FLAIR Hyperintensities in the Anterior Part of the Callosal Splenium in the Elderly Population: A Large Cohort Study.

RATIONALE AND OBJECTIVES: Although hyperintensity in the anterior portion of the callosal splenium on FLAIR (aCS-hyperintensity) is a common finding in elderly adults, no previous studies have examined the clinical significance. In this large elderly population study, we aimed to investigate the associations of aCS-hyperintensity with vascular risk factors, cognitive decline, and other MRI measurements. MATERIALS AND METHODS: This cross-sectional study included 2110 participants (median age, 69 years; 61.1% females) who underwent 3 T MRI. The participants were grouped as 215 with mild cognitive impairment (MCI) and 1895 cognitively normal older adults (NOAs). Two neuroradiologists evaluated aCS-hyperintensity by using a four-point scale (none, mild, moderate, and severe). Periventricular hyperintensities (PVHs) were also rated on a four-point scale according to the Fazekas scale. The total intracranial volume (ICV), total brain volume, choroid plexus volume (CPV), and lateral ventricle volume (LVV) were calculated. RESULTS: Logistic regression analysis showed diabetes was the main predictor of aCS-hyperintensity after adjusting for potential confounders (age, sex, hypertension, and hyperlipidemia) (p < 0.01), whereas PVH was associated with hypertension (p < 0.01). aCS-hyperintensity rated as "severe" was associated with a presence of MCI (p < 0.01). For the imaging factors, LVV was an independent predictor of aCS-hyperintensity when brain volume and PVH grade were added to the analysis (p < 0.01). CONCLUSION: Cerebral small vessel disease due to diabetes is a major contributor to the development of aCS-hyperintensity. Cerebrospinal fluid clearance failure may also relate to aCS-hyperintensity, which may offer new insights into the pathologic processes underlying MCI.

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

BACKGROUND: Enlargement 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. OBJECTIVES: To clarify the pathological significance of the enlargement of CP in multiple sclerosis (MS). METHODS: A 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. RESULTS: CP 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. CONCLUSION: CP 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.

A viewpoint on aldosterone and BMI related brain morphology in relation to treatment outcome in patients with major depression.

An abundance of knowledge has been collected describing the involvement of neuroendocrine parameters in major depression. The hypothalamic-pituitary-adrenocortical (HPA) axis regulating cortisol release has been extensively studied; however, attempts to target the HPA axis pharmacologically to treat major depression have failed. This review focuses on the importance of the adrenocortical stress hormone aldosterone, which is released by adrenocorticotropic hormone and angiotensin, and the mineralocorticoid receptor (MR) in depression. Depressed patients, in particular those with atypical depression, have signs of central hyperactivation of the aldosterone sensitive MR, potentially as a consequence of a reactive aldosterone release induced by low blood pressure and as a result of low sensitivity of peripheral MR. This is reflected in reduced heart rate variability, increased salt appetite and sleep changes in this group of patients. In addition, enlarged brain ventricles, compressed corpus callosum and changes of the choroid plexus are associated with increased aldosterone (in relation to cortisol). Furthermore, subjects with these features often show obesity. These characteristics are related to a worse antidepressant treatment outcome. Alterations in choroid plexus function as a consequence of increased aldosterone levels, autonomic dysregulation, metabolic changes and/or inflammation may be involved. The characterization of this regulatory system is in its early days but may identify new targets for therapeutic interventions.

Brain atrophy and lesion burden are associated with disability progression in a multiple sclerosis real-world dataset using only T2-FLAIR: The NeuroSTREAM MSBase study.

BACKGROUND: Methodological challenges limit the use of brain atrophy and lesion burden measures in the follow-up of multiple sclerosis (MS) patients on clinical routine datasets. OBJECTIVE: To determine the feasibility of T2-FLAIR-only measures of lateral ventricular volume (LVV) and salient central lesion volume (SCLV), as markers of disability progression (DP) in MS. METHODS: A total of 3,228 MS patients from 9 MSBase centers in 5 countries were enrolled. Of those, 2,875 (218 with clinically isolated syndrome, 2,231 with relapsing-remitting and 426 with progressive disease subtype) fulfilled inclusion and exclusion criteria. Patients were scanned on either 1.5 T or 3 T MRI scanners, and 5,750 brain scans were collected at index and on average after 42.3 months at post-index. Demographic and clinical data were collected from the MSBase registry. LVV and SCLV were measured on clinical routine T2-FLAIR images. RESULTS: Longitudinal LVV and SCLV analyses were successful in 96% of the scans. 57% of patients had scanner-related changes over the follow-up. After correcting for age, sex, disease duration, disability, disease-modifying therapy and LVV at index, and follow-up time, MS patients with DP (n = 671) had significantly greater absolute LVV change compared to stable (n = 1,501) or disability improved (DI, n = 248) MS patients (2.0 mL vs. 1.4 mL vs. 1.1 mL, respectively, ANCOVA p < 0.001, post-hoc pair-wise DP vs. Stable p = 0.003; and DP vs. DI, p = 0.002). Similar ANCOVA model was also significant for SCLV (p = 0.03). CONCLUSIONS: LVV-based atrophy and SCLV-based lesion outcomes are feasible on clinically acquired T2-FLAIR scans in a multicenter fashion and are associated with DP over mid-term.

Late onset multiple sclerosis is associated with more severe ventricle expansion.

BACKGROUND: Late-onset multiple sclerosis (LOMS) is associated with faster disability progression than persons with adult-onset MS (PwAOMS). The differences in brain atrophy are currently unknown. OBJECTIVES: To determine MRI-derived atrophy rates in persons with late-onset MS (PwLOMS) and compare them to an age-matched and disease duration-matched sample of PwAOMS. METHODS: 870 persons with MS (290 PwLOMS, 290 age-matched PwAOMS, and 290 disease duration-matched PwAOMS), and 150 healthy controls (HCs), were followed for 5 years and 3 years, respectively. Cross-sectional and longitudinal measures of T2-lesion volume (LV), lateral ventricular volume (LVV) and whole brain volume (WBV) were derived. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) were calculated. Both analyses were corrected for false discovery rate. RESULTS: Persons with MS exhibited significantly greater annualized WBV loss (-0.88% vs. -0.38%, p<0.001) and annualized LVV expansion (3.1% vs. 1.7%, p=0.002) when compared to HCs. PwLOMS had significantly higher baseline and follow-up median MSSS when compared to both age-matched and disease duration-matched PwAOMS (p<0.026). PwLOMS showed significantly greater percent LVV change (14.3% vs. 9.3% p=0.001) and greater annualized percent LVV change (4.1% vs. 1.6%, p<0.001) compared to age-matched PwAOMS. CONCLUSION: PwLOMS had higher MSSS and greater ventricle expansion when compared to PwAOMS.

New and enlarging white matter lesions adjacent to the ventricle system and thalamic atrophy are independently associated with lateral ventricular enlargement in multiple sclerosis.

OBJECTIVE: To investigate the association between new or enlarging T2-weighted (w) white matter (WM) lesions adjacent to the ventricle wall, deep grey matter (DGM) atrophy and lateral ventricular enlargement in multiple sclerosis (MS). METHODS: Patients derived from the Genetic Multiple Sclerosis Associations study. Lateral ventricles and DGM were segmented fully automated at baseline and 5 years follow-up using Automatic Lateral Ventricle delineation (ALVIN) and Multiple Automatically Generated Templates brain segmentation algorithm (MAgeT), respectively. T2w and T1w lesions were manually segmented. To investigate the association between lesion distance to the ventricle wall and the lateral ventricle volume, we parcellated the WM into concentric periventricular bands using FMRIB Software Library. Associations between clinical and MRI parameters were assessed in generalized linear models using generalized estimating equations for repeated measures. RESULTS: We studied 127 MS patients. Lateral ventricles enlarged on average by 2.4%/year. Patients with new/enlarging T2w WM lesions between baseline and follow-up at 5 years had accelerated lateral ventricular enlargement compared with patients without (p = 0.004). This was true in a multivariable analysis adjusted for age, gender, and whole brain atrophy. When looking at the T2w lesions in different periventricular bands, we found the strongest association between new/enlarging T2w lesions and lateral ventricle enlargement for WM lesions adjacent to the ventricle system (p < 0.001). Moreover, and indepedent of new/enlarging WM lesions, DGM atrophy was associated with ventricular enlargement. In a multivariable analysis, this was driven by thalamic atrophy (p < 0.001). CONCLUSION: New/enlarging T2w lesions adjacent to the ventricle system and thalamic atrophy are independently associated with lateral ventricular enlargement in MS.

Aging and Brain Atrophy in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Brain atrophy accelerates at the age of 60 in healthy individuals (HI) and at disease onset in multiple sclerosis (MS) patients. Whether there is an exacerbating effect of aging superimposed on MS-related brain atrophy is unknown. We estimated the aging effect on lateral ventricular volume (LVV) and whole brain volume (WBV) changes in MS patients. METHODS: 1,982 MS patients (mean follow-up: 4.8 years) and 351 HI (mean follow-up: of 3.1 years), aged from 20 to 79 years old (yo), were collected retrospectively. Percent LVV change (PLVVC) and percent brain volume change (PBVC) on 1.5T and 3T MRI scanners (median of 3.9 scans per subject) were calculated. These were determined between all-time points and subjects were divided in six-decade age groups. MRI differences between age groups were calculated using analysis of covariance (ANCOVA). RESULTS: Compared to HI, at first MRI, MS patients had significantly increased LVV in the age groups: 30-39 yo, 40-49 yo, 50-59 yo, 60-69 yo (all P < .0001), and 70-79 yo (P = .029), and decreased WBV in the age groups: 20-29 yo (P = .024), 30-39 yo (P = .031), 40-49 yo, and 50-59 yo (all P < .0001). Annualized PLVVC was significantly different between the age groups 20-59 and 60-79 yo in MS patients (P = .005) and HI (P < .0001), as was for PBVC in MS patients (P = .001), but not for HI (P = .521). There was a significant aging interaction effect in the annualized PLVVC (P = .001) between HI and MS patients, which was not observed for the annualized PBVC (P = .380). CONCLUSIONS: Development of brain atrophy manifests progressively in MS patients, and occurs with a different pattern, as compared to aging HI. PLVVC increased across age in HI as compared to MS, while PBVC decreased across ages in both HI and MS.

Aqueductal cerebrospinal fluid pulsatility in healthy individuals is affected by impaired cerebral venous outflow.

PURPOSE: To investigate cerebrospinal fluid (CSF) dynamics in the aqueduct of Sylvius (AoS) in chronic cerebrospinal venous insufficiency (CCSVI)-positive and -negative healthy individuals using cine phase contrast imaging. MATERIALS AND METHODS: Fifty-one healthy individuals (32 CCSVI-negative and 19 age-matched CCSVI-positive subjects) were examined using Doppler sonography (DS). Diagnosis of CCSVI was established if subjects fulfilled ≥2 venous hemodynamic criteria on DS. CSF flow and velocity measures were quantified using a semiautomated method and compared with clinical and routine 3T MRI outcomes. RESULTS: CCSVI was associated with increased CSF pulsatility in the AoS. Net positive CSF flow was 32% greater in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.008). This was accompanied by a 28% increase in the mean aqueductal characteristic signal (ie, the AoS cross-sectional area over the cardiac cycle) in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.021). CONCLUSION: CSF dynamics are altered in CCSVI-positive healthy individuals, as demonstrated by increased pulsatility. This is accompanied by enlargement of the AoS, suggesting that structural changes may be occurring in the brain parenchyma of CCSVI-positive healthy individuals.