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Brain-derived natriuretic factor (BDNF) Val66Met polymorphism has been frequently reported to be associated with Alzheimer's disease (AD) with contrasting results. Numerous studies showed that Met allele increased the risk of AD only in women, while other studies have found worse cognitive performance in Val/Val carriers. We aimed to inquire the effects of Val66Met polymorphism on the progression from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) and from MCI to AD and to ascertain if this effect is modulated by demographic and cognitive variables. For this purpose, we followed up 74 subjects (48 SCD, 26 MCI) for a mean time of 9 years. All participants underwent extensive neuropsychological assessment, cognitive reserve estimation, BDNF and apolipoprotein E (ApoE) genotype analysis at baseline. Personality traits and leisure activities were assessed in a subgroup. Each patient underwent clinical-neuropsychological follow-up, during which 18 out of 48 SCD subjects progressed to MCI and 14 out of 26 MCI subjects progressed to AD. We found that Val66Met increased the risk of progression from SCD to MCI and from MCI to AD only in women. Nevertheless, Val/Val carriers who progressed from SCD to MCI had a shorter conversion time compared to Met carriers. We concluded that Val66Met polymorphism might play different roles depending on sex and stage of the disease.

Background Subjective Cognitive Decline (SCD) is a self-experienced decline in cognitive capacity with normal performance on standardized cognitive tests, showing to increase risk of Alzheimer’s Disease (AD). Cognitive reserve seems to influence the progression from SCD to Mild Cognitive Impairment (MCI) and to AD. The aim of our study was to investigate gender differences in cognitive reserve evaluating how sex might modulate the role of cognitive reserve on SCD. Methods We included 381 SCD patients who underwent clinical evaluation, neuropsychological assessment, evaluation of premorbid intelligence by the Test di Intelligenza Breve (TIB), cognitive complaints by the Memory Assessment Clinics Questionnaire (MAC-Q), and apolipoprotein E (APOE) genotyping. Results The proportion between women and men was significantly different (68.7% [95% CI 63.9–73.4 vs 31.4%, 95% CI 26.6–36.0]). Women were younger than men at onset of SCD and at the baseline visit (p = 0.021), had lower years of education (p = 0.007), lower TIB scores (p p = 0.012). TIB was directly associated with age at onset of SCD in both women and men, while years of education was inversely associated with age at onset only in women. Multivariate analysis showed that sex influences TIB independently from years of education. TIB was directly associated with MAC-Q in men. Conclusions Sex interacts with premorbid intelligence and education level in influencing the age at onset and the severity of SCD. As the effect of education was different between men and women, we speculated that education might act as a minor contributor of cognitive reserve in women.

Background and purpose CLOCK and PER2 genes have been implicated in sleep-wake cycle alterations and neurodegenerative diseases. Our aim was to evaluate the effect of CLOCK T3111C and PER2 C111G on cognitive functioning in subjective cognitive decline (SCD) patients and mild cognitive impairment (MCI) patients at the baseline of a longitudinal study, and the effect of these two polymorphisms on the progression to Alzheimer's disease (AD) of the two groups. Methods Sixty-eight subjects (41 SCD and 27 MCI) who underwent clinical evaluation, neuropsychological assessment, CLOCK and PER2 genotyping at baseline and neuropsychological follow-up every 2 years for a mean time of 10 years were included. Subjects who developed AD (SCD-c and MCI-c) and non-converters (SCD-nc, MCI-nc) were considered. Results CLOCK T3111C was detected in 47% of cases (21 SCD, 11 MCI) and PER2 C111G in 19% of cases (eight SCD and five MCI). PER2 G carriers presented lower premorbid intelligence score (P = 0.049), fewer years of education (P = 0.007) and a lower frequency of family history of AD (P = 0.04) than G non-carriers. MCI PER2 G carriers had worse performance in tests assessing memory, executive function, language and visuospatial abilities at baseline. During follow-up, two SCD and 15 MCI subjects progressed to AD: both of the SCD-c subjects presented the PER2 G allele, while none of the SCD PER2 G non-carriers converted to AD (P = 0.003). Conclusion PER2 seems to have a role in cognitive reserve and cognition in SCD and MCI patients. Nevertheless, further studies are needed to assess the role of PER2 C111G on the risk of progression to AD.

Background: Some genes could interact with cardiovascular risk factors in the development of Alzheimer&rsquo, s disease. We aimed to evaluate the interaction between ApoE &epsilon, 4 status, Clock T3111C and Per2 C111G polymorphisms with cardiovascular profile in Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI). Methods: We included 68 patients who underwent clinical evaluation, neuropsychological assessment, ApoE, Clock and Per2 genotyping at baseline, and neuropsychological follow-up every 12&ndash, 24 months for a mean of 13 years. We considered subjects who developed AD and non-converters. Results: Clock T3111C was detected in 47% of cases, Per2 C111G in 19% of cases. ApoE &epsilon, 4 carriers presented higher risk of heart disease, Clock C-carriers were more frequently smokers than non C-carriers. During the follow-up, 17 patients progressed to AD. Age at baseline, ApoE &epsilon, 4 and dyslipidemia increased the risk of conversion to AD. ApoE &epsilon, 4 carriers with history of dyslipidemia showed higher risk to convert to AD compared to ApoE &epsilon, 4&minus, groups and ApoE &epsilon, 4+ without dyslipidemia patients. Clock C-carriers with history of blood hypertension had a higher risk of conversion to AD. Conclusions: ApoE and Clock T3111C seem to interact with cardiovascular risk factors in SCD and MCI patients influencing the progression to AD.

The aim of this study was to evaluate the effect of cognitive reserve (CR), in progression from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) and Alzheimer's disease (AD). For this purpose, we followed up 263 patients (154 SCD; 109 MCI) for a mean time of 7 years. CR was assessed by the Test di Intelligenza Breve (TIB), functionally equivalent to the National Adult Reading Test. High CR resulted as a protective factor for progression from SCD to MCI. Age at conversion to MCI was delayed 9 years on average in SCD with high CR with respect to SCD with low CR. On the contrary, high CR resulted as a risk factor for progression from MCI to AD dementia only in APOE ε4 carriers. Conversion time from MCI to AD dementia was 3 years shorter in ε4 carriers with high CR than subjects with low CR and ε4 non-carriers with high CR. Consistent with the CR hypothesis, our results showed that higher levels of CR protect against the earliest clinical manifestations of AD. In line with the previous researches, we found an interaction between CR and APOE in progression from MCI to AD dementia.

BACKGROUND AND PURPOSE Subjective cognitive decline (SCD) is a self-experienced decline in cognitive capacity with normal performance on standardized cognitive tests and has been shown to increase the risk of Alzheimer's disease (AD). SCD could also be related to other conditions such as normal aging, psychiatric, neurological or medical disorders. The SCD Initiative proposed a set of features (SCD-plus) that increase the likelihood of preclinical AD in individuals with SCD. Our aim was to assess the effect of these features on the risk of conversion from SCD to AD. METHODS In total 150 SCD subjects who underwent extensive neuropsychological investigation, assessment of cognitive complaints and apolipoprotein E (ApoE) genotyping at baseline and clinical-neuropsychological follow-up for a mean time of 11 years were included. RESULTS During the follow-up, 20 subjects developed AD. Considering SCD-plus features, age at onset ≥60 years and ApoE e4 significantly increased the risk of conversion from SCD to AD. When our sample was stratified into three groups (no risk factor, one risk factor, two risk factors), the proportion of conversion was statistically significantly different between the three groups. CONCLUSIONS Our model allows the risk of AD to be stratified in patients experiencing SCD according to age at onset and ApoE genotype.

Background: Periodic circadian protein homolog 2 (PER2) has a role in the intracellular signaling pathways of long-term potentiation and has implications for synaptic plasticity. We aimed to assess the association of PER2 C111G polymorphism with cognitive functions in subjective cognitive decline (SCD). Methods: Forty-five SCD patients were included in this study. All participants underwent extensive neuropsychological investigation, analysis of apolipoprotein E (APOE) and PER2 genotypes, and neuropsychological follow-up every 12 or 24 months for a mean time of 9.87 ± 4.38 years. Results: Nine out of 45 patients (20%) were heterozygous carriers of the PER2 C111G polymorphism (G carriers), while 36 patients (80%) were not carriers of the G allele (G non-carriers). At baseline, G carriers had a higher language composite score compared to G non-carriers. During follow-up, 15 (34.88%) patients progressed to mild cognitive impairment (MCI). In this group, we found a significant interaction between PER2 G allele and follow-up time, as carriers of G allele showed greater worsening of executive function, visual-spatial ability, and language composite scores compared to G non-carriers. Conclusions: PER2 C111G polymorphism is associated with better language performance in SCD patients. Nevertheless, as patients progress to MCI, G allele carriers showed a greater worsening in cognitive performance compared to G non-carriers. The effect of PER2 C111G polymorphism depends on the global cognitive status of patients.

KIBRA is a signal transducer protein, mainly expressed in the kidney and brain. A single-nucleotide polymorphism (SNP rs17070145, T → C exchange) has been linked to different cognitive function. In 2008, we studied 70 subjects who complained of subjective cognitive decline (SCD) and found that CT/TT carriers performed worse than CC carriers on a long-term memory test. We followed up the 70 SCD subjects and also 31 subjects affected by mild cognitive impairment (MCI) for a mean follow-up time of 7 years, during which 16 SCD subjects progressed to MCI and 14 MCI subjects progressed to Alzheimer’s disease (AD). Carrying the T allele was associated with MCI and with a two times-higher risk of developing MCI than CC carriers. In the SCD sample, CT/TT carriers showed a greater worsening on Rivermead Behavioral Memory Test (RBMT) compared to CC carriers. In the MCI sample, CT/TT carriers performed worse than CC carriers on RBMT. There is a lack of consensus on the effect of KIBRA gene variants on cognitive performances in episodic memory and on the risk of AD. Our results confirm a role of T allele on progression of cognitive decline.

Attention is the first non-memory domain affected in Alzheimer's disease (AD), before deficits in language and visuo-spatial function, and it is claimed that attention deficits are responsible for the difficulties with daily living in early demented patients. The aim of this longitudinal study in a group of 121 Caucasian, community-dwelling, mild-to-moderate AD patients (Mini-Mental State Examination (MMSE) score >17) was to detect which cognitive domains were most affected by the disease and whether one year treatment with cholinesterase inhibitors was more effective in preserving attention than memory. All subjects were evaluated by a neuropsychological battery including global measurements (MMSE, Information-Memory-Concentration Test) and tasks exploring verbal long-term memory, language, attention, and executive functions. The comparison between two evaluations, made 12 months apart, shows statistically significant differences, indicating deterioration compared to baseline, in the following tests: MMSE (with no gender differences), Composite Memory Score, Short Story Delayed Recall, Trail-Making Test A, Semantic Fluency Test, and Token Test. Conversely, there were no differences in the two evaluations of the Digit Span, Corsi Tapping Test, Short Story Immediate Recall, and Phonemic Fluency Tests. It appears that the treatment specifically attenuated the decline in tests assessing attention and executive functions. A stabilization of the ability to pay attention, with the ensuing positive effects on executive functions, recent memory, and information acquisition which depend on attention, appears to be the main neuropsychological mechanism through which the activation of the cholinergic system, resulting from cholinesterase inhibition, exerts its effect on cognition.

Chromosome 19 is one of the several prominent chromosomes related to the risk of developing late-onset Alzheimer's disease (LOAD) and frontotemporal lobar degeneration (FTLD). However, only Apolipoprotein E (APOE) has been confirmed as a risk factor for both disorders. The aim of this study was to investigate a set of polymorphisms in the translocase of the outer mitochondrial membrane 40 (TOMM40) gene, located in close proximity to APOE, to clarify if the TOMM40 gene may be considered a risk factor for AD and FTLD, independently of APOE status. We performed a case-control study in a dataset of Italian LOAD and FTLD patients, analyzing the following three single-nucleotide polymorphisms (SNPs): rs157580, rs2075650 and rs157581. The analysis was made in 710 Italian subjects: 282 LOAD patients, 156 FTLD patients and 272 healthy subjects. Our results confirm the presence of an association between TOMM40 SNPs and LOAD in our Italian population, suggesting that genetic variations proximate to APOE contributes to the LOAD risk. Genotype and allele distribution of the TOMM40 polymorphisms between the FTLD group and controls did not show any statistical difference. When we analyzed haplotype distribution of the SNPs, taking into account the presence of the APOE allele, we observed a strong association between the ε4 allele and the GAC haplotype both in LOAD and FTLD patients. In contrast, this association did not hold for ε3/GAC. These results demonstrate that the TOMM40 gene does not have an APOE-independent role in the risk of developing LOAD and FTLD.

Advantages and limits of the use of cholinesterase inhibitors (ChEI) in Alzheimer's disease (AD) are well established. Their effects result from an increase in extracellular acetylcholine (ACh) whose hydrolysis is prevented by cholinesterase inhibition. In this way, the cholinergic deficit which characterizes AD may be corrected. This overview discusses which components of the cognitive process are improved by ChEI administration. In animal experiments, the increase in ACh release, detected in brain areas during behavioral tasks designed to tax attentional processes, demonstrates that an activation of cholinergic neurons underlies arousal and attention. Since arousal and attention depend on activation of the forebrain cholinergic system, it is to be expected that the loss of cholinergic neurons occurring in AD may lead to impairment of the attentional processes. Indeed, a consensus exists that attention is the first non-memory domain to be affected in AD, before deficits in language and visuo-spatial functions. The difficulties with daily living, which occur even in mild AD, may be related to attentional deficits. ChEIs, by restoring the cholinergic activity, should improve attention. If the cognitive changes resulting from ChEI treatment in AD patients are assessed with appropriate tests or selected items of the scales, a predominant effect on attention and executive functions emerges. In a group of 121 subjects with mild to moderate AD, (MMSE score 21.88 ± 3.63) followed in the Alzheimer Unit in Florence, after a year of treatment with standard doses of ChEIs, it was observed a stabilization of the disease, characterized by no changes of the tests evaluating attention and executive functions but a worsening of those involving memory mechanisms. These findings suggest that ChEI treatment preserves attention more than memory. Finally, the electrophysiological and neurochemical mechanisms through which the activation of the cholinergic forebrain neurons enhance attention and create the condition for information acquisition are reviewed.

Serotonin-transporter-linked polymorphism (5-HTTLPR) is involved in neuropsychiatric diseases and recently the S-isoform has been correlated with a higher risk of developing emotion-induced retrograde amnesia. In order to better clarify the possible role of the 5-HTT S/L polymorphism and its effects on cognitive ability, especially on memory skills, we report here the distributions of the 5-HTT genetic variant and the Apolipoprotein E (ApoE) ɛ-4 allele and their association with neuropsychological measures in older adults reporting problems with everyday memory. Moreover, we verified the presence of a possible association between the S-allele with depression and the personal trait of neuroticism. Our results indicate an association between the 5-HTTLPR S-allele and the risk of developing MCI. No association was found in the other three groups. We found a positive dose-dependent association between the S-allele and the Rey–Osterrieth complex figure test (recall) score. Finally, our data did not find an association between the same allele and depression or neuroticism. This data, in our opinion shows a slight, non-established influence of 5-HTTLPR on memory skills exhibited in challenging memory tests but no influence on other extra-mnesic cognitive abilities.

Introduction Mild cognitive impairment (MCI) prodromic of vascular dementia is expected to have a multidomain profile. Methods In a sample of cerebral small vessel disease (SVD) patients, we assessed MCI subtypes distributions according to different operationalization of Winblad criteria and compared the neuroimaging features of single versus multidomain MCI. We applied three MCI diagnostic scenarios in which the cutoffs for objective impairment and the number of considered neuropsychological tests varied. Results Passing from a liberal to more conservative diagnostic scenarios, of 153 patients, 5% were no longer classified as MCI, amnestic multidomain frequency decreased, and nonamnestic single domain increased. Considering neuroimaging features, severe medial temporal lobe atrophy was more frequent in multidomain compared with single domain. Discussion Operationalizing MCI criteria changes the relative frequency of MCI subtypes. Nonamnestic single domain MCI may be a previously nonrecognized type of MCI associated with SVD.

A recent, large meta-analysis has reproposed the role of the angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism as a risk factor for Alzheimer's disease (AD). To further investigate the proposed association and to better clarify the role of ACE as a risk factor for AD, we analyzed the genotype and allele frequency distribution of ACE I/D and apolipoprotein E (APOE) gene polymorphisms in 235 Italian patients with sporadic AD, 153 with familial AD (FAD), 192 healthy controls and 111 centenarians. Patients with AD were consecutively gathered from among the outpatients from the Neurology Department at the University of Florence. All 691 subjects were genotyped for ACE and APOE polymorphisms. There were no significant differences in ACE genotypes or allele frequencies in all the studied groups, even after stratification for APOE epsilon4 carrier status. Centenarians show the highest allele D frequency, although the value is not significant, thus suggesting a possible implication of the D allele as an epistatic allele that has pleiotropic age-dependent effects. In conclusion, our data suggest that the ACE allelic variant is not a susceptibility factor in sporadic and familial AD (FAD), nor does it mitigate the effect of the APOE epsilon4 allele in the risk of developing AD. Moreover, our data do not suggest a possible involvement of the D allele in longevity.

This study was designed to examine the correlations between resting-state brain glucose metabolism (CMRglc), as measured with Positron Emission Tomography and performance on executive function tasks in Alzheimer's disease (AD), while taking into account the severity of cognitive deterioration. We addressed this issue in 50 AD patients, classified as very mild (n = 22) and mild (n = 28) AD on the basis of an extensive neuropsychological battery. Thirteen healthy subjects were selected as controls for the neuropsychological measures. Statistical Parametric Mapping (SPM) was used to examine voxel-wise correlations between CMRglc and scores on selected cognitive tests of executive functions: the Stroop Test, the Trail Making Test, the Dual Task and the Phonemic Fluency, while correcting for age and global CMRglc. All analyses were done separately for the two AD subgroups. The very mild AD patients showed significant associations between Stroop and Trail Making Test scores and prefrontal regions metabolism, whereas the mild AD patients exhibited more widely distributed cognitive-metabolic correlations extending to the posterior brain regions. These data suggest that a large cortical network is implicated in executive dysfunction in AD, and that the pattern of cognitive-metabolic correlations varies according to disease severity.

Cognitive impairment and gait disturbances are the most frequent clinical findings in patients with leukoaraiosis (LA). Corpus callosum (CC) atrophy has been associated with dementia in patients with LA, as well as with gait disturbances in patients with normal pressure hydrocephalus. We investigated, in patients with LA, the possible association between gait impairment and CC atrophy, taking into account cognitive deficits and the other brain lesions commonly present in these patients. Thirty patients (M:F=21:9; mean age 72.5+/-6.3 years) with gait disturbances and brain CT images consistent with LA underwent an assessment of gait and a cognitive assessment of global and selective functions. Magnetic resonance imaging (MRI) was used to measure thickness and area of the CC, total LA volume, lacunar infarcts and size of lateral ventricles. We examined the effect of every MRI change on each performance measure. Reduction of CC thickness, particularly that of the anterior segment, had a significant effect on severity of gait impairment, as measured using the gait scale's score. It was independent of any other brain changes revealed by MRI, including LA. An independent, significant association was also found between CC area and the Left Hand Praxis test results. In patients with LA, CC atrophy is associated with gait impairment independently of LA and other brain abnormalities usually present in these patients.

This study investigated the contribution that white matter changes (WMCs) make to clinical and cognitive features in Alzheimer’s disease (AD), independently ofpossible confounders such as cortical atrophy and the apolipoprotein E genotype as well as their relationship to vascular risk factors. We semiquantitatively assessed the degree and location of WMCs (global, periventricular and deep white matter), lacunes and global atrophy on brain MRI scans of 86 AD cases, extensively evaluated from a clinical and neuropsychological point of view. Multivariate logistic and linear regression analysis showed that age was the only significant predictor of all WMC measures and revealed a significant association of periventricular WMCs with performance on executive function tasks as well as of deep WMCs with history of mood depression. Our results underline the significance of WMC location over size in the occurrence of specific cognitive deficits in AD.

Since greater attention has been paid to the direct link of genetic variation to cognition and memory performance, apolipoprotein E (ApoE) and brain-derived neurotrophic factor (BDNF) have been the two most frequently studied genes. To investigate the effect of BDNF and ApoE polymorphisms on the cognitive profile of mild-moderate Alzheimer's disease (AD) cases, AD patients, genotyped for ApoE and BDNF polymorphisms, underwent extensive neuropsychological investigation. The effect of either ApoE epsilon4 allele and BDNF genetic variant on the neuropsychological pattern of mental impairment was examined both in terms of group differences in performance on the neuropsychological tests between carriers and non-carriers of each variant and by selecting the best predictor of cognitive performance among demographic and genetic factors by means of a multiple regression analysis. Our data confirm a specific effect caused by the presence and amount of ApoE epsilon4 allele, while they suggest that BDNF genetic variants are not a susceptibility factor to AD.

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 epsilon 4 (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.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 (p0.001, corrected for cluster extent) and also to compare between the subgroups (p0.001, uncorrected).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.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.

Previous positron emission tomography (PET) studies with fluorodeoxglucose (FDG) as tracer in healthy elders showed that the epsilon4 allele of the apolipoprotein E (ApoE) gene is disruptive to cerebral glucose metabolism (rCMRglu), possibly through the interaction with the aging process. The present study was aimed at assessing whether this interaction occurs in patients with Alzheimer's disease (AD). Eight-six AD patients, including 40 ApoE4 carriers and 46 non-carriers, underwent (18)F-FDG PET scanning at rest. ApoE groups were comparable for age, gender, age at onset and disease duration. SPM'99 was used to assess rCMRGlu correlations with age, differences between ApoE groups and ApoE by age interaction, correcting for disease severity. Results were reported at P0.001, uncorrected. Correlations between age and rCMRGlu confirmed the well-known negative relationship for both groups. Lower rCMRGlu was found within the frontal and cingulate areas for ApoE4 carriers as compared with the non-carriers. Additionally, a significant ApoE by age interaction was detected in the frontal and anterior cingulate cortex, with the ApoE4 carriers having a steeper regression slope with respect to the non-carriers. These results indicate that age-related regional rCMRglu decreases within the frontal and anterior cingulate areas may be more severe in AD patients carrying the ApoE4 allele.

To evaluate whether inflammation-like mechanisms present in the brain of Alzheimer’s disease (AD) patients are reflected in the periphery, the expression of CD11b in peripheral blood neutrophils and the expression and activity of inflammatory markers in cultured skin fibroblasts were examined. We found significantly higher levels of CD11b in neutrophils from sporadic AD patients than in controls and this elevation was positively correlated with disease severity and progression rate of mental decline. Cultured skin fibroblasts from familial (FAD) and sporadic AD patients and from controls were immunopositive for both isoforms of cyclooxygenase with no differences between groups. In unstimulated culture, the production of prostaglandin-E2 in the medium was significantly higher in fibroblasts from sporadic AD and FAD patients than in controls, and this elevation was reverted by the addition of 25 μM of ibuprofen. Our findings provide further evidence of the presence of inflammatory and immuno-related markers in the periphery of AD patients and support those studies indicating the beneficial effects of anti-inflammatory therapy in AD.

Background and purpose : The majority of studies on neuropsychological complications after cardiac surgery used the raw variation of selective tests scores to define the occurrence of cognitive decline. We prospectively estimated the frequency of cognitive impairment after cardiac surgery, with a particular emphasis on persistent and clinically relevant cognitive decline. Possible baseline and operative predictors were also evaluated. Methods : An extensive neuropsychological battery was administered to 110 patients (mean age 64.1±9.4 years; 70.9% males) undergoing cardiac surgery before and 6 months after the operation. After evaluating the variations in the cognitive performances, two independent neuropsychologists ranked the patients as unchanged–improved, mildly–moderately deteriorated, or severely deteriorated, using a global and functionally oriented judgement. The degree of the impairment was determined in relation to its impact on everyday life activities. Results : Ten patients (9.1%) were ranked as severely deteriorated, 22 (20%) as mildly–moderately deteriorated, and 78 (70.9%) as unchanged–improved. Cognitively impaired patients were older ( p =0.031), more often females ( p =0.005), with a low education level ( p =0.013). At multivariate analysis, female gender (odds ratio (OR) 6.14, 95% confidence interval (95% CI) 2.16–17.50), baseline use of beta-blockers (OR 4.55, 95% CI 1.30–15.92), and PaO 2 at arrival in intensive care unit (OR for 1 mm Hg increment 1.012, 95% CI 1.004–1.020) were significant predictors of cognitive impairment of any degree. Positive predictors of severe cognitive impairment were history of hypertension (OR 5.33, 95% CI 1.03–27.64) and PaO 2 at arrival intensive care unit (OR for 1 mm Hg increment 1.020, 95% CI 1.006–1.035), while education was protective (OR per year of increment 0.53, 95% CI 0.31–0.90). Conclusions : A considerable proportion of cardiac surgery patients may undergo clinically relevant cognitive impairment. The knowledge of variables influencing cognitive outcome is essential for the adoption of preventive measures.

BACKGROUND AND PURPOSE: Manually drawn VOI-based analysis shows a decrease in magnetization transfer ratio in the hippocampus of patients with Alzheimer disease. We investigated with whole-brain voxelwise analysis the regional changes of the magnetization transfer ratio in patients with mild Alzheimer disease and patients with amnestic mild cognitive impairment. MATERIALS AND METHODS: Twenty patients with mild Alzheimer disease, 27 patients with amnestic mild cognitive impairment, and 30 healthy elderly control subjects were examined with high-resolution T1WI and 3-mm-thick magnetization transfer images. Whole-brain voxelwise analysis of magnetization transfer ratio maps was performed by use of Statistical Parametric Mapping 8 software and was supplemented by the analysis of the magnetization transfer ratio in FreeSurfer parcellation-derived VOIs. RESULTS: Voxelwise analysis showed 2 clusters of significantly decreased magnetization transfer ratio in the left hippocampus and amygdala and in the left posterior mesial temporal cortex (fusiform gyrus) of patients with Alzheimer disease as compared with control subjects but no difference between patients with amnestic mild cognitive impairment and either patients with Alzheimer disease or control subjects. VOI analysis showed that the magnetization transfer ratio in the hippocampus and amygdala was significantly lower (bilaterally) in patients with Alzheimer disease when compared with control subjects (ANOVA with Bonferroni correction, at P < .05). Mean magnetization transfer ratio values in the hippocampus and amygdala in patients with amnestic mild cognitive impairment were between those of healthy control subjects and those of patients with mild Alzheimer disease. Support vector machine-based classification demonstrated improved classification performance after inclusion of magnetization transfer ratio-related features, especially between patients with Alzheimer disease versus healthy subjects. CONCLUSIONS: Bilateral but asymmetric decrease of magnetization transfer ratio reflecting microstructural changes of the residual GM is present not only in the hippocampus but also in the amygdala in patients with mild Alzheimer disease.

The aim of this 7-year inception cohort study was to determine the prognostic value of plateaux in cognitive decline in the course of Alzheimer's disease (AD) as well as their impact on the rate of progression of cognitive impairment. From a consecutive sample of 106 outpatients participating in a longitudinal study on AD, we selected 31 with a mild degree of mental deficit at presentation and a disease duration of at least 3 years when included into the study. All underwent extensive clinico-neuropsychological testing about every 6 months and there were no drop-outs. Mean period of follow-up lasted 6.8 (SD 2.9) years. Nineteen patients displayed a plateau, where a plateau refers to a patient's remaining on a mild level of cognitive decline for more than two years. Survival curves (Kaplan-Meier method) showed that patients with plateaux reached several end-points — very severe functional or cognitive impairment, urinary incontinence, death — significantly later than patients without (p < 0.04). Patients with plateaux showed a smaller cognitive loss (p < 0.01) in terms of the mean annual rate of progression of mental decline. In conclusion plateaux in an early stage of Alzheimer's Disease served to identify patients with a more favourable course.

Recently, mutations in the progranulin gene (GRN) were reported to account for the vast majority of Frontotemporal lobar Degeneration (FTLD) and a growing number of reports describe the implication of this gene in the development of the FTLD pathology with a significant variation in clinical features. To better clarify the contribution of GRN mutations to Italian FTLD, we screened 381 subjects: 171 cases and 210 healthy subjects, all from Central Italy, particularly of Tuscan origins. GRN gene was analyzed using High Resolution Melting Analysis and automated Genetic Analyzer. Human Progranulin ELISA Kit was employed to determine the plasma progranulin levels. The screening showed a total of six genetic variants in the GRN gene: 3 pathogenic and 3 non pathogenic in 13 out of 171 patients. The rare intronic variant IVS2 +7 G A was found in one patient. The pathogenetic mutation, p.T272SfsX10, is confirmed as the most common GRN mutation in Italian FTLD patients with a frequency in our study of 2.32%. Moreover, we identified the first Italian patient with the p.R493X mutation, to date described in 43 families worldwide. Our data report, for the first time, the occurrence of GRN mutations in Tuscany, Central Italy, confirming that genetic variations in this gene could be a considerable genetic cause of FTLD and that genetic screening might be useful both in familial and sporadic FTLD patients.

Some CSF protein abnormalities have been proposed as a possible marker for vascular dementia. We studied the CSF protein levels and albumin ratio in 21 patients (mean age 64.04 +/- 7.5) with progressive bilateral motor impairment, and a CT picture of leucoaraiosis. Seven of these patients also presented with dementia. Twenty-seven Alzheimer's disease patients (mean age 59.59 +/- 5.30) without leucoaraiosis were taken as controls. We also evaluated the correlations of the albumin ratio values with the diagnosis of dementia, the severity of cognitive impairment, the degree of cerebral atrophy and presence of infarcts on CT, and the abnormalities in CSF circulation, found on isotopic cisternography, in the leucoaraiosis group. After controlling for age and sex, the patients with leucoaraiosis showed greater CSF albumin levels (0.27 g/l +/- 0.11 vs. 0.21 g/l +/- 0.06; covariance analysis P = 0.066), CSF IgG values (4.68 mg/100 ml +/- 1.45 vs. 2.85 mg/100 ml +/- 1.03; covariance analysis P0.001), and a higher albumin ratio (0.0078 +/- 0.0027 vs. 0.0058 +/- 0.0019; covariance analysis P = 0.013) than those with Alzheimer's disease. The variations of these parameters were not apparently related to the presence of dementia in the leucoaraiosis group. A significantly higher albumin ratio was observed in patients with a slowed CSF circulation compared to those with normal CSF circulation (0.0086 +/- 0.0028 vs. 0.0059 +/- 0.0019; covariance analysis P = 0.05). We conclude that, independently from the presence of dementia, patients with leucoaraiosis have CSF abnormalities consistent with functional blood-brain barrier alterations.

This paper describes a protocol for identifying patients suspected of having Alzheimer''s disease (AD) which was used in a long-term multicenter study in Italy. It relies on a progressive elimination

Background: In amnestic mild cognitive impairment (aMCI), functional neuronal connectivity may be altered, as suggested by quantitative EEG and neuroimaging data. In young healthy humans, the execution of linguistic tasks modifies the excitability of the hand area of the dominant primary motor cortex (M1 hand ), as tested by transcranial magnetic stimulation (TMS). We used TMS to investigate functional connectivity between language-related cortical areas and M1 hand in aMCI. Methods: Ten elderly women with aMCI and 10 age-matched women were recruited. All participants were right handed and underwent a neuropsychological evaluation. In the first TMS experiment, participants performed three different tasks: reading aloud, viewing of non-letter strings (baseline), and nonverbal oral movements. The second experiment included the baseline condition and three visual searching/matching tasks using letters, geometric shapes, or digits as target stimuli. Results: In controls, motor evoked potentials (MEP) elicited by suprathreshold TMS of the left M1 hand were significantly larger during reading aloud (170% baseline) than during nonverbal oral movements, whereas no difference was seen for right M1 hand stimulation. Similarly, MEP elicited by left M1 hand stimulation during letter and shape searching/matching tasks were significantly larger compared to digit task. In contrast, linguistic task performance did not produce any significant MEP modulation in patients with aMCI, although neuropsychological evaluation showed normal language abilities. Conclusions: Findings suggest that functional connectivity between the language-related brain regions and the dominant M1 hand may be altered in amnestic mild cognitive impairment. Follow-up studies will reveal whether transcranial magnetic stimulation application during linguistic tasks may contribute to characterize the risk of conversion to Alzheimer disease. AD = Alzheimer disease; aMCI = amnestic mild cognitive impairment; ANOVA = analysis of variance; FDI = first dorsal interosseous; M1 = primary motor cortex; MEP = motor evoked potentials; MMSE = Mini-Mental State Examination; pvIQ = premorbid verbal intelligence; RMT = resting motor threshold; TMS = transcranial magnetic stimulation.

Introduction Previous neuropsychological, lesional and functional imaging studies deal with the lateralization of memory processes, suggesting that they could be determined by the stage of processing (encoding vs retrieval) or by content (verbal vs non-verbal stimuli). The aims of the present study were: 1) to investigate if tasks that can be carried out using different strategies depending on the verbalizability of the material induce a lateralization of the mean cerebral blood flow velocity (mCBFV) in the middle cerebral arteries (MCAs), as monitored by a functional transcranial Doppler (fTCD); 2) to evaluate if these patterns of cerebral activation differ in relation to age, gender and task performance. Method Using TCD bilateral monitoring, we recorded mCBFV variations in 35 male and 35 female healthy, right-handed volunteers, classified as “young” (age range 21–40 years, n = 35) or “old”(age range 41–60 years, n = 35), performing four different cognitive tasks: encoding and recognition of Geometric Figures (GF), encoding and recall of Object Localization (OL) on a picture, encoding of a verbal Room Description (RD) and Arithmetic Skill (AS). Results We found a significant right lateralization for the OL recall phase, and a significant left lateralization for RD and AS. When we took into consideration gender, age and performance, there was a strong effect of age on both OL encoding and recall phase, with significant right lateralization in young volunteers not seen in the older ones. No difference in gender was detected. We found a gender × performance interaction for RD, with poor performance females showing significant left lateralization. Conclusions According to our findings, hemispheric lateralization during memory encoding is material specific in both men and women, depending on the verbalizability of the material. mCBFV right lateralization during scene encoding and recall appears lost in older people, suggesting that healthy elderly could take advantage of mixed verbal and non-verbal strategies.

Amnestic mild cognitive impairment (aMCI) is considered a prodromal stage of Alzheimer's disease (AD). We measured plasma levels of amyloid-beta40 (Abeta40) and Abeta42 in 191 subjects with aMCI. Seventy-nine of them were clinically followed for two years. In the total cohort of aMCI cases, the average level of Abeta42, as well as the Abeta42/Abeta40 ratio, was significantly higher than those of the 102 cognitively normal age-matched subjects. The aMCI cases that converted to probable AD within 2 years had higher levels of Abeta42 and, to a lesser extent, Abeta40 than the stable cases. However the large variability of measured values indicates that plasma Abeta is not a suitable marker of incipient AD.

Presenilin 1 (PS1) mutation carriers provide the opportunity to asses early features of neurodegeneration in familial Alzheimer’s disease (AD). Gray matter (GM) regional volume loss and decrease of magnetization transfer ratio (MTR) consistent with microstructural changes have been reported in sporadic AD. We performed a regional volumetric and MTR analysis in carriers of PS1 mutations. Six non-demented mutated PS1 carriers (5 with memory deficits) and 14 healthy subjects were examined with high resolution T1-weighted images for volumetry and with T2* weighted images for MTR. Cortical GM volume and MTR values were derived. Compared to healthy controls, the GM volume of the left temporal and inferior parietal cortex and the MTR of the temporal cortex bilaterally were significantly decreased in PS1 gene carriers. In the latter, the temporal lobe MTR showed a trend for correlation with memory and executive function scores. Early neurodegeneration in non-demented subjects at risk for familial AD may be associated with atrophy and decreased MTR in the temporal cortex.

Background/Aims: Because of controversial results across studies, we evaluated the predictive value of premorbid intelligence and the apolipoprotein E (ApoE) genotype on baseline and progression of cognitive performance in Alzheimer’s disease (AD). Methods: Eighty-five mild AD cases, ApoE genotyped and included in a longitudinal cliniconeuropsychological-genetic study, underwent a premorbid intelligence test and up to 11 (average 5) neuropsychological assessments. We applied linear- and logistic-regression models for cross-sectional data and mixed models for longitudinal ones. Results: Higher premorbid intelligence was associated with higher global, executive and memory performance, while the ApoE Ε4 allele was specifically related to poorer memory performance. The premorbid intelligence-ApoE Ε4/Ε4 interaction was significant, with higher premorbid intelligence scores reducing the detrimental effect of ApoE Ε4 homozygosity on memory performance. Higher premorbid intelligence, but not the ApoE Ε4 allele, was related to faster memory deficit progression. Conclusion: The association of higher premorbid intelligence with better baseline cognitive performance and faster memory decline, as well as its interaction with the ApoE genotype, strengthens the role of cognitive reserve in shaping the disease’s clinical expression. Our findings confirm that the Ε4 allele affects memory deficit at baseline but does not exert any influence on the rate of cognitive decline.

A recent observation has shown that a common polymorphism in the alpha1-antichymotrypsin (ACT) gene modifies 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. We analyzed the segregation of the ApoE and ACT polymorphism in sporadic and familial AD patients. In none of the sporadic AD patients did we find the combination of the ACT/AA and ApoE epsilon4/epsilon4 genotypes. The frequency of ApoE epsilon4/epsilon4 homozygosity in the AD sample resulted highest for the ACT/ TT genotype (17.6%). Our data fail to confirm any additional association with AD beyond the ApoE epsilon4 allele with any ACT genotype, suggesting that ACT does not represent an additional risk factor for AD.

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.

Recent studies have shown a genetic association of the apolipoprotein E (ApoE) epsilon 4 allele with late onset familial and sporadic Alzheimer's 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 Alzheimer's disease (FAD) families including two early onset familial Alzheimer's (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.

This FDG-PET study with SPM99 compared 46 patients with sporadic Alzheimer disease (SAD) to 40 patients with familial AD (FAD) and to 35 matched controls. AD groups had equivalent metabolic (METglu) reductions in several cortical and limbic areas with respect to the controls. Patients with FAD showed decreased METglu in the posterior cingulate, parahippocampal, and occipital cortex as compared to the patients with SAD (p < 0.001). Genetic factors lead to phenotypic differences in AD.

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.

The aim of this study was to provide an update on the rate of progression in Alzheimer disease. In particular, we conducted a survey on European longitudinal studies that focused on the course of the disease and were performed since 1992. By means of Medline search and review papers and by personal contact with principal investigators, a census of existing studies on natural history of the disease in Europe has been carried out. We present data arising from our search and discuss methodological aspects by comparing data available from U.S. studies on disease progression and implications for clinical trials.

The ever greater emphasis on the application of a standard work-up in the clinical diagnosis of dementia -- and Alzheimer's Disease (AD) in particular -- has made it easier to identify potentially treatable and/or reversible cases. The aim of this paper is to update the issue of treatable and reversible dementias.

Objectives: To assess the evolution of cognitive dysfunction in early-onset multiple sclerosis, to identify clinical predictors of mental decline, and to determine its impact on a patient's everyday life. Design: The cognitive performance of 50 patients with multiple sclerosis on a neuropsychological battery was compared with that of 70 control subjects initially and again after a 4-year interval. Clinical predictors of cognitive impairment and its effect on daily life were analyzed by stepwise linear regression. Setting: The research clinic of a university department of neurology. Participants: A consecutive sample of 50 inpatients and outpatients with multiple sclerosis (mean disease duration, 1.58 years) and 70 demographically matched healthy control subjects selected from the patients' relatives and friends. Main Outcome Measures: Mean psychometric test scores of both groups at the initial and follow-up testing. Regression coefficients measuring the relationship between clinical parameters and cognitive capacity and between mental decline and performance of common tasks measured by the Environmental and the Incapacity Status scales. Results: Multiple sclerosis—related deficits in verbal memory and abstract reasoning on initial testing remained more or less stable on the retest, at which time linguistic disturbances on the Set and Token tests also emerged. A patient's initial disability level predicted decreased performance on only four of 13 cognitive variables, and disease duration did so on only two. Extent of intellectual decline on initial testing, initial disability level, and progressive course were independent determinants of handicap in a patient's work and social activities. Conclusions: Cognitive and neurological deficits appear not to develop in parallel. Yet cognitive dysfunction proves to be a predictor of handicap in everyday life, even in patients in the incipient phase of multiple sclerosis.

Recent studies have provided evidence of association of apolipoprotein E (ApoE) epsilon 4 allele and late onset familial and sporadic Alzheimer's 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.

We examined selective MRI features (localization and degree of white matter abnormalities, cortical and subcortical atrophy) in relation to cognitive decline in patients with cerebrovascular disease (CVD) and leukoaraiosis (LA). We enrolled 6 female and 18 male CVD patients (mean age 66.2 +/- 6.6 years) whose Magnetic Resonance Images (MRI) revealed LA and who displayed a history of stroke or TIA; none showed signs of cortical infarcts or normal pressure hydrocephalus. Two blind raters independently scored MRI scans with a high level of agreement. All patients underwent extensive clinico-neuropsychological assessment upon admission to the study and 19 were followed for an average of 48 +/- 7.6 months. Twelve patients were initially classified as non-demented and 12 as demented. Three years later, one in the former group had become demented and mental impairment had worsened for 6 patients in the latter group; these 7 subjects were labeled as "decliners". Ventricular indexes were significantly higher in the demented group and correlated with severity of mental impairment, while the degree of LA was similar in demented and non-demented subjects. Neither white matter lesions nor sulcal and ventricular enlargement differed statistically between decliners and non-decliners.

Missense mutations in the presenilin genes are implicated in the majority of early-onset familial AD (EOFAD) cases. Presenilin 1 (PS-1) is a multispanning membrane protein composed of 467 amino acids, containing six to nine transmembrane helical domains and a large hydrophilic loop between domains six and seven. To date, more than 50 missense mutations1 and a splice site mutation in PS-1 have been found to cosegregate with EOFAD. Common phenotypic features of presenilin-1 linked families include onset of memory disturbances before age 50 years, shorter disease duration, and the presence of myoclonus and generalized seizures. We have performed a clinical and genetic screening in order to search for additional missense presenilin mutations in families with EOFAD, identifying a new family with a previously undescribed missense mutation in exon 11 leading to a Leu to Pro substitution at codon 392. This mutation was not detected in 50 unrelated subjects, indicating that this is not a common polymorphism. The members of this kindred belong to a three-generation family from central Italy ( figure). The proband, (III-1), a 38-year-old man, …

For the Italian Multicentre Study on Dementia, a longitudinal survey on Alzheimer's disease (AD) initiated in 1982, we developed a neuropsychological test battery for screening, staging and monitoring cognitive impairment in AD patients and for delineating their pattern of cognitive decline. The tests measured higher cortical functions primarily involved in AD, such as short- and long-term memory, orientation, language, and praxis, and spanned a large enough range of difficulty to minimize ceiling and floor effects. We administered this battery to 143 clinically diagnosed AD patients and 146 hospital controls whose scores were corrected for age and educational level. Interrater and test-retest reliability were substantial, as were content and concurrent validity. Five of the battery's subtests proved capable of accurately screening early demented from non-demented elderly subjects and of staging mild, moderate, severe and very severe mental impairment. The mean performance of subjects classified into these categories differed significantly on all cognitive functions tested. Follow-up studies are in progress.

Background Mutations in the presenilin 1 ( PS1 ) and presenilin 2 ( PS2 ) genes, and more rarely in β-amyloid precursor protein (βAPP), underlie the pathogenesis of most cases of familial Alzheimer disease (FAD). Objective To screen the entire coding region of the PS1 and PS2 genes and exons 16 and 17 of the βAPP to find pathogenetic mutations in FAD. Patients Patients with FAD were consecutively enrolled from among the outpatients from the neurology departments at the Universities of Florence and Parma and the Santa Maria Nuova Hospital in Reggio Emilia, Italy. Design and Methods Polymerase chain reaction–single-strand conformation polymorphism and DNA se-quencing were used to investigate the affected members of families with FAD. Results We identified a family carrying a novel Ser130Leu mutation in the PS2 gene. Moreover, we found 2 novel PS1 mutations: Cys92Ser in exon 4 in 2 unrelated families and Leu174Met in exon 6 in the PS1 gene. We also found a fourth Italian family with the βAPP Val717Ile mutation. Conclusions One novel PS2 mutation associated with highly penetrant but variable age at onset (35-85 years) and 2 novel PS1 missense mutations associated with early-onset Alzheimer disease at age 49 to 54 years have been identified in Italian families. Screening for new mutations in presenilin and βAPP genes was beneficial in characterizing gene function in FAD.

To evaluate mean survival and to identify prognostic factors in a cohort of patients with Alzheimer's disease (AD).Multicentric 9-year cohort analytic study.Seven neurology departments throughout Italy between April 1982 and January 1984.We recruited a consecutive sample of 145 patients affected by probable AD (Multicenter Italian Study on Dementia protocol, National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria). Five were misdiagnosed, and 21 could not participate in the longitudinal study. The clinicodemographic characteristics of the 119 enrolled patients (49 men, 70 women; mean age, 64.7 years; SD, 4.1 years; mean duration of disease, 3.1 years; SD, 1.8 years) did not differ from those of the 26 excluded patients. All underwent extensive cliniconeuropsychological testing every 6 months for at least 2 years until the patient died or our survey ended (April 30, 1991). Mean follow-up was 5.1 years (SD, 2.5 years).Death, severe functional impairment (a scoreor = 17 on the Blessed Dementia Scale), and severe cognitive impairment (a score ofor = 7 on the Information-Memory-Concentration Test).Survival curves obtained by the Kaplan-Meier method indicated that (1) patients with early- and late-onset disease (ie, before or after age 65 years) showed no difference either in relative survival or in time to reach predetermined functional and cognitive end points; (2) severely aphasic patients became profoundly demented significantly sooner than those with mild to moderate aphasia (P.0001). Among clinicodemographic variables analyzed by a Cox model, severe language disability and functional loss proved to be the best predictors of death independent of age at onset or degree of dementia.Age at onset did not influence course and survival in AD. Severe aphasia appears to be the best predictor of death and unfavorable course.