Cinzia Valeria Russo

Cognitive impairment at diagnosis predicts 10-year multiple sclerosis progression:

Background: Cognitive impairment occurs from the early phases of multiple sclerosis (MS), and more frequently affects secondary progressive (SP) subjects than relapsing–remitting (RR). Objective: To investigate relationships between cognitive dysfunctions in newly diagnosed RRMS, and long-term MS-related outcomes. Methods: The present 10-year retrospective longitudinal study included 155 RRMS subjects, tested with the Rao Brief Repeatable Battery at MS diagnosis. The reaching of Expanded Disability Status Scale (EDSS) 4.0, and the SP conversion were recorded. Results: 67 subjects (43.2%) reached EDSS 4.0, and 34 subjects (21.9%) converted to SP during a follow-up period of 10.0±1.8 years. Subjects with cognitive impairment at diagnosis had a rate of reaching EDSS 4.0 more than three times greater (p<0.001; HR=3.183), and a rate of SP conversion more than two times greater, as compared to cognitively preserved subjects (p=0.008; HR=2.535). In particular, better scores in the Selective Reminding Test-Delayed Recall and in the Symbol Digit Modalities Test at baseline were associated with lower SP conversion rates during the follow-up period (p=0.018; HR=0.835; and p=0.001; HR=0.941, respectively). Conclusion: Cognitive impairment, with particular involvement of processing speed and memory, predicts disability progression and SP conversion in newly diagnosed RRMS, highlighting the importance of cognitive assessment from the beginning of MS.

Default-mode network changes in Huntington's disease: an integrated MRI study of functional connectivity and morphometry.

Previous MRI studies of functional connectivity in pre-symptomatic mutation carriers of Huntington’s disease (HD) have shown dysfunction of the Default-Mode Network (DMN). No data however are currently available on the DMN alterations in the symptomatic stages of the disease, which are characterized by cortical atrophy involving several DMN nodes. We assessed DMN integrity and its possible correlations with motor and cognitive symptoms in 26 symptomatic HD patients as compared to 22 normal volunteers, by analyzing resting state functional MRI data, using the Precuneal Cortex/Posterior Cingulate Cortices (PC/PCC) as seed, controlling at voxel level for the effect of atrophy by co-varying for gray matter volume. Direct correlation with PC/PCC was decreased, without correlation with atrophy, in the ventral medial prefrontal cortex (including anterior cingulate and subgenual cortex), right dorso-medial prefrontal cortex, and in the right inferior parietal cortex (mainly involving the angular gyrus). Negative correlations with PC/PCC were decreased bilaterally in the inferior parietal cortices, while a cluster in the right middle occipital gyrus presented increased correlation with PC/PCC. DMN changes in the ventral medial prefrontal cortex significantly correlated with the performance at the Stroop test (p = .0002). Widespread DMN changes, not correlating with the atrophy of the involved nodes, are present in symptomatic HD patients, and correlate with cognitive disturbances.

Central cholinergic dysfunction in the adult form of Niemann Pick disease type C: a further link with Alzheimer’s disease?

Adult patients with Niemann-Pick disease type C (NPC) usually develop cognitive impairment progressing to dementia, whose pathophysiology remains still unclear. Noteworthy parallels exist in cognitive impairment and cellular pathology of NPC and Alzheimer’s disease (AD). In particular, alterations of cholinergic system, which represent one of the pathological hallmarks and contribute to cognitive deterioration in AD, have recently been demonstrated in a human brain autopsy and in an experimental model of NPC. This finding raised the issue that central cholinergic circuits dysfunction may contribute to pathophysiology of cognitive impairment in NPC as well, and prompted us to evaluate the cholinergic functional involvement in NPC patients by applying a neurophysiologic technique, named short-latency afferent inhibition (SAI). We describe clinical, biochemical, molecular and neuropsychological features, and SAI findings in three patients affected by NPC. Diagnosis of NPC was assessed by molecular analysis of the NPC1 gene in all patients. In two of them, biochemical analysis of intracellular accumulation of unesterified cholesterol was also performed. The main clinical features were cerebellar ataxia, vertical supranuclear gaze palsy and a variable degree of cognitive impairment ranging from only memory impairment to severe dementia. Electrophysiological evaluation revealed a reduced SAI in all three patients. Our SAI findings provide evidence of cholinergic dysfunction in patients with the adult form of NPC, supporting that cholinergic alterations may play a role in cognitive impairment in NPC, and strengthening the similarities between NPC and AD.

Course and outcome of a voltage-gated potassium channel antibody negative Morvan’s syndrome

Morvan’s syndrome is a rare disease characterized by peripheral nerve hyperexcitability, associated with CNS and autonomic systems involvement. High serum voltage-gated potassium channel (VGKC) antibody titers have been reported, and, till now, Morvan’s syndrome has been considered as a VGKC antibody associated disease. We describe a patient with Morvan’s syndrome associated with myasthenia gravis and a thymoma in his previous history, with surprisingly undetectable levels of VGKC antibodies. The clinical course is similar to those cases of Morvan’s syndrome with VGKC-Ab, except for the lack of response to plasma exchange, previously considered as the first choice treatment. Nevertheless, the good response to corticosteroids therapy and the association with myasthenia confirm an autoimmune origin of the disease.

Uric acid: a potential biomarker of multiple sclerosis and of its disability

Abstract Background: Uric acid (UA) is a strong natural scavenger of reactive oxygen and nitrogen species, with evidence of possible use in the treatment of animal models of multiple sclerosis (MS). Consequently, serum UA has gained much attention as a possible biomarker of MS. We aim to investigate differences in serum UA levels between MS subjects and controls and evaluate possible relationships of UA with MS clinical features. Methods: We recruited relapsing-remitting and secondary progressive MS subjects and healthy controls and measured their serum UA levels. We excluded subjects presenting concomitant conditions affecting UA levels. Results: MS subjects (n=362) and controls (n=181) were recruited by propensity score matching (PSM). Statistical analyses were corrected for age, gender, and renal function. MS subjects presented significantly lower serum UA levels than controls (analysis of variance, p=0.014, adjusted r2=0.3036). Linear regression analysis showed a relationship between UA levels and disease duration (p<0.001, adjusted r2=0.3158, coefficient –0.00039), time from diagnosis (p<0.001, adjusted r2=0.3100, coefficient –0.0012), and Expanded Disability Status Scale (EDSS) (p<0.001, adjusted r2=0.3230, coefficient –0.1). Conclusions: Our findings support the importance of serum UA as a biomarker of MS disability and progression. Further studies with longitudinal design should be specifically designed to evaluate the importance of UA in the different stages of MS and in relation to distinct therapeutic strategies.

Insulin Sensitivity and Early-Phase Insulin Secretion in Normoglycemic Huntington's Disease Patients

BACKGROUND Huntingtons disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the HTT gene. There is increasing evidence pointing towards an involvement of the endocrine system in HD. Recent studies, investigating the increased risk of diabetes mellitus and impaired insulin sensitivity and secretion in HD patients, led to contradictory results. OBJECTIVE To investigate glucose homeostasis in HD. METHODS Twenty-eight consecutive patients with HD and 28 healthy controls were matched for age, sex, and BMI. Diagnosis of HD was confirmed genetically. Clinical tools for assessment were the Unified Huntingtons Disease Rating Scale (UHDRS) motor section and the Total Function Capacity (TFC). Basal metabolic and endocrine investigations and a 2-hour 75-g oGTT were performed. We used the homeostasis model assessment of insulin resistance (HOMA-IR) as index of insulin sensitivity and the insulinogenic index to assess insulin secretion. RESULTS HD patients did not differ from the controls with respect to fasting plasma glucose, insulin sensitivity and secretion. CAG expansion size, disease stage and duration, or BMI did not influence HOMA-IR and insulinogenic index. Patients showed lower serum glucose (-19%) and insulin levels (-48%) at 30 min and higher serum insulin levels at 90 (+132%) and 120 min (+380%). CONCLUSIONS Our data do not support an increased risk of diabetes among HD patients although they show glucose regulation abnormalities with a flat glucose curve and delayed insulin peak after oral glucose load.

Modifications of Resting State Networks in Spinocerebellar Ataxia Type 2

We aimed to investigate the integrity of the Resting State Networks in spinocerebellar ataxia type 2 (SCA2) and the correlations between the modification of these networks and clinical variables.

How many injections did you miss last month? A simple question to predict interferon β-1a adherence in multiple sclerosis

Objectives: Adherence to treatment is of utmost importance in multiple sclerosis (MS) to achieve full benefits from disease-modifying treatments. Thus, we investigated predictors of adherence to interferon β-1a. Methods: 114 relapsing-remitting MS subjects were recruited and followed-up during 1.536 ± 0.961 years. RebiSmart® (Ares Trading SA, Coinsins, Switzerland), an electronic auto-injector, allows real-time recording of adherence which was retrospectively evaluated, and subjects were categorized accordingly: fully adherent (if no doses were missed), early or late missing (if missing the first dose during the first month of observation or later). The occurrence of clinical relapses and the annualized relapse rate (ARR) were prospectively recorded. Results: Adherence was 95.0 ± 9.0%. Early missing (n = 17, 14.9%) was more likely to be associated with the occurrence of a clinical relapse (OR = 4.155; p = 0.018), but not late missing (n = 54, 47.4%) (OR = 1.454; p = 0.408), as compared to fully adherent (n = 43, 37.7%). Adherence was lower in early missing, as compared to late missing (p < 0.001). The ARR was higher in early missing, as compared to late missing and to fully adherent (p < 0.001). Conclusion: MS subjects missing an injection early presented lower adherence, and a fourfold chance of having a relapse, suggesting a simple way to assess and categorize adherence in a clinical, real-life setting, where lack of time often prevents more thorough evaluations.

Assessing association of comorbidities with treatment choice and persistence in MS: A real-life multicenter study

Objective: To assess whether the presence of concomitant diseases at multiple sclerosis (MS) diagnosis is associated with the choice and the treatment persistence in an Italian MS cohort. Methods: We included newly diagnosed patients (2010–2016) followed in 20 MS centers and collected demographic and clinical data. We evaluated baseline factors related to the presence of comorbidities and the association between comorbidities and the clinical course of MS and the time to the first treatment switch. Results: The study cohort included 2,076 patients. Data on comorbidities were available for 1,877/2,076 patients (90.4%). A total of 449/1,877 (23.9%) patients had at least 1 comorbidity at MS diagnosis. Age at diagnosis (odds ratio 1.05, 95% confidence interval [CI] 1.04–1.06; p < 0.001) was the only baseline factor independently related to the presence of comorbidities. Comorbidities were not significantly associated with the choice of the first disease-modifying treatment, but were significantly associated with higher risk to switch from the first treatment due to intolerance (hazard ratio 1.42, CI 1.07–1.87; p = 0.014). Association of comorbidities with risk of switching for intolerance was significantly heterogeneous among treatments (interferon β, glatiramer acetate, natalizumab, or fingolimod; interaction test, p = 0.04). Conclusions: Comorbidities at diagnosis should be taken into account at the first treatment choice because they are associated with lower persistence on treatment.

A longitudinal real-life comparison study of natalizumab and fingolimod.

Different retrospective studies compared natalizumab and fingolimod in relapsing‐remitting multiple sclerosis (RRMS), with conflicting results. We aimed to explore the prescriptive attitude and the clinical outcome of the two therapies.