Gray Matter Volume Differences Research Articles

Altered Brain Morphometry in Cerebral Small Vessel Disease With Cerebral Microbleeds: An Investigation Combining Univariate and Multivariate Pattern Analyses

PurposeThe objective of this study was to evaluate whether altered gray matter volume (GMV) and white matter volume (WMV) are associated with the presence of cerebral microbleeds (CMBs) in cerebral small vessel disease (CSVD).Materials and MethodsIn this study, we included 26 CSVD patients with CMBs (CSVD-c), 43 CSVD patients without CMBs (CSVD-n) and 39 healthy controls. All participants underwent cognitive assessment testing. Both univariate analysis and multivariate pattern analysis (MVPA) approaches were applied to investigate differences in brain morphometry among groups.ResultsIn univariate analysis, GMV and WMV differences were compared among groups using voxel-based morphometry (VBM) with diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL). Compared to healthy controls, the CSVD-c group and CSVD-n group showed significantly lower GMV than the control group in similar brain clusters, mainly including the right superior frontal gyrus (medial orbital), left anterior cingulate gyrus, right inferior frontal gyrus (triangular part) and left superior frontal gyrus (medial), while the CSVD-n group also showed significantly lower WMV in the cluster of the left superior frontal gyrus (medial). No significant GMV or WMV differences were found between the CSVD-c group and the CSVD-n group. Specifically, we applied the multiple kernel learning (MKL) technique in MVPA to combine GMV and WMV features, yielding an average of >80% accuracy for three binary classification problems, which was a considerable improvement over the individual modality approach. Consistent with the univariate analysis, the MKL weight maps revealed default mode network and subcortical region damage associated with CSVD compared to controls. On the other hand, when classifying the CSVD-c group and CSVD-n group in the MVPA analysis, we found that some WMVs were highly weighted regions (left olfactory cortex and right middle frontal gyrus), which hinted at the presence of different white matter alterations in the CSVD-c group.ConclusionOur findings not only suggested that the localized alterations in GMV and WMV appeared to be associated with the pathophysiology of CSVD but also indicated that altered brain morphometry could be a potential discriminative pattern to detect CSVD at the individual level.

Brain structural abnormalities in adult major depressive disorder revealed by voxel- and source-based morphometry: evidence from the REST-meta-MDD Consortium.

Neuroimaging studies on major depressive disorder (MDD) have identified an extensive range of brain structural abnormalities, but the exact neural mechanisms associated with MDD remain elusive. Most previous studies were performed with voxel- or surface-based morphometry which were univariate methods without considering spatial information across voxels/vertices. Brain morphology was investigated using voxel-based morphometry (VBM) and source-based morphometry (SBM) in 1082 MDD patients and 990 healthy controls (HCs) from the REST-meta-MDD Consortium. We first examined group differences in regional grey matter (GM) volumes and structural covariance networks between patients and HCs. We then compared first-episode, drug-naïve (FEDN) patients, and recurrent patients. Additionally, we assessed the effects of symptom severity and illness duration on brain alterations. VBM showed decreased GM volume in various regions in MDD patients including the superior temporal cortex, anterior and middle cingulate cortex, inferior frontal cortex, and precuneus. SBM returned differences only in the prefrontal network. Comparisons between FEDN and recurrent MDD patients showed no significant differences by VBM, but SBM showed greater decreases in prefrontal, basal ganglia, visual, and cerebellar networks in the recurrent group. Moreover, depression severity was associated with volumes in the inferior frontal gyrus and precuneus, as well as the prefrontal network. Simultaneous application of VBM and SBM methods revealed brain alterations in MDD patients and specified differences between recurrent and FEDN patients, which tentatively provide an effective multivariate method to identify potential neurobiological markers for depression.

The Function and Structure of Precuneus Is Associated With Subjective Sleep Quality in Major Depression.

BackgroundPoor sleep quality is related to depression. However, the investigation of the neural basis for poor sleep quality in individuals with major depression (MD) is limited.MethodsResting state functional and structural MRI data were derived from 114 MD individuals and 74 normal controls (NCs). Fractional amplitude of low-frequency fluctuation (fALFF) and gray matter volume (GMV) were used to measure function and structure of the brain. Pittsburgh Sleep Quality Index (PSQI) was performed to evaluate subjective sleep quality. Correlations were carried out to investigate links of PSQI score with brain imaging indices in MD and NCs, separately. We also examined the differences in fALFF and GMV of brain regions related to PSQI score between MD and NCs.ResultsIn contrast to NCs, MD individuals had higher PSQI score. The higher PSQI score was associated with lower fALFF and lower GMV in bilateral precuneus in MD individuals. Moreover, the MD individuals exhibited increased fALFF in bilateral precuneus compared with NCs. However, the correlation between subjective sleep quality and neuroimaging parameters was not significant in NCs.ConclusionThe implication of these findings is that the function and structure of precuneus provides a neural basis for subjective poor sleep quality in MD. Understanding this may lead to better intervention of depression and associated sleep complaints.

Increased gray matter following mindfulness-based stress reduction in breast cancer survivors with chronic neuropathic pain: preliminary evidence using voxel-based morphometry.

To investigate the impact of Mindfulness-Based Stress Reduction (MBSR) on gray matter volume (GMV) in female breast cancer survivors who suffer from chronic neuropathic pain (CNP). Voxel-based morphometry (VBM) was used to explore differences in GMV in 13 MBSR trainees and 10 waitlisted controls, with MRI scans and self-report measures completed pre- and post-8weeks of training. Compared to controls, the MBSR group had greater GMV in the angular gyrus and middle frontal gyrus post-training. The MBSR group's right parahippocampal gyrus GMV increased from pre- to post-training, whereas the control group's left parahippocampal gyrus, precuneus, middle temporal gyrus, and right cuneus GMV decreased over the same time period. Pain interference was significantly reduced and mindfulness was significantly increased following MBSR for the intervention group only. MBSR was associated with increased GMV in regions where GMV is known to (1) increase with mindfulness and reorientation of attention and (2) decrease with the experience of chronic neuropathic pain. By contrast, the control group's decreases in GMV may be due to the negative effects of CNP which potentially may be reduced with MBSR, though further research is needed. Given the poor efficiency of pharmacotherapies in a high percentage of women with neuropathic pain following breast cancer treatment, adjunct methods are required. MBSR may affect the brain to help alter attention and perception of pain, thus playing a potentially important role in the path to wellness for breast cancer survivors.

Brain volume patterns in corticobasal syndrome versus idiopathic Parkinson's disease.

Patients with a corticobasal syndrome (CBS) present a rare form of atypical parkinsonism characterized by asymmetric clinical symptoms and progressive motor and nonmotor impairment, such as apraxia, alien limb phenomenon, aphasia, myoclonus, dystonia, and cognitive impairment. At early stages, clinical differentiation between CBS and idiopathic Parkinson's disease (IPD) can be challenging. Using high-resolution T1-weighted images and voxel-based morphometry (VBM), we sought to identify disease-specific patterns of brain atrophy in a small sample of CBS and IPD patients at early stages of disease. We acquired MR images of 17 patients diagnosed with CBS and compared them with MR images of 17 subjects affected by IPD. Images were preprocessed and analyzed using VBM. When compared to each other, the CBS and IPD patients of our cohort showed differences in regional gray and white matter volume depending on the diagnosis, specifically in the superior longitudinal fascicle. In our small patients' group, VBM was able to detect changes in regional gray and white matter volume between patients affected by CBS and patients with IPD as early as 1.5-2 years after the onset of the first motor symptoms.

Altered cerebellar gray matter and cerebellar-cortex resting-state functional connectivity in patients with bipolar disorder Ⅰ

BackgroundBipolar disorder (BP) is a common psychiatric disorder characterized by extreme fluctuations in mood. Recent studies have indicated the involvement of cerebellum in the pathogenesis of BP. However, no study has focused on the precise role of cerebellum exclusively in patients with bipolar I disorder (BP-I). MethodsForty-five patients with BP-I and 40 healthy controls were recruited. All subjects underwent clinical evaluation and Magnetic Resonance diffusion Tension Imaging scans. For structural images, we used a spatially unbiased infratentorial template toolbox to isolate the cerebellum and then preformed voxel-based morphometry (VBM) analyses to assess the difference in cerebellar gray matter volume (GMV) between the two groups. For the functional images, we chose the clusters that survived from VBM analysis as seeds and performed functional connectivity (FC) analysis. Between-group differences were assessed using the independent Students t test or the nonparametric Mann‐Whitney U Test. For multiple comparisons, the results were further corrected with Gaussian random field (GRF) approach (voxel-level P < 0.001, cluster-level P < 0.05). ResultsCompared with healthy controls, BP-I patients showed significantly decreased GMV in left lobule V and left lobule VI (P < 0.05, GRF corrected). The FC of cerebellum with bilateral superior temporal gyrus, bilateral insula, bilateral rolandic operculum, right putamen, and left precentral gyrus was disrupted in BP-I patients (P < 0.05, GRF corrected). ConclusionsBP-I patients showed decreased cerebellar GMV and disrupted cerebellar-cortex resting-state FC. This suggests that cerebellar abnormalities may play an important role in the pathogenesis of BP-I.

Structural and Functional Correlates of Hallucinations and Illusions in Parkinson's Disease.

Visual illusions (VI) in Parkinson's disease (PD) are generally considered as an early feature of the psychosis spectrum leading to fully formed visual hallucinations (VH), although this sequential relationship has not been clearly demonstrated. We aimed to determine whether there are any overlapping, potentially graded patterns of structural and functional connectivity abnormalities in PD with VI and with VH. Such a finding would argue for a continuum between these entities, whereas distinct imaging features would suggest different neural underpinnings for the phenomena. In this case control study, we compared structural and resting state functional MRI brain patterns of PD patients with VH (PD-H, n = 20), with VI (PD-I, n = 19), and without VH or VI (PD-C, n = 23). 1) PD-H had hypo-connectivity between the ILO and anterior cingulate precuneus and parahippocampal gyrus compared to PD-C and PD-I; 2) In contrast, PD-I had hyper-connectivity between the inferior frontal gyrus and the postcentral gyrus compared to PD-C and PD-H. Moreover, PD-I had higher levels of functional connectivity between the amygdala, hippocampus, insula, and fronto-temporal regions compared to PD-H, together with divergent patterns toward the cingulate. 3) Both PD-I and PD-H had functional hypo-connectivity between the lingual gyrus and the parahippocampal region vs. PD-C, and no significant grey matter volume differences was observed between PD-I and PD-H. Distinct patterns of functional connectivity characterized VI and VH in PD, suggesting that these two perceptual experiences, while probably linked and driven by at least some similar mechanisms, could reflect differing neural dysfunction.

HIV-Associated Structural and Functional Brain Alterations in Homosexual Males.

Purpose:Neuroimaging elucidations have shown structural and functional brain alterations in HIV-infected (HIV+) individuals when compared to HIV-negative (HIV–) controls. However, HIV− groups used in previous studies were not specifically considered for sexual orientation, which also affects the brain structures and functions. The current study aimed to characterize the brain alterations associated with HIV infection while controlling for sexual orientation.Methods:Forty-three HIV+ and 40 HIV– homosexual men (HoM) were recruited and underwent resting-state MRI scanning. Group differences in gray matter volume (GMV) were assessed using a voxel-based morphometry analysis. Brain regions with the altered GMV in the HIV+ HoM group were then taken as regions of interest in a seed-based analysis to identify altered functional connectivity. Furthermore, the amplitude of low-frequency fluctuation (ALFF) and regional homogeneity values were compared between the two groups to evaluate the HIV-associated functional abnormalities in local brain regions.Results:HIV+ HoM showed significantly increased GMV in the bilateral parahippocampal gyrus and amygdala, and decreased GMV in the right inferior cerebellum, compared with the HIV– HoM. The brain regions with increased GMV were hyper-connected with the left superior cerebellum, right lingual gyrus, and left precuneus in the HIV+ HoM. Moreover, the ALFF values of the right fusiform gyrus, and left parahippocampal gyrus were increased in the HIV+ HoM. The regional homogeneity values of the right anterior cingulate and paracingulate gyri, and left superior cerebellum were decreased in the HIV+ HoM.Conclusion:When the study population was restricted to HoM, HIV+ individuals exhibited structural alterations in the limbic system and cerebellum, and functional abnormalities in the limbic, cerebellum, and visual network. These findings complement the existing knowledge on the HIV-associated neurocognitive impairment from the previous neuroimaging studies by controlling for the potential confounding factor, sexual orientation. Future studies on brain alternations with the exclusion of related factors like sexual orientation are needed to understand the impact of HIV infection on neurocognitive function more accurately.

Prolactin mediates the relationship between regional gray matter volume and postpartum depression symptoms

BackgroundPospartum Depression (PPD) causes significant adverse effects on mothers and their offspring. The condition is considered to have multiple pathogenic factors. However, the underlying neural basis of these factors keeps unclear. MethodsA group of 86 patients with PPD and 74 Healthy Postnatal Women (HPW) were enrolled in this structural Magnetic Resonance Imaging (MRI) study. Between-groups differences in regional gray matter volume (rGMV) were measured and association and mediation analyses were performed to investigate the relationship between rGMV, PPD severity and a range of demographic/clinical factors which could contribute to PPD. ResultsRelative to HPW, PPD patients had higher scores indicating adverse effects on most questionnaires and higher prolactin levels, as well as increased rGMV in left dorsolateral prefrontal cortex (DLPFC) and right anterior insular (anI). In PPD patients, rGMV in right anI was positively correlated with prolactin level, PPD severity, and the number of children raised, whereas rGMV in left DLPFC was negatively correlated with education and age. Besides, prolactin level was found to mediate the association between rGMV in anI and PPD symptoms. LimitationsPotentially factors such as fertility or delivery pattern were not studied. ConclusionOur results provide information on the risk and protective factors, and rGMV abnormalities, associated with PPD. The finding that prolactin level mediated the impact of rGMV in right anI on PPD symptoms is a potential mechanism for explaining the association between brain structure and PPD symptoms. Increased understanding of the neuro-pathophysiology of PPD is important for early diagnosis and treatment.

Alterations of regional homogeneity in perimenopause: a resting-state functional MRI study

Objective Regional homogeneity (ReHo) was used to evaluate the changes of brain function and the relationship with cognitive function in perimenopausal women. Methods： The cross-sectional study recruited 25 perimenopausal women and 25 postmenopausal women who underwent sex hormone level measurements, clinical and neuropsychological assessments, and magnetic resonance imaging (MRI) scans. ReHo was measured based on the resting-state functional MRI (rs-fMRI) data and the differences in ReHo between the perimenopausal and postmenopausal groups were compared. Gray matter volume (GMV) values of brain regions with differences (region of interest [ROI]) in ReHo were extracted and the differences of GMV between the two groups were compared. We analyzed the correlations of the ReHo and GMV values of these ROIs with the results of sex hormone levels, clinical and neuropsychological assessments in the two groups. Results ReHo values in the left lingual gyrus and the right precentral gyrus increased in perimenopause, whereas ReHo values in the left inferior temporal gyrus and bilateral putamen decreased. Correlation analysis showed that the ReHo values of the left inferior temporal gyrus positively correlated with the reaction time of the Stroop color word test in perimenopausal women. Conclusions Changes in abnormal patterns of the ReHo in perimenopausal women affect cognitive function. These changes in brain function may provide more insights and information on the neural mechanisms of cognitive dysfunction in perimenopausal women.

Study of Brain Structure and Function in Chronic Mountain Sickness Based on fMRI.

Objective: Headache and memory impairment are the primary clinical symptoms of chronic mountain sickness (CMS). In this study, we used voxel-based morphometry (VBM) and the amplitude of the low-frequency fluctuation method (ALFF) based on blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) to identify changes in the brain structure and function caused by CMS.Materials and Methods: T1W anatomical images and a resting-state functional MRI (fMRI) of the whole brain were performed in 24 patients diagnosed with CMS and 25 normal controls matched for age, sex, years of education, and living altitude. MRI images were acquired, followed by VBM and ALFF data analyses.Results: Compared with the control group, the CMS group had increased gray matter volume in the left cerebellum crus II area, left inferior temporal gyrus, right middle temporal gyrus, right insula, right caudate nucleus, and bilateral lentiform nucleus along with decreased gray matter volume in the left middle occipital gyrus and left middle temporal gyrus. White matter was decreased in the bilateral middle temporal gyrus and increased in the right Heschl's gyrus. Resting-state fMRI in patients with CMS showed increased spontaneous brain activity in the left supramarginal gyrus, left parahippocampal gyrus, and left middle temporal gyrus along with decreased spontaneous brain activity in the right cerebellum crus I area and right supplementary motor area.Conclusion: Patients with CMS had differences in gray and white matter volume and abnormal spontaneous brain activity in multiple brain regions compared to the controls. This suggests that long-term chronic hypoxia may induce changes in brain structure and function, resulting in CMS.

Sex Differences in Alzheimer's Disease Revealed by Free-Water Diffusion Tensor Imaging and Voxel-Based Morphometry.

Imaging biomarkers are increasingly used in Alzheimer's disease (AD), and the identification of sex differences using neuroimaging may provide insight into disease heterogeneity, progression, and therapeutic targets. The purpose of this study was to investigate differences in grey matter (GM) volume and white matter (WM) microstructural disorganization between males and females with AD using voxel-based morphometry (VBM) and free-water-corrected diffusion tensor imaging (FW-DTI). Data were downloaded from the OASIS-3 database, including 158 healthy control (HC; 86 females) and 46 mild AD subjects (24 females). VBM and FW-DTI metrics (fractional anisotropy (FA), axial and radial diffusivities (AxD and RD, respectively), and FW index) were compared using effect size for the main effects of group, sex, and their interaction. Significant group and sex differences were observed, with no significant interaction. Post-hoc comparisons showed that AD is associated with reduced GM volume, reduced FW-FA, and higher FW-RD/FW-index, consistent with neurodegeneration. Females in both groups exhibited higher GM volume than males, while FW-DTI metrics showed sex differences only in the AD group. Lower FW, lower FW-FA and higher FW-RD were observed in females relative to males in the AD group. The combination of VBM and DTI may reveal complementary sex-specific changes in GM and WM associated with AD and aging. Sex differences in GM volume were observed for both groups, while FW-DTI metrics only showed significant sex differences in the AD group, suggesting that WM tract disorganization may play a differential role in AD pathophysiology between females and males.

Structural alterations of the insula in depression patients – A 7-Tesla-MRI study

IntroductionThe insular cortex is part of a network of highly connected cerebral “rich club” - regions and has been implicated in the pathophysiology of various psychiatric and neurological disorders, of which major depressive disease is one of the most prevalent. “Rich club” vulnerability can be a contributing factor in disease development. High-resolution structural subfield analysis of insular volume in combination with cortical thickness measurements and psychological testing might elucidate the way in which the insula is changed in depression. Material and methodsHigh-resolution structural images of the brain were acquired using a 7T-MRI scanner. The mean grey matter volume and cortical thickness within the insular subfields were analysed using voxel-based morphometry (VBM) and surface analysis techniques respectively. Insular subfields were defined according to the Brainnetome Atlas for VBM - and the Destrieux-Atlas for cortical thickness - analysis. Thirty-three patients with confirmed major depressive disease, as well as thirty-one healthy controls matched for age and gender, were measured. The severity of depression in MDD patients was measured via a BDI-II score and objective clinical assessment (AMDP). Intergroup statistical analysis was performed using ANCOVA. An intragroup multivariate regression analysis of patient psychological test results was calculated. Corrections for multiple comparisons was performed using FDR. ResultsSignificant differences between groups were observed in the left granular dorsal insula according to VBM-analysis. AMDP-scores positively correlated with cortical thickness in the right superior segment of the circular insular sulcus. ConclusionsThe combination of differences in grey matter volume between healthy controls and patients with a positive correlation of cortical thickness with disease severity underscores the insula’s role in the pathogeneses of MDD. The connectivity hub insular cortex seems vulnerable to disruption in context of affective disease.

Striatal gray matter volumes, externalizing traits, and N-back task performance: An exploratory study of sex differences using the human connectome project data

The striatum is implicated in externalizing traits and cognitive dysfunction. The ventral and dorsal striatal subregions may play differentiable roles in externalizing behaviors and executive functions. We employed voxel-based morphometry to estimate the striatal gray matter volumes (GMVs) of 968 young adults (510 women) of the Human Connectome Project. We examined sex differences in striatal GMVs, tested how striatal GMVs related to an externalizing trait (Extn), and 2-back memory efficiency (Eff2), and examined whether these relationships exhibited sex differences. Men showed significantly higher ventral striatum (VS) and lentiform nucleus (LN) GMVs as well as higher Extn and Eff2 than women. Across all subjects, greater caudate and LN GMVs were correlated significantly with lower Eff2 though with limited effect sizes ( r = −0.140, p &lt; .001 and r = −0.093, p = .004, respectively) and the latter correlation was carried primarily by women ( z = −3.070, p = .002, slope test). VS GMV showed positive correlation with Extn ( r = 0.085, p = .008). Together, striatal GMVs are significantly but only weakly associated with externalizing behaviors and cognitive dysfunction in young adults. As key hubs of the fronto-striatal circuits, the ventral and dorsal striatum may contribute differently to externalizing psychopathology.

Shared Transdiagnostic Neuroanatomical Signatures Across First-episode Patients with Major Psychiatric Diseases and Individuals at Familial Risk

BackgroundNowadays, increasing evidence has found transdiagnostic neuroimaging biomarkers across major psychiatric disorders (MPDs). However, it remains to be known whether this transdiagnostic pattern of abnormalities could also be seen in individuals at familial high-risk for MPDs (FHR). We aimed to examine shared neuroanatomical endophenotypes and protective biomarkers for MPDs. MethodsThis study examined brain grey matter volume (GMV) of individuals by voxel-based morphometry method. A total of 287 individuals were included, involving 100 first-episode medication-naive MPDs, 87 FHR, and 110 healthy controls (HC). They all underwent high-resolution structural magnetic resonance imaging (MRI). ResultsAt the group level, we found MPDs were characterized by decreased GMV in the right fusiform gyrus, the right inferior occipital gyrus, and the left anterior and middle cingulate gyri compared to HC and FHR. Of note, the GMV of the left superior temporal gyrus was increased in FHR relative to MPDs and HC. At the subgroup level, the comparisons within the FHR group did not return any significant difference, and we found GMV difference among subgroups within the MPDs group only in the opercular part of the right inferior frontal gyrus. ConclusionTogether, our findings uncover common structural disturbances across MPDs and substantial changes in grey matter that may relate to high hereditary risk across FHR, potentially underscoring the importance of a transdiagnostic way to explore the neurobiological mechanisms of major psychiatric disorders.

Decreased gray matter volume of the anterior insular cortex in patients with psychogenic erectile dysfunction: A voxel-based morphometry study

This study aimed to explore the gray matter morphological alteration and its correlation with the severity of symptoms in patients with psychogenic erectile dysfunction (pED). Fifty patients with pED and 50 healthy controls (HCs) were included. The whole-brain voxel-based morphometry analysis was conducted to compare the differences in gray matter volume (GMV) between patients with pED and HCs. And then, the region-of-interest-based correlation analyses were performed between the GMV of these regions with the most pronounced between-group differences and clinical symptoms in patients. The results demonstrated that patients with pED manifested decreased GMV in the bilateral anterior insula (aINS), bilateral precentral gyrus, left postcentral gyrus, bilateral anterior cingulate cortex, bilateral middle cingulate cortex, bilateral fusiform gyrus, and cerebellum when compared to HCs. Taking the bilateral aINS as the region-of-interest, the results of voxel-based correlation analyses showed that the GMV of the bilateral aINS were positively correlated with the International Index of Erectile Function 5 (IIEF-5) and Quality of Erection Questionnaire score, and the GMV of right aINS was positively associated with duration and sexual craving score in patients with pED. Furthermore, the significant correlations between the total GMV of the right aINS and IIEF-5 and sexual craving score, as well as between the total GMV of the left aINS and sexual craving score were also detected. In conclusion, these results suggested that the decreased GMV of aINS might be a critical neuropathological characteristic of pED, which provided new evidence for understanding the neurobiological basis of pED from the perspective of brain structure alterations.

Depressive symptoms in cognitively unimpaired older adults are associated with decreased structural and functional integrity in the limbic network

AbstractBackgroundSubclinical depressive symptoms are prevalent in older adults. They are associated with increased risk for both clinical depression and Alzheimer’s disease (AD), and may at least partly reflect early AD manifestations. However, the brain mechanisms underlying the relationship between depressive symptoms and AD remain to be elucidated. The aim of this study was to provide a comprehensive overview of the brain substrates of subclinical depressive symptoms in cognitively unimpaired older adults using complementary multimodal neuroimaging data in two independent cohorts.MethodWe selected 135 cognitively unimpaired older adults from the baseline data of the primary cohort Age‐Well, and 252 from the replication cohort ADNI. In both cohorts, subclinical depressive symptoms were assessed using the 15‐item version of the Geriatric Depression Scale (GDS); based on this scale, participants were classified as having depressive symptoms (DepS; GDS &gt; 0) or not (NoDepS; GDS = 0). Voxelwise between‐group comparisons were performed to highlight differences in gray matter volume and amyloid deposition (both cohorts), as well as white matter integrity, brain perfusion (Age‐Well) and glucose metabolism (ADNI). Analyses were corrected for age, sex and education (and anxiety when available i.e. in Age‐Well) and thresholded at p&lt;0.005.ResultOlder adults with subclinical depressive symptoms had significantly lower gray matter volume, perfusion and glucose metabolism in the hippocampus compared to participants without symptoms (Fig. 1). Glucose hypometabolism extended to the amygdala, precuneus/posterior cingulate and medial prefrontal cortex, insula, and temporoparietal cortex. Older adults with subclinical depressive symptoms also showed lower white matter integrity in the fornix and the posterior parts of the cingulum and corpus callosum. Brain amyloid deposition was not associated with the presence of subclinical depressive symptoms in either cohort.ConclusionThe presence of subclinical depressive symptoms in cognitively unimpaired older adults are associated with brain structural and functional changes in regions of the limbic network known to be particularly vulnerable to AD. Structural and functional changes overlapped in the hippocampus, indicating that deterioration in this region could underlie the relationship between depressive symptoms and AD while amyloid deposition does not appear to be involved at this stage.

Structural, metabolic and cognitive characteristics of cognitively unimpaired subjects with mismatching β‐amyloid biomarkers

AbstractBackgroundSeveral reports have described higher gray matter volumes and glucose consumption in cognitively unimpaired individuals with abnormal amyloid biomarkers, typically interpreted to be caused by inflammatory or compensatory mechanisms. In this study, we investigated structural and metabolic differences in cognitively unimpaired individuals with mismatching amyloid cerebrospinal fluid (CSF) and PET biomarkers (CSF+/PET‐), thought to be the earliest detectable Alzheimer's disease (AD) pathologic change. Additionally, we investigated whether inflammatory CSF biomarkers could explain such differences.MethodIn 302 cognitively unimpaired participants of the ALFA study, we measured CSF Aβ42/40, phosphorylated tau (p‐tau), total tau (t‐tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100b and α‐synuclein using the exploratory Roche NeuroToolKit assays, a panel of robust prototype immunoassays (Roche Diagnostics International Ltd). Participants also underwent T1 MRI, [18F]flutemetamol amyloid PET, [18F]FDG PET and cognitive assessment (PACC). Amyloid PET was quantified with a validated pipeline to render Centiloid (CL) values. Individuals were classified into three groups: CSF‐/PET‐, CSF+/PET‐ and CSF+/PET+ using previously determined thresholds for positivity (Aβ42/40&lt;0.071 and CL&gt;30). Between‐group differences in Gray Matter volume (GMv) and [18F]FDG uptake were evaluated voxel‐wise with SPM12 (p&lt;0.005, k&gt;100) including age and sex as covariates. Additional models were implemented to measure possible mediation effects by inflammatory biomarkers (sTREM2, YKL40, GFAP, IL6, S100). Between‐group differences in cognition were also studied (p&lt;0.05).ResultA total of 195 participants were CSF‐/PET‐, 82 were CSF+/PET‐ and 25 were CSF+/PET+ (Table 1). CSF+/PET‐ individuals displayed widespread higher GMv with respect to the reference CSF‐/PET‐ group as well as the CSF+/PET+ group (Fig. 1A). These differences were not mediated by inflammatory biomarkers. No significant between‐group differences were found in [18F]FDG uptake. PACC values were significantly higher in CSF+/PET‐ than the other groups (Fig. 1B)ConclusionIn cognitively unimpaired individuals, increases in GMv and cognitive functioning were observed in participants ]with abnormal amyloid CSF but PET negative. These increases could not be explained by measured neuroinflammatory CSF biomarkers. Even at the earliest stages of the AD continuum, factors enhancing resistance to amyloid plaque deposition might have a beneficial impact on cognition and could be used to inform prevention strategies.

Impaired recognition of disgust is related to subcortical volume loss in amyotrophic lateral sclerosis

AbstractBackgroundThe impairment in detecting disgust in Amyotrophic Lateral Sclerosis (ALS) has been hypothesized to be related with the integrity of subcortical structures. However, this has not been demonstrated yet and was the aim of the study.MethodTwenty ALS patients without cognitive/behavioural symptoms and 52 matched healthy controls (HC) underwent a brain MRI scan and a neuropsychological assessment including the Comprehensive Affect Testing System (CATS) investigating emotion recognition. Composite scores were calculated by summing up the correct answers for each emotion. Gray matter (GM) volumes of the subcortical structures were obtained using FIRST in FSL. Sociodemographic, cognitive and MRI data were compared between groups. In ALS patients, CATS significant findings were correlated with the subcortical volumes, ECAS performances, patients’ mood and behaviour.ResultALS patients performed significantly worse than HC at the CATS, and they were significantly less able to recognize disgust. No GM volume differences were observed between groups. In ALS patients, a low performance in disgust recognition was related with a reduced volume of the left pallidum and with low performances at the ECAS.ConclusionIn a sample of cognitively/behaviourally unimpaired ALS, we demonstrated an altered ability to correctly recognize disgust and a potential role of basal ganglia in the altered processing of this emotion. These findings, together with the relationship between the altered disgust recognition with lower ECAS performances in patients, suggest that disgust could be the first emotion to be hit in ALS cognitive decline. These findings offer new potential markers for monitoring extra‐motor progression in ALS. Supported by: Italian Ministry of Health (GR‐2013‐02357415); European Research Council (StG‐2016_714388_NeuroTRACK).

Dementia with Lewy bodies subtypes identified by cluster analysis on structural MRI

AbstractBackgroundDementia with Lewy bodies (DLB) is a neurodegenerative disorder that presents with a variety of clinical symptoms. Part of the clinical heterogeneity within DLB has been related to the atrophy/sparing of the hippocampus. We extended that previous research by investigating whether different atrophy patterns exist in DLB, beyond and above the atrophy/sparing of the hippocampus, and whether those patterns contribute to the clinical heterogeneity in DLB. We aimed to identify DLB atrophy subtypes using a hypothesis‐free data‐driven clustering approach based on regional gray matter (GM) volumes and characterize the resulting subtypes across key measures.MethodWe included data from three centers of the European DLB consortium. A high‐resolution 3D T1‐weigthed magnetization prepared rapid gradient echo (MPRAGE) sequence was acquired for 97 DLB patients. Eighty‐four cortical regions and 12 subcortical regions from Mayo Clinic Adult Lifespan Template (https://www.nitrc.org/projects/mcalt/) atlases were obtained. Clusters of DLB patients were then determined using the random forest method. Between‐group differences in key demographic, clinical, MRI volumes and cerebrospinal fluid biomarkers (CSF) (amyloid‐beta, phosphorylated‐tau) were performed for clusters characterization.ResultWe identified three subtypes of DLB patients, with distinct patterns of GM volumes and differences in several clinical and demographic measures. Cluster 1 (C1) included 32 DLB patients (33%), cluster 2 (C2) included 29 DLB patients (30%), and cluster 3 (C3) included 36 DLB patients (37%). The clusters differed in age, with C1 being significantly older (72±8.6) than C3 (66±9.5) (F=3.93, p=0.02). C1 was characterized by lower volumes in fronto‐temporal regions and had a higher frequency of visual hallucinations (68%, vs. C2 35%). C2 showed lower volumes in occipital regions. C3 had higher GM volumes overall compared with the other two clusters and presented with a higher frequency of cognitive fluctuations (91%, vs. C1 67%). There were no differences between groups in CSF biomarkers. These results were independent of cluster differences in age and global GM volume.ConclusionThere are distinct patterns of brain atrophy in patients with DLB. These patterns seem to differentially contribute to the frequencies of visual hallucinations and cognitive fluctuations, independently of differences in age and global GM volume across subtypes.