Laura Bracco

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.

MCI conversion to dementia and the APOE genotype: A prediction study with FDG-PET.

Objectives: To investigate whether the combination of fluoro-2-deoxy-d-glucose (FDG) PET measures with the APOE genotype would improve prediction of the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). Method: After 1 year, 8 of 37 patients with MCI converted to AD (22%). Differences in baseline regional glucose metabolic rate (rCMRglc) across groups were assessed on a voxel-based basis using a two-factor analysis of variance with outcome (converters [n = 8] vs nonconverters [n = 29]) and APOE genotype (E4 carriers [E4+] [n = 16] vs noncarriers [E4−] [n = 21]) as grouping factors. Results were considered significant at p < 0.05, corrected for multiple comparisons. Results: All converters showed reduced rCMRglc in the inferior parietal cortex (IPC) as compared with the nonconverters. Hypometabolism in AD-typical regions, that is, temporoparietal and posterior cingulate cortex, was found for the E4+ as compared with the E4− patients, with the E4+/converters (n = 5) having additional rCMRglc reductions within frontal areas, such as the anterior cingulate (ACC) and inferior frontal (IFC) cortex. For the whole MCI sample, IPC rCMRglc predicted conversion to AD with 84% overall diagnostic accuracy (p = 0.003). Moreover, ACC and IFC rCMRglc improved prediction for the E4+ group, yielding 100% sensitivity, 90% specificity, and 94% accuracy (p < 0.0005), thus leading to an excellent discrimination. Conclusion: Fluoro-2-deoxy-d-glucose-PET measures may improve prediction of the conversion to Alzheimer disease, especially in combination with the APOE genotype.

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.

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.

ApoE allele frequencies in Italian sporadic and familial Alzheimer's disease

Recent studies have provided evidence of association of apolipoprotein E (ApoE) epsilon 4 allele and late onset familial and sporadic Alzheimers disease (AD). Epidemiological studies have established allelic variation at the ApoE locus. We have analyzed the ApoE gene polymorphism in a sample of 446 Italian subjects. Our data confirm a significant association between epsilon 4 allele and sporadic AD. The frequency of epsilon 4 allele in early onset familial AD patients was comparable to control values suggesting that epsilon 4 allele does not represent a risk factor for early onset familial AD (EOFAD). Moreover, we found a not previously reported association between ApoE epsilon 2 allele and sporadic AD and EOFAD.

Effects of ganglioside treatment in rats with a lesion of the cholinergic forebrain nuclei

The effects of GM1 ganglioside (30 mg/kg i.p.) administration for 22 days on choline acetyltransferase (ChAT) activity and noradrenaline (NA) levels in the cerebral cortex and on the acquisition of active and passive avoidance-conditioned responses were investigated in both sham-operated rats and in rats with a unilateral electrolytic lesion of the magnocellular forebrain nuclei (MFN). A statistically significant ChAT decrease in cortical areas ipsilateral to the lesion was found in saline-treated lesioned rats. In the lesioned GM1-treated rats, ChAT activity was only reduced in the frontoparietal areas and was significantly increased in the ipsilateral parietooccipital areas as well as in both contralateral regions. NA levels in the cortex were neither significantly affected by the lesion nor by GM1 treatment. The lesion impaired the acquisition of active and passive conditioned avoidance responses. GM1 treatment improved acquisition of the active avoidance response in the lesioned rats as indicated by a larger number of avoidances and a smaller number of escape failures during training in comparison with saline treatment. Ganglioside had no effect on the passive avoidance responses. These results demonstrate that GM1 administration facilitates the recovery of the cortical cholinergic system and of behavioral responses impaired by an electrolytic lesion of the cholinergic forebrain nuclei.

ApoE genotype and familial Alzheimer's disease: a possible influence on age of onset in APP717 Val-->Ile mutated families.

Recent studies have shown a genetic association of the apolipoprotein E (ApoE) epsilon 4 allele with late onset familial and sporadic Alzheimers disease (AD). In this study we analysed the possible association of the genetic polymorphism of the ApoE gene with age of onset in Italian familial Alzheimers disease (FAD) families including two early onset familial Alzheimers (EOFAD) families with the APP717 Val-->Ile mutation in the amyloid precursor protein (APP) gene on chromosome 21. In none of the FAD families analysed was there a significant effect of the ApoE genotype on the age of onset with the exception of one of the two mutated EOFAD families in which the epsilon 2 allele delayed the age of onset.

Brain metabolic decreases related to the dose of the ApoE e4 allele in Alzheimer’s disease

Objectives: Declines in brain glucose metabolism have been described early in Alzheimer’s disease (AD), and there is evidence that a genetic predisposition to AD contributes to accelerate this process. The epsilon4 (e4) allele of the apolipoprotein E (ApoE) gene has been implicated as a major risk factor in this process. The aim of this FDG-PET study was to assess the ApoE e4 dose related effect on regional cerebral glucose metabolism (METglc) in clinical AD patients, with statistical voxel based methods. Methods: Eighty six consecutive mild to moderate AD patients included in the Network for Efficiency and Standardisation of Dementia Diagnosis database underwent FDG-PET scans at rest. PCR was used to determine the ApoE genotype. Patients were grouped as e4 non-carriers (n = 46), e3/e4 (n = 27) and e4/e4 (n = 13) carriers. A voxel-based mapping program was used to compare each AD subgroup with a database of 35 sex and age matched controls (p<0.001, corrected for cluster extent) and also to compare between the subgroups (p<0.001, uncorrected). Results: No difference was found as to age at examination, age at onset, sex, disease duration, educational level, or severity of dementia between AD subgroups. Compared with controls, all AD subgroups had equivalent METglc reductions in the precuneus, posterior cingulate, parietotemporal, and frontal regions. Direct comparisons between AD subgroups indicated that patients with at least one e4 allele had METglc reductions within additional associative and limbic areas compared with e4 non-carriers. Conclusions: The present FDG-PET study showed different metabolic phenotypes related to the ApoE genotype in clinical AD patients, as revealed with voxel based statistical methods. The results suggest a generalised disorder in e4 carriers impairing metabolism globally, in addition to the more localised changes typical of AD patients.

The use of surrogate respondents to obtain questionnaire data in case-control studies of neurologic diseases

In 1984-85, the authors assessed the reliability of surrogate respondents to provide interview data for the specific items of a case-control study of Alzheimers disease conducted in Italy. For all questions of the interview, responses of 52 non-demented subjects were compared to responses of their next-of-kin. In 21-27% of the pairs the next-of-kin was unable to answer questions about general anesthesia, antacid drug use, and age of mother and father at index birth. However, the surrogate respondent was able to answer 45 of 57 tested items with agreement greater than 80%. Questions about use of hard liquor and behavior pattern yielded agreement of 71-75%, while those about number of jobs, and number of cigarettes per day yielded 62-63% agreement. For those who provided information about antacid drug use, agreement was poor. These findings are encouraging for the use of next-of-kin respondents in case-control studies of Alzheimers disease or other neurologic conditions for which the subject cannot provide historical information.

Study of epidemiological and etiological factors of amyotrophic lateral sclerosis in the province of Florence, Italy

An epidemiological survey of amyotrophic lateral sclerosis (ALS) based on 83 patients living in the province of Florence (central Italy) showed an incidence of 0.714 X 100,000 inhabitants and a prevalence of 2.142 X 100,000 inhabitants. The disease was found to be more prevalent in males (sex ratio 1.3‐1). Average age of onset was 59 years (57 ± 4 for males and 61.6 ± 3 for females). No particular geographical distribution was noted. 59 % of the patients presented the conventional amyotrophic form, while 10% and 30 % were those with the bulbar and polyneuritic type, respectively. A survey of the social and economic status showed ALS to be more frequent in manual workers (P<0.001). Among all patients 31 % presented evidence of trauma; however only in 15 % of them could the trauma be chronically and topographically related to the onset of ALS. The presence of other diseases associated with ALS was examined but the combination found may be only casual.