Metformin plus chemotherapy versus chemotherapy alone in the first-line treatment of HER2-negative metastatic breast cancer. The MYME randomized, phase 2 clinical trial.

PURPOSE: To investigate the efficacy of metformin (M) plus chemotherapy versus chemotherapy alone in metastatic breast cancer (MBC). METHODS: Non-diabetic women with HER2-negative MBC were randomized to receive non-pegylated liposomal doxorubicin (NPLD) 60 mg/m2 + cyclophosphamide (C) 600 mg/m2 × 8 cycles Q21 days plus M 2000 mg/day (arm A) versus NPLD/C (arm B). The primary endpoint was progression-free survival (PFS). RESULTS: One-hundred-twenty-two patients were evaluable for PFS. At a median follow-up of 39.6 months (interquartile range [IQR] 24.6-50.7 months), 112 PFS events and 71 deaths have been registered. Median PFS was 9.4 months (95% CI 7.8-10.4) in arm A and 9.9 (95% CI 7.4-11.5) in arm B (P = 0.651). In patients with HOMA index < 2.5, median PFS was 10.4 months (95% CI 9.6-11.7) versus 8.5 (95% CI 5.8-9.7) in those with HOMA index ≥ 2.5 (P = 0.034). Grade 3/4 neutropenia was the most common toxicity, occurring in 54.4% of arm A patients and 72.3% of the arm B group (P = 0.019). M induced diarrhea (G2) was observed in 8.8% of patients in Arm A. The effect of M was similar in patients with HOMA index < 2.5 and ≥ 2.5, for PFS and OS. CONCLUSIONS: The MYME trial failed to provide evidence in support of an anticancer activity of M in combination with first line CT in MBC. A significantly shorter PFS was observed in insulin-resistant patients (HOMA ≥ 2.5). Noteworthy, M had a significant effect on CT induced severe neutropenia. Further development of M in combination with CT in the setting of MBC is not warranted.

Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study‡.

Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety. Results: A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001). Conclusions: This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse. Trial Registration: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Lifestyle-related risk factors for Parkinson's disease: a population-based study.

OBJECTIVES: To investigate the association of major lifestyle-related risk factors with the prevalent cases of Parkinson's disease (PD) identified by the Italian Longitudinal Study on Aging. METHODS: A total of 5632 individuals randomly selected from the population registers of eight centers were screened for parkinsonism using both a questionnaire and a neurologic examination. Screened positives underwent a structured clinical work-up for the diagnosis of parkinsonism and parkinsonism subtypes. RESULTS: We identified 113 prevalent cases of PD. Age, male gender, and pesticide-use license were significantly related to PD. Heavy smoking was inversely related to PD. Age (OR = 1.1; 95% CI, 1.06-1.15) and pesticide-use license (OR = 3.7; 95% CI, 1.6-8.6) kept their significant correlation with the disease in the multivariate analysis to adjust for all the variables under investigation. Multivariate analyses were made for men and women separately: pesticide exposure was positively associated with PD only in men. CONCLUSIONS: Pesticide exposure might represent a candidate for environmental factors involved in PD.

Maurice Ravel and right-hemisphere musical creativity: influence of disease on his last musical works?

The problem of finding correspondence between a particular neuronal organization and a specific function of the human brain remains a central question of neuroscience. It is sometimes thought that language and music are two sides of the same intellectual coin, but research on brain-damaged patients has shown that the loss of verbal functions (aphasia) is not necessarily accompanied by a loss of musical abilities (amusia). Amusia without aphasia has also been described. This double dissociation indicates functional autonomy in these mental processes. Yet verbal and musical impairments often occur together. The global picture that emerges from studies of music and its neural substrate is by no means clear and much depends on which subjects and which aspect of musical abilities are investigated. An illustration of these concepts is provided by the case of the French composer Maurice Ravel, who suffered from a progressive cerebral disease of uncertain aetiology, with prominent involvement of the left hemisphere. As a result, Ravel experienced aphasia and apraxia and became unable to compose. The available facts favour a clinical diagnosis of primary progressive aphasia (PPA), with the possibility of an overlap with corticobasal degeneration (CBD). In view of Ravel's clinical history, we propose that two of his final compositions, the Bolero and the Concerto for the Left Hand, include certain patterns characteristic of right-hemisphere musical abilities and may show the influence of disease on the creative process.

Parkinson's disease and parkinsonism in a longitudinal study: two-fold higher incidence in men. ILSA Working Group. Italian Longitudinal Study on Aging.

OBJECTIVE: To determine the incidence of parkinsonism and PD in the Italian elderly, and to explore the relation with age and gender. METHODS: In eight Italian municipalities, a population-based, parkinsonism-free cohort was followed for an average of 3 years. At the end of the follow-up, the cohort survivors were directly contacted (screening and clinical examination). Cohort members who had died were studied using death certificates, clinical records, and information gathered from relatives and general practitioners. Parkinsonism diagnosis and subtyping were made according to specified diagnostic criteria. RESULTS: The cohort consisted of 4,341 individuals (65 to 84 years of age): 596 died before the examination, 2,863 (76.4% of the survivors) completed the screening procedure, and 882 refused to participate. The authors found 68 incident cases of parkinsonism: 42 PD (62%), 7 drug-induced parkinsonism (10%), 8 parkinsonism in dementia (12%), 8 vascular parkinsonism (12%), and 3 parkinsonism, unspecified (5.8%). Average annual incidence rate (per 100,000 person-years) in the population aged 65 to 84 years, adjusted to the 1992 Italian population, was 529.7 (95% CI, 400.5 to 658.9) for parkinsonism, and 326.3 (95% CI, 224.1 to 427.5) for PD. Incidence rates for both parkinsonism and PD increased with age in both men and women; men had higher rates in every age group. Age-adjusted relative risk in men compared with women was 1.66 (95% CI, 1.02 to 2.70) for parkinsonism and 2.13 (95% CI, 1.11 to 4.11) for PD. CONCLUSIONS: Incidence of parkinsonism and PD increased with age, PD was the most common type of parkinsonism, and men had a risk of developing PD twice that of women.

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. DESIGN: Cross-sectional examination in the context of the Italian Longitudinal Study on Aging. SETTING: Random population sample from eight Italian municipalities. PARTICIPANTS: A total of 3,425 individuals aged 65-84 years, residing in the community or institutionalized. MEASUREMENTS: Study participants were screened for cognitive impairment by using the Mini-Mental State Examination. Trained neurologists examined those scoring <24. CIND diagnosis relied on clinical and neuropsychological examination, informant interview, and assessment of functional activities. Age-related cognitive decline (ARCD) was diagnosed in CIND cases without neuropsychiatric disorders responsible for the cognitive impairment. RESULTS: Prevalence was 10.7% for CIND and 7.5% for ARCD, increased with age, and was higher in women. Age (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.06-1.12), stroke (OR, 2.05; 95% CI, 1.26-3.35) and heart failure (OR, 1.73; 95% CI, 1.11-2.68) were significantly and positively associated with CIND at multivariate analysis. Education (OR, 0.61; 95% CI, 0.56-0.65) and smoking (OR, 0.72; 95% CI, 0.54-0.98) showed a negative correlation. Age and myocardial infarction were positively associated with ARCD, whereas a negative correlation was found for education and smoking. The effect of smoking was no more significant either on CIND or ARCD considering current habits or "pack year" exposure. CIND showed an independent impact on ADL (OR, 1.88; 95% CI, 1.41-2.49). CONCLUSIONS: CIND is very frequent in older people. The effect of demographic variables and vascular conditions offers opportunities for prevention. The association with functional impairment is useful to evaluate the burden of disability and healthcare demands.

Magnetic resonance measures in Alzheimer disease: their utility in early diagnosis and evaluating disease progression.

We sought to identify the most reliable magnetic resonance (MR) measures for the diagnosis and staging of Alzheimer disease (AD) in a clinical setting and to estimate, for different degrees of dementia, the rate of change of cerebral atrophy in certain regions of interest (ROIs). Forty-two probable AD patients and eight normal controls underwent MR brain scans, neurological examinations, and neuropsychological testing. We computed each subject's corpus callosum width, ventricular size, right and left temporal lobe areas, interuncal distance, and assessed the degree of cortical atrophy. We also estimated the rate of change for Information-Memory-Concentration Test scores and for temporal lobe areas and corpus callosum width. Measures of temporal lobe area and subjective evaluation of temporal lobe atrophy both served to distinguish controls from mild AD cases (p < 0.05), whereas only the latter differentiated moderate from severe patients (p < 0.05). The rate of change for temporal lobe areas remained constant over different AD stages, whereas those for corpus callosum width and for cognitive impairment were greater for severe cases (p < 0.05). Our findings imply that measurements of temporal lobe area and ratings of temporoparietal atrophy can be useful in the diagnosis and staging of AD and suggest that atrophy progressed at different rates in selected ROIs for various stages of AD severity.

Influence of different screening procedures on the stroke prevalence estimates: the Italian Longitudinal Study on Aging.

Stroke prevalence surveys are more and more needed for health care and facility planning. Prevalence estimates and costs of the definition procedure may vary depending on different screening strategies. We evaluated the impact of these different strategies on the overall diagnostic procedure and on stroke prevalence estimates in the Italian Longitudinal Study on Aging. A population sample of 5, 632 individuals aged 65-84 years was screened for stroke by a simple question on previous stroke diagnosis, questions on possible stroke symptoms and a simple neurological examination. Those screened positive by any of these procedures were fully examined by a neurologist for conclusive diagnosis. We determined the positive predictive value of each procedure on the final stroke diagnosis and calculated prevalence as if each procedure had been used separately. Using the three procedures combined, the prevalence rate was 6.0% (95% confidence interval, 5.4-6.7%). If each procedure had been used as the unique screening tool, the rates would have been 5.1% (4.5-5. 7%), 4.1% (3.6-4.7%) and 2.3% (1.9-2.7%), and positive predictive values 66.4, 55.2 and 45.1%, respectively. Different screening procedures can affect stroke prevalence estimates. Compared to more complex screening strategies, the use of a simple question about previous diagnosis as the unique screening tool leads to only a slight underestimation of stroke prevalence and avoids a 66% increase in the number of subjects to be examined in a second-level specialist evaluation, potentially reducing the costs of the overall diagnostic procedure.

Validity of different linguistic versions of the Alzheimer's Disease Assessment Scale in an international multicentre Alzheimer's disease trial.

Owing to the involvement of Italian Centres in a multicentre, German-Italian therapeutical trial with Alzheimer's dementia patients, to be assessed with the Alzheimer's Disease Assessment Scale (ADAS), it was decided that the Italian centres would use an Italian version of the scale, derived from that used by the German centres. However, the lists of words for exploring verbal memory are not merely translated from the German version, but are composed of selective Italian words chosen according to linguistic criteria. This Italian version was validated following the same procedure adopted for validating the German version. We submitted this Italian version to an interrater reliability, test-retest reliability, concurrent validity, internal consistency and sensitivity evaluation, using demented patients. Based on the results of these tests this Italian version of the ADAS proved valid and reliable. Moreover, the results were strikingly comparable to those from the validation of the German version. Our work supports the validity, reliability and transnational comparability of national versions of the ADAS constructed following definite linguistic criteria.

Dementia is a major predictor of death among the Italian elderly. ILSA Working Group. Italian Longitudinal Study on Aging.

BACKGROUND: Neurologic diseases are rarely listed on death certificates because death is more often attributed to cardiovascular and pneumonic events occurring during terminal stages. OBJECTIVE: To evaluate the effect of major age-associated neurologic and non-neurologic diseases on survival in a cohort of Italian elderly. METHODS: A population-based multicenter survey, carried out in eight Italian municipalities, with a sample of 5,632 individuals aged 65 to 84 years. The entire sample was screened for all the diseases under study, and all individuals were interviewed about risk factors. Those who screened positive underwent clinical assessments by specialists. Two years after the baseline survey, the study population was followed up to determine the vital status either directly from the individuals or from proxy respondents. A copy of the death certificate was obtained for each individual who had died. The risk of dying (mortality risk ratio [MRR]) was calculated using the Cox proportional hazards model in which we included all the diseases under study, age, gender, and years of education. RESULTS: At follow-up (mean duration 26.7 +/- 5.4 months) 444 individuals had died. The Cox proportional hazards model selected the following as significant predictors of death: age (for year of age MRR = 1.12; 95% confidence interval [CI], 1.08 to 1.15), male gender (MRR = 1.72; 95% CI, 1.27 to 2.34), institutionalization (MRR = 4.17; 95% CI, 2.20 to 7.94), dementia (MRR = 3.61; 95% CI, 2.55 to 5.11), neoplasm (MRR = 2.01; 95% CI, 1.20 to 3.38), heart failure (MRR = 1.87; 95% CI, 1.27 to 2.76), and diabetes (MRR = 1.62; 95% CI, 1.12 to 2.34). CONCLUSIONS: These data provide further evidence on the malignancy of dementia, which proved the major predictor of death in the elderly, with an MRR higher than neoplastic diseases and other severe age-associated conditions.

Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of Dementia.

OBJECTIVE: To investigate the risk of AD associated with a family history of dementia, female gender, low levels of education, smoking, and head trauma. BACKGROUND: These putative factors have been identified in cross-sectional studies. However, those studies are prone to bias due to systematic differences between patients and control subjects regarding survival and how risk factors are recalled. METHODS: The authors performed a pooled analysis of four European population-based prospective studies of individuals 65 years and older, with 528 incident dementia patients and 28,768 person-years of follow-up. Patients were detected by screening the total cohort with brief cognitive tests, followed by a diagnostic assessment of those who failed the screening tests. Dementia was diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. (revised), and AD was diagnosed according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria. Incident rates and relative risk (95% CI) express the association of a risk factor for dementia. RESULTS: Incident rates for dementia and AD were similar across studies. The incidence of AD increased with age. At 90 years of age and older the incidence was 63.5 (95% CI, 49.7 to 81.0) per 1,000 person-years. Female gender, current smoking (more strongly in men), and low levels of education (more strongly in women) increased the risk of AD significantly. A history of head trauma with unconsciousness and family history of dementia did not increase risk significantly. CONCLUSION: Contrary to previous reports, head trauma was not a risk factor for AD, and smoking did not protect against AD. The association of family history with the risk of AD is weaker than previously estimated on the basis of cross-sectional studies. Female gender may modify the risk of AD, whether it be via biological or behavioral factors.

Education and the risk of physical disability and mortality among men and women aged 65 to 84: the Italian Longitudinal Study on Aging.

BACKGROUND: Most studies report that people with higher education enjoy better health and longer life. Although it is well known that most risk factors are more common among individuals with a lower level of education, the underlying mechanism of this association is not fully understood. The objective of this study was to assess the association between education, disability, and mortality. METHODS: We analyzed data on 1,817 men and 1,643 women, aged 65-84 years, to assess the association of educational level with physical disability and mortality adjusting for age, sex, smoking habit, occupation, and major chronic conditions. RESULTS: The association between educational level and disability was characterized by a dose-response effect, with the relative odds significantly decreased by about 30%, 60%, and 79% in those with 4 or 5, 6 to 8, and more than 8 years of education, compared to those with 3 or less years of education. Death rates were lower among persons with 4 or more years of education compared to those with less education. However, after adjusting for disability status, education was no longer associated with mortality (RR=0.97, CI=0.65-1.43). CONCLUSIONS: The strong association of low education with disability found in this study may explain the inverse association with mortality reported in previous studies. Disability, indeed, seems to be the mediator between education and mortality and might be due to the higher severity level of diseases, leading to death, in the lower educated group.

Sex-related differences in human cerebral hemodynamics.

OBJECTIVES: To identify possible inter-hemispheric sex-related cerebral hemodynamic differences at rest, in healthy subjects by transcranial Doppler (TCD). SUBJECTS AND METHODS: Mean flow velocity (MV) was recorded by TCD in 96 (48 males, 48 females) right-handed volunteers. Mean age was similar in males and females, distribution of age-groups by sex was similar, too. RESULTS: Examining by sex MV values in each basal artery, left middle cerebral artery (MCA) showed a statistically significant difference (53.5+/-8.2 cm x s(-1) in males versus 58.5+/-10.4 cm x s(-1) in females, P=0.005, one-way ANOVA). Multiple regression models show a significant correlation between age and MV on each side, while sex correlates with MV on the left side. CONCLUSION: A sex-dependent hemispheric difference in MV in the left MCA at rest (females>males) in the younger population subgroup was identified. These data support recent observations on anatomical differences between sexes, referring a proportionally larger Broca area in females compared to males.

Detection of skewed T-cell receptor V-beta gene usage in the peripheral blood of patients with multiple sclerosis.

The ex vivo analysis of the T-cell receptor V-beta (TCRBV) gene usage by circulating T lymphocytes in Multiple Sclerosis (MS) patients may contribute to understanding disease pathogenesis. In the present study, TCRBV gene usage was analyzed in freshly collected unstimulated peripheral blood mononuclear cells (PBMC) isolated from 40 MS patients and 20 healthy controls. Nine patients presented abnormal repertoires, with expansion of one or more TCRBV segments. Among these patients, six presented expansion of TCRBV9 chain expression, three also having an expansion of TCRBV1, TCRBV11 and TCRBV22 segments. The most frequently observed TCRBV chain expansion, TCRBV9, was further analyzed and identified as polyclonal. Evaluation of clinical variables showed that median disease duration was shorter in patients with TCRBV gene expression abnormalities. Longitudinal evaluation of five patients with a skewed repertoire showed regression of expanded TCRBV chains expression to normal values. These data indicate that certain MS patients have abnormal TCRBV gene expression. Such abnormalities are caused by polyclonal expansions of T lymphocyte subpopulations that use the same TCRBV gene families, are unstable and preferentially observed early in the course of the disease.

Implication of alpha1-antichymotrypsin polymorphism in familial Alzheimer's disease.

A common polymorphism in the alpha1-antichymotrypsin (ACT) gene has been shown to modify the Apolipoprotein E (ApoE) epsilon4-associated Alzheimer's disease (AD) risk identifying the combination of the ACT/AA and ApoE epsilon4/epsilon4 genotypes as a potential susceptibility marker for AD. Using the polymerase chain reaction, we analyzed the segregation of the ACT and ApoE polymorphisms in familial Alzheimer's disease (FAD) patients carrying mutations in Presenilin (PS) and APP genes and in both early onset (EO) and late onset (LO) FAD patients without known mutations. Our data suggest that ACT does not represent an additional risk factor for PS and APP mutated families. However, in LOFAD patients a high frequency of the combined ACT/AA and ApoE epsilon4/epsilon4 genotypes suggest that ACT may interact with ApoE and play a role in LOFAD.

No implication of apolipoprotein E polymorphism in Italian schizophrenic patients.

Numerous studies have provided evidence for a genetic association of the Apolipoprotein E (ApoE) epsilon4 allele and late onset familial and sporadic Alzheimer's disease (AD). Clinical observations show that a proportion of schizophrenic patients may suffer from severe cognitive impairment. That could reflect a particular clinical aspect of this mental disorder or a common, yet unknown, neurodegenerative mechanism. We analysed the ApoE gene polymorphism in a sample of 69 Italian patients with schizophrenia, 140 AD patients and 121 controls. In schizophrenic patients, the distribution of ApoE genotypes does not significantly differ from that of controls. No effect of the ApoE genotype on age of onset was found. The frequency of ApoE alleles in Italian schizophrenic patients is comparable with control values, suggesting that ApoE polymorphism does not represent a risk factor for schizophrenia.

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 Alzheimer's disease in postmenopausal women. BACKGROUND: Postmenopausal estrogen use has been reported to lower the risk of Alzheimer's 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 Alzheimer's disease was diagnosed according to NINCDS-ADRDA criteria for possible and probable Alzheimer's 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 Alzheimer's disease patients (odds ratio, 0.24; 95% confidence interval, 0.07 to 0.77). The inverse association between estrogen therapy and Alzheimer's 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 Alzheimer's 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.

Growth properties and growth factor responsiveness in skin fibroblasts from centenarians.

Human fibroblast cultures, which have a finite replicative lifespan in vitro, are the most widely used model for the study of senescence at the cellular level. An inverse relationship between replicative capability and donor age has been reported in human fibroblast strains. We studied the growth capacity of fibroblast primary cultures derived from people whose lifespan was as closer as possible to the expected maximum human lifespan, i.e. people over one hundred. Our data suggest that outgrowth of fibroblasts from biopsies, growth kinetics at different population doubling levels, capability to respond to a classical mitogenic stimulus (such as 20% serum) and a variety of growth factors, were remarkably similar in fibroblasts from centenarians and young controls. On the whole, our data challenge the tenet of a simple and strict relationship between in vivo aging and in vitro proliferative capability of human fibroblasts, at least at the individual level.

Alzheimer's disease: patterns of cognitive impairment at different levels of disease severity.

The aim of this study was to establish the presence and the consistency of different cognitive profiles in AD patients taking into consideration the severity of mental impairment. Therefore we stratified 679 neuropsychological observations on 119 probable AD patients followed longitudinally on the basis of overall degree of cognitive impairment. To compare performance on tests with different score ranges we transformed raw test scores into coefficients; to summarize our results in terms of language versus visuo-spatial performance we computed indices of prevalent impairment of performance (IPIP) by subtracting the coefficients for constructional praxis from coefficients for language-related tests. Finally, we converted these indices into z-scores for each level of mental decline to identify patients with generalized, language (L) or visuo-spatial (V) prevalent impairment. The latter, 30% of the sample, can be detected at all stages of dementia. There was a higher percentage of males among language impaired patients (P<0.05). Approximately half of patients with L/V prevalent impairment continued to show such a focality when followed longitudinally. The groups did not differ in the annual rate of cognitive decline.