G. Scarlato

In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria.

A severe mitochondrial protein synthesis defect in myoblasts from a patient with mitochondrial myopathy was transferred with myoblast mitochondria into two genetically unrelated mitochondrial DNA (mtDNA)-less human cell lines, pointing to an mtDNA alteration as being responsible and sufficient for causing the disease. The transfer of the defect correlated with marked deficiencies in respiration and cytochrome c oxidase activity of the transformants and the presence in their mitochondria of mtDNA carrying a tRNA(Lys) mutation. Furthermore, apparently complete segregation of the defective genotype and phenotype was observed in the transformants derived from the heterogeneous proband myoblast population, suggesting that the mtDNA heteroplasmy in this population was to a large extent intercellular. The present work thus establishes a direct link between mtDNA alteration and a biochemical defect.

Cognitive impairment without dementia in older people : prevalence, vascular risk factors, impact on disability. The Italian Longitudinal Study on aging

OBJECTIVES: To investigate prevalence of “cognitive impairment, no dementia” (CIND) in the Italian older population, evaluating the association with cardiovascular disease and the impact on activities of daily living (ADL). CIND may provide pathogenic clues to dementia and independently affect ADL.

Estrogen-replacement therapy and Alzheimer's disease in the Italian Longitudinal Study on Aging

Objective: To study the association of estrogen-replacement therapy and other estrogen-related variables with Alzheimers disease in postmenopausal women. Background: Postmenopausal estrogen use has been reported to lower the risk of Alzheimers disease. Design: A population-based, multicenter survey was carried out in eight Italian municipalities. The sample of 2,816 women, aged 65 to 84 years, was randomly selected from the population register of each municipality and stratified in 5-year age groups. All women were screened using the Mini-Mental State Examination and interviewed concerning risk factors. Those who screened positive underwent a clinical assessment. Dementia syndrome was diagnosed according to DSM-III-R criteria, and Alzheimers disease was diagnosed according to NINCDS-ADRDA criteria for possible and probable Alzheimers disease. Results: The estimated prevalence of postmenopausal estrogen use adjusted to the 1991 Italian female population was 12.3%. The frequency of estrogen use was higher among nonpatients compared with Alzheimers disease patients (odds ratio, 0.24; 95% confidence interval, 0.07 to 0.77). The inverse association between estrogen therapy and Alzheimers disease remained significant after adjustment for age, education, age at menarche, age at menopause, smoking and alcohol habits, body weight at the age of 50 years, and number of children(odds ratio, 0.28; 95% confidence interval, 0.08 to 0.98). Conclusions: Our data from a population-based study support the hypothesis that estrogen-replacement therapy is associated with a reduced prevalence of Alzheimers disease in postmenopausal women. Prospective clinical trials are required to enable women and their physicians to weigh risks and benefits of estrogen-replacement therapy for the prevention of dementia.

Glial activation in Alzheimer’s disease: the role of Aβ and its associated proteins

A common feature of Alzheimers disease (AD) pathology is the abundance of reactive astrocytes and activated microglia in close proximity to neuritic plaques containing amyloid-beta protein (Abeta). The relationship between glial activation and neurodegeneration remains unclear, although several cytokines and inflammatory mediators produced by activated glia have the potential to initiate or exacerbate the progression of neuropathology. Assuming that glial activation plays a central role in the development and progression of AD, a prominent feature is to understand which stimuli drive this activation in senile plaques and to define their effects in vitro. There is a growing body of evidence to suggest that deposition of Abeta and expression of its associated molecules represent important trigger factors in glial activation leading to an inflammatory reaction in the brain. Thus, unraveling the mechanisms by which these proteins exert their effect on glial cells may provide significant insight into the pathophysiology of AD, and may lead to the identification of new strategies for AD treatment.

Proinflammatory profile of cytokine production by human monocytes and murine microglia stimulated with β-amyloid[25–35]

Growing evidence indicates that amyloid (A beta) deposition and phagocyte activation participate in inflammatory reactions in the brain during the course of Alzheimers disease. To further investigate the effects of A beta-phagocyte interaction, we examined the production of proinflammatory (IL-1beta, IL-6), chemotactic (MIP-1alpha, IP-10) and inhibitory (IL-1Ra, IL-10 and TGFbeta1) cytokines by cultured human monocytes and mouse microglial cells upon stimulation with A beta[25-35]. Northern blot analysis and specific immunoassays demonstrated that A beta[25-35] triggers mRNA expression and release of IL-1beta, IL-1Ra and MIP-1alpha but not of IL-6, IL-10, TGFbeta1 and IP-10 from human monocytes. Similar results were obtained by examining the production of IL-1beta, IL-6 and IL-10 from mouse microglial cells in the same experimental conditions. Taken together, these data indicate that A beta-phagocyte interaction can drive a different response towards cytokine production by monocytes and microglia, with a particular proinflammatory trend, and further support a role for A beta deposition as a triggering factor of inflammatory events in Alzheimers disease.

Incidence of Dementia, Alzheimer's Disease, and Vascular Dementia in Italy. The ILSA Study

OBJECTIVES: To estimate the incidence of dementia, Alzheimers disease (AD), and vascular dementia (VaD) in older Italians and evaluate the relationship of age, gender, and education to developing dementia.

High‐dose intravenous immunoglobulin therapy in multifocal motor neuropathy

We treated five consecutive patients with multifocal motor neuropathy (MMN) with high-dose intravenous immunoglobulin (IVIg). Four patients had increased levels of anti-asialo-GM1 IgM and two of anti-GM1 IgM as well; one patient had no reactivity. We treated them twice with 0.4 g/kg IVIg for 5 consecutive days at a 2-month interval, followed by maintenance infusions up to 6 to 12 months. All patients with high anti-asialo-GM1 had a consistent clinical improvement starting 3 to 10 days after the first IVIg course; in one patient, recovery was complete and persistent for 12 months without additional treatment, while in three patients, improvement only lasted 20 to 30 days. There was a similar improvement in these patients after the second course of IVIg which was maintained by periodic 2-day IVIg infusions. Clinical improvement in these patients was associated with a reduction of conduction block in most, but not all, motor nerves, while antibody titers were not consistently modified by treatment. There was no clinical or electrophysiologic improvement in the patient without antiglycolipid activity after 6 months of IVIg. IVIg may be a safe and effective therapy for MMN.

The Italian Longitudinal Study on Aging (ILSA): Design and methods

The Italian Longitudinal Study on Aging (ILSA) is a population-based, longitudinal study of the health status of Italians aged 65–84 years. The main objectives of ILSA are the study of the prevalence and incidence rates of common chronic conditions in the older population, and the identification of their risk and protective factors. ILSA is also designed to assess age-associated physical and mental functional changes. A random sample of 5632 individuals, stratified by age and gender using the equal allocation strategy, was identified on the demographic lists of the registry office of eight municipalities: Genova, Segrate (Milano), Selvazzano-Rubano (Padova), Impruneta (Firenze), Fermo (Ascoli Piceno), Napoli, Casamassima (Bari), and Catania. An extensive investigation, including interviews, physical exams, and laboratory tests, was conducted at baseline to identify the presence of cardiovascular disease (ischemic heart disease, hypertension, congestive heart failure, arrhythmia, intermittent claudication), diabetes, impaired glucose tolerance, thyroid dysfunction, dementia, parkinsonism, stroke, and peripheral neuropathy, as well as assess physical and mental functional status. The baseline examination was carried out between March 1992 and June 1993; a second comprehensive examination will begin in March 1995. An interim hospital discharge data survey and a mortality survey are currently ongoing to assess the hospitalization rate and the cause-specific mortality rate in this study cohort. (Aging Clin. Exp. Res. 6: 464-473, 1994)

Cognitive impairment in Duchenne muscular dystrophy

Cognitive function and dystrophin gene mutations were investigated in 50 DMD patients (mean age 11.1 yr; range 3.5-20.3). General intelligence assessment showed 31% of patients with Wechsler full intelligence quotient (FIQ) lower than 75 (normal values: 100 +/- 14), and only 24% with appropriate FIQ level. Modal distribution of Wechsler verbal, performance, and FIQs, and Raven IQs was normal. Verbal IQ was more affected than performance IQ (PIQ) only in the younger group of subjects. Low PIQ correlated with the presence of macroglossia, detected in 13 out of 50 patients. Impairment of productive language was of non-dysphasic nature and correlated with defects of short-term memory, which was also affected in non-verbal skills. DMD patients shared the same spectrum of neuropsychological defects, regardless of whether they were or were not mentally retarded. The proportion of patients with dystrophin gene deletions was 64%. No statistically significant correlations were found between genetic data and psychometric assessment. Finally, (18F)-fluorodeoxyglucose positron emission tomography studies demonstrated cerebellar hypometabolism in all the DMD patients examined and variable involvement of associative cortical areas. These findings suggest a possible role of the cerebral and cerebellar hypometabolism in the cognitive impairment of DMD.

Limb immobilization for the treatment of focal occupational dystonia

Background: Occupational focal upper-limb dystonia is characterized by involuntary muscle contractions that selectively interfere with the execution of specific motor tasks such as writing or playing a musical instrument. Occupational dystonias have a severe social impact, especially in certain professions. The available medical treatments offer little benefit. Methods: In eight patients with idiopathic occupational focal dystonia of the upper limb, the dystonic forearm and hand were immobilized with a plastic splint for mean (±SD) 4.5 ± 0.75 weeks. Before splinting (base line) and at various intervals afterwards (4, 12, and 24 weeks), the authors assessed the severity of dystonia and the patients’ motor performance objectively (Arm Dystonia Disability Scale and Tubiana and Chamagne Score) and subjectively (Self-Rating Score). Results: Assessment 4 weeks after splint removal, when patients had regained normal voluntary movements, showed that the severity of dystonia and the patients’ performance of the impaired motor task had improved; the benefit persisted unchanged at later follow-up visits (Arm Dystonia Disability Scale: base line 20.6 ± 30.2%; after 4 weeks 83.9 ± 23.8%, p = 0.007; after 12 weeks 83.9 ± 23.8%, p = 0.007; after 24 weeks 79.7 ± 29.5%, p = 0.015. Tubiana and Chamagne Score: base line 28.6 ± 22.7%; after 4 weeks 80.0 ± 23.1%, p = 0.015; after 12 weeks 80.0 ± 23.1%, p = 0.015; after 24 weeks 74.3 ± 32.1%, p = 0.031. Self-Rating Score: base line 20.6 ± 19.3%; after 4 weeks 63.7 ± 25.2%, p = 0.015; after 12 weeks 66.9 ± 28.1%, p = 0.015; after 24 weeks 70.6 ± 31.8%, p = 0.015). At the 24-week visit the improvement disappeared in one patient, was moderate in three, and marked in four. Conclusions: Limb immobilization can be a simple, effective, safe, and inexpensive treatment for focal occupational upper-limb dystonia.