Paolo Livrea

Risk factors for clinically diagnosed Alzheimer's disease A case‐control study of an Italian population

We conducted a case-control study of 116 patients with the clinical diagnosis of Alzheimers disease (AD) in seven Italian centers. One hundred sixteen hospital controls and 97 population controls were matched by age, sex, and region of residence to the cases. A structured questionnaire was administered to the next-of-kin of cases and controls by trained interviewers to identify possible risk factors. Genetic, viral, toxic, immunologic, medical, surgical, and personality factors were investigated. Dementia among first- or second-degree relatives and advanced age of the mother at subjects birth (age over 40) were associated with AD. Head trauma was more frequent in cases than in either hospital or population controls, but the differences were not significant. Our data did not confirm the previously reported association with antecedent thyroid disease or family history of Downs syndrome.

Course and prognosis in early-onset MS Comparison with adult-onset forms

Objectives: To establish the prognostic role of clinical and demographic factors in a hospital-based cohort of MS patients categorized by age at clinical onset and clinical course. Methods: Eighty-three patients with MS had a clinical onset of the disease in childhood (age <16 years; early-onset MS [EOMS]) and 710 in adult age (between 16 and 65 years; adult-onset MS [AOMS]). Patients were followed for a mean period of observation of 5 years. Univariate and multivariate analyses of clinical and demographic predictors for rapid progression and disability were performed using a stepwise Cox regression model with time-dependent covariates. Results: In EOMS, the Expanded Disability Status Scale (EDSS) evaluated at last clinical examination was lower than in AOMS, despite a longer disease duration. The probability to reach growth disability and progression was significantly lower in EOMS than in AOMS. Median times to reach EDSS score of 4 and secondary progression were longer in EOMS than in AOMS, but the age at both endpoints was significantly lower in EOMS. In EOMS and AOMS, an irreversible disability was related to a secondary progressive course, a sphincteric system involvement at onset, and an older age at onset (in EOMS only for the group >14 years); in AOMS, other unfavorable factors were a pyramidal involvement at onset and a high relapse frequency in the first 2 years. The risk of entering secondary progression was significantly influenced by a high number of relapses in EOMS and by a higher age at onset and a short interattack interval in AOMS. Conclusion: A slower rate of progression of disease characterized EOMS patients, suggesting more plasticity to recover in developing CNS, but the early clinical manifestation cannot be considered a positive prognostic factor.

New natural history of interferon‐β–treated relapsing multiple sclerosis

To investigate the impact of interferon‐beta (IFNβ) on disease progression in relapsing‐remitting multiple sclerosis patients.

Brain atrophy and lesion load in a large population of patients with multiple sclerosis

Objective: To measure white matter (WM) and gray matter (GM) atrophy and lesion load in a large population of patients with multiple sclerosis (MS) using a fully automated, operator-independent, multiparametric segmentation method. Methods: The study population consisted of 597 patients with MS and 104 control subjects. The MRI parameters were abnormal WM fraction (AWM-f), global WM-f (gWM-f), and GM fraction (GM-f). Results: Significant differences between patients with MS and control subjects included higher AWM-f and reduced gWM-f and GM-f. MRI data showed significant differences between patients with relapsing-remitting and secondary progressive forms of MS. Significant correlations between MRI parameters and between MRI and clinical data were found. Conclusions: Patients with multiple sclerosis have significant atrophy of both white matter (WM) and gray matter (GM); secondary progressive patients have significantly more atrophy of both WM and GM than do relapsing-remitting patients and a significantly higher lesion load (abnormal WM fraction); lesion load is related to both WM and even more to GM atrophy; lesion load and WM and GM atrophy are significantly related to Expanded Disability Status Scale score and age at onset (suggesting that the younger the age at disease onset, the worse the lesion load and brain atrophy); and GM atrophy is the most significant MRI variable in determining the final disability.

Epidemiology of primary dystonia

The prevalence estimates for primary dystonia range from two to 50 cases per million for early-onset dystonia and from 30 to 7320 cases per million for late-onset dystonia. From analysis of methodological information from 14 selected studies, we concluded that all studies on the basis of treatment settings or record-linkage systems, and two population-based surveys were probably flawed by incomplete ascertainment; the third population-based study provided the largest prevalence for late-onset dystonia but probably overestimated the prevalence of the disorder. Age and ethnic differences among study populations further biased comparisons of estimates. On the basis of methodologically more robust service-based studies and the likely percentage of underdiagnosis in a given area, more accurate prevalence estimates may be 111 per million for early-onset dystonia in Ashkenazi Jews from New York area, 600 per million for late-onset dystonia in northern England, and 3000 per million for late-onset dystonia in the Italian population over age 50 years.

Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes.

In multiple sclerosis (MS), matrix metalloproteinase (MMP) activity in tissues is the result of a balance between MMPs and their tissue inhibitors (TIMPs). MMP-9 predominates in acute MS lesions and is inhibited by TIMP-1, while MMP-2 may participate in the remodeling of the extracellular matrix (ECM) such as in chronic disease and is inhibited by TIMP-2. These differences may be reflected in serum and cerebrospinal fluid (CSF). We have tried to characterize MMP-2 and MMP-9 activities, in relation to their respective TIMPs, 2 and 1, as a factor of different types of the disease, as this information was not previously clearly stated. We found the MMP-2/TIMP-2 ratio in serum to show higher values in secondary progressive (SP, p=0.02) and primary progressive (PP, p=0.01) MS than short disease duration (SDD) relapsing-remitting (RR) MS, but not different from the healthy control (HC) group. Whereas the MMP-9/TIMP-1 ratio in serum showed higher (p=0.04) values in SDD RR MS than PP but also in active patients, evaluated either clinically (p=0.006) or from the magnetic resonance imaging (MRI, p<0.05), compared to inactive disease. CSF MMP to TIMP ratios did not differ between MS subtypes, suggesting systemic rather CNS-restricted changes. These results show that an increase in MMP-2/TIMP-2 ratio marks chronic progression in MS, but it is as high as in HC, and also confirm that high MMP-9 activity characterizes short duration relapsing and active forms of the disease.

Changes of serum sICAM-1 and MMP-9 induced by rIFNβ-1b treatment in relapsing-remitting MS

OBJECTIVE To correlate changes in serum levels of intercellular adhesion molecule-1 (sICAM-1) and matrix metalloproteinases (MMP) with clinical and MRI evidence of disease activity in MS patients receiving treatment with interferon-beta (rIFNbeta)-1b. BACKGROUND rIFNbeta reduces the frequency of gadolinium-enhancing (Gd+) MRI in relapsing-remitting MS (RRMS). Its mechanism of action on improving the integrity of the blood-brain barrier remains unclear. METHODS sICAM-1 and MMP-9 and MMP-2 serum levels were longitudinally (24 months) investigated (ELISA; zymography) in correlation with the modifications of the integrated area under the curve of Expanded Disability Status Scale scores normalized to entry baseline (deltaEDSS AUC) and of GD+ MRI scans, and with neutralizing antibodies (NAB) to rIFNbeta-1b production (MxA) in 36 RRMS patients. RESULTS During the first 12 months of treatment, levels of sICAM-1 increased and MMP-9 decreased significantly. After 12 months, levels returned toward baseline. Levels of sICAM-1 and MMP-9 were significantly negatively correlated. MMP-2 levels did not change significantly during the same period. During the second semester of the study, deltaEDSS AUC was significantly reduced. The percentage of patients with Gd+ MRI decreased significantly in the first (33%), second (29%), third (20%), and fourth (28%) semesters of treatment compared to baseline (62%). The NAB+ patients (14%) tended to have lower sICAM-1 levels at the ninth month; a higher MMP-9 activity at the sixth, 12th, and 18th months; and a greater deltaEDSS AUC in the third semester of treatment in comparison with the NAB- patients. CONCLUSIONS These results show that rIFNbeta-1b therapy increases sICAM-1 serum levels and reduces serum MMP-9 activity.

Multivariate analysis of predictive factors of multiple sclerosis course with a validated method to assess clinical events.

The clinical data of 309 patients with definite multiple sclerosis were recorded in the European data base for multiple sclerosis (EDMUS) to determine the prognostic significance of several demographic and clinical variables. An interview with closed questions structured according to standardised criteria of disease phases and courses was used to assess the clinical course. The reliability was evaluated by four trained neurologists in a sample of 33 patients with multiple sclerosis. Both the within and between rater agreement on data collection was fair to high for the historical variables (K = 0.33-1). Between rater agreement was more variable for the evaluation of 12 different EDMUS event categories (K = 0.3-0.95). The predictive model for the time to reach a secondary progression showed that an age at onset older than 25 (p = 0.006) and an event at onset followed by disability > or = 3 on the Kurtzke expanded disability status scale (EDSS; p = 0.004) were the most unfavourable clinical variables in 249 patients with relapsing remitting (180) or relapsing progressive (69) courses. In the 69 patients with relapsing progressive disease, the time to reach severe disability (EDSS > or = 6) was negatively influenced by a first interval between attacks shorter than one year, a number of bouts with EDSS > 2 in the first two years of the disease, and involvement of the pyramidal system at onset (p < 0.05). In 60 patients with chronic progressive disease this outcome was negatively influenced by pyramidal, brainstem, and sensory involvement at onset (p < 0.01).

Age‐related disability in multiple sclerosis

There is evidence that the clinical course of multiple sclerosis is age related. The present study evaluated the relationship between age and rate of disability progression in a large hospital‐based cohort of definite cases of multiple sclerosis (n= 1,463). Patients were followed every 6 to 12 months for a total period of observation of 11,387.8 person‐years. Expanded Disability Status Scale scores increased significantly with increasing current age and longer duration of disease (p=0.007). Median times to reach Expanded Disability Status Scale scores of 4.0 and 6.0, assessed using an extended Kaplan–Meier method with age as a categorical time‐varying covariate, were significantly longer among patients aged 20 to 35 years compared with patients aged 36 to 50 and 51 to 65 years (p < 0.0001). Significant associations were observed between mean Expanded Disability Status Scale scores and age at disease onset, current age, and the interaction of age at disease onset and current age (p < 0.001). Current age had a greater effect (59% of variability in the model) on disease severity than did age at disease onset. Furthermore, a multiplicative effect on Expanded Disability Status Scale score was observed for age at disease onset and current age combined, indicating a faster rate of disease progression in older patients. In conclusion, the results of the current study demonstrate the impact of age on rate of disability progression in multiple sclerosis and suggest that an age‐adjusted progression index may be a more relevant criterion for defining differences between multiple sclerosis groups.

Possible risk factors for primary adult onset dystonia: a case-control investigation by the Italian Movement Disorders Study Group

OBJECTIVES Little is known about the aetiology of idiopathic adult onset dystonia. The Italian Movement Disorders Study Group promoted a case-control study on some hypothetical risk factors including past medical events, life events, life habits, occupational hazards, and family hystory of dystonia, parkinsonism, and tremor. METHODS Cases affected by idiopathic adult onset dystonia (age at symptom onset >20 years, duration of disease >one year and <five years) were selected among consecutive outpatients attending 14 Italian centres. Control outpatients matched for age (±5 years), sex, and referral centre were identified among diagnostic categories thought to be unassociated with study exposures. Information was obtained by a standardised questionnaire administered by medical interviewers. Conditional logistic univariate and multivariate regression analyses were performed by a standard statistical package. RESULTS Multivariate analysis on 202 cases and 202 age and sex matched control outpatients indicated that head or facial trauma with loss of consciousness, family history of dystonia, and family history of postural tremor independently increased the risk of developing adult onset dystonia, whereas hypertension and cigarette smoking exerted a protective effect. The findings also suggested a positive association between local body injury—for example, previous ocular diseases and neck or trunk trauma—and dystonia of the same body part. CONCLUSIONS The results support the idea that environmental and genetic factors may both be important in the aetiology of adult onset dystonia, and suggest aetiological clues worthy of further analytical investigation.