Gray Matter Loss Research Articles

Multimodal MRI changes associated with non-motor symptoms of rapid eye movement sleep behaviour disorder in Parkinson's disease patients.

Parkinson's disease (PD), a prevalent neurodegenerative disorder, assumes a more adverse prognosis when accompanied by rapid eye movement sleep disorder (RBD). Non-motor symptoms, particularly sleep and emotional disturbances, significantly impair patients' quality of life. This study aimed to investigate the neuroimaging underpinnings of PD-RBD using structural and functional magnetic resonance imaging (MRI) and to explore the associations between these imaging biomarkers and non-motor symptoms. Brain scans were acquired from 33 PD patients without and 21 with probable RBD (PD-pRBD). Comparative analyses were performed to evaluate structural and functional alterations between the two groups. Additionally, the correlations between neuroimaging metrics and clinical assessment scales were assessed. PD-pRBD patients demonstrated more pronounced grey matter atrophy, particularly in the putamen and insula. Functional MRI revealed decreased amplitude of low-frequency fluctuations (ALFF) in the bilateral posterior cingulate cortex and left precuneus of PD-pRBD patients. Furthermore, reduced functional connectivity (FC) was observed in specific regions of the whole brain and within the default mode network (DMN) in PD-pRBD. Notably, a negative correlation was found between mean ALFF values in the left posterior cingulate cortex of PD-pRBD patients and Hamilton Depression Rating Scale scores. PD-pRBD is characterized by more severe grey matter loss and functional MRI abnormalities compared to PD alone. Dysfunction of the posterior cingulate cortex is implicated in more pronounced affective impairments, providing novel insights into the complex pathophysiology of PD-RBD.

Slowly expanding lesions are associated with disease activity and gray matter loss in relapse-onset multiple sclerosis.

Slowly expanding lesions (SELs) have been proposed as novel MRI markers of chronic active lesions in multiple sclerosis (MS). However, the mechanism through which SELs affect brain volume loss in patients with MS remains unknown. Additionally, the prevalence and significance of SELs in Asian patients with MS remain unclear. This study aimed to investigate the association between SELs and no evidence of disease activity (NEDA)-3 status as well as brain volume loss in Japanese patients. A total of 99 patients with relapse-onset MS were retrospectively evaluated. SELs were identified on brain MRI based on local deformation when consecutive scans were registered longitudinally. We developed a logistic regression model and generalized linear mixed models (GLMMs) to evaluate the association between the number of SELs and disease activity and changes in brain volume. During the observation period (2.0±0.22years), 35 patients developed at least one SEL. Multivariable logistic regression analysis showed that ≥2 SELs were associated with 0.2 times the risk of achieving a NEDA-3 status. GLMMs revealed that the number of SELs was negatively associated with volume changes in the cortex (p=.00169) and subcortical gray matter (p=.00964) after correction for multiple comparisons. SELs were identified in Japanese patients with MS during the 2-year observation period. The number of SELs is associated with disease activity and brain volume loss, suggesting that the number of SELs could be a biomarker of disease activity in MS.

Cardiovascular Disease, Brain Glucose Metabolism, and Neurocognitive Decline in People With Human Immunodeficiency Virus.

Cardiovascular disease (CVD) and neuroinflammation are thought to exacerbate neurocognitive dysfunction in treated people with human immunodeficiency virus (PWH). Here, we longitudinally measured brain glucose metabolism as a measure of neuronal integrity in treated PWH using [18F]Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in correlation with atherosclerotic cardiovascular disease (ASCVD) scores, cerebrospinal fluid (CSF) neuroinflammatory markers, neurocognitive outcomes, and other clinical and laboratory variables (CLVs). Well-controlled PWH (n = 36) underwent baseline and follow-up FDG PET/CT obtained 3.5 years apart on average. Longitudinal changes in whole brain and regional relative FDG uptake, brain volumes, CLVs, CSF cytokines, and neuropsychological measures were measured. A variable selection model identified baseline variables related to future brain metabolic changes while multivariable models explored neuropsychological implications of brain metabolism and volumetrics. High ASCVD scores predicted future decreased thalamic uptake (slope = -0.0068, P = .027) and decreasing thalamic uptake correlated with worsening cognition (slope = 15.80, P = .020). Despite longitudinal greater than expected gray matter loss, whole brain FDG uptake did not change over the follow-up period. Most CSF cytokines decreased longitudinally but were not predictive of FDG changes. We found that high ASCVD scores in a group of treated PWH were related to thalamic hypometabolism, which in turn correlated with neurocognitive decline. Our findings support the contribution of CVD to neurocognitive dysfunction. More proactive CVD management may have a role in mitigating progression of cognitive impairment. Lack of change in global brain glucose metabolism despite documented accelerated gray matter volume loss over the same period suggests that FDG PET might underestimate neuronal injury in PWH compared to structural magnetic resonance imaging.

Morphometry of medial temporal lobe subregions using high-resolution T2-weighted MRI in ADNI3: Why, how, and what's next?

This paper for the 20th anniversary of the Alzheimer's Disease Neuroimaging Initiative (ADNI) provides an overview of magnetic resonance imaging (MRI) of medial temporal lobe (MTL) subregions in ADNI using a dedicated high-resolution T2-weighted sequence. A review of the work that supported the inclusion of this imaging modality into ADNI Phase 3 is followed by a brief description of the ADNI MTL imaging and analysis protocols and a summary of studies that have used these data. This review is supplemented by a new study that uses novel surface-based tools to characterize MTL neurodegeneration across biomarker-defined AD stages. This analysis reveals a pattern of spreading cortical thinning associated with increasing levels of tau pathology in the presence of elevated amyloid beta, with apparent epicenters in the transentorhinal region and inferior hippocampal subfields. The paper concludes with an outlook for high-resolution imaging of the MTL in ADNI Phase 4. HIGHLIGHTS: As of Phase 3, the Alzheimer's Disease Neuroimaging Initiative (ADNI) magnetic resonance imaging (MRI) protocol includes a high-resolution T2-weighted MRI scan optimized for imaging hippocampal subfields and medial temporal lobe (MTL) subregions. These scans are processed by the ADNI core to obtain automatic segmentations of MTL subregions and to derive morphologic measurements. More detailed granular examination of MTL neurodegeneration in response to disease progression is achieved by applying surface-based modeling techniques. Surface-based analysis of gray matter loss in MTL subregions reveals increasing and spatially expanding patterns of neurodegeneration with advancing stages of Alzheimer's disease (AD), as defined based on amyloid and tau positron emission tomography biomarkers in accordance with recently proposed criteria. These patterns closely align with post mortem literature on spread of pathological tau in AD, supporting the role of tau pathology in the presence of elevated levels of amyloid beta as the driver of neurodegeneration.

Involvement of the basal forebrain and hippocampus in memory deficits in Parkinson's disease

IntroductionMagnetic resonance imaging (MRI)-determined atrophy of the nucleus basalis of Meynert (Ch4) predicts cognitive decline in Parkinson's disease (PD). However, interactions with other brain regions causing the decline remain unclear. This study aimed to describe how MRI-determined Ch4 atrophy leads to cognitive decline in patients with PD. MethodsWe evaluated 137 patients with PD and 39 healthy controls using neuropsychological examinations, MRI, and 123I-ioflupane single-photon emission computed tomography. First, we explored brain areas with regional gray matter loss correlated with Ch4 volume reduction using voxel-based morphometry (VBM). We then assessed the correlation between Ch4 volume reduction and cognitive impairments in PD using partial correlation coefficients (rpar). Finally, we examined whether the regional gray matter loss mediated the association between Ch4 volume reduction and cognitive impairments using mediation analysis. ResultsOur PD cohort was “advanced-stage enriched.” VBM analyses revealed that Ch4 volume loss was correlated with volume reduction in the medial temporal lobe in PD (P < 0.05, family-wise error corrected, >29 voxels). Ch4 volume reduction was significantly correlated with verbal memory deficits in PD when adjusted for age, sex, total brain volume, and 123I-ioflupane uptake in the caudate (rpar = 0.28, P < 0.001). The mediation analysis revealed that the hippocampus mediated the effects of Ch4 volumes on verbal memory (average causal mediation effect = 0.013, 95 % CI = 0.006–0.020, P < 0.001). ConclusionParticularly in advanced-stage PD, Ch4 atrophy was associated with medial temporal lobe atrophy, which played an intermediary role in the relationship between Ch4 atrophy and verbal memory impairments.

The uniqueness of human vulnerability to brain aging in great ape evolution.

Aging is associated with progressive gray matter loss in the brain. This spatially specific, morphological change over the life span in humans is also found in chimpanzees, and the comparison between these great ape species provides a unique evolutionary perspective on human brain aging. Here, we present a data-driven, comparative framework to explore the relationship between gray matter atrophy with age and recent cerebral expansion in the phylogeny of chimpanzees and humans. In humans, we show a positive relationship between cerebral aging and cortical expansion, whereas no such relationship was found in chimpanzees. This human-specific association between strong aging effects and large relative cortical expansion is particularly present in higher-order cognitive regions of the ventral prefrontal cortex and supports the "last-in-first-out" hypothesis for brain maturation in recent evolutionary development of human faculties.

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome

Wolfram syndrome (WS) is a rare childhood disease characterized by diabetes mellitus, diabetes insipidus, blindness, deafness, neurodegeneration and eventually early death, due to autosomal recessive mutations in the WFS1 (and WFS2) gene. While it is categorized as a neurodegenerative disease, it is increasingly becoming clear that other cell types besides neurons may be affected and contribute to the pathogenesis. MRI studies in patients and phenotyping studies in WS rodent models indicate white matter/myelin loss, implicating a role for oligodendroglia in WS-associated neurodegeneration. In this study, we sought to determine if oligodendroglia are affected in WS and whether their dysfunction may be the primary cause of the observed optic neuropathy and brain neurodegeneration. We demonstrate that 7.5-month-old Wfs1∆exon8 mice display signs of abnormal myelination and a reduced number of oligodendrocyte precursor cells (OPCs) as well as abnormal axonal conduction in the optic nerve. An MRI study of the brain furthermore revealed grey and white matter loss in the cerebellum, brainstem, and superior colliculus, as is seen in WS patients. To further dissect the role of oligodendroglia in WS, we performed a transcriptomics study of WS patient iPSC-derived OPCs and pre-myelinating oligodendrocytes. Transcriptional changes compared to isogenic control cells were found for genes with a role in ER function. However, a deep phenotyping study of these WS patient iPSC-derived oligodendroglia unveiled normal differentiation, mitochondria-associated endoplasmic reticulum (ER) membrane interactions and mitochondrial function, and no overt signs of ER stress. Overall, the current study indicates that oligodendroglia functions are largely preserved in the WS mouse and patient iPSC-derived models used in this study. These findings do not support a major defect in oligodendroglia function as the primary cause of WS, and warrant further investigation of neurons and neuron-oligodendroglia interactions as a target for future neuroprotective or -restorative treatments for WS.

Clinicopathologic and Neuroimaging Correlations of Nonverbal Oral Apraxia in Patients With Neurodegenerative Disease.

Nonverbal oral apraxia (NVOA) is the inability to plan, sequence, and execute voluntary oromotor movements in the absence of weakness. In the context of neurodegenerative disease, it remains unclear whether it is linked to a specific underlying pathologic, clinical, or neuroimaging finding. Thus, we aimed to assess the clinicopathologic and neuroimaging associations of NVOA. We conducted a retrospective study of autopsy-confirmed patients previously assessed through an NVOA evaluation tool with a previously published cutpoint to screen for NVOA. We compared demographic and clinical characteristics and postmortem pathology between those who developed NVOA and those who did not. We also compared clinicopathologic characteristics in mild vs greater than mild NVOA and early vs late-emerging NVOA. SPM12 was used to assess patterns of gray matter loss in NVOA vs non-NVOA with age and sex included as covariates. A total of 104 patients (median age at symptom onset 63 years, 43% female) were included in the study. 63 (60.6%) developed NVOA. NVOA appeared at a median of 4.3 years from symptom onset. 29% developed NVOA within the first 3 years. Primary progressive apraxia of speech and the nonfluent variant of primary progressive aphasia were the most common baseline diagnoses in the NVOA group while progressive supranuclear palsy (PSP) syndrome and logopenic progressive aphasia (LPA) were the most common in patients without NVOA. Atrophy of the left lateral and medial posterior frontal cortex was related to NVOA. The most common pathologies associated with NVOA were PSP (36.5%) and corticobasal degeneration (CBD) (33.3%). In patients without NVOA, PSP (26.8%) and other pathologies (26.8%) were the most frequent. 11% of patients with NVOA had persistently mild NVOA and were more likely to have baseline diagnoses of LPA, PSP syndrome, or semantic dementia. The most frequent pathologies in this group were Alzheimer disease and PSP. The pathologic associations of greater than mild NVOA were CBD and PSP. NVOA is present in several clinical syndromes. It is most associated with PSP and CBD. NVOA is a manifestation of left lateral and medial posterior frontal cortex damage rather than a particular pathology.

Associations between white and grey matter damage and gait impairment in cerebral amyloid angiopathy

BackgroundCerebral amyloid angiopathy (CAA) is associated with white matter damage and neurodegeneration. Gait is impaired in CAA; however, the neural basis of this impairment is unclear. Research questionAre gait impairments in patients with CAA associated with altered cerebral white matter diffusivity and/or atrophy of cortical and subcortical grey matter. MethodsParticipants with CAA (n=29), Alzheimer’s disease (AD; n=16), and normal controls (n=47) were included. Gait was assessed using a 6 m walkway with parameters categorized into rhythm, pace, postural control, and variability domains. The dual-task cost (DTC) of gait speed was calculated for counting backwards, animal fluency, and serial sevens tasks. Whole-brain white matter disruption was quantified using the peak width of skeletonized mean diffusivity (PSMD), and thickness and volume of select cortical, subcortical, and cerebellar regions were quantified using FreeSurfer. ResultsIn CAA participants, associations were found between PSMD and pace (standardized parameter estimate (β), 95 % confidence interval (CI): 0.17, 0.03–0.32), and medial orbital frontal cortical thickness and counting backwards DTC (parameter estimate (PE), 95 % CI: −5.7 %/SD, −0.24 to −11.23). Across all groups, including CAA, associations were found between PSMD and pace, variability, counting backwards DTC, and animal fluency DTC; between frontal cortical thickness and pace, counting backwards DTC, and animal fluency DTC; between cortical regions affected by AD (inferior parietal cortex, inferior and middle temporal gyrus) and counting backwards DTC; and between thalamus volume and postural control. SignificanceReduced white matter structural integrity and grey matter loss is associated with poor overall gait performance in CAA, AD, and normal controls.

MRI evidence of gray matter loss in COVID-19 patients with cognitive and olfactory disorders.

The aim of this study was to assess COVID-19-related gray matter (GM) structural alterations in two distinct groups of patients presenting with the prevailing and distinctive COVID-19-related neurological symptoms - isolated olfactory disorders as sole neurological manifestation (COVID-OD) and cognitive disorders (COVID-CD) - as compared to a control group of unaffected individuals. The study included 61 COVID-CD patients (57 [60-63] years, 62% females), 84 COVID-OD patients (49 [35-57] years, 60% females), and 17 controls (51 [41-52] years, 41% females). Region-based morphometry (RBM) and voxel-based morphometry (VBM) were performed on T1-weighted MRI scans to assess GM regional volume and voxel-wise density differences between COVID-19 patients and controls. Surface-based morphometry (SBM) was applied to investigate cortical thickness alterations. The statistical models built to assess GM structural differences among groups included total intracranial volume and age as nuisance variables. The multi-morphometric analysis revealed statistically significant (p < 0.05 corrected for multiple comparisons) reduction in GM regional volumes, in voxel-wise GM density and in cortical thickness in both COVID-CD and COVID-OD patient groups as compared to controls. Across all three analyses, COVID-CD patients showed more distributed and severe GM loss than COVID-OD patients. The most prominently affected GM regions in the COVID-CD group included the hippocampus, putamen, cingulate gyrus, precuneus, precentral and postcentral gyri, amygdala, lingual gyrus, and caudate nucleus. Our MRI findings show that COVID-19-related olfactory and cognitive disorders both induce GM atrophy, although at different degrees of severity, likely indicative of neurodegeneration and neuroinflammation.

Can gray matter loss in early adolescence be explained by white matter growth?

AbstractA fundamental puzzle about brain development is why the volume of gray matter (GM) apparently declines as white matter (WM) grows when children enter adolescence. Since pruned synapses are too small to affect GM volume, a prevailing theory posits that an expanded distribution of myelin causes the inner edge of the GM to “whiten” while total brain volume remains steady, shifting the MRI‐measured WM:GM boundary closer to the brain's outer surface. This theory inherently predicts that GM volume loss is concurrent with WM volume growth across regions, within sexes and over time, although these predictions have yet to be explicitly tested. In this study, we test these predictions by mapping regional GM and WM volumetric changes in 2333 participants of the Adolescent Brain Cognitive Development study aged 9–14 years who each received three MRI scans 2 years apart. We show that average GM and WM volume changes follow distinct spatial, temporal, and sex‐specific patterns, indicating that GM volume loss is not balanced by WM volume growth, although cortical GM thinning is weakly correlated with WM growth in some regions. We conclude that myelin is not the main source of measured GM volume loss, and we propose alternative candidates.

Alzheimer’s-linked axonal changes accompany elevated antidromic action potential failure rate in aged mice

Alzheimer’s disease (AD) affects both grey and white matter (WM), but considerably more is known about the former. Interestingly, WM disruption has been consistently observed and thoroughly described using imaging modalities, particularly MRI which has shown WM functional disconnections between the hippocampus and other brain regions during AD pathogenesis when early neurodegeneration and synapse loss are also evident. Nonetheless, high-resolution structural and functional analyses of WM during AD pathogenesis remain scarce. Given the importance of the myelinated axons in the WM for conveying information across brain regions, such studies will provide valuable information on the cellular drivers and consequences of WM disruption that contribute to the characteristic cognitive decline of AD. Here, we employed a multi-scale approach to investigate hippocampal WM disruption during AD pathogenesis and determine whether hippocampal WM changes accompany the well-documented grey matter losses. Our data indicate that ultrastructural myelin disruption is elevated in the alveus in human AD cases and increases with age in 5xFAD mice. Unreliable action potential propagation and changes to sodium channel expression at the node of Ranvier co-emerged with this deterioration. These findings provide important insight to the neurobiological substrates and functional consequences of decreased WM integrity and are consistent with the notion that hippocampal disconnection contributes to cognitive changes in AD.

Diabetes mellitus in older persons with neurocognitive disorder: overtreatment prevalence and associated structural brain MRI findings

BackgroundTight diabetes control is often applied in older persons with neurocognitive disorder resulting in increased hypoglycemic episodes but little is known about the pattern of brain injury in these overtreated patients. This study aims to: (a) quantify the prevalence of diabetes overtreatment in cognitively impaired older adults in a clinical population followed in an academic memory clinic (b) identify risk factors contributing to overtreatment; and (c) explore the association between diabetes overtreatment and specific brain region volume changes.MethodsRetrospective study of older patients with type 2 diabetes and cognitive impairment who were diagnosed in a memory clinic from 2013 to 2020. Patients were classified into vulnerable and dependent according to their health profile. Overtreatment was defined when glycated hemoglobin was under 7% for vulnerable and 7.6% for dependent patients. Characteristics associated to overtreatment were examined in multivariable analysis. Grey matter volume in defined brain regions was measured from MRI using voxel-based morphometry and compared in patients over- vs. adequately treated.ResultsAmong 161 patients included (median age 76.8 years, range 60.8–93.3 years, 32.9% women), 29.8% were considered as adequately treated, 54.0% as overtreated, and 16.2% as undertreated. In multivariable analyses, no association was observed between diabetes overtreatment and age or the severity of cognitive impairment. Among patients with neuroimaging data (N = 71), associations between overtreatment and grey matter loss were observed in several brain regions. Specifically, significant reductions in grey matter were found in the caudate (adj β coeff: -0.217, 95%CI: [-0.416 to -0.018], p = .033), the precentral gyri (adj βcoeff:-0.277, 95%CI: [-0.482 to -0.073], p = .009), the superior frontal gyri (adj βcoeff: -0.244, 95%CI: [-0.458 to -0.030], p = .026), the calcarine cortex (adj βcoeff:-0.193, 95%CI: [-0.386 to -0.001], p = .049), the superior occipital gyri (adj βcoeff: -0.291, 95%CI: [-0.521 to -0.061], p = .014) and the inferior occipital gyri (adj βcoeff: -0.236, 95%CI: [-0.456 to – 0.015], p = .036).ConclusionA significant proportion of older patients with diabetes and neurocognitive disorder were subjected to excessively intensive treatment. The association identified with volume loss in several specific brain regions highlights the need to further investigate the potential cerebral damages associated with overtreatment and related hypoglycemia in larger sample.

History of traumatic brain injury is associated with increased grey-matter loss in patients with mild cognitive impairment.

To investigate whether a history of traumatic brain injury (TBI) is associated with greater long-term grey-matter loss in patients with mild cognitive impairment(MCI). 85 patients with MCI were identified, including 26 with a previous history of traumatic brain injury (MCI[TBI-]) and 59 without (MCI[TBI+]). Cortical thickness was evaluated by segmenting T1-weighted MRI scans acquired longitudinally over a 2-year period. Bayesian multilevel modelling was used to evaluate group differences inbaseline cortical thickness and longitudinalchange, as well as group differences in neuropsychological measures of executive function. At baseline, theMCI[TBI+] group had less grey matter within right entorhinal, left medial orbitofrontal and inferior temporal cortexareas bilaterally. Longitudinally, theMCI[TBI+] group also exhibited greater longitudinal declines in left rostral middle frontal, the left caudal middle frontal and left lateral orbitofrontalareas sover the span of 2years (median = 1-2%, 90%HDI [-0.01%: -0.001%], probability of direction(PD) = 90-99%). The MCI[TBI+] group also displayedgreater longitudinal declines in Trail-Making-Test (TMT)-derived ratio (median: 0.737%, 90%HDI: [0.229%: 1.31%], PD = 98.8%) and differences scores (median: 20.6%, 90%HDI: [-5.17%: 43.2%], PD = 91.7%). Our findings support the notion that patients with MCI and a history of TBI are at risk of accelerated neurodegeneration, displayinggreatest evidence for cortical atrophy within the left middle frontal and lateral orbitofrontal frontal cortex. Importantly, these results suggest that long-term TBI-mediated atrophy is more pronounced in areas vulnerable to TBI-related mechanical injury, highlighting their potential relevance for diagnostic forms of intervention in TBI.

Glymphatic abnormality in systemic lupus erythematosus detected by diffusion tensor image analysis along the perivascular space.

This study aimed to evaluate the activity of the glymphatic system in systemic lupus erythematosus (SLE) by a diffusion-based method termed "Diffusion Tensor Image Analysis aLong the Perivascular Space (DTI-ALPS)", and examined its correlations with morphological changes in the brain. In this cross-sectional study, forty-five female patients with SLE and thirty healthy controls (HCs) were included. Voxel-based and surface-based morphometric analyses were performed to examine T1 weighted images, and diffusion tensor images were acquired to determine diffusivity along the x-, y-, and z-axes in the plane of the lateral ventricle body. The ALPS-index was calculated. The differences in values between SLE patients and HC group were compared using the independent samples t test or Mann-Whitney U test. For the correlations between the ALPS-index and brain morphological parameters, partial correlation analysis and Pearson's correlation analysis were conducted. SLE patients showed lower values for the ALPS-index in left (1.543 ± 0.141 vs 1.713 ± 0.175, p < 0.001), right (1.428 ± 0.142 vs 1.556 ± 0.139, p < 0.001) and whole (1.486 ± 0.121 vs 1.635 ± 0.139, p < 0.001) brain compared with the HC group. The reduced ALPS-index showed significant positive correlations with gray matter loss. The non-invasive ALPS-index could serve as a sensitive and effective neuroimaging biomarker for individually quantifying glymphatic activity in patients with SLE. Glymphatic system abnormality may be involved in the pathophysiologic mechanism underlying central nervous system damage in SLE patients.

Gray matter volume in women with the BRCA mutation with and without ovarian removal: evidence for increased risk of late-life Alzheimer's disease or dementia.

Ovarian removal prior to spontaneous/natural menopause (SM) is associated with increased risk of late life dementias including Alzheimer's disease. This increased risk may be related to the sudden and early loss of endogenous estradiol. Women with breast cancer gene mutations (BRCAm) are counseled to undergo oophorectomy prior to SM to significantly reduce their risk of developing breast, ovarian, and cervical cancers. There is limited evidence of the neurological effects of ovarian removal prior to the age of SM showing women without the BRCAm had cortical thinning in medial temporal lobe structures. A second study in women with BRCAm and bilateral salpingo-oophorectomy (BSO) noted changes in cognition. The present, cross-sectional study examined whole-brain differences in gray matter (GM) volume using high-resolution, quantitative magnetic resonance imaging in women with BRCAm and intact ovaries (BRCA-preBSO [study cohort with BRCA mutation prior to oophorectomy]; n = 9) and after surgery with (BSO + estradiol-based therapy [ERT]; n = 10) and without (BSO; n = 10) postsurgical estradiol hormone therapy compared with age-matched women (age-matched controls; n = 10) with their ovaries. The BRCA-preBSO and BSO groups showed significantly lower GM volume in the left medial temporal and frontal lobe structures. BSO + ERT exhibited few areas of lower GM volume compared with age-matched controls. Novel to this study, we also observed that all three BRCAm groups exhibited significantly higher GM volume compared with age-matched controls, suggesting continued plasticity. The present study provides evidence, through lower GM volume, to support both the possibility that the BRCAm, alone, and early life BSO may play a role in increasing the risk for late-life dementia. At least for BRCAm with BSO, postsurgical ERT seems to ameliorate GM losses.

Data-driven decomposition and staging of flortaucipir uptake in Alzheimer's disease.

Previous approaches pursuing in vivo staging of tau pathology in Alzheimer's disease (AD) have typically relied on neuropathologically defined criteria. In using predefined systems, these studies may miss spatial deposition patterns which are informative of disease progression. We selected discovery (n=418) and replication (n=132) cohorts with flortaucipir imaging. Non-negative matrix factorization (NMF) was applied to learn tau covariance patterns and develop a tau staging system. Flortaucipir components were also validated by comparison with amyloid burden, gray matter loss, and the expression of AD-related genes. We found eight flortaucipir covariance patterns which were reproducible and overlapped with relevant gene expression maps. Tau stages were associated with AD severity as indexed by dementia status and neuropsychological performance. Comparisons of flortaucipir uptake with amyloid and atrophy also supported our model of tau progression. Data-driven decomposition of flortaucipir uptake provides a novel framework for tau staging which complements existing systems. NMF reveals patterns of tau deposition in AD. Data-driven staging of flortaucipir tracks AD severity. Learned flortaucipir patterns overlap with AD-related gene expression.

7T MP2RAGE for cortical myelin segmentation: Impact of aging.

Myelin and iron are major contributors to the cortical MR signal. The aim of this study was to investigate 1. Can MP2RAGE-derived contrasts at 7T in combination with k-means clustering be used to distinguish between heavily and sparsely myelinated layers in cortical gray matter (GM)? 2. Does this approach provide meaningful biological information? The following contrasts were generated from the 7T MP2RAGE images from 45 healthy controls (age: 19-75, f/m = 23/22) from the ATAG data repository: 1. T1 weighted image (UNI). 2. T1 relaxation image (T1map). 3. INVC/T1map ratio (RATIO). K-means clustering identified 6 clusters/tissue maps (csf, csf/gm-transition, wm, wm/gm transition, heavily myelinated cortical GM (dGM), sparsely myelinated cortical GM (sGM)). These tissue maps were then processed with SPM/DARTEL (volume-based analyses) and Freesurfer (surface-based analyses) and dGM and sGM volume/thickness of young adults (n = 27, 19-27 years) compared to those of older adults (n = 18, 42-75 years) at p<0.001 uncorrected. The resulting maps showed good agreement with histological maps in the literature. Volume- and surface analyses found age-related dGM loss/thinning in the mid-posterior cingulate and parahippocampal/entorhinal gyrus and age-related sGM losses in lateral, mesial and orbitofrontal frontal, insular cortex and superior temporal gyrus. The MP2RAGE derived UNI, T1map and RATIO contrasts can be used to identify dGM and sGM. Considering the close relationship between cortical myelo- and cytoarchitecture, the findings reported here indicate that this new technique might provide new insights into the nature of cortical GM loss in physiological and pathological conditions.

Biophysical models applied to dementia patients reveal links between geographical origin, gender, disease duration, and loss of neural inhibition

BackgroundThe hypothesis of decreased neural inhibition in dementia has been sparsely studied in functional magnetic resonance imaging (fMRI) data across patients with different dementia subtypes, and the role of social and demographic heterogeneities on this hypothesis remains to be addressed.MethodsWe inferred regional inhibition by fitting a biophysical whole-brain model (dynamic mean field model with realistic inter-areal connectivity) to fMRI data from 414 participants, including patients with Alzheimer’s disease, behavioral variant frontotemporal dementia, and controls. We then investigated the effect of disease condition, and demographic and clinical variables on the local inhibitory feedback, a variable related to the maintenance of balanced neural excitation/inhibition.ResultsDecreased local inhibitory feedback was inferred from the biophysical modeling results in dementia patients, specific to brain areas presenting neurodegeneration. This loss of local inhibition correlated positively with years with disease, and showed differences regarding the gender and geographical origin of the patients. The model correctly reproduced known disease-related changes in functional connectivity.ConclusionsResults suggest a critical link between abnormal neural and circuit-level excitability levels, the loss of grey matter observed in dementia, and the reorganization of functional connectivity, while highlighting the sensitivity of the underlying biophysical mechanism to demographic and clinical heterogeneities in the patient population.

Widespread cortical and subcortical gray matter loss and an increase of globus pallidus volume in treatment-resistant schizophrenia

Introduction It is still being discussed whether treatment-resistant schizophrenia (TRS) is a biological subtype which differs from non-treatment-resistant schizophrenia or is it a more severe condition that affects brain worse than non-treatment-resistant schizophrenia. However, there are few and heterogeneous studies and the etiology of TRS remains quite unclear.ObjectivesThis study aimed to explore cortical and subcortical morphometric characteristics in TRS patients and its associations with the clinical features. The pilot stage comprises the comparison to the mentally healthy subjects.Methods 21 right-handed male patients (mean age 28.99 ± 8.08 years) fulfilling TRS criteria and 21 matched healthy controls (mean age 29.35 ± 7.41 years) underwent T1-weighted structural MRI at 3T Philips scanner and clinical examination. Images were processed using FreeSurfer 7.1.1. Cortical thickness and area, volumes of subcortical structures and separately volumes of the amygdala nuclei and hippocampal subregions were compared between groups. The morphometry data, PANSS (Positive and Negative Syndrome Scale), CDSS (Calgary Depression Scale for Schizophrenia) and daily chlorpromazine equivalent doses of antipsychotics were included in correlational analysis. Results were considered significant if they retained significance after correction for multiple comparisons.Results Compared to healthy controls, TRS patients showed decreased gray matter thickness in frontal, temporal, parietal, occipital, cingulate and insular regions (Figure 1). The temporal lobe showed the most prominent thinning of the cortex. The volumes of the amygdala, hippocampus (Figure 2) and nucleus accumbens, a number of amygdala nuclei and hippocampal subregions bilaterally were also decreased in TRS patients. The volume of the right globus pallidus, on the contrary, was increased (Figure 2). No correlations between altered cortical thickness, PANSS (positive, negative, general psychopathology scales and total score), CDSS and chlorpromazine equivalent doses of antipsychotics were found.Image:Image 2:Conclusions The widespread gray matter cortical and subcortical loss in TRS finds confirmation in the literature. The increased globus pallidus volume is an unexpected and intriguing result. Other studies demonstrated conflicting results on that point. Some studies reported possible therapy influence, others suggested possible associations with symptoms. We did not find any correlations with psychometric or therapy characteristics. It is possible that there are non-linear relationships or relationships that exist only at a certain stage of the disease. As for therapy, patients took individual medication, consisting of various antipsychotics and drugs from other pharmacological groups, and such heterogeneity could affect the results of the study. Further research is going to be carried out.Disclosure of InterestNone Declared