Voxel-based assessment of gray and white matter volumes in Alzheimer's disease

Using the study-specific templates and optimized voxel-based morphometry (VBM), this study investigated abnormalities in gray and white matter to provide depiction of the concurrent structural changes in 13 patients with Alzheimer's disease (AD) compared with 14 age- and sex-matched normal controls. Consistent with previous studies, patients with AD exhibited significant gray matter volume reductions mainly in the hippocampus, parahippocampal gyrus, insula, superior/middle temporal gyrus, thalamus, cingulate gyrus, and superior/inferior parietal lobule. In addition, white matter volume reductions were found predominately in the temporal lobe, corpus callosum, and inferior longitudinal fasciculus. Furthermore, a number of additional white matter regions such as precentral gyrus, cingulate fasciculus, superior and inferior frontal gyrus, and sub-gyral in parietal lobe were also affected. The pattern of gray and white matter volume reductions helps us understand the underlying pathologic mechanisms in AD and potentially can be used as an imaging marker for the studies of AD in the future.     

Gray matter network associated with risk for Alzheimer's disease in young to middle-aged adults

The apolipoprotein E (APOE) ε4 allele increases the risk for late-onset Alzheimer's disease (AD) and age-related cognitive decline. We investigated whether ε4 carriers show reductions in gray matter volume compared with ε4 non-carriers decades before the potential onset of AD dementia or healthy cognitive aging. Fourteen cognitively normal ε4 carriers, aged 26 to 45 years, were compared with 10 age-matched, ε4 non-carriers using T1-weighted volumetric magnetic resonance imaging (MRI) scans. All had reported first- or second-degree family histories of dementia. Group differences in gray matter were tested using voxel-based morphometry (VBM) and a multivariate model of regional covariance, the Scaled Subprofile Model (SSM). A combination of the first two SSM MRI gray matter patterns distinguished the APOE ε4 carriers from non-carriers. This combined pattern showed gray matter reductions in bilateral dorsolateral and medial frontal, anterior cingulate, parietal, and lateral temporal cortices with covarying relative increases in cerebellum, occipital, fusiform, and hippocampal regions. With these gray matter differences occurring decades before the potential onset of dementia or cognitive aging, the results suggest longstanding, gene-associated differences in brain morphology that may lead to preferential vulnerability for the later effects of late-onset AD or healthy brain aging.     

White matter microstructural damage in Alzheimer's disease at different ages of onset

White matter (WM) microstructural damage and its relationship with cortical abnormalities were explored in early-onset Alzheimer's disease (EOAD) compared with late-onset AD (LOAD) patients. Structural and diffusion tensor magnetic resonance images were obtained from 22 EOAD patients, 35 LOAD patients, and 40 healthy controls. Patterns of WM microstructural damage and cortical atrophy, as well as their relationships, were assessed using tract-based spatial statistics, tractography and voxel-based morphometry. Compared with LOAD, EOAD patients had a more severe and distributed pattern of WM microstructural damage, in particular in the posterior fibers of cingulum and corpus callosum. In both groups with Alzheimer's disease, but especially in LOAD patients, correlations between cingulum and corpus callosum fractional anisotropy and parietal, temporal, and frontal cortical volumes were found. In conclusion, WM microstructural damage is more severe in EOAD compared with LOAD patients. Such damage follows different patterns of topographical distribution in the 2 patient groups.     

Gray matter atrophy rate as a marker of disease progression in AD

Global gray matter (GM) atrophy rates were quantified from magnetic resonance imaging (MRI) over 6- and 12-month intervals in 37 patients with Alzheimer's disease (AD) and 19 controls using: (1) nonlinear registration and integration of Jacobian values, and (2) segmentation and subtraction of serial GM volumes. Sample sizes required to power treatment trials using global GM atrophy rate as an outcome measure were estimated and compared between the 2 techniques, and to global brain atrophy measures quantified using the boundary shift integral (brain boundary shift integral; BBSI) and structural image evaluation, using normalization, of atrophy (SIENA). Increased GM atrophy rates (approximately 2% per year) were observed in patients compared with controls. Although mean atrophy rates provided by Jacobian integration were smaller than those from segmentation and subtraction of GM volumes, measurement variance was reduced. The number of patients required per treatment arm to detect a 20% reduction in GM atrophy rate over a 12-month follow-up (90% power) was 202 (95% confidence interval [CI], 118-423) using Jacobian integration and 2047 (95% CI 271 to > 10,000) using segmentation and subtraction. Comparable sample sizes for whole brain atrophy were 240 (95% CI, 142-469) using the BBSI and 196 (95% CI, 110-425) using SIENA. Jacobian integration could be useful for measuring GM atrophy rate in Alzheimer's disease as a marker of disease progression and treatment efficacy.     

Age-related gray matter volume changes in the brain during non-elderly adulthood

Previous magnetic resonance imaging (MRI) studies described consistent age-related gray matter (GM) reductions in the fronto-parietal neocortex, insula and cerebellum in elderly subjects, but not as frequently in limbic/paralimbic structures. However, it is unclear whether such features are already present during earlier stages of adulthood, and if age-related GM changes may follow non-linear patterns at such age range. This voxel-based morphometry study investigated the relationship between GM volumes and age specifically during non-elderly life (18-50 years) in 89 healthy individuals (48 males and 41 females). Voxelwise analyses showed significant (p < 0.05, corrected) negative correlations in the right prefrontal cortex and left cerebellum, and positive correlations (indicating lack of GM loss) in the medial temporal region, cingulate gyrus, insula and temporal neocortex. Analyses using ROI masks showed that age-related dorsolateral prefrontal volume decrements followed non-linear patterns, and were less prominent in females compared to males at this age range. These findings further support for the notion of a heterogeneous and asynchronous pattern of age-related brain morphometric changes, with region-specific non-linear features.     

Cortical thickness and voxel-based morphometry in posterior cortical atrophy and typical Alzheimer's disease

A significant minority of Alzheimer's disease patients present with posterior cortical atrophy (PCA). PCA is characterized by visuospatial and visuoperceptual deficits, and relatively preserved memory, whereas patients with typical Alzheimer's disease (tAD) mostly present with early episodic memory deficits. We used two unbiased image analysis techniques to assess atrophy patterns in 48 PCA, 30 tAD, and 50 healthy controls. FreeSurfer was used to measure cortical thickness, and volumetric grey matter differences were assessed using voxel-based morphometry (VBM). Both PCA and tAD showed widespread reductions compared with controls using both techniques. Direct comparison of PCA and tAD revealed thinner cortex predominantly in the right superior parietal lobe in the PCA group compared with tAD, whereas the tAD group showed thinning in the left entorhinal cortex compared with PCA. Similar results were obtained in the VBM analysis. These distinct patterns of atrophy may have diagnostic utility. In a clinical context, a relatively spared medial temporal lobe in the presence of posterior parietal atrophy may imply PCA, and should not discount AD.     

Effect of Met66 allele of the BDNF rs6265 SNP on regional gray matter volumes in patients with multiple sclerosis: A voxel-based morphometry study

The rs6265 single nucleotide polymorphism (SNP) is a genetic variation in the brain-derived neurotrophic factor (BDNF) gene wherein the presence of the A-allele at rs6265 causes replacement of a valine (Val) at position 66 by methionine (Met). We reported recently that the Met66 allele was associated with lower brain damage as evidenced by measurement of gray matter (GM) volume in multiple sclerosis (MS) patients. The objective of this study was to determine the voxel-wise regional GM differences between the Val66Val and Met66 allele groups in MS patients by using voxel-based morphometry (VBM)-optimized analysis corrected for lesion misclassification in Statistical Parametric Mapping (SPM5). High-resolution 3D-T1-weighted SPGR images from a total of 188 MS patients were acquired on a 1.5 T MRI. The Val66Val group included 129 MS patients and the Met66 allele group (comprised of Val66Met or Met66Met genotypes) included 59 MS patients. The SPM analysis of covariance tool was used to assess group differences after controlling for variation in head size, MS disease course and gender. VBM analysis did not yield significant family wise error (FWE) corrected results. This was also confirmed with the non-parametric analysis using threshold-free cluster enhancement (TFCE) method. However, the results from VBM as well as the TFCE analyses (p < 0.001, uncorrected) showed higher GM volume in the cingulate of MS patients with Met66 allele than those with Val66Val. Future studies are warranted to investigate longitudinally possible protective role of the Met66 allele of the BDNF rs6265 SNP in relation to specific GM regions.     

Gray matter density and white matter integrity in pianists' brain: a combined structural and diffusion tensor MRI study

The current study combined structural magnetic resonance imaging (sMRI) and diffusion tensor MRI (DT-MRI) to investigate both gray matter density (GMD) and white matter integrity (WMI) in 18 pianists and 21 age-matched non-musicians. The pianists began their piano training at a mean age of 12. Voxel-based morphometry of the sMRI data showed that the pianists had higher GMD in the left primary sensorimotor cortex and right cerebellum. Voxel-based analysis of the DT-MRI data showed that pianists had higher fractional anisotropy (FA) (indicating higher WMI) in the right posterior limb of the internal capsule. The sMRI and DT-MRI results indicate that both the GMD and WMI of pianists may exhibit movement-related increases during adolescence or even early adulthood compared with non-musicians.     

Mapping joint grey and white matter reductions in Alzheimer's disease using joint independent component analysis

Alzheimer's disease (AD) is a neurodegenerative disease concomitant with grey and white matter damages. However, the interrelationship of volumetric changes between grey and white matter remains poorly understood in AD. Using joint independent component analysis, this study identified joint grey and white matter volume reductions based on structural magnetic resonance imaging data to construct the covariant networks in twelve AD patients and fourteen normal controls (NC). We found that three networks showed significant volume reductions in joint grey–white matter sources in AD patients, including (1) frontal/parietal/temporal-superior longitudinal fasciculus/corpus callosum, (2) temporal/parietal/occipital-frontal/occipital, and (3) temporal-precentral/postcentral. The corresponding expression scores distinguished AD patients from NC with 85.7%, 100% and 85.7% sensitivity for joint sources 1, 2 and 3, respectively; 75.0%, 66.7% and 75.0% specificity for joint sources 1, 2 and 3, respectively. Furthermore, the combined source of three significant joint sources best predicted the AD/NC group membership with 92.9% sensitivity and 83.3% specificity. Our findings revealed joint grey and white matter loss in AD patients, and these results can help elucidate the mechanism of grey and white matter reductions in the development of AD.     

Aging in deep gray matter and white matter revealed by diffusional kurtosis imaging

Diffusion tensor imaging has already been extensively used to probe microstructural alterations in white matter tracts, and scarcely, in deep gray matter. However, results in literature regarding age-related degenerative mechanisms in white matter tracts and parametric changes in the putamen are inconsistent. Diffusional kurtosis imaging is a mathematical extension of diffusion tensor imaging, which could more comprehensively mirror microstructure, particularly in isotropic tissues such as gray matter. In this study, we used the diffusional kurtosis imaging method and a white-matter model that provided metrics of explicit neurobiological interpretations in healthy participants (58 in total, aged from 25 to 84 years). Tract-based whole-brain analyses and regions-of-interest (anterior and posterior limbs of the internal capsule, cerebral peduncle, fornix, genu and splenium of corpus callosum, globus pallidus, substantia nigra, red nucleus, putamen, caudate nucleus, and thalamus) analyses were performed to examine parametric differences across regions and correlations with age. In white matter tracts, evidence was found supportive for anterior–posterior gradient and not completely supportive for retrogenesis theory. Age-related degenerations appeared to be broadly driven by axonal loss. Demyelination may also be a major driving mechanism, although confined to the anterior brain. In terms of deep gray matter, higher mean kurtosis and fractional anisotropy in the globus pallidus, substantia nigra, and red nucleus reflected higher microstructural complexity and directionality compared with the putamen, caudate nucleus, and thalamus. In particular, the unique age-related positive correlations for fractional anisotropy, mean kurtosis, and radial kurtosis in the putamen opposite to those in other regions call for further investigation of exact underlying mechanisms. In summary, the results suggested that diffusional kurtosis can provide measurements in a new dimension that were complementary to diffusivity metrics. Kurtosis together with diffusivity can more comprehensively characterize microstructural compositions and age-related changes than diffusivity alone. Combined with proper model, it may also assist in providing neurobiological interpretations of the identified alterations.     

Regional brain gray matter abnormalities in patients with bipolar II disorder: A comparison study with bipolar I patients and healthy controls

Despite the high prevalence and clinical significance of bipolar II disorder (BD II), the underlying pathophysiology is not well explored in previous studies. The purpose of the current study was to investigate brain gray matter abnormalities in BD II. High resolution magnetic resonance brain images from 23 BD II patients, 23 sex- and age-matched patients with bipolar I disorder (BD I) and 23 healthy controls were acquired and processed according to the optimized voxel-based morphometry protocol. The processed gray matter tissue volumes were compared among the three groups. Both the BD II and BD I group showed gray matter deficits in the ventromedial prefrontal regions, compared to controls. The BD I group had widespread gray matter reductions in the bilateral frontal, temporal, parietal and parahippocampal cortices, compared to controls. However, gray matter reductions in these regions were not found in the BD II group. With a less conservative statistical threshold, the BD II group showed additional gray matter deficits in the anterior limbic cortices. Our data suggest that gray matter deficits in the ventromedial prefrontal and anterior limbic cortices are common in both BD II and BD I. On the other hand, different pattern of gray matter abnormalities between BD II and BD I found in this study supports that two subtypes may have different neurobiological characteristics.     

Nogo-A及其受体在阿尔茨海默病中的作用

Nogo-A是一种重要的髓鞘相关生长抑制因子,在成体动物中枢神经系统损伤再生中发挥了关键的抑制作用。近年来许多研究表明, Nogo-A及其受体NgR可以影响淀粉样蛋白Aβ的代谢,其下游的ROCK激酶可以影响Aβ、tau蛋白的水平以及血脑屏障的通透性,这些均提示Nogo-A及其受体与阿尔茨海默病（AD）的发病机制有着密切的联系。此外,最近的研究还发现了Nogo-A的另外两种受体PirB和S1PR2,可能为Nogo-A在神经系统疾病中的作用提供新的研究方向。我们将着重阐释Nogo-A及其受体的基本结构和功能的新发现,以及其在AD中的作用等方面的最新研究进展。     

Personality and resilience to Alzheimer’s disease neuropathology: a prospective autopsy study

Alzheimer’s disease (AD) neuropathology is found at autopsy in approximately 30% of cognitively normal older individuals. We examined whether personality traits are associated with such resilience to clinical dementia in individuals with AD neuropathology. Broad factors and specific facets of personality were assessed up to 28 years (mean 11 ± 7 years) before onset of dementia and up to 30 years (mean 15 ± 7 years) before death in a cohort (n = 111) evaluated for AD neuropathology at autopsy. Individuals with higher baseline scores on vulnerability to stress, anxiety, and depression (neuroticism: odds ratio, 2.0; 95% confidence interval, 1.2–3.5), or lower scores on order and competence (conscientiousness: odds ratio, 0.4; 95% confidence interval, 0.2–0.9) were less likely to remain asymptomatic in the presence of AD neuropathology. Neuroticism (r = 0.26), low agreeableness (r = −0.34), and some facets were also significantly associated with advanced stages of neurofibrillary tangles, but the associations between personality traits and risk of clinical dementia were mostly unchanged by controlling for the extent of neurofibrillary tangles and Aβ neuritic plaques. In sum, a resilient personality profile is associated with lower risk or delay of clinical dementia even in persons with AD neuropathology.     

Visual contrast sensitivity in Alzheimer’s disease,mild cognitive impairment,and older adults with cognitive complaints

Deficits in contrast sensitivity (CS) have been reported in Alzheimer’s disease (AD). However, the extent of these deficits in prodromal AD stages, including mild cognitive impairment (MCI) or even earlier, has not been investigated. In this study, CS was assessed using frequency doubling technology in older adults with AD (n = 10), amnestic MCI (n = 28), cognitive complaints without performance deficits (CC; n = 20), and healthy controls (HC; n = 29). The association between CS and cognition was also evaluated. Finally, the accuracy of CS measures for classifying MCI versus HC was evaluated. CS deficits were found in AD and MCI, while CC showed intermediate performance between MCI and HC. Upper right visual field CS showed the most significant difference among groups. CS was also associated with cognitive performance. Finally, CS measures accurately classified MCI versus HC. The CS deficits in AD and MCI, and intermediate performance in CC, indicate that these measures are sensitive to early AD-associated changes. Therefore, frequency doubling technology-based measures of CS may have promise as a novel AD biomarker.     

Allelic mRNA expression of sortilin-1 (SORL1) mRNA in Alzheimer’s autopsy brain tissues

Polymorphisms in the gene encoding SORL1, involved in cellular trafficking of APP, have been implicated in late-onset Alzheimer’s disease, by a mechanism thought to affect mRNA expression. To search for regulatory polymorphisms, we have measured allele-specific mRNA expression of SORL1 in human autopsy tissues from the prefrontal cortex of 26 Alzheimer’s patients, and 51 controls, using two synonymous marker SNPs (rs3824968 in exon 34 (11 heterozygous AD subjects and 16 controls), and rs12364988 in exon 6 (8 heterozygous AD subjects)). Significant allelic expression imbalance (AEI), indicative of the presence of cis-acting regulatory factors, was detected in a single control subject, while allelic ratios were near unity for all other subjects. We genotyped 7 SNPs in two haplotype blocks that had previously been implicated in Alzheimer’s disease. Since each of these SNPs was heterozygous in several subjects lacking AEI, this study fails to support a regulatory role for SORL1 polymorphisms in mRNA expression.     

Extravascular fibrinogen in the white matter of Alzheimer’s disease and normal aged brains: implications for fibrinogen as a biomarker for Alzheimer’s disease

The blood–brain barrier (BBB) regulates cerebrovascular permeability and leakage of blood‐derived fibrinogen. Dysfunction of the BBB has been associated with cerebral arteriolosclerosis small vessel disease (SVD) and white matter lesions (WML). Furthermore, BBB dysfunction is associated with the pathogenesis of Alzheimer’s disease (AD) with the presence of CSF plasma proteins suggested to be a potential biomarker of AD. We aimed to determine if extravascular fibrinogen in the white matter was associated with the development of AD hallmark pathologies, i.e., hyperphosphorylated tau (HPτ) and amyloid‐β (Aβ), as well as SVD, cerebral amyloid angiopathy (CAA) and measures of white matter damage. Using human post‐mortem brains, parietal tissue from 20 AD and 22 non‐demented controls was quantitatively assessed for HPτ, Aβ, white matter damage severity, axonal density, demyelination and the burden of extravascular fibrinogen in both WML and normal appearing white matter (NAWM). SVD severity was determined by calculating sclerotic indices. WML‐ and NAWM fibrinogen burden was not significantly different between AD and controls nor was it associated with the burden of HPτ or Aβ pathology, or any measures of white matter damage. Increasing severity of SVD was associated with and a predictor of both higher WML‐ and NAWM fibrinogen burden (all P < 0.05) in controls only. In cases with minimal SVD NAWM fibrinogen burden was significantly higher in the AD cases (P < 0.05). BBB dysfunction was present in both non‐demented and AD brains and was not associated with the burden of AD‐associated cortical pathologies. BBB dysfunction was strongly associated with SVD but only in the non‐demented controls. In cases with minimal SVD, BBB dysfunction was significantly worse in AD cases possibly indicating the influence of CAA. In conclusion, extravascular fibrinogen is not associated with AD hallmark pathologies but indicates SVD, suggesting that the presence of fibrinogen in the CSF is not a surrogate marker for AD pathology.     

Focusing on the structure and the function of Pin1: New insights into the opposite effects of fever on cancers and Alzheimer’s disease

A new molecular mechanism is proposed to explain the opposite effects of fever on cancers and Alzheimer’s disease (AD). The proposal is based on the experimental discovery that the fever stress interferes the structure and the activity of Pin1, which plays uniquely opposite roles in the pathogenesis of cancers and AD. Pin1 is the only known cis–trans isomerase that specifically isomerizes the pSer/pThr-Pro motifs in proteins, facilitating kinds of signaling pathways. The up-regulation of Pin1 can amplify multiple oncogenic signaling pathways, resulting in cancers, while the down-regulation of Pin1 can cause many pathological characteristics of AD. Recently, we found that Pin1 is sensitive to heat treatment, and heating can gradually damage both of the structure and the function of Pin1. So, we hypothesize that the fever stress, which is usually induced by febrile diseases or hyperthermia treatment, may lead to the damaged structure of Pin1 and the decreased activity of it in vivo, resulting in the decreased risk of cancers and the increased risk of AD. Numerous epidemiological and experimental researches on cancers and AD support the hypothesis. The hypothesis not only provides new insights into the opposite effects of fever on cancers and AD, but also gives new clues for understanding the interacting effects of the environmental and the genetic factors in the complicated pathogenesis of cancers and AD.     

Longitudinal changes of cortical thickness in early- versus late-onset Alzheimer's disease

Early-onset Alzheimer's disease (EOAD) has been shown to progress more rapidly than late-onset Alzheimer's disease (LOAD). However, no studies have compared the topography of brain volume reduction over time. The purpose of this 3-year longitudinal study was to compare EOAD and LOAD in terms of their rates of decline in cognitive testing and topography of cortical thinning. We prospectively recruited 36 patients with AD (14 EOAD and 22 LOAD) and 14 normal controls. All subjects were assessed with neuropsychological tests and with magnetic resonance imaging at baseline, Year 1, and Year 3. The EOAD group showed more rapid decline than the LOAD group in attention, language, and frontal-executive tests. The EOAD group also showed more rapid cortical thinning in widespread association cortices. In contrast, the LOAD group presented more rapid cortical thinning than the EOAD group only in the left parahippocampal gyrus. Our study suggests that patients with EOAD show more rapid cortical atrophy than patients with LOAD, which accounts for faster cognitive decline on neuropsychological tests.     

Overlapping clusters of gray matter deficits in paranoid schizophrenia and psychotic bipolar mania with family history

The purpose of this study was to assess volumetric abnormalities of gray matter throughout the entire brain in patients with paranoid schizophrenia or with bipolar mania compared with control groups. We obtained weighted 3D T1 magnetic resonance images from 23 patients with paranoid schizophrenia, 24 patients with psychotic bipolar mania, and 36 healthy controls. Gray matter volume differences were assessed using optimized volumetric voxel-based morphometry (VBM). Both paranoid schizophrenia and bipolar mania group showed reduction of gray matter volume in the superior temporal gyrus (STG) (Brodmann Area, BA 22 areas), and the inferior parietal lobule, and enlargement of putamen, although different sides of the inferior parietal lobule and putamen were affected in the groups. Our findings showed the presence of overlapping clusters of gray matter deficits in paranoid-type schizophrenia and psychotic bipolar mania. The overlap in gray matter pathology between the two disorders may be attributed to risk factors common to both disorders.