Cognitive performance in multiple sclerosis: what is the role of the gamma-aminobutyric acid system?

Cognitive impairment occurs in 40-65% of persons with multiple sclerosis and may be related to alterations in glutamatergic and GABAergic neurotransmission. Therefore, the aim of this study was to determine how glutamatergic and GABAergic changes relate to cognitive functioning in multiple sclerosis in vivo. Sixty persons with multiple sclerosis (mean age 45.5 ± 9.6 years, 48 females, 51 relapsing-remitting multiple sclerosis) and 22 age-matched healthy controls (45.6 ± 22.0 years, 17 females) underwent neuropsychological testing and MRI. Persons with multiple sclerosis were classified as cognitively impaired when scoring at least 1.5 standard deviations below normative scores on ≥30% of tests. Glutamate and GABA concentrations were determined in the right hippocampus and bilateral thalamus using magnetic resonance spectroscopy. GABA-receptor density was assessed using quantitative [11C]flumazenil positron emission tomography in a subset of participants. Positron emission tomography outcome measures were the influx rate constant (a measure predominantly reflecting perfusion) and volume of distribution, which is a measure of GABA-receptor density. Twenty persons with multiple sclerosis (33%) fulfilled the criteria for cognitive impairment. No differences were observed in glutamate or GABA concentrations between persons with multiple sclerosis and healthy controls, or between cognitively preserved, impaired and healthy control groups. Twenty-two persons with multiple sclerosis (12 cognitively preserved and 10 impaired) and 10 healthy controls successfully underwent [11C]flumazenil positron emission tomography. Persons with multiple sclerosis showed a lower influx rate constant in the thalamus, indicating lower perfusion. For the volume of distribution, persons with multiple sclerosis showed higher values than controls in deep grey matter, reflecting increased GABA-receptor density. When comparing cognitively impaired and preserved patients to controls, the preserved group showed a significantly higher volume of distribution in cortical and deep grey matter and hippocampus. Positive correlations were observed between both positron emission tomography measures and information processing speed in the multiple sclerosis group only. Whereas concentrations of glutamate and GABA did not differ between multiple sclerosis and control nor between cognitively impaired, preserved and control groups, increased GABA-receptor density was observed in preserved persons with multiple sclerosis that was not seen in cognitively impaired patients. In addition, GABA-receptor density correlated to cognition, in particular with information processing speed. This could indicate that GABA-receptor density is upregulated in the cognitively preserved phase of multiple sclerosis as a means to regulate neurotransmission and potentially preserve cognitive functioning.

A multimodal marker for cognitive functioning in multiple sclerosis: the role of NfL, GFAP and conventional MRI in predicting cognitive functioning in a prospective clinical cohort.

BACKGROUND: Cognitive impairment in people with MS (PwMS) has primarily been investigated using conventional imaging markers or fluid biomarkers of neurodegeneration separately. However, the single use of these markers do only partially explain the large heterogeneity found in PwMS. OBJECTIVE: To investigate the use of multimodal (bio)markers: i.e., serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) and conventional imaging markers in predicting cognitive functioning in PwMS. METHODS: Eighty-two PwMS (56 females, disease duration = 14 ± 9 years) underwent neuropsychological and neurological examination, structural magnetic resonance imaging, blood sampling and lumbar puncture. PwMS were classified as cognitively impaired (CI) if scoring ≥ 1.5SD below normative scores on ≥ 20% of test scores. Otherwise, PwMS were defined as cognitively preserved (CP). Association between fluid and imaging (bio)markers were investigated, as well as binary logistics regression to predict cognitive status. Finally, a multimodal marker was calculated using statistically important predictors of cognitive status. RESULTS: Only higher NfL levels (in serum and CSF) correlated with worse processing speed (r = - 0.286, p = 0.012 and r = - 0.364, p = 0.007, respectively). sNfL added unique variance in the prediction of cognitive status on top of grey matter volume (NGMV), p = 0.002). A multimodal marker of NGMV and sNfL yielded most promising results in predicting cognitive status (sensitivity = 85%, specificity = 58%). CONCLUSION: Fluid and imaging (bio)markers reflect different aspects of neurodegeneration and cannot be used interchangeably as markers for cognitive functioning in PwMS. The use of a multimodal marker, i.e., the combination of grey matter volume and sNfL, seems most promising for detecting cognitive deficits in MS.

Inhibitory synaptic loss drives network changes in multiple sclerosis: An ex vivo to in silico translational study.

BACKGROUND: Synaptic and neuronal loss contribute to network dysfunction and disability in multiple sclerosis (MS). However, it is unknown whether excitatory or inhibitory synapses and neurons are more vulnerable and how their losses impact network functioning. OBJECTIVE: To quantify excitatory and inhibitory synapses and neurons and to investigate how synaptic loss affects network functioning through computational modeling. METHODS: Using immunofluorescent staining and confocal microscopy, densities of glutamatergic and GABAergic synapses and neurons were compared between post-mortem MS and non-neurological control cases. Then, a corticothalamic biophysical model was employed to study how MS-induced excitatory and inhibitory synaptic loss affect network functioning. RESULTS: In layer VI of normal-appearing MS cortex, excitatory and inhibitory synaptic densities were significantly lower than controls (reductions up to 14.9%), but demyelinated cortex showed larger losses of inhibitory synapses (29%). In our computational model, reducing inhibitory synapses impacted the network most, leading to a disinhibitory increase in neuronal activity and connectivity. CONCLUSION: In MS, excitatory and inhibitory synaptic losses were observed, predominantly for inhibitory synapses in demyelinated cortex. Inhibitory synaptic loss affected network functioning most, leading to increased neuronal activity and connectivity. As network disinhibition relates to cognitive impairment, inhibitory synaptic loss seems particularly relevant in MS.

A randomized trial predicting response to cognitive rehabilitation in multiple sclerosis: Is there a window of opportunity?

BACKGROUND: Cognitive training elicits mild-to-moderate improvements in cognitive functioning in people with multiple sclerosis (PwMS), although response heterogeneity limits overall effectiveness. OBJECTIVE: To identify patient characteristics associated with response and non-response to cognitive training. METHODS: Eighty-two PwMS were randomized into a 7-week attention training (n = 58, age = 48.4 ± 10.2 years) or a waiting-list control group (n = 24, age = 48.5 ± 9.4 years). Structural and functional magnetic resonance imaging (MRI) was obtained at baseline and post-intervention. Twenty-one healthy controls (HCs, age = 50.27 ± 10.15 years) were included at baseline. Responders were defined with a reliable change index of 1.64 on at least 2/6 cognitive domains. General linear models and logistic regression were applied. RESULTS: Responders (n = 36) and non-responders (n = 22) did not differ on demographics, clinical variables and baseline cognition and structural MRI. However, non-responders exhibited a higher baseline functional connectivity (FC) between the default-mode network (DMN) and the ventral attention network (VAN), compared with responders (p = 0.018) and HCs (p = 0.001). Conversely, responders exhibited no significant baseline differences in FC compared with HCs. Response to cognitive training was predicted by lower DMN-VAN FC (p = 0.004) and DMN-frontoparietal FC (p = 0.029) (Nagelkerke R2 = 0.25). CONCLUSION: An intact pre-intervention FC is associated with cognitive training responsivity in pwMS, suggesting a window of opportunity for successful cognitive interventions.

miR-150-5p and let-7b-5p in Blood Myeloid Extracellular Vesicles Track Cognitive Symptoms in Patients with Multiple Sclerosis.

Cognitive deficits strongly affect the quality of life of patients with multiple sclerosis (MS). However, no cognitive MS biomarkers are currently available. Extracellular vesicles (EVs) contain markers of parental cells and are able to pass from the brain into blood, representing a source of disease biomarkers. The aim of this study was to investigate whether small non-coding microRNAs (miRNAs) targeting synaptic genes and packaged in plasma EVs may reflect cognitive deficits in MS patients. Total EVs were precipitated by Exoquick from the plasma of twenty-six cognitively preserved (CP) and twenty-three cognitively impaired (CI) MS patients belonging to two independent cohorts. Myeloid EVs were extracted by affinity capture from total EVs using Isolectin B4 (IB4). Fourteen miRNAs targeting synaptic genes were selected and measured by RT-PCR in both total and myeloid EVs. Myeloid EVs from CI patients expressed higher levels of miR-150-5p and lower levels of let-7b-5p compared to CP patients. Stratification for progressive MS (PMS) and relapsing-remitting MS (RRMS) and correlation with clinical parameters suggested that these alterations might be attributable to cognitive deficits rather than disease progression. This study identifies miR-150-5p and let-7b-5p packaged in blood myeloid EVs as possible biomarkers for cognitive deficits in MS.

Longitudinal Network Changes and Conversion to Cognitive Impairment in Multiple Sclerosis.

OBJECTIVE: To characterize functional network changes related to conversion to cognitive impairment in a large sample of patients with multiple sclerosis (MS) over a period of 5 years. METHODS: Two hundred twenty-seven patients with MS and 59 healthy controls of the Amsterdam MS cohort underwent neuropsychological testing and resting-state fMRI at 2 time points (time interval 4.9 ± 0.9 years). At both baseline and follow-up, patients were categorized as cognitively preserved (CP; n = 123), mildly impaired (MCI; z < -1.5 on ≥2 cognitive tests, n = 32), or impaired (CI; z < -2 on ≥2 tests, n = 72), and longitudinal conversion between groups was determined. Network function was quantified with eigenvector centrality, a measure of regional network importance, which was computed for individual resting-state networks at both time points. RESULTS: Over time, 18.9% of patients converted to a worse phenotype; 22 of 123 patients who were CP (17.9%) converted from CP to MCI, 10 of 123 from CP to CI (8.1%), and 12 of 32 patients with MCI converted to CI (37.5%). At baseline, default-mode network (DMN) centrality was higher in CI individuals compared to controls (p = 0.05). Longitudinally, ventral attention network (VAN) importance increased in CP, driven by stable CP and CP-to-MCI converters (p < 0.05). CONCLUSIONS: Of all patients, 19% worsened in their cognitive status over 5 years. Conversion from intact cognition to impairment is related to an initial disturbed functioning of the VAN, then shifting toward DMN dysfunction in CI. Because the VAN normally relays information to the DMN, these results could indicate that in MS normal processes crucial for maintaining overall network stability are progressively disrupted as patients clinically progress.

A pilot study of the effects of running training on visuospatial memory in MS: A stronger functional embedding of the hippocampus in the default-mode network?

BACKGROUND/OBJECTIVE: Endurance exercise can improve memory function in persons with multiple sclerosis (pwMS), but the effects on hippocampal functioning are currently unknown. We investigated the effects of a running intervention on memory and hippocampal functional connectivity in pwMS. METHODS/RESULTS: Memory and resting-state functional magnetic resonance imaging (fMRI) data were collected in a running intervention (n = 15) and waitlist group (n = 14). Visuospatial memory improvement was correlated to increased connectivity between the hippocampus and the default-mode network (DMN) in the intervention group only. CONCLUSION: As a result of endurance exercise, improvements in visuospatial memory may be mediated by a stronger functional embedding of the hippocampus in the DMN.