White Matter Atrophy Research Articles

Longitudinal enlargement of choroid plexus is associated with chronic lesion expansion and neurodegeneration in RRMS patients

Background and Objective: We explored dynamic changes in the choroid plexus (CP) in patients with relapsing-remitting multiple sclerosis (RRMS) and assessed its relationship with chronic lesion expansion and atrophy in various brain compartments. Methods: Fifty-seven RRMS patients were annually assessed for a minimum of 48 months with 3D FLAIR, pre- and post-contrast 3D T1 and diffusion-weighted magnetic resonance imaging (MRI). The CP was manually segmented at baseline and last follow-up. Results: The volume of CP significantly increased by 1.4% annually. However, the extent of CP enlargement varied considerably among individuals (ranging from −3.6 to 150.8 mm3 or −0.2% to 6.3%). The magnitude of CP enlargement significantly correlated with central (r = 0.70, p < 0.001) and total brain atrophy (r = −0.57, p < 0.001), white (r = −0.61, p < 0.001) and deep grey matter atrophy (r = −0.60, p < 0.001). Progressive CP enlargement was significantly associated with the volume and extent of chronic lesion expansion (r = 0.60, p < 0.001), but not with the number or volume of new lesions. Conclusion: This study provides evidence of progressive CP enlargement in patients with RRMS. Our findings also demonstrate that enlargement of the CP volume is linked to the expansion of chronic lesions and neurodegeneration of periventricular white and grey matter in RRMS patients.

Quantitative brain morphometry identifies cerebellar, cortical, and subcortical gray and white matter atrophy in late-onset Tay-Sachs disease

Quantitative brain morphometry identifies cerebellar, cortical, and subcortical gray and white matter atrophy in late-onset Tay-Sachs disease

Hypertensive and Non-hypertensive Hospital Admission Blood Pressure Association with Cognitive Function in Stroke Patients

Highlight: A comparative study of hypertension and non-hypertension on cognitive function. Hospital admission blood pressure and cognitive function in acute-phase stroke patients. Blood pressure is not associated with cognitive function. ABSTRACT Introduction: Cognitive impairment is one of the many stroke effects. White matter damage, microinfarcts, microbleeding, atrophy, and amyloid buildup in the brain due to stroke are all potential causes of this condition. Cognitive impairment studies have yet to provide a definitive explanation for how this condition develops following a stroke. Blood pressure is one of several risk factors for stroke. Meanwhile, few studies have been conducted on the association between blood pressure and cognitive function in stroke patients, and no definitive results have been established. Objective: This research was designed to examine and evaluate the difference in the measured cognitive function category between hypertensive and non-hypertensive hospital admission blood pressure stroke patients. Methods: This research used a cross-sectional design with a consecutive sampling method on acute stroke patients at Dr. Soetomo General Academic Hospital. The MMSE (Mini Mental State Examination) was carried out to assess the degree of cognitive function. The blood pressure measured is the hospital admission blood pressure. Results: There were 40 patients included in this study. A total of 36 patients (90%) were in the hypertension group (blood pressure ≥ 130/80 mmHg), and 4 patients (10%) were in the non-hypertension group (blood pressure &lt; 130/80 mmHg). The MMSE results showed that 10 patients performed with no cognitive impairment, 12 patients performed with mild cognitive impairment, and 18 patients performed with severe cognitive impairment. Statistical analysis of the Mann-Whitney U test showed that p = 0.561. Conclusion: There was no difference in the measured cognitive function category between hypertensive and non-hypertensive hospital admission blood pressure stroke patients.

Enlarged choroid plexus in multiple sclerosis is associated with increased lesion load and atrophy in white matter but not gray matter atrophy

BackgroundEnlargement of the choroid plexus (CP) is reported to associate with inflammatory activity and contribute to brain atrophy in patients with multiple sclerosis (pwMS). However, a recent study in healthy volunteers (HVTs) has suggested that CP enlargement can be attributed to ventriculomegaly. ObjectivesTo clarify the pathological significance of the enlargement of CP in multiple sclerosis (MS). MethodsA total of 102 pwMS (89 with relapsing-remitting MS and 13 with secondary progressive MS) and 41 HVTs were cross-sectionally evaluated using brain volumetry. The CP volume was compared between disease groups and investigated for the relationships with other brain regional volumes. ResultsCP volume was significantly larger in pwMS than in HVTs in the univariate analysis, but not in multivariable analysis. Meanwhile, the CP and lateral ventricle (LV) volumes were significantly correlated. CP enlargement was significantly associated with increased lesion load and cerebral white matter (WM) atrophy, even after adjusting for LV volume. In contrast, multivariable analyses revealed that LV enlargement, but not CP enlargement, was associated with total gray matter (GM) atrophy. ConclusionCP enlargement was closely associated with LV enlargement. After adjusting for LV volume, CP enlargement in pwMS was associated with increased lesion load and WM atrophy but not GM atrophy.

Voxel-Based Morphometry of Progressive Supranuclear Palsy Using a 3D Fast Low-angle Shot Localizer Image: A Comparison with Magnetization-Prepared Rapid Gradient Echo.

Voxel-based morphometry (VBM) is widely used to investigate white matter (WM) atrophy in patients with progressive supranuclear palsy (PSP). In contrast to high-resolution 3D T1-weighted imaging such as magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequences, the utility of other 3D sequences has not been sufficiently evaluated. This study aimed to assess the feasibility of using a 3D fast low-angle shot sequence captured as a localizer image (L3DFLASH) for VBM analysis of WM atrophy patterns in patients with PSP. This retrospective study included 12 patients with pathologically or clinically confirmed PSP, and 18 age- and sex-matched healthy controls scanned with both L3DFLASH and MPRAGE sequences. Image processing was conducted with the Computational Anatomy Toolbox 12 in statistical parametric mapping 12. In addition to the atrophic WM pattern of PSP on VBM, we assessed the WM volume agreement between the two sequences using simple linear regression and Bland-Altman plots. Despite the slightly larger clusters on MPRAGE, VBM using both sequences showed similar characteristics of PSP-related WM atrophy, including in the midbrain, pons, thalamus, and precentral gyrus. In contrast, VBM showed gray matter (GM) atrophy of the precuneus and right superior parietal lobule exclusively on L3DFLASH. Unlike the measured values of total intracranial volume, GM, and cerebrospinal fluid on MPRAGE, the value of WM was larger on L3DFLASH. In contrast to the total intracranial volume, brainstem, and frontal and occipital lobes, the correlation with WM volume in other regions was relatively low. However, the Bland-Altman plots demonstrated strong agreement, with over 90% of the values falling within the agreement limits. Both MPRAGE and L3DFLASH are useful for detecting PSP-related WM atrophy using VBM.

In Vivo Detection of Age-Related Tortuous Cerebral Small Vessels using Ferumoxytol-enhanced 7T MRI.

Histopathological studies suggest that cerebral small vessel tortuosity is crucial in age-related blood flow reduction and cellular degeneration. However, in vivo evidence is lacking. Here, we used Ferumoxytol-enhanced 7T MRI to directly visualize cerebral small vessels (<300 µm), enabling the identification of vascular tortuosity and exploration of its links to age, tissue atrophy, and vascular risk factors. High-resolution 2D/3D gradient echo MRI at 7T enhanced with Ferumoxytol, an ultrasmall superparamagnetic iron oxide (USPIO), was obtained and analyzed for cerebral small medullary artery tortuosity from 37 healthy participants (21-70 years; mean/SD: 38±14 years; 19 females). Tortuous artery count and tortuosity indices were compared between young and old groups. Age effects on vascular tortuosity were examined through partial correlations and multiple linear regression, adjusting for sex, body mass index (BMI), blood pressure (BP), and other vascular risk factors. Associations between tortuous medullary arteries and tissue atrophy, perivascular spaces (PVS), and white matter (WM) hyperintensities were explored. Age and BMI, rather than BP, showed positive correlations with both tortuous artery count and tortuosity indices. A significant correlation existed between the number of tortuous arteries and WM atrophy. WM lesions were found in proximity to or at the distal ends of tortuous medullary arteries, especially within the deep WM. Moreover, the elderly population displayed a higher prevalence of PVS, including those containing enclosed tortuous arteries. Leveraging the blooming effect of Ferumoxytol, 7T MRI excels in directly detecting cerebral small arterial tortuosity in vivo, unveiling its associations with age, BMI, tissue atrophy, WMH and PVS.

Longitudinal fibre-specific white matter damage predicts cognitive decline in multiple sclerosis.

During the course of multiple sclerosis, many patients experience cognitive deficits which are not simply driven by lesion number or location. By considering the full complexity of white matter structure at macro- and microstructural levels, our understanding of cognitive impairment in multiple sclerosis may increase substantially. Accordingly, this study aimed to investigate specific patterns of white matter degeneration, the evolution over time, the manifestation across different stages of the disease and their role in cognitive impairment using a novel fixel-based approach. Neuropsychological test scores and MRI scans including 30-direction diffusion-weighted images were collected from 327 multiple sclerosis patients (mean age = 48.34 years, 221 female) and 95 healthy controls (mean age = 45.70 years, 55 female). Of those, 233 patients and 61 healthy controls had similar follow-up assessments 5 years after. Patients scoring 1.5 or 2 standard deviations below healthy controls on at least two out of seven cognitive domains (from the Brief Repeatable Battery of Neuropsychological Tests, BRB-N) were classified as mildly cognitively impaired or cognitively impaired, respectively, or otherwise cognitively preserved. Fixel-based analysis of diffusion data was used to calculate fibre-specific measures (fibre density, reflecting microstructural diffuse axonal damage; fibre cross-section, reflecting macrostructural tract atrophy) within atlas-based white matter tracts at each visit. At baseline, all fixel-based measures were significantly worse in multiple sclerosis compared with healthy controls (P < 0.05). For both fibre density and fibre cross-section, a similar pattern was observed, with secondary progressive multiple sclerosis patients having the most severe damage, followed by primary progressive and relapsing-remitting multiple sclerosis. Similarly, damage was least severe in cognitively preserved (n = 177), more severe in mildly cognitively impaired (n = 63) and worst in cognitively impaired (n = 87; P < 0.05). Microstructural damage was most pronounced in the cingulum, while macrostructural alterations were most pronounced in the corticospinal tract, cingulum and superior longitudinal fasciculus. Over time, white matter alterations worsened most severely in progressive multiple sclerosis (P < 0.05), with white matter atrophy progression mainly seen in the corticospinal tract and microstructural axonal damage worsening in cingulum and superior longitudinal fasciculus. Cognitive decline at follow-up could be predicted by baseline fixel-based measures (R2 = 0.45, P < 0.001). Fixel-based approaches are sensitive to white matter degeneration patterns in multiple sclerosis and can have strong predictive value for cognitive impairment. Longitudinal deterioration was most marked in progressive multiple sclerosis, indicating that degeneration in white matter remains important to characterize further in this phenotype.

SHARED AND DISTINCT ASSOCIATIONS OF MANUAL DEXTERITY AND GROSS MOTOR FUNCTION WITH BRAIN ATROPHY

Abstract Poor motor function is associated with brain volume and cognitive impairment. Less is known about the associations among motor domains and brain atrophy and whether associations are affected by cerebrovascular burden and/or physical activity. We analyzed data from 726 Baltimore Longitudinal Study of Aging participants (mean age 70.6±10.1 years, 56%women, 27%Black), 525 of whom had repeat MRI scans over 5.0±2.1 years. Two motor domains were operationalized as latent variables. Manual dexterity using the Purdue Pegboard and gross motor function using grip strength and comprehensive physical performance testing. Associations between the latent variables and cortical and subcortical brain volumes of interest were examined using latent growth curve modeling, adjusted for demographics, white matter hyperintensities, and physical activity. Both higher manual dexterity and gross motor function were cross-sectionally associated with smaller ventricular volume and greater white matter volumes in the frontal, parietal, and temporal lobes (all p&amp;lt;.05). Higher manual dexterity was also cross-sectionally associated with greater parietal gray matter ( =0.14;95%CI:0.05,0.23), hippocampal ( =0.10;95%CI:0.01,0.20), postcentral gyrus ( =0.11;95%CI:0.01,0.20), and occipital white matter ( =0.10;95%CI:0.01,0.21) volumes, and better gross motor function with greater temporal gray matter volume ( =0.16;95%CI:0.05,0.26). Longitudinally, higher manual dexterity and gross motor function were associated with lower temporal white matter and occipital gray matter atrophy (all p&amp;lt;0.05). Greater manual dexterity was also associated with a slower rate of ventricular enlargement ( =-0.17;95%CI:-0.29,-0.05) and less atrophy of occipital white matter ( =0.39;95%CI:0.04,0.71). Among cognitively normal middle- and older-aged adults, manual dexterity and gross motor function exhibited shared as well as distinct associations with brain atrophy over time.

Quantitative brain morphometry identifies cerebellar, cortical, and subcortical gray and white matter atrophy in late-onset Tay-Sachs disease.

Cerebellar atrophy is a characteristic sign of late-onset Tay-Sachs disease (LOTS). Other structural neuroimaging abnormalities are inconsistently reported. Our study aimed to perform a detailed whole-brain analysis and quantitatively characterize morphometric changes in LOTS patients. Fourteen patients (8 M/6F) with LOTS from three centers were included in this retrospective study. For morphometric brain analyses, we used deformation-based morphometry, voxel-based morphometry, surface-based morphometry, and spatially unbiased cerebellar atlas template. The quantitative whole-brain morphometric analysis confirmed the finding of profound pontocerebellar atrophy with most affected cerebellar lobules V and VI in LOTS patients. Additionally, the atrophy of structures mainly involved in motor control, including bilateral ventral and lateral thalamic nuclei, primary motor and sensory cortex, supplementary motor area, and white matter regions containing corticospinal tract, was present. The atrophy of the right amygdala, hippocampus, and regions of occipital, parietal and temporal white matter was also observed in LOTS patients in contrast with controls (p < 0.05, FWE corrected). Patients with dysarthria and those initially presenting with ataxia had more severe cerebellar atrophy. Our results show predominant impairment of cerebellar regions responsible for speech and hand motor function in LOTS patients. Widespread morphological changes of motor cortical and subcortical regions and tracts in white matter indicate abnormalities in central motor circuits likely coresponsible for impaired speech and motor function.

Cortical gray matter and cerebral white matter atrophy and asymmetry in Parkinson’s disease patients with normal cognitive precede

Background Parkinson’s disease is the second most common neurodegenerative disorder with complex and distributed motor and non-motor symptoms. In this study, cortical gray matter (GM) and cerebral white matter (WM) overall atrophy, and asymmetry of atrophy are investigated in PD with normal cognitive function. Method Forty-eight male Parkinson’s disease(PD) patients with normal cognitive precede (PD-NC), and thirty matched healthy control (HC) subjects were selected from the Parkinson’s Progression Markers Initiative (PPMI) database. Brain structures volumes were extracted using Freesurfer software based on subject 3 tesla MRI images. The normalized volume of cortical GM and cerebral WM were compared in two study groups, and then the asymmetry index (AI) of GM and WM atrophy was also assessed in two groups. Statistical analysis was constructed using a t-test with p < 0.05 of significance. Results No significant difference was observed in the volume of cortical GM and cerebral WM in the two study groups. The cortical GM asymmetry index in the PD-NC group was significantly (p = 0.01) higher than the HC group, however, no difference was observed for the cerebral WM asymmetry index. Conclusion Atrophy in cortical GM and WM was not observed between the PD-NC and the HC group, however, the asymmetry index in GM was significant between the two group. It seems that the brain’s bilateral balance has ruptured in PD. Cortical GM asymmetry in PD-NC can be considered a potent biomarker and should be investigated more in the future. In future studies, construction of a longitudinal study on this issue could be useful.

Machine‐learning derived white matter signatures and the risk of dementia, stroke and mortality: the Rotterdam Study

AbstractBackgroundWhite matter hyperintensities (WMH), loss of white matter (WM) volume and WM microstructural integrity are important risk indicators of stroke and dementia, albeit of heterogeneous nature. Use of machine learning techniques may unravel different patterns of white matter injury, with distinct underlying pathologies and disease risk.MethodWe measured WMH volume, WM volume, global fractional anisotropy (FA) and global mean diffusivity (MD) in 5205 participants (mean age 64.9 years, 56.0% women) of the population‐based Rotterdam study with brain MRI between 2005 and 2016. We performed hierarchical clustering on age‐standardized imaging parameters to identify separate clusters of white matter injury, and compare determinants across clusters. We then determined the association between clusters and risk of dementia, stroke and mortality, using Cox proportional hazard models adjusted for sex, education, APOE‐ε4 and cardiovascular risk factors.ResultWe identified four distinct white matter signatures: (i) cluster with above‐average microstructural integrity and little WM atrophy and WMH, (ii) cluster with above‐average microstructural integrity and little WMH, yet substantial WM atrophy, (iii) cluster with poor microstructural integrity and substantial WMH, yet little WM atrophy, and (iv) cluster with poor microstructural integrity, substantial WM atrophy, and average WMH load. There were no clear differences between clusters in APOE genotype and cardiometabolic risk factors, except for higher prevalence of hypertension in cluster (iv). Cluster (iii) contained more women, and participants in clusters (iii) and (iv) had more microbleeds and lacunes. During a median 10.7 years of follow‐up, 272, 210, and 844 cases of dementia, stroke, death occurred, respectively. In fully adjusted models, dementia risk was increased for clusters (ii) (HR 1.57 [95%CI:1.04‐2.37]), (iii) (HR 2.43 [95%CI:1.68‐3.52]) and (iv) (HR 1.78 [95%CI:1.22‐2.62], compared to cluster (i). Moderate associations of clusters (iii) and (iv) with incidence stroke attenuated and were no longer statistically significant after adjustment for cardiovascular risk factors, while only cluster (iii) was associated with a small increase in mortality (HR 1.30 [95%CI:1.07‐1.58]).ConclusionMachine‐learning derived white matter signatures are differentially associated with dementia, stroke and mortality. Further research is needed to pinpoint differences in underlying pathology, and assess potential benefit of clusters for risk stratification.

Deep Learning Derived Visceral Abdominal Fat Predicts Brain Atrophy at Midlife in 10,001 Individuals

AbstractBackgroundVisceral abdominal fat can predict health outcomes with increasing interest in applications on brain health.MethodA total of 10,001 healthy participants from four sites were scanned on 1.5T MR machines with a short whole‐body MR imaging protocol. Core whole body sequences included coronal T1, STIR from vertex to feet, whole‐body axial DWI from vertex to proximal‐thighs and axial T2 TSE without fat suppression from skull base to pelvis. Brain sequences were T1 MPRAGE and 2D FLAIR. Deep learning with FastSurfer trained on 134 participants aged 27‐66 and segmented 96 brain regions. A separate deep learning model was trained to segment abdominal visceral fat from the whole‐body coronal T1. Partial correlation analysis of visceral abdominal fat volume and brain volumes were evaluated, controlling for age, sex, and total intracranial volume. Benjamini‐Hochberg False Discovery Rate of 5% controlled for multiple comparisons. Logistic regression models determined risk of brain total gray and white matter atrophy based upon the highest quartile of visceral fat and lowest quartile of these brain volumes.ResultThis cohort had an average age of 52.97 ± 13.04 years with a range of 11‐97 years with 52.8% men and 47.2% women. Mean visceral abdominal fat was 3417.81 ± 514.88 ml for overweight persons (BMI ³ 25) and 5355.24 ± 505.04 for obese persons (BMI ³ 30). Even accounting for co‐variates and multiple comparisons, deep learning segmented visceral abdominal fat predicted atrophy in multiple brain regions including: total gray matter volume (Partial R = ‐.09, p = 1.17e‐19), total white matter volume (Partial R = ‐.09, p = 2.25e‐21), hippocampus (Partial R = ‐.02, p = .005), frontal cortex (Partial R = ‐.09, p = 1.79e‐19), temporal lobes (Partial R = ‐.12, p = 2.6e‐30), parietal lobes (Partial R = ‐.04, p = .0004), occipital lobe (Partial R = ‐.03, p = .002), orbital frontal cortex (Partial R = ‐.09, p = 3.76e‐21). Visceral fat predicted increased risk for lower total gray matter (age 20‐39: OR = 5.9; age 40‐59, OR = 5.4; 60‐80, OR = 5.1) and white matter atrophy: (age 20‐39: OR = 3.78; age 40‐59, OR = 4.4; 60‐80, OR = 5.1).ConclusionDeep learning determined increased visceral abdominal fat volume predicts brain volume loss and may represent a novel modifiable factor in determining brain health.

Deep Learning Derived Visceral Abdominal Fat Predicts Brain Atrophy at Midlife in 10,001 Individuals

AbstractBackgroundVisceral abdominal fat can predict health outcomes with increasing interest in applications on brain health.MethodA total of 10,001 healthy participants from four sites were scanned on 1.5T MR machines with a short whole‐body MR imaging protocol. Core whole body sequences included coronal T1, STIR from vertex to feet, whole‐body axial DWI from vertex to proximal‐thighs and axial T2 TSE without fat suppression from skull base to pelvis. Brain sequences were T1 MPRAGE and 2D FLAIR. Deep learning with FastSurfer trained on 134 participants aged 27‐66 and segmented 96 brain regions. A separate deep learning model was trained to segment abdominal visceral fat from the whole‐body coronal T1. Partial correlation analysis of visceral abdominal fat volume and brain volumes were evaluated, controlling for age, sex, and total intracranial volume. Benjamini‐Hochberg False Discovery Rate of 5% controlled for multiple comparisons. Logistic regression models determined risk of brain total gray and white matter atrophy based upon the highest quartile of visceral fat and lowest quartile of these brain volumes.ResultThis cohort had an average age of 52.97 ± 13.04 years with a range of 11‐97 years with 52.8% men and 47.2% women. Mean visceral abdominal fat was 3417.81 ± 514.88 ml for overweight persons (BMI ³ 25) and 5355.24 ± 505.04 for obese persons (BMI ³ 30). Even accounting for co‐variates and multiple comparisons, deep learning segmented visceral abdominal fat predicted atrophy in multiple brain regions including: total gray matter volume (Partial R = ‐.09, p = 1.17e‐19), total white matter volume (Partial R = ‐.09, p = 2.25e‐21), hippocampus (Partial R = ‐.02, p = .005), frontal cortex (Partial R = ‐.09, p = 1.79e‐19), temporal lobes (Partial R = ‐.12, p = 2.6e‐30), parietal lobes (Partial R = ‐.04, p = .0004), occipital lobe (Partial R = ‐.03, p = .002), orbital frontal cortex (Partial R = ‐.09, p = 3.76e‐21). Visceral fat predicted increased risk for lower total gray matter (age 20‐39: OR = 5.9; age 40‐59, OR = 5.4; 60‐80, OR = 5.1) and white matter atrophy: (age 20‐39: OR = 3.78; age 40‐59, OR = 4.4; 60‐80, OR = 5.1).ConclusionDeep learning determined increased visceral abdominal fat volume predicts brain volume loss and may represent a novel modifiable factor in determining brain health.

Age related neuropathology in a novel mouse model of Adult‐onset leukoencephalopathy

AbstractBackgroundAdult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare human disease that is caused by mutations in CSF1R, a gene that is critical for the differentiation, proliferation, and survival of microglia. ALSP patients typically develop dementia, motor impairments, and seizures during their 30s or 40s. Upon autopsy, patients’ brains exhibit decreased numbers of microglia, white matter atrophy, astrocytosis, axonal spheroids, enlarged ventricles, and calcification. Two recent reports have further described rare cases of homozygous CSF1R mutations that lead to perinatal lethality, a complete absence of microglia, and an acceleration of ALSP pathologies. Unfortunately, there is currently no effective treatment for this devastating disease.MethodTo better understand the role of microglia in the development and progression of ALSP we utilized the ‘FIRE’ mouse model that harbors a homozygous deletion in a microglial‐specific enhancer within the CSF1R gene.ResultSurprisingly, at 2 months of age, despite absence of microglia, FIRE mice exhibit normal brain gross anatomy, minimal white matter alterations, and little to no pathology. However, by 10‐months of age FIRE mice exhibit many of the pathologies and symptoms observed in ALSP patients, including axonal spheroids, calcification, demyelination, seizures, and behavioral deficits. Importantly, postnatal transplantation of wildtype murine microglia prevents nearly all of these pathologies, demonstrating the importance of decreased microglial numbers on the development of ALSP. Additional ongoing examinations of 2‐ and 10‐month‐old FIRE mice are exploring the sex‐related impact of microglia absence on synaptic density and utilizing MRI imaging to examine white matter integrity and calcification.ConclusionTaken together, these data suggest that aged FIRE mice may provide a novel and informative, albeit rapidly progressing, model of human ALSP.

Decay in Entorhinal White Matter/Gray Matter contrast in Alzheimer’s Disease Patients is reduced by 40Hz sensory stimulation

AbstractBackgroundPrevious research has shown that white matter (WM) and gray matter (GM) tissues exhibit regionally selective pathological changes in Alzheimer’s disease (AD). The contrast between WM and GM signal intensities (WM/GM contrast) measured by magnetic resonance imaging (MRI) has previously been proposed as a method for quantifying these changes. It has been shown that WM/GM contrast can provide sensitive, independent, and distinct information about pathologies compared with traditional MRI measures. Studies have also shown, including entorhinal WM/GM contrast to traditional MRI measures resulted in better discrimination between AD and controls. We previously demonstrated that 40Hz auditory‐visual stimulation therapy reduced WM atrophy and myelin loss in AD patients. The present study quantified the effects of the therapy on the WM/GM contrast in the entorhinal region.MethodThis study used neuroimaging data from Overture, a phase I/II randomized, placebo‐controlled feasibility study (NCT03556280) in patients on the AD spectrum. Treatment group received 40Hz gamma sensory stimulation daily at home for six months, whereas placebo group received sham stimulation. Structural MRI was obtained at baseline, month 3 and month 6 visits using 1.5 Tesla scanner. FreeSurfer was used to process T1 MRI including entorhinal parcellation and cortical reconstructions for 38 participants (66% Treatment, 34% Placebo). For each vertex, WM signal intensity (WMI) is sampled at 1mm below, and GM signal intensity (GMI) is sampled at 30% of cortical thickness above the WM/GM border. WM/GM contrast was calculated as 100*(WMI–GMI)/(0.5*(WMI+GMI)) %. Bayesian linear mixed effects modeling was used to model changes in WM/GM contrast in the entorhinal region.ResultFollowing 6 months of treatment, we observed that the treatment group demonstrated 0.06±0.99% decrease and the placebo group demonstrated 1.26±1.04% decrease in WM/GM contrast (p&lt;0.022).ConclusionWe found that six months of 40Hz gamma sensory therapy reduced the decline in WM/GM contrast in the entorhinal region. Since WM/GM contrast is associated with AD severity, and the entorhinal region is of particular interest in the early stages of AD, early intervention of the therapy may result in enhanced tissue preservation and reduced neurological damage.

Serum biomarkers and disease progression in CT-negative mild traumatic brain injury.

Blood proteins are emerging as potential biomarkers for mild traumatic brain injury (mTBI). Molecular pathology of mTBI underscores the critical roles of neuronal injury, neuroinflammation, and vascular health in disease progression. However, the temporal profile of blood biomarkers associated with the aforementioned molecular pathology after CT-negative mTBI, their diagnostic and prognostic potential, and their utility in monitoring white matter integrity and progressive brain atrophy remain unclear. Thus, we investigated serum biomarkers and neuroimaging in a longitudinal cohort, including 103 CT-negative mTBI patients and 66 matched healthy controls (HCs). Angiogenic biomarker vascular endothelial growth factor (VEGF) exhibited the highest area under the curve of 0.88 in identifying patients from HCs. Inflammatory biomarker interleukin-1β and neuronal cell body injury biomarker ubiquitin carboxyl-terminal hydrolase L1 were elevated in acute-stage patients and associated with deterioration of cognitive function from acute-stage to 6-12mo post-injury period. Notably, axonal injury biomarker neurofilament light (NfL) was elevated in acute-stage patients, with higher levels associated with impaired white matter integrity in acute-stage and progressive gray and white matter atrophy from 3- to 6-12mo post-injury period. Collectively, our findings emphasized the potential clinical value of serum biomarkers, particularly NfL and VEGF, in diagnosing mTBI and monitoring disease progression.

Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer's Disease.

Alzheimer's disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized. Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI). Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios. Montreal Cognitive Assessment scores (p < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons.

Shared and Distinct Associations of Manual Dexterity and Gross Motor Function With Brain Atrophy.

Poor motor function is associated with brain atrophy and cognitive impairment. Less is known about the relationship between motor domains and brain atrophy and whether associations are affected by cerebrovascular burden and/or physical activity. We analyzed data from 726 Baltimore Longitudinal Study of Aging participants (mean age 70.6 ± 10.1 years, 56% women, 27% Black), 525 of whom had repeat MRI scans over an average of 5.0 ± 2.1 years. Two motor domains, manual dexterity and gross motor, were operationalized as latent variables. Associations between the latent variables and cortical and subcortical brain volumes of interest were examined using latent growth curve modeling, adjusted for demographics, white matter hyperintensities, and physical activity. Both higher manual dexterity and gross motor function were cross-sectionally associated with smaller ventricular volume and greater white matter volumes in the frontal, parietal, and temporal lobes (all p < .05). Manual dexterity was also cross-sectionally associated with parietal gray matter (B = 0.14; 95% CI: 0.05, 0.23), hippocampus (B = 0.10; 95% CI: 0.01, 0.20), postcentral gyrus (B = 0.11; 95% CI: 0.01, 0.20), and occipital white matter (B = 0.10; 95% CI: 0.01, 0.21) volumes, and gross motor function with temporal gray matter volume (B = 0.16; 95% CI: 0.05, 0.26). Longitudinally, both higher manual dexterity and gross motor function were associated with less temporal white matter and occipital gray matter atrophy (all p < .05). Manual dexterity was also associated with a slower rate of ventricular enlargement (B = -0.17; 95% CI: -0.29, -0.05) and less atrophy of occipital white matter (B = 0.39; 95% CI: 0.04, 0.71). Among cognitively normal middle- and older-aged adults, manual dexterity and gross motor function exhibited shared as well as distinct associations with brain atrophy over time.

P01.09.A THE NEUROCOGNITIVE FUNCTIONING OF LOWER GRADE GLIOMA PATIENTS BEFORE START OF RADIOTHERAPY IS ASSOCIATED WITH THE RADIOLOGICAL APPEARANCE OF THE BRAIN

Abstract BACKGROUND The cause for neurocognitive function (NCF) impairments in patients with lower grade glioma (LGG) is typically multifactorial. The aim of this study was to explore the relationship between NCF and the radiological appearance of the brain before start of radiotherapy (RT) in LGG patients. MATERIAL AND METHODS Around start of RT we evaluated NCF of LGG patients treated with proton therapy. The assessment included 10 neuropsychological tests with 20 measures that could be categorized over 6 cognitive domains. Raw test scores were converted to Z scores based on normative data. Mild cognitive impairment (MCI) was defined as a Z score of less than -2 on a single measure, or Z score of less than -1.5 on multiple measures. An impaired cognitive domain was defined as a mean composite Z score of less than -1.5. The radiological appearance of the brain outside the tumor region was assessed on a pre-RT planning MRI using the Fazekas score and Global Cortical Atrophy (GCA) score. For statistical analysis we used Chi Square tests and Mann-Whitney U tests. RESULTS Between 2018 and March 2022, 126 LGG patients started RT treatment, 119 patients (94%) had NCF assessment pre-RT and were available for analysis. Median age was 41 years, 51% of patients was male, reported comorbidities included hypertension in 7%, diabetes mellitus in 3% and cardiovascular 13% of patients. The World Health Organization (WHO) performance scores and the Neurologic Assessment in Neuro-Oncology (NANO) scores were 0 - 1, in 98%, and 92% of patients. The Fazekas score was 0 in 75%, 1 in 18% and 2 in 6% and 3 in 2% of patients. The GCA score was 0 in 59%, 1 in 38%, 2 in 3% of patients. In 77 (65%) patients the performance on the NCF assessment indicated the presence of MCI. Patients with MCI had a significant radiologically worse appearance of the brain (Fazekas score 1 or higher 31.2% versus 14.3%, p = 0.043; and GCA score 1 or higher 49.4% versus 26.2%, p = 0.014). Domain impairments were present in executive functions and attention (26%); verbal memory (23%); verbal functions (20%); non-verbal memory (20%); processing speed (18%); and working memory (14%). Fazekas score 1 or higher was significantly associated with lower composite Z scores of verbal functions (median (IQR) -0.84 (1.12) versus -0.40 (0.94), p=0.014); verbal memory (median (IQR) -0.66 (1.26) versus -0.20 (1.35), p=0.045) and non-verbal memory (median (IQR) -0.45 (2.10) versus -0.20 (1.36), p=0.037). There were no significant associations found between the GCA score and domain composite scores. CONCLUSION This cohort of LGG patients had a good clinical and neurological baseline function pre-RT. We found significant relationships between NCF and both white matter damage and atrophy of the brain. The Fazekas and GCA score are objective and easily obtained radiological measures, that could be a relevant parameter to record in LGG patients.

Higher longitudinal brain white matter atrophy rate in aquaporin-4 IgG-positive NMOSD compared with healthy controls

We aimed to compare longitudinal brain atrophy in patients with neuromyelitis optica spectrum disorder (NMOSD) with healthy controls (HCs). The atrophy rate in patients with anti-aquaporin-4 antibody-positive NMOSD (AQP4 + NMOSD) was compared with age-sex-matched HCs recruited from the Japanese Alzheimer’s Disease Neuroimaging Initiative study and another study performed at Chiba University. Twenty-nine patients with AQP4 + NMOSD and 29 HCs were enrolled in the study. The time between magnetic resonance imaging (MRI) scans was longer in the AQP4 + NMOSD group compared with the HCs (median; 3.2 vs. 2.9 years, P = 0.009). The annualized normalized white matter volume (NWV) atrophy rate was higher in the AQP4 + NMOSD group compared with the HCs (median; 0.37 vs. − 0.14, P = 0.018). The maximum spinal cord lesion length negatively correlated with NWV at baseline MRI in patients with AQP4 + NMOSD (Spearman’s rho = − 0.41, P = 0.027). The annualized NWV atrophy rate negatively correlated with the time between initiation of persistent prednisolone usage and baseline MRI in patients with AQP4 + NMOSD (Spearman’s rho = − 0.43, P = 0.019). Patients with AQP4 + NMOSD had a greater annualized NWV atrophy rate than HCs. Suppressing disease activity may prevent brain atrophy in patients with AQP4 + NMOSD.