (1523 cases and 1568 controls) found the association of rs2854117 polymorphism with NAFLD. Overall, a statistically significant association between rs2854116 polymorphism of APOC3 gene and NAFLD risk was found only under dominant model. However, association of rs2854117 polymorphism with NAFLD risk was not detected under all four genetic models. In sub-group analysis of NAFLD subjects based on country, no association among them in China was detected. Besides, four studies analyze the association between the two polymorphisms and clinical characteristics in all subjects or NAFLD patients, and we also failed detect any association between the wild carriers and variant carriers.ConclusionThe meta-analyses suggests that the rs2854116 polymorphism but not rs2854117 polymorphism in APOC3 gene might be a risk factor for NAFLD among Asians. That is, individuals with CT+CC genotype have higher risk of developing NAFLD. However, studies with sufficient sample size are needed for the further validation.     

Cerebral microbleeds are related to subjective cognitive failures: the RUN DMC study

Cerebral small vessel disease (SVD), including white matter lesions (WML) and lacunar infarcts, is related to objective cognitive impairment but also to subjective cognitive failures (SCF). SCF have reported to be an early predictor of dementia. Cerebral microbleeds (MB) are another manifestation of SVD and have been related to cognitive impairment, but the role of MB in SCF has never been studied. We therefore investigated whether MB are related to SCF among non-demented elderly individuals with SVD, independent of coexisting WML and lacunar infarcts. The RUN DMC study is a prospective cohort study among 503 older persons with cerebral SVD between 50 and 85 years of age. All participants underwent FLAIR and T2* scanning. SCF, subjective memory failures (SMF), and subjective executive failures (SEF) were assessed. The relation between SCF and the presence, number and location of MB was assessed by linear regression analyses adjusted for age, sex, education, depressive symptoms, cognitive function, total brain volume, normalized hippocampal volume, territorial infarcts, WML, and lacunar infarcts. MB were present in 11%. We found a relation between the presence, total number and lobar located MB, and SCF, SMF, and SEF and the reported progression of these failures, especially in participants with good objective cognitive function. In conclusion, MB are related to SCF independent of co-existing WML and lacunar infarcts, especially in those with good objective cognitive performance. These results suggest that MB are associated with the earliest manifestations of cognitive impairment. MB may help us to understand the role of the ever-expanding spectrum of SVD in cognitive impairment.     

Matrix metalloproteinase 3 haplotypes and dementia and Alzheimer's disease. The Rotterdam Study

Evidence by post-mortem and animal studies suggests that matrix metalloproteinases (MMPs) may play an important role in the pathophysiology of Alzheimer's disease (AD) through degradation of amyloid beta. We investigated in 5999 elderly whether MMP3-haplotypes are associated with cognitive performance over time, dementia and AD. We also explored the association of MMP-3 haplotypes with changes in hippocampal volume and severity of periventricular and subcortical white matter lesions (WML). There was no association between any individual polymorphism or MMP-3 haplotypes and performance in MMSE over time, dementia or AD, and there was no association between MMP-3 genotypes or haplotypes with hippocampal volume or severity of periventricular or subcortical WML. These associations did not differ between strata of APOE4 genotype. Our observations do not suggest that variation in the MMP3 gene is causally involved in dementia or AD.     

Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults

The apolipoprotein E genotype (APOE) is an established risk factor for Alzheimer disease, with the age-at-onset occurring earlier in individuals having at least one APOE epsilon 4 allele, relative to the APOE epsilon 3 or APOE epsilon 2 isoforms. Moreover, nondemented older adults with the APOE epsilon 4 allele also show diminished cognitive performance, particularly on tests of learning and memory, and an accelerated decline in memory performance with increasing age. The current investigation extends the study of the APOE epsilon 4 allele and cognitive performance to healthy, middle-aged adults. A community sample of 220 non-Hispanic Caucasian men and women, aged 24-60 (average age = 46), were genotyped for the APOE polymorphism and completed a battery of neuropsychological tests. Multivariate analyses were conducted on measures of verbal learning and memory (e. g., learning a list of words and recalling them 30 min later), visual memory (e.g., reproducing a previously copied figure from memory), and attention span (e.g., repeating long lists of digits), after adjustments for age, and estimated IQ. Results indicated that performance on learning and memory tasks was significantly poorer in adults having any APOE epsilon 4 allele, relative to adults with APOE epsilon 2 and epsilon 3 genotypes (P <.01). Attention span did not differ by genotype. These findings, the first in a sample of middle-aged adults, suggest that the APOE polymorphism is a marker for age-related decline in memory (detectable prior to overt, clinical manifestations of memory loss), and/or a marker for individual differences in memory ability across the life span. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:707-711, 2000.     

White matter lesions and brain gray matter volume in cognitively normal elders

Cerebral white matter lesions (WMLs) reflect small vessel disease, are common in elderly individuals, and are associated with cognitive impairment. We sought to determine the relationships between WMLs, age, gray matter (GM) volume, and cognition in the Cardiovascular Health Study (CHS). From the Cardiovascular Health Study we selected 740 cognitively normal controls with a 1.5 T magnetic resonance imaging (MRI) scan of the brain and a detailed diagnostic evaluation. WML severity was determined using a standardized visual rating system. GM volumes were analyzed using voxel-based morphometry implemented in the Statistical Parametric Mapping software. WMLs were inversely correlated with GM volume, with the greatest volume loss in the frontal cortex. Age-related atrophy was observed in the hippocampus and posterior cingulate cortex. Regression analyses revealed links among age, APOE*4 allele, hypertension, WMLs, GM volume, and digit symbol substitution test scores. Both advancing age and hypertension predict higher WML load, which is itself associated with GM atrophy. Longitudinal data are needed to confirm the temporal sequence of events leading to a decline in cognitive function.     

Longitudinal change in memory performance associated with HTR2A polymorphism

We present a fresh approach to evaluating association with candidate genes and cognitive change by testing association for parameters describing individual growth curves from twins. Moderate genetic influences on memory in aging adults has been shown in quantitative genetic studies. A recently reported, association of a HTR2A polymorphism with episodic memory in young unrelated adults led us to investigate the association between a nearby polymorphism and longitudinal memory performance in the Swedish Adoption/Twin Study of Aging (SATSA). Analysis of growth curve parameters suggests that both how well individuals perform on figural memory at age 65 years and nonlinear change in figural memory performance across age are associated with HTR2A. Individuals with two copies of the common G allele demonstrated higher figural memory performance longitudinally than those with the less frequent A allele, with performance trajectories differing by 2-6% per year. These findings imply a role for the 5-HT2A serotonin receptor on the formation of episodic memories in older adults.     

A functional genetic variation of the 5-HTR2A receptor affects age at onset in patients with temporal lobe epilepsy

The 1354C>T polymorphism of the 5-hydroxytryptamine receptor 2A gene (5-HTR2A) was implicated in human memory performance. We investigated the relationship between this polymorphism and cognitive function in patients with temporal lobe epilepsy (TLE). We also evaluated if this polymorphism could influence the phenotype. There were 138 patients with TLE: 25% (34/138) of them found to be cognitively impaired, while the remaining 104 of 138 (75%) were found to be cognitively preserved after a comprehensive neuropsychological evaluation. dHPLC followed by DNA sequencing was used to detect the genetic variation. The distribution of 1354C>T did not differ between these two TLE groups, both in the comparison of genotype distribution (P= 0.177) and allele frequencies (P = 0.065). Nonetheless, patients with the T allele had a significantly earlier age at onset of the disease (P= 0.006). This effect was even stronger in patients with impaired memory (P= 0.00015). A second independent sample of 86 individuals with TLE satisfactorily confirmed the relationship between T allele and age at epilepsy onset. The results of this study have demonstrated that the T variant of 5-HTR2A may influence an earlier age of onset of TLE, especially in those with impaired memory. Nonetheless, this polymorphism has no major impact on memory functions in such TLE patients.     

Population prevalence of APOE,APOC3 and PPAR-α mutations associated to hypertriglyceridemia in French Canadians

Hypertriglyceridemia (HTG) is known as a common metabolic disorder associated with increased production, decrease catabolism and/or decreased hepatic uptake of triglyceride (TG)-rich particles. We assessed, in the Québec City population, the allele frequency and haplotype distributions of mutations in genes related to HTG, such as the apolipoprotein E (APOE) (C112R and C158R), the apolipoprotein CIII (APOC3) (C-482T and C3238G) and the peroxisome proliferator-activated receptor alpha (PPAR) (L162V) genes. A total of 938 anonymous unlinked newborns from the metropolitan Québec City area have been genotyped. Allele frequencies observed in the Québec City population differed from known frequencies determined in other Caucasian populations. The co-transmitted allele distribution between the two-marker genotypes APOE/APOC3(C3238G) and APOC3(C-482T)/PPAR(L162V) presented a weak deviation from the assumption of genetic independence. Also, we observed a non-independent distribution of the T-482/G3238 allele combinations within the APOC3 gene, suggesting strong linkage disequilibrium between the C-482T and C3238G polymorphisms. Moreover, comparisons of allele frequencies observed in the population of Québec City to those obtained in other Caucasian populations suggested that the population of Québec City may be at a lower risk of developing HTG due to APOE, APOC3 and PPAR genetic variants. However, the strong linkage disequilibrium and the two-marker genotype distributions observed in the APOC3 gene suggest that these two variants may functionally interact in the Québec City population.     

Functional effects of genetic polymorphism in inflammatory genes in subjective memory complainers

A number of genetic risk factors have been identified for Alzheimer's disease (AD) including genes involved in the inflammatory response (interleukin 1A, [IL-1α (-889)], interleukin 1B (IL-1β [+3953]), and tumor necrosis factor (TNF [-308 and -850]). We investigated the prevalence and functional consequences (baseline cognitive performance, plasma cytokine levels) of possession of these putative genetic risk factors within a group of subjective memory complainers (SMC, n = 226) and age and sex matched noncomplainers (NMC, n = 167). We observed no effect of any of the genetic factors investigated on cognitive performance. Further, there was no difference in the frequency of the disease-associated alleles, or cytokine levels between subjective memory complainers and noncomplainer participants. There was no relationship between TNF polymorphisms and TNF levels. There was a significant increase in plasma IL-1β levels in those homozygous for the disease-associated allele (i.e., IL-1β +3953 TT). Follow-up longitudinal assessments on this cohort will provide insight as to how these polymorphisms may affect the risk of cognitive decline over time.     

Disturbances in selective information processing associated with the BDNF Val66Met polymorphism: evidence from cognition, the P300 and fronto-hippocampal systems

In this study, we examined whether the Met allele of the BDNF Val66Met polymorphism is associated with selective disruptions to task-relevant information processing. In 475 non-clinical participants for whom BDNF genotype status was determined we used the 'IntegNeuro' computerized battery of neuropsychological tests to assess cognitive performance, an auditory oddball task to elicit the P300 event-related potential (ERP) and, in smaller subsets of these subjects, high resolution structural MRI imaging to quantify fronto-hippocampal grey matter (n=161), and functional magnetic resonance imaging to assess fronto-hippocampal BOLD activation (n=37). Met/Met (MM) homozygotes had higher verbal recall errors, in the absence of differences in attention, executive function, verbal ability or sensori-motor function. Further, MM homozygotes demonstrated a slowed P300 ERP during the oddball task, with corresponding alterations in hippocampal and lateral prefrontal activation, and a localized reduction in hippocampal grey matter. These results are consistent with a subtle impact of the Met allele on fronto-hippocampal systems involved in selective information processing of stimulus context and memory updating within the normal population. The findings also indicate that heritable endophenotypes such as the P300 have value in elucidating genotype-phenotype relationships.     

糖尿病对脑白质病变伴轻度认知功能障碍患者认知功能的影响

目的 探讨糖尿病与脑白质病变(WML)伴轻度认知功能障碍(MCI)患者认知功能减退的关系。方法 2012年1—12月在大坪医院神经内科住院病人中选择257例WML伴MCI患者进行前瞻性研究,随访时间为1年。收集患者血管危险因素(VRFs)及颅脑MRI检查结果,同时行神经心理学测试了解认知功能状态;根据1年内简易精神状态检查量表(MMSE)减少值分为认知功能下降组(≥3分)及无认知功能下降组(≤2分),并比较两组各种危险因素的差异。结果 257例中有246例(95.7%)患者完成了1年的观察随访过程,11例删失者中8例死亡、3例退出观察。246例中,认知功能下降组154例(62.6%),无认知功能下降组92例(37.4%);其中36例在观察期间发生卒中,余210例患者纳入线性回归分析。除受教育水平及血脂异常外,年龄、性别、高血压、糖尿病、短暂性脑缺血发作等各危险因素两组比较差异均有统计学意义 (P值均＜0.05)。糖尿病、基线WML程度及随访期间WML程度的加重与1年内MMSE减少值呈显著的线性关系,且对认知功能减退的影响由大至小依次为基线WML程度(β_j′=0.570)、随访期间WML加重程度(β_j′=0.244)、糖尿病(β_j′=0.171)。结论 糖尿病可使WML伴MCI患者认知功能进一步减退。重度WML伴MCI的糖尿病患者应作为痴呆的高危人群进行早期干预。     

Brain-derived neurotrophic factor, apolipoprotein E genetic variants and cognitive performance in Alzheimer's disease

Since greater attention has been paid to the direct link of genetic variation to cognition and memory performance, apolipoprotein E (ApoE) and brain-derived neurotrophic factor (BDNF) have been the two most frequently studied genes. To investigate the effect of BDNF and ApoE polymorphisms on the cognitive profile of mild-moderate Alzheimer's disease (AD) cases, AD patients, genotyped for ApoE and BDNF polymorphisms, underwent extensive neuropsychological investigation. The effect of either ApoE epsilon4 allele and BDNF genetic variant on the neuropsychological pattern of mental impairment was examined both in terms of group differences in performance on the neuropsychological tests between carriers and non-carriers of each variant and by selecting the best predictor of cognitive performance among demographic and genetic factors by means of a multiple regression analysis. Our data confirm a specific effect caused by the presence and amount of ApoE epsilon4 allele, while they suggest that BDNF genetic variants are not a susceptibility factor to AD.     

Brain tissue volumes in relation to cognitive function and risk of dementia

We investigated in a population-based cohort study the association of global and lobar brain tissue volumes with specific cognitive domains and risk of dementia. Participants (n=490; 60-90 years) were non-demented at baseline (1995-1996). From baseline brain MRI-scans we obtained global and lobar volumes of CSF, GM, normal WM, white matter lesions and hippocampus. We performed neuropsychological testing at baseline to assess information processing speed, executive function, memory function and global cognitive function. Participants were followed for incident dementia until January 1, 2005. Larger volumes of CSF and WML were associated with worse performance on all neuropsychological tests, and an increased risk of dementia. Smaller WM volume was related to poorer information processing speed and executive function. In contrast, smaller GM volume was associated with worse memory function and increased risk of dementia. When investigating lobar GM volumes, we found that hippocampal volume and temporal GM volume were most strongly associated with risk of dementia, even in persons without objective and subjective cognitive deficits at baseline, followed by frontal and parietal GM volumes.