Resting state functional connectivity modifications in monoaminergic circuits underpin fatigue development in patients with multiple sclerosis.

Dysregulation of monoaminergic networks might have a role in the pathogenesis of fatigue in multiple sclerosis (MS). We investigated longitudinal changes of resting state (RS) functional connectivity (FC) in monoaminergic networks and their association with the development of fatigue in MS. Eighty-nine MS patients and 49 age- and sex-matched healthy controls (HC) underwent neurological, fatigue, and RS functional MRI assessment at baseline and after a median follow-up of 1.3 years (interquartile range = 1.01-2.01 years). Monoaminergic-related RS FC was estimated with an independent component analysis constrained to PET atlases for dopamine (DA), noradrenaline (NA), and serotonin (5-HT) transporters. At baseline, 24 (27%) MS patients were fatigued (F) and 65 were not fatigued (NF). Of these, 22 (34%) developed fatigue (DEV-FAT) at follow-up and 43 remained not fatigued (NO-FAT). At baseline, F-MS patients showed increased monoaminergic-related RS FC in the caudate nucleus vs NF-MS and in the hippocampal, postcentral, temporal, and occipital cortices vs NF-MS and HC. Moreover, F-MS patients exhibited decreased RS FC in the frontal cortex vs NF-MS and HC, and in the thalamus vs NF-MS. During the follow-up, no RS FC changes were observed in HC. NO-FAT patients showed limited DA-related RS FC modifications, whereas DEV-FAT MS patients showed increased DA-related RS FC in the left hippocampus, significant at time-by-group interaction analysis. In the NA-related network, NO-FAT patients showed decreased RS FC over time in the left superior frontal gyrus. This region showed increased RS FC in both DEV-FAT and F-MS patients; this divergent behavior was significant at time-by-group interaction analysis. Finally, DEV-FAT MS patients presented increased 5-HT-related RS FC in the angular and middle occipital gyri, while this latter region showed decreased 5-HT-related RS FC during the follow-up in F-MS patients. In MS patients, distinct patterns of alterations were observed in monoaminergic networks based on their fatigue status. Fatigue was closely linked to specific changes in the basal ganglia and hippocampal, superior frontal, and middle occipital cortices.

Cognitive Impairment Is Related to Glymphatic System Dysfunction in Pediatric Multiple Sclerosis.

OBJECTIVE: The aim of this study was to investigate whether, compared to pediatric healthy controls (HCs), the glymphatic system is impaired in pediatric multiple sclerosis (MS) patients according to their cognitive status, and to assess its association with clinical disability and MRI measures of brain structural damage. METHODS: Sixty-five pediatric MS patients (females = 62%; median age = 15.5 [interquartile range, IQR = 14.5;17.0] years) and 23 age- and sex-matched HCs (females = 44%; median age = 14.1 [IQR = 11.8;16.2] years) underwent neurological, neuropsychological and 3.0 Tesla MRI assessment, including conventional and diffusion tensor imaging (DTI). We calculated the diffusion along the perivascular space (DTI-ALPS) index, a proxy of glymphatic function. Cognitive impairment (Co-I) was defined as impairment in at least 2 cognitive domains. RESULTS: No significant differences in DTI-ALPS index were found between HCs and cognitively preserved (Co-P) pediatric MS patients (estimated mean difference [EMD] = -0.002 [95% confidence interval = -0.069; 0.065], FDR-p = 0.956). Compared to HCs and Co-P patients, Co-I pediatric MS patients (n = 20) showed significantly lower DTI-ALPS index (EMD = -0.136 [95% confidence interval = -0.214; -0.058], FDR-p ≤ 0.004). In HCs, no associations were observed between DTI-ALPS index and normalized brain, cortical and thalamic volumes, and normal-appearing white matter (NAWM) fractional anisotropy (FA) and mean diffusivity (MD) (FDR-p ≥ 0.348). In pediatric MS patients, higher brain WM lesion volume (LV), higher NAWM MD, lower normalized thalamic volume, and lower NAWM FA were associated with lower DTI-ALPS index (FDR-p ≤ 0.016). Random Forest selected lower DTI-ALPS index (relative importance [RI] = 100%), higher brain WM LV (RI = 59.5%) NAWM MD (RI = 57.1%) and intelligence quotient (RI = 51.3%) as informative predictors of cognitive impairment (out-of-bag area under the curve = 0.762). INTERPRETATION: Glymphatic system dysfunction occurs in pediatric MS, is associated with brain focal lesions, irreversible tissue loss accumulation and cognitive impairment. ANN NEUROL 2024.

Spatial correspondence among regional gene expressions and gray matter volume loss in multiple sclerosis.

In multiple sclerosis (MS), a non-random and clinically relevant pattern of gray matter (GM) volume loss has been described. Whether differences in regional gene expression might underlay distinctive pathological processes contributing to this regional variability has not been explored yet. Two hundred eighty-six MS patients and 172 healthy controls (HC) underwent a brain 3T MRI, a complete neurological evaluation and a neuropsychological assessment. Using Allen Human Brain Atlas, voxel-based morphometry and MENGA platform, we integrated brain transcriptome and neuroimaging data to explore the spatial cross-correlations between regional GM volume loss and expressions of 2710 genes involved in MS (p < 0.05, family-wise error-corrected). Enrichment analyses were performed to evaluate overrepresented molecular functions, biological processes and cellular components involving genes significantly associated with voxel-based morphometry-derived GM maps (p < 0.05, Bonferroni-corrected). A diffuse GM volume loss was found in MS patients compared to HC and it was spatially correlated with 74 genes involved in GABA neurotransmission and mitochondrial oxidoreductase activity mainly expressed in neurons and astrocytes. A more severe GM volume loss was spatially associated, in more disabled MS patients, with 44 genes involved in mitochondrial integrity of all resident cells of the central nervous system (CNS) and, in cognitively impaired MS patients, with 64 genes involved in mitochondrial protein heterodimerization and oxidoreductase activities expressed also in microglia and endothelial cells. Specific differences in the expressions of genes involved in synaptic GABA receptor activities and mitochondrial functions in resident CNS cells may influence regional susceptibility to MS-related excitatory/inhibitory imbalance and oxidative stress, and subsequently, to GM volume loss.

COVID-19 has no impact on disease activity, progression and cognitive performance in people with multiple sclerosis: a 2-year study.

BACKGROUND: Sequelae of COVID-19 in people with multiple sclerosis (PwMS) have not been characterised. We explored whether COVID-19 is associated with an increased risk of disease activity, disability worsening, neuropsychological distress and cognitive dysfunction during the 18-24 months following SARS-COV-2 infection. METHODS: We enrolled 174 PwMS with history of COVID-19 (MS-COVID) between March 2020 and March 2021 and compared them to an age, sex, disease duration, Expanded Disability Status Scale (EDSS), and a line of treatment-matched group of 348 PwMS with no history of COVID-19 in the same period (MS-NCOVID). We collected clinical, MRI data and SARS-CoV2 immune response in the 18-24 months following COVID-19 or baseline evaluation. At follow-up, PwMS also underwent a complete neuropsychological assessment with brief repeatable battery of neuropsychological tests and optimised scales for fatigue, anxiety, depression and post-traumatic stress symptoms. RESULTS: 136 MS-COVID and 186 MS-NCOVID accepted the complete longitudinal evaluation. The two groups had similar rate of EDSS worsening (15% vs 11%, p=1.00), number of relapses (6% vs 5%, p=1.00), disease-modifying therapy change (7% vs 4%, p=0.81), patients with new T2-lesions (9% vs 11%, p=1.00) and gadolinium-enhancing lesions (7% vs 4%, p=1.00) on brain MRI. 22% of MS-COVID and 23% MS-NCOVID were cognitively impaired at 18-24 months evaluation, with similar prevalence of cognitive impairment (p=1.00). The z-scores of global and domain-specific cognitive functions and the prevalence of neuropsychiatric manifestations were also similar. No difference was detected in terms of SARS-CoV2 cellular immune response. CONCLUSIONS: In PwMS, COVID-19 has no impact on disease activity, course and cognitive performance 18-24 months after infection.

Monoaminergic network dysfunction and development of depression in multiple sclerosis: a longitudinal investigation.

BACKGROUND: Monoaminergic network dysfunction is thought to underpin depression in multiple sclerosis (MS) patients. However, longitudinal studies are lacking. OBJECTIVES: Here, we investigated the association between development of depressive symptoms in MS and changes of resting-state functional connectivity (RS FC) within monoaminergic networks. METHODS: Forty-nine MS patients without depression [Montgomery-Asberg Depression Scale (MADRS) ≤ 9] and 27 healthy controls underwent clinical and 3.0 T RS FC assessment at baseline and after a median follow-up of 1.6 years (interquartile range 1.0-2.1 years). Monoamine-related RS FC was derived by independent component analysis, constrained to PET atlases for dopamine, noradrenaline and serotonin transporters. Longitudinal changes of RS FC within monoaminergic networks and their correlations with MADRS scores were assessed. RESULTS: At baseline, MS patients showed decreased RS FC vs healthy controls in all PET-guided monoaminergic networks in frontal, cingulate and cerebellar cortices, and increased RS FC in parieto-occipital regions. Fourteen (29%) MS patients developed depressive symptoms (MADRS > 9) at follow-up (D-MS) and exhibited widespread RS FC decrease over time in the PET-guided dopamine network, mainly in orbitofrontal, occipital, anterior cingulate and precuneal cortices compared to patients who did not develop depressive symptoms. In D-MS, decreased RS FC over time was also observed in parahippocampal and occipital regions of the PET-guided noradrenaline network. Decreased RS FC over time in dopamine and noradrenaline PET-guided networks correlated with concomitant increased MADRS scores (r = range - 0.65/- 0.61, p < 0.001). CONCLUSIONS: The development of depressive symptoms in MS patients was associated with specific RS FC changes within the dopamine and noradrenaline networks.

Cognitive phenotypes in multiple sclerosis: mapping the spectrum of impairment.

BACKGROUND: Available criteria for cognitive phenotypes in multiple sclerosis (MS) do not consider the severity of impairment. OBJECTIVES: To identify cognitive phenotypes with varying degrees of impairment in MS patients and describe their demographic, clinical and MRI characteristics. METHODS: Two hundred and forty-three MS patients and 158 healthy controls underwent neuropsychological tests to assess memory, attention, and executive function. For each domain, mild impairment was defined as performing 1.5 standard deviations below the normative mean on two tests, while the threshold for significant impairment was 2 standard deviations. Patients were classified into cognitive phenotypes based on severity of the impairment (mild/significant) and number of domains affected (one/more). RESULTS: Five cognitive phenotypes emerged: Preserved cognition (PC; 56%), Mild Single-Domain Impairment (MSD; 15%), Mild Multi-Domain Impairment (MMD; 9%), Significant Single-Domain Impairment (SSD; 12%), Significant Multi-Domain Impairment (SMD; 8%). Compared with PC, MSD patients were older, had longer disease duration (DD) and higher T2-hyperintense lesion volume (LV; all p ≤ 0.02); MMD patients were older, had longer DD, higher disability, higher T2 LV and lower thalamic volume (all p ≤ 0.01); SSD patients had longer DD and lower gray matter cortical volume, thalamic, caudate, putamen and accumbens volumes (all p ≤ 0.04); and SMD patients were older, had longer DD, higher disability and more extensive structural damage in all brain regions explored (all p ≤ 0.03), except white matter and amygdala volumes. CONCLUSIONS: We identified five cognitive phenotypes with graded levels of impairment. These phenotypes were characterized by distinct demographic, clinical and MRI features, indicating potential variations in the neural substrates of dysfunction throughout disease stages.

Cognitive function in primary and secondary progressive multiple sclerosis: A multiparametric magnetic resonance imaging study.

BACKGROUND AND PURPOSE: The differences in cognitive function between primary progressive and secondary progressive multiple sclerosis (MS) remain unclear. We compared cognitive performance between primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS), and explored the structural and functional magnetic resonance imaging (MRI) correlates of their cognitive functions. METHODS: Seventy-five healthy controls and 183 MS patients (60 PPMS and 123 SPMS) underwent 3.0-T MRI. MS patients were administered the Brief Repeatable Battery of Neuropsychological Tests; cognitive domain z-scores were calculated and then averaged to obtain a measure of global cognition. Using hierarchical linear regression analysis, the contribution of lesion volumes, normalized brain volumes, white matter (WM) fractional anisotropy (FA) and mean diffusivity abnormalities, and resting state (RS) functional connectivity (FC) alterations to global cognition in PPMS and SPMS was investigated. RESULTS: PPMS and SPMS had similar z-scores in all investigated cognitive domains. Poor global cognitive function was associated with decreased FA of the medial lemniscus (ΔR 2 = 0.11, p = 0.011) and lower normalized gray matter volume (ΔR 2 = 0.29, p < 0.001) in PPMS, and with decreased FA of the fornix (ΔR 2 = 0.35, p < 0.001) and lower normalized WM volume (ΔR 2 = 0.05; p = 0.034) in SPMS. CONCLUSIONS: PPMS and SPMS had similar neuropsychological performance. Cognitive dysfunction in PPMS and SPMS was related to distinct patterns of structural MRI abnormalities and involvement of different WM tracts, whereas RS FC alterations did not contribute to explaining their global cognitive functioning.

Correspondence among gray matter atrophy and atlas-based neurotransmitter maps is clinically relevant in multiple sclerosis.

In multiple sclerosis (MS), gray matter (GM) atrophy progresses in a non-random manner, possibly in regions with a high distribution of specific neurotransmitters involved in several relevant central nervous system functions. We investigated the associations among regional GM atrophy, atlas-based neurotransmitter distributions and clinical manifestations in a large MS patients' group. Brain 3 T MRI scans, neurological examinations and neuropsychological evaluations were obtained from 286 MS patients and 172 healthy controls (HC). Spatial correlations among regional GM volume differences and atlas-based nuclear imaging-derived neurotransmitter maps, and their associations with MS clinical features were investigated using voxel-based morphometry and JuSpace toolbox. Compared to HC, MS patients showed widespread GM atrophy being spatially correlated with the majority of neurotransmitter maps (false discovery rate [FDR]-p ≤ 0.004). Patients with a disease duration ≥ 5 vs < 5 years had significant cortical, subcortical and cerebellar atrophy, being spatially correlated with a higher distribution of serotoninergic and dopaminergic receptors (FDR-p ≤ 0.03). Compared to mildly-disabled patients, those with Expanded Disability Status Scale ≥ 3.0 or ≥ 4.0 had significant cortical, subcortical and cerebellar atrophy being associated with serotonergic, dopaminergic, opioid and cholinergic maps (FDR-p ≤ 0.04). Cognitively impaired vs cognitively preserved patients had widespread GM atrophy being spatially associated with serotonergic, dopaminergic, noradrenergic, cholinergic and glutamatergic maps (FDR-p ≤ 0.04). Fatigued vs non-fatigued MS patients had significant cortical, subcortical and cerebellar atrophy, not associated with neurotransmitter maps. No significant association between GM atrophy and neurotransmitter maps was found for depression. Regional GM atrophy with specific neurotransmitter systems may explain part of MS clinical manifestations, including locomotor disability, cognitive impairment and fatigue.

Monoaminergic network abnormalities: a marker for multiple sclerosis-related fatigue and depression.

OBJECTIVE: To investigate monoaminergic network abnormalities in patients with multiple sclerosis (MS) according to their fatigue and depressive status through a positron emission tomography (PET)-based constrained independent component analysis (ICA) on resting state (RS) functional MRI (fMRI). METHODS: In this prospective study, 213 patients with MS (mean age=40.6±12.5 years; 94/119 men/women; 153 relapsing-remitting; 60 progressive) and 62 healthy controls (HCs, mean age=39.0±10.4 years; 30/32 men/women) underwent neurological, fatigue, depression and RS fMRI assessment. Patterns of dopamine, norepinephrine-related and serotonin-related RS functional connectivity (FC) were derived by ICA, constrained to PET atlases for dopamine, norepinephrine and serotonin transporters, obtained in HCs' brain. RESULTS: Compared with HCs, patients with MS showed abnormalities in all three explored monoaminergic networks, mostly with decreased RS FC within PET-guided monoaminergic networks in frontal regions and subcortical areas including the cerebellum and thalamus, and increased RS FC in temporo-parieto-occipital cortical areas, including bilateral precunei.MS-related fatigue was associated with decreased RS FC within the PET-guided dopamine network in the left thalamus and left cerebellum, and with increased RS FC within the PET-guided serotonin network in the left middle occipital gyrus. MS-related depression was associated with more distributed abnormalities involving the three explored monoaminergic networks, resulting in overall reduced RS FC in the frontal lobe, limbic areas and the precuneus. CONCLUSIONS: Patients with MS present diffuse dysregulation in the monoaminergic networks. Specific alterations in these networks were associated with fatigue and depression, providing a pathological marker for these bothersome symptoms and putative targets for their treatment.

Time-varying connectivity of the precuneus and its association with cognition and depressive symptoms in neuromyelitis optica: A pilot MRI study.

BACKGROUND: The precuneus is involved in cognition and depression; static functional connectivity (SFC) abnormalities of this region have been observed in neuromyelitis optica spectrum disorders (NMOSD). Time-varying functional connectivity (TVC) underpins dynamic variations of brain connectivity. OBJECTIVE: The aim of this study was to explore precuneus SFC and TVC in NMOSD patients and their associations with neuropsychological features. METHODS: This retrospective study includes 27 NMOSD patients and 30 matched healthy controls undergoing resting state functional magnetic resonance imaging (MRI) and a neuropsychological evaluation of cognitive performance and depressive symptoms. A sliding-window correlation analysis using bilateral precuneus as seed region assessed TVC, which was quantified by the standard deviation of connectivity across windows. Mean connectivity indicated SFC. RESULTS: Compared to controls, patients had reduced SFC between precuneus, temporal lobe, putamen and cerebellum, and reduced TVC between precuneus and prefronto-parietal-temporo-occipital cortices and caudate. Patients also had increased intra-precuneal TVC and increased TVC between the precuneus and the temporal cortex. More severe depressive symptoms correlated with increased TVC between the precuneus and the temporal lobe; worse cognitive performance mainly correlated with higher TVC between the precuneus and the parietal lobe. CONCLUSION: TVC rather than SFC of the precuneus correlates with NMOSD neuropsychological features; different TVC abnormalities underlie depressive symptoms and cognitive impairment.

Magnetic Resonance Imaging Evaluation of Perivascular Space Abnormalities in Neuromyelitis Optica.

OBJECTIVE: Astrocytes outline the perivascular space (PVS) and regulate fluid exchange through the aquaporin-4 water channel. As neuromyelitis optica is an autoimmune astrocytopathy targeting aquaporin-4, we hypothesized that it could be associatied with PVS abnormalities. METHODS: A total of 34 patients, and 46 age- and sex-matched healthy controls from two independent cohorts (exploratory and validation dataset) underwent a standardized 3.0-T magnetic resonance imaging protocol including conventional and diffusion tensor imaging. Susceptibility-weighted imaging was also acquired in the exploratory dataset. We evaluated macroscopic and microstructural abnormalities of PVS in terms of enlargement and water diffusivity (DTI-ALPS index). In the exploration dataset, a susceptibility-weighted sequence was used to draw the regions of interest for the DTI-ALPS index calculation in areas having veins perpendicular to lateral ventricles. Between-group comparisons, correlations, and regression models were run to assess associations between PVS abnormalities, and clinical and magnetic resonance imaging variables. RESULTS: Patients had a higher frequency of severe PVS enlargement in the centrum semiovale (29.4% vs 8.7%), which correlated with brain atrophy, deep grey matter atrophy, and poorer cognitive performance (r-values range: -0.44, -0.36; p values: 0.01-0.046). In both datasets, patients had reduced DTI-ALPS index compared with controls (p values 0.004-0.038). Lower DTI-ALPS index, deep gray matter volume, and cortical volume could discriminate between patients and controls (R2  = 0.62), whereas lower DTI-ALPS index, higher number of myelitis, and higher T2-lesion volume were associated with worse disability (R2  = 0.55). INTERPRETATION: Patients with neuromyelitis optica spectrum disorder are characterized by abnormal enlargement and impaired water diffusion along the PVS, whose clinical implications suggest a direct correlation with disease pathogenesis and severity. ANN NEUROL 2022;92:173-183.

The association between cognition and motor performance is beyond structural damage in relapsing-remitting multiple sclerosis.

BACKGROUND: Previous studies demonstrated an association between motor and cognitive performance in multiple sclerosis (MS). However, disease-related brain damage might represent a common substrate to both phenomena, which was not considered before. OBJECTIVE: Aim of this study is to investigate whether the association between cognition and motor function is beyond structural damage in patients with MS. METHODS: Eighty-one healthy controls and 106 relapsing-remitting (RR) MS patients underwent a 3.0 T MRI with quantification of T2-lesion volumes, T1-lesion volumes and normalized brain volumes. A functional examination [Nine-Hole Peg Test (9-HPT), Timed 25-Foot Walk test (T25FW) and Expanded Disability Status Scale] and a neuropsychological evaluation (Brief Repeatable Battery of Neuropsychological Tests) were also administered. Association between demographic, clinical, cognitive, MRI and functional measures were analysed with univariate analyses and hierarchical linear regression. RESULTS: In RRMS patients, Spatial Recall Test and Symbol Digit Modalities Test were positively correlated with 9-HPT (p < 0.001) and T25FW (p ≤ 0.035); Paced Auditory Serial Addition Test (PASAT) correlated with 9-HPT (p ≤ 0.009). 9-HPT and T25FW were significantly associated with normalized brain volumes (p ≤ 0.016), T2- and T1-lesion volumes (p ≤ 0.009). Hierarchical regression models selected age and normalized deep gray matter volume as predictors of T25FW (adjusted-R2 = 0.109). Younger age, female sex, higher normalized gray matter volume and higher PASAT 2″ scores predicted higher 9-HPT scores (adjusted-R2 = 0.337). CONCLUSIONS: In RRMS patients, deficit in information processing speed and executive function may contribute to hand motor dysfunction beyond the effect of structural disease-related burden, supporting the integration of motor and cognitive assessment in clinical settings.

Functional and structural MRI correlates of executive functions in multiple sclerosis.

BACKGROUND: Executive dysfunctions, including difficulties in attention, working memory, planning, and inhibition affect 15%-28% of multiple sclerosis (MS) patients. OBJECTIVES: To investigate structural and functional magnetic resonance imaging (MRI) abnormalities underlying executive function (EF) in MS patients. METHODS: A total 116 MS patients and 65 controls underwent resting-state (RS) and diffusion-weighted sequences and neuropsychological examination, including Wisconsin Card Sorting Test (WCST) to test EF. Brain RS cognitive networks and fractional anisotropy (FA) from a priori selected white matter tracts were derived. Associations of WCST scores with RS functional connectivity (FC) and FA abnormalities were investigated. RESULTS: In MS patients, predictors of working memory/updating were: lower corpus callosum (CC) FA, lower left working-memory network (WMN), right WMN RS FC for worse performance; lower executive control network (ECN), higher default-mode network (DMN), and salience network (SN) RS FC for better performance (R2 = 0.35). Predictors of attention were lower CC genu FA, lower left WMN, and DMN RS FC for worse performance; higher left WMN and ECN RS FC for better performance (R2 = 0.24). Predictors of worse shifting/inhibition were lower CC genu and superior cerebellar peduncle (SCP) FA, lower left WMN RS FC for worse performance; and higher ECN RS FC for better performance (R2 = 0.24). CONCLUSIONS: CC and SCP microstructural damage and RS FC abnormalities in cognitive networks underlie EF frailty in MS.

Association Between Motor and Cognitive Performances in Elderly With Atrial Fibrillation: Strat-AF Study.

Background/Objective: Growing evidence suggests a close relationship between motor and cognitive abilities, but possible common underlying mechanisms are not well-established. Atrial fibrillation (AF) is associated with reduced physical performance and increased risk of cognitive decline. The study aimed to assess in a cohort of elderly AF patients: (1) the association between motor and cognitive performances, and (2) the influence and potential mediating role of cerebral lesions burden. Design: Strat-AF is a prospective, observational study investigating biological markers for cerebral bleeding risk stratification in AF patients on oral anticoagulants. Baseline cross-sectional data are presented here. Setting: Thrombosis outpatient clinic (Careggi University Hospital). Participants: One-hundred and seventy patients (mean age 77.7 ± 6.8; females 35%). Measurements: Baseline protocol included: neuropsychological battery, motor assessment [Short Physical Performance Battery (SPPB), and walking speed], and brain magnetic resonance imaging (MRI) used for the visual assessment of white matter hyperintensities, lacunar and non-lacunar infarcts, cerebral microbleeds, and global cortical and medial temporal atrophies. Results: Mean Montreal Cognitive Assessment (MoCA) total score was 21.9 ± 3.9, SPPB total score 9.5 ± 2.2, and walking speed 0.9 ± 0.2. In univariate analyses, both SPPB and walking speed were significantly associated with MoCA (r = 0.359, r = 0.372, respectively), visual search (r = 0.361, r = 0.322), Stroop (r = -0.272, r = -0.263), short story (r = 0.263, r = 0.310), and semantic fluency (r = 0.311, r = 0.360). In multivariate models adjusted for demographics, heart failure, physical activity, and either stroke history (Model 1) or neuroimaging markers (Model 2), both SPPB and walking speed were confirmed significantly associated with MoCA (Model 1: ß = 0.256, ß = 0.236; Model 2: ß = 0.276, ß = 0.272, respectively), visual search (Model 1: ß = 0.350, ß = 0.313; Model 2: ß = 0.344, ß = 0.307), semantic fluency (Model 1: ß = 0.223, ß = 0.261), and short story (Model 2: ß = 0.245, ß = 0.273). Conclusions: In our cohort of elderly AF patients, a direct association between motor and cognitive functions consistently recurred using different evaluation of the performances, without an evident mediating role of cerebral lesions burden.

Role of Biological Markers for Cerebral Bleeding Risk STRATification in Patients with Atrial Fibrillation on Oral Anticoagulants for Primary or Secondary Prevention of Ischemic Stroke (Strat-AF Study): Study Design and Methodology.

Background and Objectives: In anticoagulated atrial fibrillation (AF) patients, the validity of models recommended for the stratification of the risk ratio between benefits and hemorrhage risk is limited. Cerebral small vessel disease (SVD) represents the pathologic substrate for primary intracerebral hemorrhage and ischemic stroke. We hypothesize that biological markers-both circulating and imaging-based-and their possible interaction, might improve the prediction of bleeding risk in AF patients under treatment with any type of oral anticoagulant. Materials and Methods: The Strat-AF study is an observational, prospective, single-center hospital-based study enrolling patients with AF, aged 65 years or older, and with no contraindications to magnetic resonance imaging (MRI), referring to Center of Thrombosis outpatient clinic of our University Hospital for the management of oral anticoagulation therapy. Recruited patients are evaluated by means of a comprehensive protocol, with clinical, cerebral MRI, and circulating biomarkers assessment at baseline and after 18 months. The main outcome is SVD progression-particularly microbleeds-as a selective surrogate marker of hemorrhagic complication. Stroke occurrence (ischemic or hemorrhagic) and the progression of functional, cognitive, and motor status will be evaluated as secondary outcomes. Circulating biomarkers may further improve predictive potentials. Results: Starting from September 2017, 194 patients (mean age 78.1 ± 6.7, range 65-97; 61% males) were enrolled. The type of AF was paroxysmal in 93 patients (48%), and persistent or permanent in the remaining patients. Concerning the type of oral anticoagulant, 57 patients (29%) were on vitamin K antagonists, and 137 (71%) were on direct oral anticoagulants. Follow-up clinical evaluation and brain MRI are ongoing. Conclusions: The Strat-AF study may be an essential step towards the exploration of the role of a combined clinical biomarker or multiple biomarker models in predicting stroke risk in AF, and might sustain the incorporation of such new markers in the existing stroke prediction schemes by the demonstration of a greater incremental value in predicting stroke risk and improvement in clinical outcomes in a cost-effective fashion.