Default mode network changes in multiple sclerosis: a link between depression and cognitive impairment?

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), depression is a common disorder whose pathophysiology is still debated. To gain insights into the pathophysiology of depression in MS, resting-state (RS) functional connectivity (FC) changes of the default mode network (DMN), salience network (SN) and executive control network (ECN) were assessed in a group of depressed MS (D-MS) patients and in appropriately matched control groups. METHODS: Sixteen D-MS patients, 17 non-depressed MS (ND-MS) patients, 17 non-depressed healthy controls and 15 depressed subjects (D-S), age, sex and education matched, cognitively preserved and non-fatigued, were enrolled. All participants underwent a neuropsychological evaluation and RS functional magnetic resonance imaging study. RESULTS: Comparing D-MS patients with D-S, within the DMN, a significant RS-FC suppression was found in the posterior cingulate cortex (PCC); comparing D-MS with ND-MS, FC was significantly increased in the anterior cingulate cortex and significantly reduced in the PCC. Within the SN increased FC in the right supramarginal gyrus and right middle frontal gyrus was found in D-MS patients compared to D-S and to ND-MS; within the ECN increased FC in the right inferior parietal cortex was found in D-MS patients compared to ND-MS patients. CONCLUSIONS: In cognitively preserved D-MS patients, FC derangement occurs in the SN, ECN and DMN. In the latter, changes occurring both in the anterior cingulate cortex and PCC suggest that depression in MS may be linked to MS itself and, in particular, to a peculiar pattern of network abnormalities favored by MS pathology through disconnection mechanisms. Reduced FC in the PCC, similar to MS patients with cognitive impairment, suggests a functional link between depression and cognitive impairment in MS.

Cognitive impairment and memory disorders in relapsing-remitting multiple sclerosis: the role of white matter, gray matter and hippocampus.

Cognitive disorders occur in up to 65 % of multiple sclerosis (MS) patients; they have been correlated with different MRI measures of brain tissue damage, whole and regional brain atrophy. The hippocampal involvement has been poorly investigated in cognitively impaired (CI) MS patients. The objective of this study is to analyze and compare brain tissue abnormalities, including hippocampal atrophy, in relapsing-remitting MS (RRMS) patients with and without cognitive deficits, and to investigate their role in determining cognitive impairment in MS. Forty-six RRMS patients [20 CI and 26 cognitively preserved (CP)] and 25 age, sex and education-matched healthy controls (HCs) underwent neuropsychological evaluation and 3-Tesla anatomical MRI. T2 lesion load (T2-LL) was computed with a semiautomatic method, gray matter volume and white matter volume were estimated using SIENAX. Hippocampal volume (HV) was obtained by manual segmentation. Brain tissues volumes were compared among groups and correlated with cognitive performances. Compared to HCs, RRMS patients had significant atrophy of WM, GM, left and right Hippocampus (p < 0.001). Compared to CP, CI RRMS patients showed higher T2-LL (p = 0.02) and WM atrophy (p = 0.01). In the whole RRMS group, several cognitive tests correlated with brain tissue abnormalities (T2-LL, WM and GM atrophy); only verbal memory performances correlated with left hippocampal atrophy. Our results emphasize the role of T2-LL and WM atrophy in determining clinically evident cognitive impairment in MS patients and provide evidence that GM and hippocampal atrophy occur in MS patients regardless of cognitive status.

Computer-aided cognitive rehabilitation improves cognitive performances and induces brain functional connectivity changes in relapsing remitting multiple sclerosis patients: an exploratory study.

To better understand the effects of short-term computer-based cognitive rehabilitation (cCR) on cognitive performances and default mode network (DMN) intrinsic functional connectivity (FC) in cognitively impaired relapsing remitting (RR) multiple sclerosis (MS) patients. Eighteen cognitively impaired RRMS patients underwent neuropsychological evaluation by the Rao's brief repeatable battery and resting-state functional magnetic resonance imaging to evaluate FC of the DMN before and after a short-term (8 weeks, twice a week) cCR. A control group of 14 cognitively impaired RRMS patients was assigned to an aspecific cognitive training (aCT), and underwent the same study protocol. Correlations between DMN and cognitive performances were also tested. After cCR, there was a significant improvement of the following tests: SDMT (p < 0.01), PASAT 3" (p < 0.00), PASAT 2" (p < 0.03), SRT-D (p < 0.02), and 10/36 SPART-D (p < 0.04); as well as a significant increase of the FC of the DMN in the posterior cingulate cortex (PCC) and bilateral inferior parietal cortex (IPC). After cCR, a significant negative correlation between Stroop Color-Word Interference Test and FC in the PCC emerged. After aCT, the control group did not show any significant effect either on FC or neuropsychological tests. No significant differences were found in brain volumes and lesion load in both groups when comparing data acquired at baseline and after cCR or aCT. In cognitively impaired RRMS patients, cCR improves cognitive performances (i.e., processing speed and visual and verbal sustained memory), and increases FC in the PCC and IPC of the DMN. This exploratory study suggests that cCR may induce adaptive cortical reorganization favoring better cognitive performances, thus strengthening the value of cognitive exercise in the general perspective of building either cognitive or brain reserve.

Frontotemporal cortical thinning in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The extensive application of advanced MR imaging techniques has undoubtedly improved our knowledge of the pathophysiology of amyotrophic lateral sclerosis. Nevertheless, the precise extent of neurodegeneration throughout the central nervous system is not fully understood. In the present study, we assessed the spatial distribution of cortical damage in amyotrophic lateral sclerosis by using a cortical thickness measurement approach. MATERIALS AND METHODS: Surface-based morphometry was performed on 20 patients with amyotrophic lateral sclerosis and 18 age- and sex-matched healthy control participants. Clinical scores of disability and disease progression were correlated with measures of cortical thickness. RESULTS: The patients with amyotrophic lateral sclerosis showed a significant cortical thinning in multiple motor and extramotor cortical areas when compared with healthy control participants. Gray matter loss was significantly related to disease disability in the left lateral orbitofrontal cortex (P = .04), to disease duration in the right premotor cortex (P = .007), and to disease progression rate in the left parahippocampal cortex (P = .03). CONCLUSIONS: Cortical thinning of the motor cortex might reflect upper motor neuron impairment, whereas the extramotor involvement seems to be related to disease disability, progression, and duration. The cortical pattern of neurodegeneration depicted resembles what has already been described in frontotemporal dementia, thereby providing further structural evidence of a continuum between amyotrophic lateral sclerosis and frontotemporal dementia.

Distributed corpus callosum involvement in amyotrophic lateral sclerosis: a deterministic tractography study using q-ball imaging.

Diffusion tensor imaging (DTI) has become a useful tool for investigating early white matter (WM) abnormalities in motor neuron disease. Furthermore, fiber tracking packages that apply multi-tensorial algorithms, such as q-ball imaging (QBI), have been proposed as alternative approaches to overcome DTI limitations in depicting fiber tracts with different orientations within the same voxel. We explored motor and extra-motor WM tract abnormalities in phenotypically heterogeneous amyotrophic lateral sclerosis (ALS) cases aiming to establish a consistent QBI-based WM signature of disease. We performed a whole-brain, QBI tract-based spatial statistics analysis with deterministic tractography of genu, body and splenium of corpus callosum (CC) and corticospinal tracts (CST) in 20 ALS patients (12 classical and 8 lower motor neuron variants) compared to 20 healthy controls. Mean tract length, fiber volume and density, and generalized fractional anisotropy were extracted and related to clinical indices of pyramidal impairment (upper motor neuron score), disease disability (ALS functional rating scale-revised) and progression. ALS patients showed significantly decreased fiber density and volume, and increased tract length in all regions of CC and left CST (p < 0.05, corrected). In CC body, pyramidal impairment was inversely correlated to fiber density (p = 0.01), while in CC splenium, clinical disability (p = 0.01) and progression (p = 0.02) were inversely correlated to tract length. Our findings further suggest that QBI tractography might represent a promising approach for investigating structural alterations in neurodegenerative diseases and confirm that callosal involvement is a consistent feature of most ALS variants, significantly related to both pyramidal dysfunction and disease disability.

Regional gray matter atrophy in patients with Parkinson disease and freezing of gait.

BACKGROUND AND PURPOSE: FOG is a troublesome symptom of PD. Despite growing evidence suggesting that FOG in PD may be associated with cognitive dysfunction, the relationship between regional brain atrophy and FOG has been poorly investigated. MATERIALS AND METHODS: Optimized VBM was applied to 3T brain MR images of 24 patients with PD and 12 HC. Patients were classified as either FOG- or FOG+ (n = 12) based on their responses to a validated FOG Questionnaire and clinical observation. All patients with PD also underwent a detailed neuropsychological evaluation. RESULTS: The VBM analysis in patients with FOG+ showed a reduced GM volume in the left cuneus, precuneus, lingual gyrus, and posterior cingulate cortex compared with both patients with FOG- and HC. We did not detect any significant change of GM volume when comparing HC versus all patients with PD (FOG- and FOG+). FOG clinical severity was significantly correlated with GM loss in posterior cortical regions. Finally, patients with FOG+ scored lower on tests of frontal lobe function. CONCLUSIONS: Our findings provide the first evidence that the development of FOG in patients with PD is associated with posterior GM atrophy, which may play a role in the complex pathophysiology of this disabling symptom.

Stability, potency, and preservative effectiveness of epoetin alfa after addition of a bacteriostatic diluent.

The stability, potency, and preservative effectiveness of two dilutions of epoetin alfa containing a bacteriostatic diluent were studied. Epoetin alfa 10,000 units/mL in single-use vials was diluted 1:1 and 1:1.5 with bacteriostatic 0.9% sodium chloride injection. USP tests of preservative effectiveness were performed on samples from two batches each of the 1:1 and the 1:1.5 dilutions. Appearance assessment, Western blot analysis, radioimmunoassay, and bioassay were used to determine the stability or potency of samples from three batches of each dilution that were stored at 5 degrees C or at 30 degrees C for 12 weeks. Both batches of the 1:1.5 dilution (epoetin alfa 4,000 units/mL with 0.54% benzyl alcohol) met the USP criteria for preserved solutions, while one batch of the 1:1 dilution (epoetin alfa 5,000 units/mL with 0.45% benzyl alcohol) did not. Epoetin alfa 10,000 units/mL diluted either 1:1 or 1:1.5 with bacteriostatic 0.9% sodium chloride injection and stored at 5 degrees C or at 30 degrees C remained stable and potent for 12 weeks. The addition of 1.5 mL of bacteriostatic 0.9% sodium chloride injection to a vial containing 1 mL of epoetin alfa 10,000 units/mL makes a solution of epoetin alfa 4,000 units/mL that meets the USP criteria for preservative effectiveness and remains stable and potent for 12 weeks at 5 degrees C.

Characterization of the barrier properties of mucosal membranes.

The barrier properties of the nasal, rectal, and vaginal membranes were investigated in the rabbit by comparing physical characteristics and permeability to model hydrophilic and lipophilic compounds. It was found that the nasal, rectal, and vaginal mucosae differ in their physical characteristics and interactions. The nasal mucosa had the highest in vitro transport of both the model hydrophilic compound, mannitol, and the model lipophilic compound, progesterone. Although the nasal mucosa was found to have some hydrophilic character, it appears that these mucosae are primarily lipophilic in nature. The role of the lipid domain in the barrier properties of these mucosal membranes was investigated using progesterone and a series of its hydroxyprogesterone analogues. Membrane permeability was found to decrease as the order of hydrophilicity of the progestins increased, indicating that the lipid domain plays an important role in the barrier function of these membranes. The changes observed in the physical properties and permeability of the mucosal membranes after extraction of the lipids also demonstrated the importance of the lipid domain in the maintenance of the mucosal barrier.

Drug absorption through mucosal membranes: effect of mucosal route and penetrant hydrophilicity.

The influence of mucosal route and penetrant hydrophilicity on the in vivo absorption of a model lipophilic compound, progesterone, was investigated in ovariectomized rabbits. The absorption rate and systemic bioavailability of progesterone and its monohydroxy, dihydroxy, and trihydroxy derivatives were evaluated and compared following oral, nasal, rectal, and vaginal administrations. Nasal delivery resulted in a significantly higher rate and extent of progesterone absorption than oral, rectal, or vaginal administration. The rate and extent of mucosal absorption decreased as penetrant hydrophilicity increased for the nasal, rectal, and vaginal routes. The results of this investigation indicate that the absorption characteristics of a lipophilic compound, such as progesterone, are influenced by the properties of both the mucosa and the drug.