In vivo microstructural heterogeneity of white matter and cognitive correlates in aging using tissue compositional analysis of diffusion magnetic resonance imaging.

BACKGROUND: Age-related cognitive decline is linked to changes in the brain, particularly the deterioration of white matter (WM) microstructure that accelerates after the age of 60. WM deterioration is associated with mild cognitive impairment and dementia, but the origin and role of white matter signal abnormalities (WMSA) seen in standard MRI remain debated due to their heterogeneity. This study explores the potential of single-shell 3-tissue constrained spherical deconvolution (SS3T-CSD), a novel technique that models diffusion data in terms of gray matter (TG ), white matter (Tw ), and cerebrospinal fluid (TC ), to differentiate WMSA from normal-appearing white matter and better understand the interplay between changes in WM microstructure and decline in cognition. METHODS: A total of 189 individuals from the GENIC cohort were included. MRI data, including T1-weighted and diffusion images, were obtained. Preprocessing steps were performed on the diffusion MRI data, followed by the SS3T-CSD. WMSA were segmented using FreeSurfer. Statistical analyses were conducted to assess the association between age, WMSA volume, 3-tissue signal fractions (Tw , TG , and TC ), and neuropsychological variables. RESULTS: Participants above 60 years old showed worse cognitive performance and processing speed compared to those below 60 (p < .001). Age was negatively associated with Tw in normal-appearing white matter (p < .001) and positively associated with TG in both WMSA (p < .01) and normal-appearing white matter (p < .001). Age was also significantly associated with WMSA volume (p < .001). Higher processing speed was associated with lower Tw and higher TG , in normal-appearing white matter (p < .01 and p < .001, respectively), as well as increased WMSA volume (p < .001). Similarly, lower MMSE scores correlated with lower Tw and higher TG in normal-appearing white matter (p < .05). High cholesterol and hypertension were associated with higher WMSA volume (p < .05). CONCLUSION: The microstructural heterogeneity within normal-appearing white matter and WMSA is associated with increasing age and cognitive variation, in cognitively unimpaired individuals. Furthermore, the 3-tissue signal fractions are more specific to potential white matter alterations than conventional MRI measures such as WMSA volume. These findings also support the view that the WMSA volumes may be more influenced by vascular risk factors than the 3-tissue metrics. Finally, the 3-tissue metrics were able to capture associations with cognitive tests and therefore capable of capturing subtle pathological changes in the brain in individuals who are still within the normal range of cognitive performance.

Vascular cognitive impairment - Past, present, and future challenges.

Vascular cognitive impairment (VCI) is a lifelong process encompassing a broad spectrum of cognitive disorders, ranging from subtle or mild deficits to prodromal and fully developed dementia, originating from cerebrovascular lesions such as large and small vessel disease. Genetic predisposition and environmental exposure to risk factors such as unhealthy lifestyles, hypertension, cardiovascular disease, and metabolic disorders will synergistically interact, yielding biochemical and structural brain changes, ultimately culminating in VCI. However, little is known about the pathological processes underlying VCI and the temporal dynamics between risk factors and disease mechanisms (biochemical and structural brain changes). This narrative review aims to provide an evidence-based summary of the link between individual vascular risk/disorders and cognitive dysfunction and the potential structural and biochemical pathophysiological processes. We also discuss some key challenges for future research on VCI. There is a need to shift from individual risk factors/disorders to comorbid vascular burden, identifying and integrating imaging and fluid biomarkers, implementing a life-course approach, considering possible neuroprotective influences of positive life exposures, and addressing biological sex at birth and gender differences. Finally, this review highlights the need for future researchers to leverage and integrate multidimensional data to advance our understanding of the mechanisms and pathophysiology of VCI.

Endocannabinoid System Biomarkers in Alzheimer's Disease.

Background: Alterations in the endocannabinoid system (ES) have been described in Alzheimer's disease (AD) pathophysiology. In the past years, multiple ES biomarkers have been developed, promising to advance our understanding of ES changes in AD. Discussion: ES biomarkers, including positron emission tomography with cannabinoid receptors tracers and biofluid-based endocannabinoids, are associated with AD disease progression and pathological features. Conclusion: Although not specific enough for AD diagnosis, ES biomarkers hold promise for prognosis, drug-target engagement, and a better understanding of the disease. Here, we summarize currently available ES biomarker findings and discuss their potential applications in the AD research field.

Cerebrovascular damage in subjective cognitive decline: A systematic review and meta-analysis.

BACKGROUND: Subjective cognitive decline (SCD) has been postulated as an early marker of Alzheimer's Disease (AD) but it can also be associated to other non-AD pathologies such as Vascular Dementia (VaD). Nevertheless, there is scarce data about SCD as a potential harbinger of cerebrovascular pathology. Thus, we conducted a systematic review and meta-analysis on the association between SCD and cerebrovascular damage measured by neuroimaging markers. METHOD: This study was performed following the PRISMA guidelines. The search was conducted in 3 databases (PubMed, Scopus and Web of Science) from origin to December 8th, 2021. Primary studies including cognitively unimpaired adults with SCD and neuroimaging markers of cerebrovascular damage (i.e., white matter signal abnormalities, WMSA) were selected. Qualitative synthesis and meta-analysis of studies with a case-control design was performed. RESULTS: Of 241 articles identified, 21 research articles were selected. Eight case-control studies were included for the meta-analysis. A significant overall effect-size was observed for the mean WMSA burden in SCD relative to controls, where the WMSA burden was higher in SCD. CONCLUSION: Our findings show the potential usefulness of SCD as a harbinger of cerebrovascular disease in cognitively healthy individuals. Further research is needed in order to elucidate the role of SCD as a preclinical marker of vascular cognitive impairment.

Relationship Between Arterial Stiffness Index, Pulse Pressure, and Magnetic Resonance Imaging Markers of White Matter Integrity: A UK Biobank Study.

Background: Alzheimer's disease and dementia in general constitute one of the major public health problems of the 21st century. Research in arterial stiffness and pulse pressure (PP) play an important role in the quest to reduce the risk of developing dementia through controlling modifiable risk factors. Objective: The aim of the study is to investigate the association between peripheral PP, arterial stiffness index (ASI) and brain integrity, and to discover if ASI is a better predictor of white matter integrity than peripheral PP. Materials and Methods: 17,984 participants 63.09 ± 7.31 from the UK Biobank were used for this study. ASI was estimated using infrared light (photoplethysmography) and peripheral PP was calculated by subtracting the diastolic from the systolic brachial blood pressure value. Measure of fractional anisotropy (FA) was obtained from diffusion imaging to estimate white matter microstructural integrity. White matter hyperintensities were segmented from the combined T1 and T2-weighted FLAIR images as a measure of irreversible white matter damage. Results: An important finding is that peripheral PP better predicts white matter integrity when compared to ASI. This finding is consistent until 75 years old. Interestingly, no significant relationship is found between either peripheral PP or ASI and white matter integrity after 75 years old. Conclusion: These results suggest that ASI from plethysmography should not be used to estimate cerebrovascular integrity in older adults and further question the relationship between arterial stiffness, blood pressure, and white matter damage after the age of 75 years old.

Arterial stiffness and age moderate the association between physical activity and global cognition in older adults.

BACKGROUND: Evidence supports that time spent on physical activity has beneficial effects on cognition in older adults. Nevertheless, whether these beneficial effects are still present at the intersection of different levels of arterial stiffness and age is uncertain. METHODS: One hundred and ten healthy older adults aged 60-75 years were examined for arterial stiffness [carotid-femoral pulse wave velocity (cf-PWV)], global cognition (composite score of Montreal Cognitive Assessment, and Mini-Mental State Examination), and self-reported physical activity (PACED diary). Using PROCESS macro for SPSS, we evaluated if cf-PWV (moderator 1), and age (moderator 2) moderate the relationship between physical activity (X) and global cognition (Y). The threshold for high stiffness was set at 8.5 m/s based on previous studies that reported this cut-off as more appropriate for classifying cerebrovascular risk groups. RESULTS: Physical activity had a positive effect on cognition in young-elderly adults (<68.5 years) with a cf-PWV of at least 8.5 m/s (ß = 0.48, SE = 0.193, P = 0.014, 95% CI = 0.100--0.868) and in elderly adults (≥68.5 years) with a cf-PWV of less than 8.5 m/s (ß = 0.56, SE = 0.230, P = 0.017, 95% CI = 0.104-1.018). This was not the case in elderly adults with a cf-PWV of at least 8.5 m/s (ß = 0.00, SE = 0.193, P = 0.998, 95% CI = -0.362 to 361), or in young-elderly adults with a cf-PWV of less than 8.5 m/s (ß = 0.16, SE = 0.247, P = 0.501, 95% CI = -0.326 to 656). CONCLUSION: The interaction between arterial stiffness and age moderated the effect of physical activity on global cognition. Time spent on physical activity alone might not be sufficient to achieve cognitive benefit over a specific threshold of arterial stiffness and age.

Demographic and Clinical Characteristics of Individuals with Mild Cognitive Impairment Related to Grade of Alcohol Consumption.

INTRODUCTION: While alcohol overconsumption is regarded as a risk factor for Alzheimer's disease, the specific relationship between alcohol consumption and cognitive impairment remains unclear and poorly understood. Our primary objective is to investigate whether alcohol consumption is associated with lower cognitive performance at an early phase of the development of cognitive impairment (mild cognitive impairment [MCI] stage) and second to present the clinical and demographic characteristics depending on the grade of alcohol consumption. METHODS: This is a cross-sectional observational study, including 251 subjects with the diagnosis MCI, having caregiving contact with Memory Clinic, Karolinska University Hospital, under year 2015. We compared subgroups with different levels of alcohol consumption, concerning social parameters, cognitive, radiological, laboratory profile as well as comorbidities and burden of drugs. RESULTS: Mini-mental State Examination score was not associated with alcohol consumption. Light to moderate drinkers were significantly higher educated. There were significantly more subjects using antianxiety medications among heavy drinkers in comparison with light to moderate drinkers. Finally, never/rare drinkers had significantly lower levels of erythrocyte mean corpuscular volume in their blood tests. DISCUSSION/CONCLUSION: Alcohol consumption was not correlated with a more pronounced cognitive deficit or a distinct clinical severity at an early stage of cognitive impairment apart from higher usage of antianxiety medications. We are planning to follow up all individuals to ascertain if heavy drinkers have a different outcome compared with the other groups.

Associations Between Relative Morning Blood Pressure, Cerebral Blood Flow, and Memory in Older Adults Treated and Controlled for Hypertension.

[Figure: see text].

Cerebrospinal Fluid Biomarkers, Brain Structural and Cognitive Performances Between Normotensive and Hypertensive Controlled, Uncontrolled and Untreated 70-Year-Old Adults.

Background: Hypertension is an important risk factor for Alzheimer's disease (AD). The pathophysiological mechanisms underlying the relationship between AD and hypertension are not fully understood, but they most likely involve microvascular dysfunction and cerebrovascular pathology. Although previous studies have assessed the impact of hypertension on different markers of brain integrity, no study has yet provided a comprehensive comparison of cerebrospinal fluid (CSF) biomarkers and structural brain differences between normotensive and hypertensive groups in a single and large cohort of older adults in relationship to cognitive performances. Objective: The aim of the present work was to investigate the differences in cognitive performances, CSF biomarkers and magnetic resonance imaging (MRI) of brain structure between normotensive, controlled hypertensive, uncontrolled hypertensive, and untreated hypertensive older adults from the Gothenburg H70 Birth Cohort Studies. Methods: As an indicator of vascular brain pathology, we measured white matter hyperintensities (WMHs), lacunes, cerebral microbleeds, enlarged perivascular space (epvs), and fractional anisotropy (FA). To assess markers of AD pathology/neurodegeneration, we measured hippocampal volume, temporal cortical thickness on MRI, and amyloid-ß42, phosphorylated tau, and neurofilament light protein (NfL) in cerebrospinal fluid. Various neuropsychological tests were used to assess performances in memory, attention/processing speed, executive function, verbal fluency, and visuospatial abilities. Results: We found more white matter pathology in hypertensive compared to normotensive participants, with the highest vascular burden in uncontrolled participants (e.g., lower FA, more WMHs, and epvs). No significant difference was found in any MRI or CSF markers of AD pathology/neurodegeneration when comparing normotensive and hypertensive participants, nor among hypertensive groups. No significant difference was found in most cognitive functions between groups. Conclusion: Our results suggest that good blood pressure control may help prevent cerebrovascular pathology. In addition, hypertension may contribute to cognitive decline through its effect on cerebrovascular pathology rather than AD-related pathology. These findings suggest that hypertension is associated with MRI markers of vascular pathology in the absence of a significant decline in cognitive functions.

Cerebrovascular pathology in Alzheimer's disease: Hopes and gaps.

Alzheimer's disease (AD) is recognized as multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. Given that a revision of the AT(N) classification is expected in the near future, the present work supports the importance to add an additional vascular (V) category to the framework. In particular, we attempt to shed light on the vascular markers and risk factors that are currently ready-to-be-added to the framework: i) lacunes, ii) white matter hyperintensities and iii) microbleeds seen in Flair, T2* weighted imaging and susceptibility images (SWI). Next, we discuss the added value of other types of imaging, such as diffusion-based metrics and advanced perfusion sequences to encompass more subtle vascular dysfunction. Finally, we highlight the importance to add information about the following cardiovascular risk factors to the framework: history of hypertension, obesity, and diabetes. We believe that adding a V category to the AT(N) framework will improve AD classification and foster efforts to apply the right drug(s) at the right time in the right AD subgroups. Brief communication The present work supports the importance to add an additional vascular (V) category to the AT(N) framework and shed light on the vascular MRI markers and risk factors that are currently ready-to-be-added to the framework.

A Cross-Sectional Study on the Impact of Arterial Stiffness on the Corpus Callosum, a Key White Matter Tract Implicated in Alzheimer's Disease.

BACKGROUND: Vascular risk factors such as arterial stiffness play an important role in the etiology of Alzheimer's disease (AD), presumably due to the emergence of white matter lesions. However, the impact of arterial stiffness to white matter structure involved in the etiology of AD, including the corpus callosum remains poorly understood. OBJECTIVE: The aims of the study are to better understand the relationship between arterial stiffness, white matter microstructure, and perfusion of the corpus callosum in older adults. METHODS: Arterial stiffness was estimated using the gold standard measure of carotid-femoral pulse wave velocity (cfPWV). Cognitive performance was evaluated with the Trail Making Test part B-A. Neurite orientation dispersion and density imaging was used to obtain microstructural information such as neurite density and extracellular water diffusion. The cerebral blood flow was estimated using arterial spin labelling. RESULTS: cfPWV better predicts the microstructural integrity of the corpus callosum when compared with other index of vascular aging (the augmentation index, the systolic blood pressure, and the pulse pressure). In particular, significant associations were found between the cfPWV, an alteration of the extracellular water diffusion, and a neuronal density increase in the body of the corpus callosum which was also correlated with the performance in cognitive flexibility. CONCLUSION: Our results suggest that arterial stiffness is associated with an alteration of brain integrity which impacts cognitive function in older adults.

Multiple sclerosis lesions in motor tracts from brain to cervical cord: spatial distribution and correlation with disability.

Despite important efforts to solve the clinico-radiological paradox, correlation between lesion load and physical disability in patients with multiple sclerosis remains modest. One hypothesis could be that lesion location in corticospinal tracts plays a key role in explaining motor impairment. In this study, we describe the distribution of lesions along the corticospinal tracts from the cortex to the cervical spinal cord in patients with various disease phenotypes and disability status. We also assess the link between lesion load and location within corticospinal tracts, and disability at baseline and 2-year follow-up. We retrospectively included 290 patients (22 clinically isolated syndrome, 198 relapsing remitting, 39 secondary progressive, 31 primary progressive multiple sclerosis) from eight sites. Lesions were segmented on both brain (T2-FLAIR or T2-weighted) and cervical (axial T2- or T2*-weighted) MRI scans. Data were processed using an automated and publicly available pipeline. Brain, brainstem and spinal cord portions of the corticospinal tracts were identified using probabilistic atlases to measure the lesion volume fraction. Lesion frequency maps were produced for each phenotype and disability scores assessed with Expanded Disability Status Scale score and pyramidal functional system score. Results show that lesions were not homogeneously distributed along the corticospinal tracts, with the highest lesion frequency in the corona radiata and between C2 and C4 vertebral levels. The lesion volume fraction in the corticospinal tracts was higher in secondary and primary progressive patients (mean = 3.6 ± 2.7% and 2.9 ± 2.4%), compared to relapsing-remitting patients (1.6 ± 2.1%, both P < 0.0001). Voxel-wise analyses confirmed that lesion frequency was higher in progressive compared to relapsing-remitting patients, with significant bilateral clusters in the spinal cord corticospinal tracts (P < 0.01). The baseline Expanded Disability Status Scale score was associated with lesion volume fraction within the brain (r = 0.31, P < 0.0001), brainstem (r = 0.45, P < 0.0001) and spinal cord (r = 0.57, P < 0.0001) corticospinal tracts. The spinal cord corticospinal tracts lesion volume fraction remained the strongest factor in the multiple linear regression model, independently from cord atrophy. Baseline spinal cord corticospinal tracts lesion volume fraction was also associated with disability progression at 2-year follow-up (P = 0.003). Our results suggest a cumulative effect of lesions within the corticospinal tracts along the brain, brainstem and spinal cord portions to explain physical disability in multiple sclerosis patients, with a predominant impact of intramedullary lesions.

Arterial stiffness cut-off value and white matter integrity in the elderly.

OBJECTIVE: Central artery stiffness is a confirmed predictor of cardiovascular health status that has been consistently associated with cognitive dysfunction and dementia. The European Society of Hypertension has established a threshold of arterial stiffness above which a cardiovascular event is likely to occur. However, the threshold at which arterial stiffness alters brain integrity has never been established. METHODS: The aim of this study is to determine the arterial stiffness cut-off value at which there is an impact on the white matter microstructure. This study has been conducted with 53 cognitively elderly without dementia. The integrity of the white matter was assessed using diffusion tensor metrics. Central artery stiffness was evaluated by measuring the carotid-femoral pulse wave velocity (cfPWV). The statistical analyses included 4 regions previously denoted vulnerable to increased central arterial stiffness (the corpus callosum, the internal capsule, the corona radiata and the superior longitudinal fasciculus). RESULTS: The results of this study call into question the threshold value of 10 m/s cfPWV established by the European Society of Hypertension to classify patients in neuro-cardiovascular risk groups. Our results suggest that the cfPWV threshold value would be approximately 8.5 m/s when the microstructure of the white matter is taken as a basis for comparison. CONCLUSIONS: Adjustment of the cfPWV value may be necessary for a more accurate distinction between lower and higher risk group of patients for white matter microstructural injury related to arterial stiffness. Targeting the highest risk group for prevention methods may, in turn, help preserve brain health and cognitive functions.

Diurnal blood pressure loads are associated with lower cognitive performances in controlled-hypertensive elderly individuals.

INTRODUCTION: Hypertension in midlife adults is associated with cognitive decline later in life. In individuals treated for hypertension, blood pressure (BP) loads have been associated with end organ damages. This study examines whether BP load inversely correlates with performance in cognitive tasks in normotensive or controlled hypertensive (CHT) individuals. METHODS: Participants between 60 and 75 years old were divided into normotensive participants who did not receive antihypertensive treatment (n = 49) and CHT patients (n = 28). They were evaluated for BP using ambulatory blood pressure monitoring and cognitive functions with tests assessing cognitive flexibility, working and episodic memory, and processing speed. RESULTS: Analysis of covariance between normotensive and CHT participants revealed lower cognitive performances on immediate and delayed recall and total number of words of the Rey Auditory Verbal Learning Test (P < 0.001). Spearman's correlations between BP loads and cognitive performances revealed inversed associations between diurnal systolic (SBP) loads and performances on the Trail Making Test Part B (TMTB) (P = 0.009), the TMTB-TMT Part A (P = 0.013), the Switching Cost of the color-word interference test (P = 0.020) and the Digit-Symbol Substitution Score tests (P = 0.018) in CHT. Diurnal diastolic (DBP) loads were inversely correlated to the TMTB (P = 0.014) and TMTB-TMT Part A (P = 0.006). In normotensive subjects, diurnal SBP loads were associated with the delayed recall of the Rey Auditory Verbal Learning Test (P = 0.031) and to the three components of the digit span (P < 0.05). CONCLUSION: Diurnal BP loads are associated with lower cognitive performances in CHT individuals. These results suggest a lowering of target levels of diurnal BPs and/or its variability.

Arterial stiffness and brain integrity: A review of MRI findings.

BACKGROUND: Given the increasing incidence of vascular diseases and dementia, a better understanding of the cerebrovascular changes induced by arterial stiffness is important for early identification of white and gray matter abnormalities that might antedate the appearance of clinical cognitive symptoms. Here, we review the evidence from neuroimaging demonstrating the impact of arterial stiffness on the aging brain. METHOD: This review presents findings from recent studies examining the association between arterial stiffness, cognitive function, cerebral hypoperfusion, and markers of neuronal fiber integrity using a variety of MRI techniques. RESULTS: Overall, changes associated with arterial stiffness indicates that the corpus callosum, the internal capsule and the corona radiata may be the most vulnerable regions to microvascular damage. In addition, the microstructural integrity of these regions appears to be associated with cognitive performance. Changes in gray matter structure have also been found to be associated with arterial stiffness and are present as early as the 5th decade. Moreover, low cerebral perfusion has been associated with arterial stiffness as well as lower cognitive performance in age-sensitive tasks such as executive function. CONCLUSION: Considering the established relationship between arterial stiffness, brain and cognition, this review highlights the need for future studies of brain structure and function in aging to implement measurements of arterial stiffness in parallel with quantitative imaging.

Spatial distribution of multiple sclerosis lesions in the cervical spinal cord.

Spinal cord lesions detected on MRI hold important diagnostic and prognostic value for multiple sclerosis. Previous attempts to correlate lesion burden with clinical status have had limited success, however, suggesting that lesion location may be a contributor. Our aim was to explore the spatial distribution of multiple sclerosis lesions in the cervical spinal cord, with respect to clinical status. We included 642 suspected or confirmed multiple sclerosis patients (31 clinically isolated syndrome, and 416 relapsing-remitting, 84 secondary progressive, and 73 primary progressive multiple sclerosis) from 13 clinical sites. Cervical spine lesions were manually delineated on T2- and T2*-weighted axial and sagittal MRI scans acquired at 3 or 7 T. With an automatic publicly-available analysis pipeline we produced voxelwise lesion frequency maps to identify predilection sites in various patient groups characterized by clinical subtype, Expanded Disability Status Scale score and disease duration. We also measured absolute and normalized lesion volumes in several regions of interest using an atlas-based approach, and evaluated differences within and between groups. The lateral funiculi were more frequently affected by lesions in progressive subtypes than in relapsing in voxelwise analysis (P < 0.001), which was further confirmed by absolute and normalized lesion volumes (P < 0.01). The central cord area was more often affected by lesions in primary progressive than relapse-remitting patients (P < 0.001). Between white and grey matter, the absolute lesion volume in the white matter was greater than in the grey matter in all phenotypes (P < 0.001); however when normalizing by each region, normalized lesion volumes were comparable between white and grey matter in primary progressive patients. Lesions appearing in the lateral funiculi and central cord area were significantly correlated with Expanded Disability Status Scale score (P < 0.001). High lesion frequencies were observed in patients with a more aggressive disease course, rather than long disease duration. Lesions located in the lateral funiculi and central cord area of the cervical spine may influence clinical status in multiple sclerosis. This work shows the added value of cervical spine lesions, and provides an avenue for evaluating the distribution of spinal cord lesions in various patient groups.

Focal and diffuse cervical spinal cord damage in patients with early relapsing-remitting MS: A multicentre magnetisation transfer ratio study.

BACKGROUND: Studies including patients with well-established multiple sclerosis (MS) have shown a significant and disability-related reduction in the cervical spinal cord (SC) magnetisation transfer ratio (MTR). OBJECTIVES: The objectives are to (1) assess whether MTR reduction is already measurable in the SC of patients with early relapsing-remitting multiple sclerosis (RRMS) and (2) describe its spatial distribution. METHODS: We included 60 patients with RRMS <12 months and 34 age-matched controls at five centres. Axial T2*w, sagittal T2w, sagittal phase-sensitive inversion recovery (PSIR), 3DT1w, and axial magnetisation transfer (MT) images were acquired from C1 to C7. Lesions were manually labelled and mean MTR values computed both for the whole SC and for normal-appearing SC in different regions of interest. RESULTS: Mean whole SC MTR was significantly lower in patients than controls (33.7 vs 34.9 pu, p = 0.00005), even after excluding lesions (33.9 pu, p = 0.0003). We observed a greater mean reduction in MTR for vertebral levels displaying the highest lesion loads (C2-C4). In the axial plane, we observed a greater mean MTR reduction at the SC periphery and barycentre. CONCLUSION: Cervical SC tissue damage measured using MTR is not restricted to macroscopic lesions in patients with early RRMS and is not homogeneously distributed.

Automatic segmentation of the spinal cord and intramedullary multiple sclerosis lesions with convolutional neural networks.

The spinal cord is frequently affected by atrophy and/or lesions in multiple sclerosis (MS) patients. Segmentation of the spinal cord and lesions from MRI data provides measures of damage, which are key criteria for the diagnosis, prognosis, and longitudinal monitoring in MS. Automating this operation eliminates inter-rater variability and increases the efficiency of large-throughput analysis pipelines. Robust and reliable segmentation across multi-site spinal cord data is challenging because of the large variability related to acquisition parameters and image artifacts. In particular, a precise delineation of lesions is hindered by a broad heterogeneity of lesion contrast, size, location, and shape. The goal of this study was to develop a fully-automatic framework - robust to variability in both image parameters and clinical condition - for segmentation of the spinal cord and intramedullary MS lesions from conventional MRI data of MS and non-MS cases. Scans of 1042 subjects (459 healthy controls, 471 MS patients, and 112 with other spinal pathologies) were included in this multi-site study (n = 30). Data spanned three contrasts (T1-, T2-, and T2∗-weighted) for a total of 1943 vol and featured large heterogeneity in terms of resolution, orientation, coverage, and clinical conditions. The proposed cord and lesion automatic segmentation approach is based on a sequence of two Convolutional Neural Networks (CNNs). To deal with the very small proportion of spinal cord and/or lesion voxels compared to the rest of the volume, a first CNN with 2D dilated convolutions detects the spinal cord centerline, followed by a second CNN with 3D convolutions that segments the spinal cord and/or lesions. CNNs were trained independently with the Dice loss. When compared against manual segmentation, our CNN-based approach showed a median Dice of 95% vs. 88% for PropSeg (p ≤ 0.05), a state-of-the-art spinal cord segmentation method. Regarding lesion segmentation on MS data, our framework provided a Dice of 60%, a relative volume difference of -15%, and a lesion-wise detection sensitivity and precision of 83% and 77%, respectively. In this study, we introduce a robust method to segment the spinal cord and intramedullary MS lesions on a variety of MRI contrasts. The proposed framework is open-source and readily available in the Spinal Cord Toolbox.

Arterial stiffness and white matter integrity in the elderly: A diffusion tensor and magnetization transfer imaging study.

BACKGROUND AND PURPOSE: The stiffness of large arteries and increased pulsatility can have an impact on the brain white matter (WM) microstructure, however those mechanisms are still poorly understood. The aim of this study was to investigate the association between central artery stiffness, axonal and myelin integrity in 54 cognitively unimpaired elderly subjects (65-75 years old). METHODS: The neuronal fiber integrity of brain WM was assessed using diffusion tensor metrics and magnetization transfer imaging as measures of axonal organization (Fractional anisotropy, Radial diffusivity) and state of myelination (Myelin volume fraction). Central artery stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). Statistical analyses included 4 regions (the corpus callosum, the internal capsule, the corona radiata and the superior longitudinal fasciculus) which have been previously denoted as vulnerable to increased central artery stiffness. RESULTS: cfPWV was significantly associated with fractional anisotropy and radial diffusivity (p < 0.05, corrected for multiple comparisons) but not with myelin volume fraction. Findings from this study also show that improved executive function performance correlates with Fractional anisotropy positively (p < 0.05 corrected) as well as with myelin volume fraction and radial diffusivity negatively (p < 0.05 corrected). CONCLUSIONS: These findings suggest that arterial stiffness is associated with axon degeneration rather than demyelination. Controlling arterial stiffness may play a role in maintaining the health of WM axons in the aging brain.

Changes in structural network are associated with cortical demyelination in early multiple sclerosis.

The aim of this study was to investigate the interplay between structural connectivity and cortical demyelination in early multiple sclerosis. About 27 multiple sclerosis patients and 18 age-matched controls underwent two MRI scanning sessions. The first was done at 7T and involved acquiring quantitative T1 and T2 * high-resolution maps to estimate cortical myelination. The second was done on a Connectom scanner and consisted of acquiring high angular resolution diffusion-weighted images to compute white matter structural connectivity metrics: strength, clustering and local efficiency. To further investigate the interplay between structural connectivity and cortical demyelination, patients were divided into four groups according to disease-duration: 0-1 year, 1-2 years, 2-3 years, and >3 years. ANOVA and Spearman's correlations were used to highlight relations between metrics. ANOVA detected a significant effect between disease duration and both cortical myelin (p = 2 × 10-8 ) and connectivity metrics (p < 10-4 ). We observed significant cortical myelin loss in the shorter disease-duration cohorts (0-1 year, p = .0015), and an increase in connectivity in the longer disease-duration cohort (2-3 years, strength: p = .01, local efficiency: p = .002, clustering: p = .001). Moreover, significant covariations between myelin estimation and white matter connectivity metrics were observed: Spearman's Rho correlation coefficients of 0.52 (p = .0003), 0.55 (p = .0001), and 0.53 (p = .0001) for strength, local efficiency, and clustering, respectively. An association between cortical myelin loss and changes in white matter connectivity in early multiple sclerosis was detected. These changes in network organization might be the result of compensatory mechanisms in response to the ongoing cortical diffuse damage in the early stages of multiple sclerosis.