Over ninety years old: Does high cognitive reserve still help brain efficiency?

Nonagenarians and centenarians, also called oldest-old, are a very heterogeneous population that counts a limited number of individuals as it is a real challenge to reach this goal. Even if it is well known that cognitive reserve can be considered a factor in maintaining good cognitive functioning in ageing, only very few studies have been carried out on the role of cognitive reserve (CR) in the oldest-old people. The aim of this study is to investigate the relationship between cognitive reserve and cognitive functioning in a population living in a specific region of Italy, the Blue Zone in Sardinia. This population is characterised by extreme longevity and distinctive historical, geographic, social, linguistic and nutritional features. The cognitive Reserve Index questionnaire (CRIq) and the short cognitive Esame Neuropsicologico Breve-2 (ENB-2, Brief Neuropsychological Examination) were administered to 67 participants, all aged between 90 and 105 years old. The CRIq was a predictor of neuropsychological performance for the global score of the battery of tests, ENB-2 (ENB-tot) and also for 7 out of 16 of its sub-tests. All except one (Token) tapped executive functions (Interference memory at 10 and 30 s, TMT-B, Overlapping figures, Abstraction, Fluency). Results highlight that also in the oldest-old population CR has a positive effect on cognition, especially on executive functioning.

Clinical Profiles in Multiple Sclerosis: Cognitive Reserve and Motor Impairment along Disease Duration.

(i) Background: Cognitive impairment in people with multiple sclerosis (MS) has been studied in relation to certain clinical variables (e.g., motor disability and disease duration) and lifestyle factors such as cognitive reserve (CR). However, only very few studies have considered the interaction of clinical variables and cognitive reserve in preserving the integrity of the neuropsychological profile. In this paper, we hypothesised that a higher level of CR might predict good cognitive efficiency by modulating the clinical outcome of the disease. (ii) Methods: A sample of 100 participants with MS (age range 30-74), was recruited and assessed remotely with a questionnaire to measure CR and a cognitive screening test. Data were analysed through generalized additive models. (iii) Results: We found that the model analysing the interaction between CR and disease duration, and between CR and motor disability, was able to explain a significant percentage of cognitive performance. In particular, higher levels of CR predicted a better cognitive performance despite a long disease duration, unless the motor disability was severe. (iv) Conclusion: This study highlights the crucial role of CR in modulating cognitive efficiency in people with MS.

Sexual Dysfunction in Multiple Sclerosis: The Role of Executive Function.

Cognitive impairment and sexual dysfunction are common symptoms in persons with Multiple Sclerosis (MS). The present study focuses on the relationship between these two dimensions by means of a specific assessment commonly used in clinical practice with this population. Fifty-five persons with a diagnosis of MS underwent specific cognitive tests and answered clinical questionnaires. Two cognitive tests, one for memory (the Selective Reminding Test), and one for attention (the Symbol Digit Modalities Test), were administered together with two tests for executive functions (the D-KEFS Sorting Test and Stroop Test). Two self-report questionnaires to investigate clinical, psychological and sexual features (the Beck Depression Inventory-II and Self-perception of Cognition in Multiple Sclerosis and Multiple Sclerosis Intimacy and Sexuality Questionnaire-19), were also administered. The main result highlights that sexual difficulties are associated with cognitive deficits, particularly with executive disorders, but not with memory and attention. Furthermore, sexual difficulties are better explained when depression symptoms are also taken into account. This study disentangles the interaction between sexual dysfunction, cognitive impairment and depression in persons with MS by emphasising the role of very high cognitive processing (i.e., executive functioning) in determining human behaviour.

Tele-Global Examination of Mental State (Tele-GEMS): an open tool for the remote neuropsychological screening.

Tele-neuropsychology, i.e., the application of remote audio-visual technologies to neuropsychological evaluation or rehabilitation, has become increasingly popular and widespread during and after the COVID-19 pandemic. New tools with updated normative data and appropriate methodological developments are necessary. We present Tele-GEMS, a telephone-based cognitive screening developed on N = 601 Italian participants. It yields a global score tapping on orientation, memory, spatial representation, language, and pragmatic abilities. Its administration lasts about 10 min. Clinical cut-offs are provided, accounting for demographic variables (age, education, and sex) and also for a comprehensive index taking into account cognitively stimulating life experiences that can build up a cognitive reserve. Tele-GEMS shows good internal consistency and a good inter-rater agreement. The test includes the thresholds for estimating a significant change after repeated measurements. Tele-GEMS has a good construct validity as assessed with MoCA and a suitable criterion validity assessed with its in-person version (GEMS). All the materials and the instructions, including scripts and an online Application for the automatic calculation of cut-offs, are accessible on OSF at https://osf.io/t3bma/ under a Creative Commons license.

Long-term Cognitive Outcomes and Socioprofessional Attainment in People With Multiple Sclerosis With Childhood Onset.

BACKGROUND AND OBJECTIVES: Patients with pediatric-onset multiple sclerosis (MS) can be especially vulnerable to cognitive impairment (CI) due to the onset of MS during a critical period for CNS development and maturation. The objective of this longitudinal study was to assess long-term cognitive functioning and socioprofessional attainment in the Italian pediatric MS cohort, previously assessed at baseline and 2 and 5 years. METHODS: The 48 patients evaluated at the 5-year assessment were screened for inclusion. All participants were assessed with a cognitive test battery exploring 4 different cognitive abilities. Depression, fatigue, and socioprofessional attainment were also assessed. Mean cognitive z scores were calculated for the whole cohort, and their evolution over time was analyzed with an analysis of variance for repeated measurements test. Predictors of cognitive worsening or improvement were assessed with a linear mixed-model analysis. RESULTS: Thirty-three participants were included (mean follow-up 12.8 ± 0.8 years). The global cognitive performance worsened at year 2 and improved at year 5, although the z score remained significantly lower than at baseline (-0.9 ± 1.2 vs -0.3 ± 0.9, p = 0.002). There was no significant variation between years 5 and 12 (-0.7 ± 1.1, p = 0.452). Higher IQ (>90) at baseline (effect 0.3, 95% CI 0.1-0.5, p = 0.017) and lower number of relapses in the 2 years before baseline (effect -0.1, 95% CI -0.1 to 0.1, p = 0.025) predicted better cognitive performances. Eighteen (54.5%) patients failed at least 2 tests compared with healthy controls and were defined as cognitively impaired. The presence of CI predicted worse socioprofessional attainment (ß = 4.8, 95% CI 1.4-8.2, p = 0.008). DISCUSSION: The longitudinal cognitive trajectory in pediatric-onset MS has a heterogeneous course over time, with a decline in the first years followed by a partial recovery over the long term. However, at the last follow-up evaluation, the proportion of impaired patients was more than double compared with baseline, with a negative impact on the individual's socioprofessional attainment in adulthood. This study underscores how cognitive reserve may partially mitigate the negative effects of brain damage, highlighting the critical importance of intellectual enrichment early during the disease course.

Designing a Self-Perception Cognitive Questionnaire for Italian Multiple Sclerosis Patients (Sclerosi Multipla Autovalutazione Cognitiva, SMAC). A Preliminary Exploratory Pilot Study.

Background: Although cognition in multiple sclerosis (MS) is assessed by means of several neuropsychological tests, only a few tools exist to investigate patients' perspectives on cognitive functioning. Objective: To develop a new questionnaire aimed at exploring patients' self-perception with respect to cognition in Italian MS patients. Methods: A total of 120 relapsing-remitting MS (RRMS) patients and 120 matched healthy controls (HC) completed a 25-item questionnaire called the Sclerosi Multipla Autovalutazione Cognitiva (SMAC). The Symbol Digit Modalities Test (SDMT), the Delis-Kaplan Executive Function System Sorting Test (D-KEFS ST), the Beck Depression Inventory (BDI-II), and the Fatigue Scale (FSS) were also administered to the patients. Results: Significantly higher SMAC scores were displayed by RRMS patients compared with HC (30.1 ± 16.9 vs. 23.4 ± 10.4, p = 0.003). SMAC inversely correlated with SDMT (r = -0.31, p < 0.001), D-KEFS ST FSC (r = -0.21, p = 0.017), D-KEFS ST FSD (r = -0.22, p = 0.015) and D-KEFS ST SR (r = -0.19, p = 0.035) and positively correlated with FSS (r = 0.42, p < 0.001) and BDI-II (r = 0.59, p < 0.001). Cronbach's alpha coefficient for the questionnaire was 0.94. Conclusion: Preliminary findings suggest that SMAC is a promising patient-reported outcome to be included in MS neuropsychological evaluation and thus warrants being further tested and developed.

Cerebellar gray matter lesions are common in pediatric multiple sclerosis at clinical onset.

BACKGROUND: No data are available on the occurrence of gray matter lesions (GML) in the cerebellum of pediatric multiple sclerosis (pedMS). OBJECTIVES: We analyzed frequency, number and topography of GML, and their correlation with cerebellar-related disability in pedMS at clinical onset. METHODS: Fifteen adolescents with pedMS (12F/3M; mean age 14.9 ± 2.2, range 11-17) were studied. Neurological and cognitive evaluations were done by means of EDSS, Trail Making Test-Part B (TMT-B) and Symbol Digit Modalities Test-oral version (SDMT). Cerebellar GML were investigated with double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) sequences obtained with a 3 T-MRI scan. RESULTS: All patients had white matter lesions (WML) and/or GML in the cerebellum. A significantly higher GML number was observed on PSIR compared to DIR (mean 2.3 ± 2.3 vs 1.1 ± 1.6; median 2.0 (IQR 1.0-2.0) vs 1.0 (IQR 0.0-1.5); p = 0.004). GML were observed in 14/15 (93.3%) patients and were more frequent in the posterior than in the anterior lobe (mean 1.8 ± 2.2 vs 0.47 ± 0.74; median 2.0 (IQR 0.5-2.0) vs 0.0 (IQR 0.0-1.0); p = 0.044). No correlation was found between lesion number or topography and EDSS (r = 0.12, p = 0.69), TMT-B and SDMT. CONCLUSION: At clinical onset, cerebellar GML are common in pedMS, are very often asymptomatic, do not correlate with physical and cognitive disability, and more frequently affect the posterior lobe.

Selective Cerebellar Atrophy Associates with Depression and Fatigue in the Early Phases of Relapse-Onset Multiple Sclerosis.

Cerebellar dysfunctions have been associated to depressive disorders and cognitive impairment in neurodegenerative diseases. The objective is to analyze the associations between cerebellar atrophy, depression, and fatigue in the early phases of relapse-onset multiple sclerosis (RRMS). Sixty-one RRMS patients and 50 healthy controls (HC) were enrolled and clinically evaluated by means of expanded disability status scale (EDSS), Rao's brief repeatable battery of neuropsychological tests (BRB-NT), Delis-Kaplan executive function system sorting test, beck depression inventory II (BDI-II), and fatigue severity scale (FSS). The relationships between MRI variables and clinical scores were assessed. Depressed RRMS (dRRMS) had significantly lower Vermis Crus I volume compared with not depressed RRMS (ndRRMS) (p = 0.009). Vermis Crus I volume was lower in dRRMS suffering from fatigue than in ndRRMS without fatigue (p = 0.01). The hierarchical regression models which included demographic and clinical data (age, sex, and disease duration, FSS or BDI-II) and cerebellar volumes disclosed that cerebellar lobule right V atrophy explained an increase of 4% of the variability in FSS (p = 0.25) and Vermis Crus I atrophy explained an increase of 6% of variability in BDI-II (p = 0.049). Since clinical onset, atrophy of specific cerebellar lobules associates with important clinical aspects of RRMS. Cerebellar pathology may be one of the determinants of fatigue and depression that contribute to worsen disability in RRMS.

No evidence of disease activity including cognition (NEDA-3 plus) in naïve pediatric multiple sclerosis patients treated with natalizumab.

BACKGROUND: Pediatric-onset multiple sclerosis (POMS) is characterized by high inflammatory activity, aggressive course and early development of physical and cognitive disability. A highly effective early treatment must be considered in POMS. OBJECTIVE: To evaluate safety and efficacy of natalizumab (NTZ) in naïve POMS. METHODS: 20 naïve POMS (13F, 7 M; mean age: 13.8 ± 2.7 years) were treated with NTZ for at least 24 months (mean number of infusions: 42 ± 20). No evidence of disease activity (NEDA)-3 plus status, i.e., no relapse, no disease progression (EDSS score), no radiological activity and no cognitive decline, was evaluated. RESULTS: After 2 years of NTZ treatment, a significant reduction in the mean EDSS score (p < 0.0001) was observed in the whole cohort. During the follow-up, evidence of disease activity on MRI was observed in two patients (10%) and a mild decline in cognition was observed in other two. No patient had clinical relapse. At the time of last visit NEDA-3 plus status was maintained in 16 (80%) patients. No major adverse event was observed. CONCLUSION: Early treatment of aggressive POMS with NTZ proved to be highly effective in achieving and maintaining the NEDA-3 plus status. Our data support the use of NTZ as first treatment choice in POMS.

Correction to: Cognitive assessment in multiple sclerosis-an Italian consensus.

In the original article, Maria Pia Amato's second affiliation was not included. The second affiliation is IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy. The correct affiliation is presented here.

D-KEFS ST Failure Identifies Multiple Sclerosis Patients With Worse Objective and Self-Perceived Physical and Cognitive Disability.

Background and Objectives: The Brief Repeatable Battery of Neuropsychological Test (BRB-NT) does not explore the executive functions. We combined BRB-NT and Delis-Kaplan Executive Function System Sorting Test (D-KEFS ST) to obtain a more comprehensive evaluation of cognitive impairment in Multiple Sclerosis (MS) patients. Methods: 137 Relapsing Remitting MS (RRMS) patients underwent a detailed neuropsychological assessment including BRB-NT, D-KEFS ST and self-administrated questionnaires, namely the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ), the Fatigue Severity Scale (FSS) and the Beck Depression Inventory-Second Edition (BDI-II). Results: Fifty-four patients (39.4%) had normal scores in each item of both batteries (cognitive normal), while 64 patients (46.7%) failed in at least one test of BRB-NT but not of D-KEFS ST (BRB-NT impaired) and 18 (13.1%) failed in at least one test of both batteries (BRB-NT+D-KEFS ST impaired). Only one patient (0.7%) failed in D-KEFS ST, but not in BRB-NT and was excluded from further analysis. BRB-NT+D-KEFS ST impaired patients had a significant higher mean disease duration and median EDSS score (15.5 ± 13.6 years and 3.5, respectively) compared to those with only BRB-NT impaired (7.9 ± 9.2, p < 0.01 and 2.5, p < 0.05) and with cognitive normal patients (6.7 ± 9.4, p < 0.005 and 2.0, p < 0.01). SDMT was more frequently impaired in BRB-NT+D-KEFS ST impaired patients (77.8%) compared to only BRB-NT impaired ones (20.0%, p < 0.001). The failure in D-KEFS ST was associated with the number of failed BRB-NT items (OR 1.46, IC95% 1.07-1.99, p < 0.05) and with pathological SDMT z-value (OR 10.56, IC95% 2.50-44.66, p < 0.005). Compared to BRB-NT impaired patients and the cognitive normal ones, BRB-NT+D-KEFS ST impaired patients had significant higher MSNQ (p < 0.01) and BDI-II (p < 0.05) values. Conclusion: D-KEFS ST did not increase the number of cognitively impaired MS patients identified by BRB-NT, but provided a more comprehensive evaluation of cognitive decline. D-KEFS ST identified a subgroup of patients with increased self-perception of cognitive decline, depression and higher physical disability.

Cognitive assessment in multiple sclerosis-an Italian consensus.

The aim of this consensus paper was to define the state of the art on cognitive assessment of persons with multiple sclerosis (PwMS), with the purpose of providing recommendations for the Italian centers involved in MS management. While there are no formal guidelines published regarding the assessment of cognitive function in MS, on the basis of an expert opinion meeting, held in Milan (Italy) on July 4, 2016, we report the recommendations of a panel of Italian experts including MS neurologists and neuropsychologists for the assessment and follow-up of cognitive function in adult MS subjects.

Enlarged Virchow Robin spaces associate with cognitive decline in multiple sclerosis.

The clinical significance of Virchow Robin spaces (VRS) in inflammatory brain disorders, especially in multiple sclerosis (MS), is still undefined. We analysed enlarged VRS (eVRS) by means of phase sensitive inversion recovery (PSIR) MRI sequence and investigated their association with inflammation or brain atrophy, and to clinical or physical disability. Forty-three MS patients (21 clinically isolated syndrome suggestive of MS [CIS], 15 RRMS, 7 progressive [PMS]) and 10 healthy controls (HC) were studied. 3DT1, 3DFLAIR and 2DPSIR images were obtained with a 3T MRI scanner. eVRS number and volume were calculated by manual segmentation (ITK-SNAP). Freesurfer was used to assess brain parenchymal fraction (BPF). All patients underwent clinical (EDSS) and cognitive (Rao's BRB and DKEFS) evaluation. eVRS number and volume resulted significantly higher on 2D-PSIR compared to both 3D-T1 (p<0.001) and 3D-FLAIR (p<0.001) and were significantly increased in CIS compared to HC (p<0.05), in PMS and RRMS compared to CIS (p<0.001) and in male versus female patients (p<0.05). eVRS volume increased significantly with disease duration (r = 0.6) but did not correlate with EDSS. eVRS significantly correlated with SPARTd (r = -0.47) and DKEFSfs (r = -0.46), especially when RRMS and PMS were merged in a single group (r = 0.89, p = 0.002 and r = 0.66, p = 0.009 respectively), while no correlation was found with BPF (r = 0.3), gadolinium-enhancing lesions (r = 0.2) and WMT2 lesion volume (r = 0.2). 2DPSIR allowed the detection of an impressive higher number of eVRS compared to 3DT1 and 3DFLAIR. eVRS associate with SPARTd and DKEFSfs failure in relapse-onset MS, suggesting they may contribute to cognitive decline in MS.

Two Years Follow up of Domain Specific Cognitive Training in Relapsing Remitting Multiple Sclerosis: A Randomized Clinical Trial.

Cognitive rehabilitation in multiple sclerosis (MS) has been reported to induce neuropsychological improvements, but the persistence of these effects has been scarcely investigated over long follow ups. Here, the results of a multicenter randomized clinical trial are reported, in which the efficacy of 15 week domain specific cognitive training was evaluated at 2 years follow up in 41 patients. Included patients were randomly assigned either to domain specific cognitive rehabilitation, or to aspecific psychological intervention. Patients who still resulted to be cognitively impaired at 1 year follow up were resubmitted to the same treatment, whereas the recovered ones were not. Neuropsychological tests and functional scales were administered at 2 years follow up to all the patients. Results revealed that both at 1 and at 2 years follow up more patients in the aspecific group (18/19, 94% and 13/17, 76% respectively) than in the specific group (11/22, 50% and 5/15, 33% respectively) resulted to be cognitively impaired. Furthermore patients belonging to the specific group showed significantly less impaired tests compared with the aspecific group ones (p = 0.02) and a significant amelioration in the majority of the tests. On the contrary patients in the aspecific group did not change. The specific group subjects also perceived a subjective improvement in their cognitive performance, while the aspecific group patients did not. These results showed that short time domain specific cognitive rehabilitation is a useful treatment for patients with MS, shows very long lasting effects, compared to aspecific psychological interventions. Also subjective cognitive amelioration was found in patients submitted to domain specific treatment after 2 years.