Early diagnosis of Alzheimer's disease: the role of biomarkers including advanced EEG signal analysis. Report from the IFCN-sponsored panel of experts.

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD.

Time to generalization and prediction of survival in patients with amyotrophic lateral sclerosis: a retrospective observational study.

BACKGROUND AND PURPOSE: A strong association between time to generalization (TTG), considered as the time of spreading of the clinical signs from spinal or bulbar localization to both, and survival was recently identified in patients with amyotrophic lateral sclerosis (ALS). Thus, TTG may be used as an early to intermediate end-point in survival studies. The aim of the present study was to test TTG as a predictor of survival in ALS. METHODS: This was an observational retrospective study of ALS patients from a tertiary referral centre over a 5-year follow-up period. RESULTS: In 212 ALS patients, TTG was associated with time to death/tracheostomy [R 0.62, 95% confidence interval (CI) 0.53-0.70; P < 0.001]. In a time-to-event analysis, longer TTG resulted in lower risk to reach a composite outcome (death or tracheostomy) both in univariate [hazard ratio (HR) 0.98, 95% CI 0.97-0.99] and multivariate Cox analyses (HR 0.98, 95% CI 0.96-0.99). TTG predicted death/tracheostomy at 4 years (C-statistic 0.58; 95% CI 0.53-0.63) and at 5 years (C-statistic 0.58; 95% CI 0.53-0.62). CONCLUSIONS: Based on the present results from a large clinical cohort, TTG may be used as a new early to intermediate end-point to describe the ALS natural history. TTG may be potentially useful as a new primary outcome measure for clinical trials.

Uranium decay daughters from isolated mines: Accumulation and sources.

This study combines in situ gamma spectrometry performed at different scales, in order to accurately locate the contamination pools, to identify the concerned radionuclides and to determine the distribution of the contaminants from soil to bearing phase scale. The potential mobility of several radionuclides is also evaluated using sequential extraction. Using this procedure, an accumulation area located downstream of a former French uranium mine and concentrating a significant fraction of radioactivity is highlighted. We report disequilibria in the U-decay chains, which are likely related to the processes implemented on the mining area. Coupling of mineralogical analyzes with sequential extraction allow us to highlight the presence of barium sulfate, which may be the carrier of the Ra-226 activities found in the residual phase (Ba(Ra)SO4). In contrast, uranium is essentially in the reducible fraction and potentially trapped in clay-iron coatings located on the surface of minerals.

Fingerprinting of anti-citrullinated protein antibodies (ACPA): specificity, isotypes and subclasses.

Anti-citrullinated protein antibodies (ACPA) are a family of rheumatoid arthritis (RA)-specific autoantibodies that recognize the amino acid citrulline, resulting from the post-translational modification of arginine. Peptidyl arginine deiminase, the enzyme responsible for citrullination, is present in humans in different isoforms with different tissue distribution, enzymatic activity and target specificity; nonetheless, the number of proteins citrullinated in physiological or pathological conditions is wide, but not every citrullinated protein is a target for antibodies. In pre-RA patients the immune response to citrullinated antigens is initially restricted, expands with time and, after the onset of the disease, is relatively stable. ACPA are heterogeneous in terms of not only fine specificity but also isotype and IgG subclasses usage. This heterogeneity may be relevant for the immunopathogenesis of RA, conditioning the interaction of antibodies with complement and Fc receptors.

Coffee, tea, and caffeine consumption and prevention of late-life cognitive decline and dementia: a systematic review.

A prolonged preclinical phase of more than two decades before the onset of dementia suggested that initial brain changes of Alzheimer's disease (AD) and the symptoms of advanced AD may represent a unique continuum. Given the very limited therapeutic value of drugs currently used in the treatment of AD and dementia, preventing or postponing the onset of AD and delaying or slowing its progression are becoming mandatory. Among possible reversible risk factors of dementia and AD, vascular, metabolic, and lifestyle-related factors were associated with the development of dementia and late-life cognitive disorders, opening new avenues for the prevention of these diseases. Among diet-associated factors, coffee is regularly consumed by millions of people around the world and owing to its caffeine content, it is the best known psychoactive stimulant resulting in heightened alertness and arousal and improvement of cognitive performance. Besides its short-term effect, some case-control and cross-sectional and longitudinal population-based studies evaluated the long-term effects on brain function and provided some evidence that coffee, tea, and caffeine consumption or higher plasma caffeine levels may be protective against cognitive impairment/decline and dementia. In particular, several cross-sectional and longitudinal population-based studies suggested a protective effect of coffee, tea, and caffeine use against late-life cognitive impairment/decline, although the association was not found in all cognitive domains investigated and there was a lack of a distinct dose-response association, with a stronger effect among women than men. The findings on the association of coffee, tea, and caffeine consumption or plasma caffeine levels with incident mild cognitive impairment and its progression to dementia were too limited to draw any conclusion. Furthermore, for dementia and AD prevention, some studies with baseline examination in midlife pointed to a lack of association, although other case-control and longitudinal population-based studies with briefer follow-up periods supported favourable effects of coffee, tea, and caffeine consumption against AD. Larger studies with longer follow-up periods should be encouraged, addressing other potential bias and confounding sources, so hopefully opening new ways for diet-related prevention of dementia and AD.

Safety and efficacy of incobotulinum toxin type A (NT 201-Xeomin) for the treatment of post-stroke lower limb spasticity: a prospective open-label study.

BACKGROUND: In recent years, NT 201, a new botulinum toxin type A (BTX-A) free of complexing proteins, has been used for treating several movement disorders, showing safety and efficacy in upper limb spasticity. AIM: To assess the safety and evaluate the effects of BTX-A NT 201 free from complexing proteins for the treatment of post-stroke lower limb spasticity evaluating spasticity grade, passive ankle dorsi-flexion motion, and muscle's spasms, as well as its efficacy and rate of satisfaction for patients and for the physicians. DESIGN: Prospective open-label study. POPULATION: Patients (71) with post-stroke lower limb spasticity at least 5 months by the event. METHODS: Intramuscular injections of BTX-A NT 201 in soleus, medial, and lateral gastrocnemius with a maximum total dose of 180 U. Each patients was assessed at baseline, 30, and 90 days after treatment using Modified Ashworth Scale, Spasm Frequency Scale, evaluating passive ankle dorsi-flexion motion, and the rate of satisfaction for patients and investigators. RESULTS: Patients treated with BTX-A NT 201 reported a statistically significant reduction in muscle tone and spasms daily increasing passive ankle dorsi-flexion at 30 days, persisting also at 90 days of follow-up. CONCLUSION: BTX-A NT 201 for the treatment of post-stroke lower limb spasticity was safe and efficacious reducing muscle tone and spasms, and improving passive ankle dorsi-flexion movement. CLINICAL REHABILITATION IMPACT: These results confirmed the safety and effectiveness of a new type of BTX-A, with low immunogenity, useful to improve rehabilitative treatment of post-stroke lower limb spasticity.

Free IL-18 and IL-33 cytokines in chronic spontaneous urticaria.

Overproduction of IL-18 has been described in chronic urticaria. To evaluate free IL-18 and IL-33 in chronic spontaneous urticaria (CSU). IL-18, its inhibitor IL-18BP, IL-33 and its soluble receptor ST2 (sST2) were measured (ELISA) in the sera of 73 CSU patients. Free IL-18 was calculated (law of mass action). Autologous serum skin test (ASST) was performed in all patients. Total IL-18, IL-18BP and free IL-18 serum levels were significantly higher in CSU than in controls. IL-18 and IL-18BP increased significantly in both ASST-positive and negative subgroups. Free IL-18 resulted significantly higher in the ASST-negative, but not in the ASST-positive subgroup. No differences in IL-33/sST2 levels were detected between CSU and controls. Increased levels of free IL-18 and IL-18BP, but not IL-33, was detected in CSU. Whether IL-18 up-regulation is a consequence of inflammation or one of the causes of the pathology needs to be addressed.

Treatment of upper limb spasticity after stroke: one-year safety and efficacy of botulinum toxin type A NT201.

A new preparation of botulinum toxin type A called NT 201, free from complexing proteins, potentially with low antigenicity has been used in the therapy of spasticity in stroke patients. This was an open-label study reported the safety and the efficacy of one-year treatment with NT 201 evaluating the therapeutic effect on functional disability and on quality of life in upper limb spasticity after stroke. Patients received a botulinum toxin therapy in the upper injected intramuscularly. After inoculation, patients were submitted to a motor rehabilitation program for upper limb injected three times/week. Re-treatment was permitted at 12 weeks after the prior treatment. Safety assessment included evaluation of adverse events and efficacy was measured by Modified Ashworth Scale for spasticity (MAS), Spasm Frequency Score (SFS) for the daily spasms, and Disability Assessment Scale (DAS) for disability. Of 35 consecutive patients (13 women and 12 men) screened for study eligibility, 20 (6 women and 14 men) patients (mean age 63,4±7,03) were included in this study and were submitted to NT 201 therapy for one year. At the baseline, botulinum toxin dose in the upper limb ranged from 160 to 450U, whereas total dose in the last treatment administrated was reduced respect the first injections ranging from 120 to 350U. All the enrolled patients completed the year-long study and reported an improvement of clinical picture. MAS, was statistically (px003C;0,001) reduced in all muscles at T1 (mean score ±SD: 2.65±0.67) and T2 (mean score±SD: 2.55±0.60) in comparison to the baseline T0 (mean score±SD: 3.9 ±0.78). Significant reduction (px003C;0,001) from baseline T0 (mean score ±SD: 3.25±0.78) was also noted in SFS at T1 (mean score ±SD: 1.55±0.51) and T2 (mean score±SD :1.30±0.47). The DAS score showed a reduction of the T1score (mean score ±SD: 1.70±0.47) and T2 score (mean score ±SD: 1,40 ±0,50) respect to baseline T0 score (mean score ±SD: 2,65 ±0,48) statistically significant (p≤003C;0,001). No adverse effects were observed in these patients. NT 201 appeared to be an efficacious and well-tolerated long-term treatment option for patients with upper limb spasticity after stroke, obtaining a substantial improvement in functional disability, muscle hypertone, and daily spasms.

Changes in severity of depressive symptoms and mortality: the Italian Longitudinal Study on Aging.

BACKGROUND: Depression is recognized as being associated with increased mortality. However, there has been little previous research on the impact of longitudinal changes in late-life depressive symptoms on mortality, and of their remission in particular. METHOD: As part of a prospective, population-based study on a random sample of 5632 subjects aged 65-84 years, with a 10-year follow-up of vital status, depressive symptoms were assessed by the 30-item Italian version of the Geriatric Depression Scale (GDS). The number of participants in the GDS measurements was 3214 at baseline and 2070 at the second survey, 3 years later. Longitudinal changes in depressive symptoms (stable, remitted, worsened) were examined in participants in both evaluations (n=1941). Mortality hazard ratios (MHRs) according to severity of symptoms and their changes over time were obtained by means of Cox proportional hazards regression models, adjusting for age and other potentially confounding factors. RESULTS: Severity is significantly associated with excess mortality in both genders. Compared to the stability of depressive symptoms, a worsened condition shows a higher 7-year mortality risk [MHR 1.46, 95% confidence interval (CI) 1.15-1.84], whereas remission reduces by about 40% the risk of mortality in both genders (women MHR 0.55, 95% CI 0.32-0.95; men MHR 0.59, 95% CI 0.37-0.93). Neither sociodemographic nor medical confounders significantly modified these associations. CONCLUSIONS: Consistent with previous reports, the severity and persistence of depression are associated with higher mortality risks. Our findings extend the magnitude of the association demonstrating that remission of symptoms is related to a significant reduction in mortality, highlighting the need to enhance case-finding and successful treatment of late-life depression.

Pulmonary rehabilitation for patients with bronchiectasis: case reports.

The effectiveness of pulmonary rehabilitation (PR) has been recognized in national and international guidelines and highlighted by the National Institute of Clinical Excellence as one of the six key priorities for improving the care of chronic obstructive pulmonary disease (COPD) patients. PR is likely to be effective in bronchiectasis as it is in COPD. We evaluated the efficacy of PR in the management of bronchiectasis. Three outpatients affected by bronchiectasis, with cough, sputum production, dyspnea, and decreased exercise tolerance, were submitted to five months of PR program consisting in treadmill walking, cycle ergometry, breathing exercises, and postural drainage with clapping percussion-vibratory-shaking. In all patients, after PR, chest X-ray showed that the obstructive disease decreased with bronchial wall thickness reduction. This improvement facilitated the performance of breath actions increasing the exercise tolerance and quality of life, evaluated respectively with the 6-minute walk test, the SF36, and the RPE Borg scale. The improvements in both exercise capacity and health status observed at the end of the PR program were maintained in a 6-month follow-up after the cessation of training with also a reduction of acute bronchial exacerbations. These results highlighted the potential role of PR in patients with bronchiectasis, however further investigations are needed to identify the most eligible patients and to optimize the training programs to maintain long term benefit. Chest x-ray may represent a relevant instrument to observe the clinical improvement of these patients, also when spirometric values do not change significantly.

Interacting with γ-secretase for treating Alzheimer's disease: from inhibition to modulation.

Drugs currently used for the treatment of Alzheimer's disease (AD) produce limited clinical benefits, and there is no disease-modifying therapy yet available. Compounds that inhibit or modulate γ-secretase, the pivotal enzyme that generates ß-amyloid (Aß), are potential therapeutics for AD. This article briefly reviews the profile of γ-secretase inhibitors and modulators that have reached the clinic. Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aß concentrations. However, scanty data are available on the effects of these compounds on brain Aß deposition after prolonged administration. γ-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen, skin, and decrease in lymphocytes and alterations in hair color in experimental animals and in man, effects believed to be associated with the inhibition of the cleavage of Notch, a transmembrane receptor involved in regulating cell-fate decisions. Unfortunately, two large Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of a detrimental cognitive and functional effect of the drug. These detrimental effects were mainly ascribed to the inhibition of the processing of an unknown substrate of γ-secretase. It has been also hypothesized that the detrimental cognitive effects observed after semagacestat administration are due to the accumulation of the neurotoxic precursor of Aß (the carboxy-terminal fragment of amyloid precursor protein, APP, or CTFß) resulting from the block of the γ-secretase cleavage activity on APP. Some non-steroidal anti-inflammatory drugs and other small organic molecules have been found to modulate γ-secretase shifting its cleavage activity from longer to shorter Aß species without affecting Notch cleavage. However, two large Phase III studies in mild AD patients with tarenflurbil, a putative γ-secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New more selective γ-secretase inhibitors and more potent, more brain penetrant γ-secretase modulators are being developed with the hope of overcoming the previous setbacks. Further understanding of the reasons of the failures of these γ-secretase-based drugs in AD may be important for the future research on effective treatments for this devastating disease.

Different models of frailty in predementia and dementia syndromes.

Dementia is an increasingly common disease in the aging population, and the numbers are expected to rise exponentially in coming years. Therefore, there is a critical need to potentially individualize new strategies able to prevent and to slow down the progression of predementia and dementia syndromes. Despite a substantial increase in the epidemiological and clinical evidence on frailty, there is no consensus on its definition or on what criteria should be used to identify older individuals with frailty. Frailty appears to be a nonspecific state of vulnerability, which reflects multisystem physiological change. In fact, current thinking is that not only physical but also psychological, cognitive and social factors contribute to this multidimensional syndrome and need to be taken into account in its definition and treatment. Cognition has already been considered as a component of frailty, and it has been demonstrated that it is associated with adverse health outcomes. In a recent population-based study, physical frail demented patients were at higher risk of all-cause mortality over 3- and 7-year follow-up periods. Several studies have also reported that physical frailty is associated with low cognitive performance, incidence of Alzheimer's disease (AD), and mild cognitive impairment, and AD pathology in older persons with and without dementia. Most frailty instruments use a dichotomous scoring system classifying a person as either frail or not frail, while a continuous or an ordinal scoring system on multiple levels would be preferable to be used as an outcome measure. Recently, a Multidimensional Prognostic Index (MPI), derived from a standardized comprehensive geriatric assessment, was effective in predicting short- and long-term mortality risk in hospitalized patients with dementia. Overall taken together these findings supported the concept that outcome measures linked to multidimensional impairment may be extremely important in making clinical decisions, especially for monitoring drug treatment in randomized clinical trials also for predementia and dementia syndromes.

Short-term effects of high-intensity laser therapy versus ultrasound therapy in the treatment of low back pain: a randomized controlled trial.

BACKGROUND: Low back pain (LBP) is a common musculoskeletal disorder that is highly prevalent in the general population. Management of this pathology includes numerous interventions depending on pain severity: analgesic, nonsteroidal anti-inflammatory drugs, steroid injections. However, the effect size and duration of symptom relief are limited. Physical therapy (ultrasound [US], laser therapy, manual therapy, interferential current therapy, Back School, aerobic work, therapeutic aquatic exercise acupuncture) have been reported often with mixed results. AIM: To evaluate the short-term effectiveness of high-intensity laser therapy (HILT) versus ultrasound (US) therapy in the treatment of LBP. DESIGN: Randomized clinical trial. SETTING: University hospital. POPULATION: Thirty patients with LBP were randomly assigned to a HILT group or a US therapy group. METHODS: Study participants received fifteen treatment sessions of HILT or US therapy over a period of three consecutive weeks (five days/week). RESULTS: For the 30 study participants there were no between-group differences at baseline in Visual Analogic Scale (VAS) and Oswestry Low Back Pain Disability Questionnaire (OLBPDQ) scores. At the end of the 3-week intervention, participants in the HILT group showed a significantly greater decrease in pain (measured by the VAS) and an improvement of related disability (measured by the OLBPDQ) compared with the group treated with US therapy. CONCLUSION: Our findings obtained after 15 treatment sessions with the experimental protocol suggested greater effectiveness of HILT than of US therapy in the treatment of LBP, proposing HILT as a promising new therapeutic option into the rehabilitation of LBP.

APOE and Alzheimer disease: a major gene with semi-dominant inheritance.

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

Mediterranean diet in predementia and dementia syndromes.

There is a critical need to potentially individualize new strategies able to prevent and to slow down the progression of predementia and dementia syndromes. Only recently higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline although the Mediterranean diet (MeDi) combines several foods, micro- and macronutrients already separately proposed as potential protective factors against dementia and predementia syndromes. In fact, elevated saturated fatty acids could have negative effects on age-related cognitive decline and mild cognitive impairment (MCI). Furthermore, at present, epidemiological evidence suggested a possible association among fish consumption, monounsaturated fatty acids and polyunsaturated fatty acids (PUFA) (particularly, n-3 PUFA) and reduced risk of cognitive decline and dementia. Light to moderate alcohol use may be associated with a reduced risk of incident dementia and Alzheimer's disease (AD), while for vascular dementia, cognitive decline, and predementia syndromes the current evidence is only suggestive of a protective effect. Finally, the limited epidemiological evidence available on fruit and vegetable consumption and cognition generally supported a protective role of these macronutrients against cognitive decline, dementia, and AD. Moreover, recent prospective studies provided evidence that higher adherence to a Mediterranean-type diet could be associated with slower cognitive decline, reduced risk of progression from MCI to AD, reduced risk of AD, and decreased all-causes mortality in AD patients. These findings suggested that adherence to the MeDi may affect not only the risk for AD, but also for predementia syndromes and their progression to overt dementia. Nonetheless, at present, no definitive dietary recommendations are possible. However, high levels of consumption of fats from fish, vegetable oils, non-starchy vegetables, low glycemic fruits, and diet low in foods with added sugars and with moderate wine intake should be encouraged. In fact, this dietary advice is in accordance with recommendations for lowering the risk of cardiovascular disease, obesity, diabetes, and hypertension and might open new ways for the prevention and management of cognitive decline and dementia.

Metabolic syndrome, mild cognitive impairment, and dementia.

At present, the search for preventive strategies for cognitive decline and dementia appears to be of crucial importance, given that the therapeutic options currently available have demonstrated limited efficacy. Cumulative epidemiological evidence suggested that vascular and vascular-related factors may be important for the development of age-related cognitive decline (ARCD), mild cognitive impairment (MCI), and cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD). Among vascular-related factors, metabolic syndrome (MetS) has been associated with the reduced risk of predementia syndromes (ARCD and MCI), overall dementia, and VaD, but contrasting findings also exist on the possible role of MetS in AD. In the next future, trials could then be undertaken to determine if modifications of these risks including inflammation, another factor probably related to MetS, could lower risk of developing cognitive decline. If MetS is associated with increased risk of developing cognitive impairment, then early identification and treatment of these individuals at risk might offer new avenues for disease course modification. Future research aimed at identifying mechanisms that underlie comorbid associations will not only provide important insights into the causes and interdependencies of predementia and dementia syndromes, but will also inspire novel strategies for treating and preventing these disorders. At present, vascular risk factor management could be decisive in delaying the onset of dementia syndromes or in preventing the progression of predementia syndromes.

Towards disease-modifying treatment of Alzheimer's disease: drugs targeting beta-amyloid.

Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of beta-amyloid (Abeta) peptides may cause Alzheimer's disease (AD). Drugs currently used for the treatment of AD produce limited clinical benefits and do not treat the underlying causes of the disease. In the last 10 years, new therapeutic approaches targeting Abeta have been discovered and developed with the hope of modifying the natural history of the disease. Several active and passive immunotherapy approaches are under investigation in clinical trials with the aim of accelerating Abeta clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Abeta monoclonal antibodies, that is being tested in two large late-stage trials. Compounds that interfere with proteases regulating Abeta formation from amyloid precursor protein (APP) are also actively pursued. Unfortunately, the most biologically attractive of these proteases, beta-secretase, that regulates the first step of the amyloidogenic APP metabolism, was found to be particularly problematic to block and only one compound (CTS21166) has reached clinical testing so far. Conversely, several inhibitors of gamma-secretase, the protease that regulates the last metabolic step generating Abeta, have been identified, the most advanced being LY-450139 (semagacestat), presently in Phase III clinical development. Compounds that stimulate alpha-secretase, the enzyme responsible for the non-amyloidogenic metabolism of APP, are also being developed one of them, EHT-0202, has recently started a Phase II study. Furthermore, brain penetrant inhibitors of Abeta aggregation have been identified and one of such compounds, PBT-2, has produced encouraging neuropsychological results in a recently completed Phase II study. With all these anti-Abeta approaches in clinical testing, we will know in few years if the Abeta hypothesis of AD is correct.

Vascular risk factors, alcohol intake, and cognitive decline.

Since the therapeutic options currently available have demonstrated limited efficacy, the search for preventive strategies for cognitive decline and dementia is mandatory. A possible role of vascular and lifestyle-related factors was recently proposed for age-related changes of cognitive function, predementia syndromes, and cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin. At present, cumulative evidence suggested that vascular risk factors may be important in the development of mild cognitive impairment (MCI), dementia, and AD. Among vascular-related factors, metabolic syndrome has been associated with the risk of cognitive decline and overall dementia. Moderate alcohol drinking has been proposed as a protective factor against MCI and dementia in several longitudinal studies, but contrasting findings also exist. However, in most cases, these were only observational studies, and results are awaited from large multicenter randomized clinical trials in older persons. At present, vascular risk factor management, lifestyle changes, and drugs could be employed together to delay the onset of dementia syndromes.

Dietary fatty acids, age-related cognitive decline, and mild cognitive impairment.

Currently available epidemiological evidence suggested that an increase of saturated fatty acids (SFA) could have negative effects on cognitive functions, while increased polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA) may be protective against cognitive decline. In a Southern Italian elderly population from the Italian Longitudinal Study on Aging (ILSA), a clear reduction of risk of age-related cognitive decline (ARCD) has been found with elevated intake of PUFA and MUFA. Furthermore, in the ILSA, while dietary fatty acids intakes were not associated with incident mild cognitive impairment (MCI), high PUFA intake appeared to have borderline non-significant trend for a protective effect against the development of MCI. These epidemiological findings on predementia syndromes, i.e. MCI or ARCD, together with a recent randomised controlled trial on a possible effect on cognitive and depressive symptoms of omega-3 PUFA supplementation in patients with very mild AD, suggested a possible role of fatty acids intake in maintaining adequate cognitive functioning and possibly in preventing or delaying the onset of dementia.