Grazia D’Onofrio

Bapineuzumab: anti-β-amyloid monoclonal antibodies for the treatment of Alzheimer’s disease

In the last decade, new therapeutic approaches targeting β-amyloid (Aβ) have been discovered and developed with the hope of modifying the natural history of Alzheimers disease (AD). The most revolutionary of these approaches consists in the removal of brain Aβ via anti-Aβ antibodies. After an active vaccine (AN1792) was discontinued in 2002 due to occurrence of meningoencephalitis in approximately 6% of patients, several other second-generation active Aβ vaccines and passive Aβ immunotherapies have been developed and are under clinical investigation with the aim of accelerating Aβ clearance from the brain of AD patients. The most advanced of these immunological approaches is bapineuzumab, which is composed of humanized anti-Aβ monoclonal antibodies that has been tested in two Phase II trials. Bapineuzumab has been shown to reduce Aβ burden in the brain of AD patients. However, its preliminary cognitive efficacy appears uncertain, particularly in ApoE ε4 carriers, and vasogenic edema may limit its clinical use. The results of four ongoing large Phase III trials on bapineuzumab will provide answers regarding whether passive anti-Aβ immunization is able to alter the course of this devastating disease.

Neuropsychiatric Symptoms and Functional Status in Alzheimer’s Disease and Vascular Dementia Patients

Neuropsychiatric symptoms (NPS) are increasingly recognized as common in patients with dementia, both of degenerative (Alzheimers disease, AD) or vascular origin (vascular dementia, VaD). In this study, 302 demented patients, 166 with AD and 136 with VaD, were evaluated for NPS according to the Neuropsychiatric Inventory (NPI) score at the Alzheimers Evaluation Unit of Casa Sollievo della Sofferenza Hospital-IRCCS, San Giovanni Rotondo, Italy. A comprehensive geriatric assessment was also performed in all demented patients. The means of NPI scores did not differ in two groups. The overall prevalence of NPS was similar in both groups of patients (69.7% vs. 69.4%). Patients with AD had higher frequency in agitation/aggression and irritability/lability than VaD patients. Logistic analysis demonstrated a significant association between severity of the cognitive impairment and depression and eating disorders in both AD and VaD patients. The association with agitation/aggression, irritability/lability, and aberrant motor activity was found in AD only, and with apathy in VaD patients only. In both AD and VaD patients, there was a significant association between the impairment in activities of daily living (ADL) and the majority of NPI domains. A significant association was also found between the impairment of the instrumental activities of daily living (IADL) and agitation/aggression, anxiety, aberrant motor activity in AD and depression, apathy, irritability/lability, sleep disturbance and eating disorders in both AD and VaD patients. In particular, a causal mediation analysis was performed to better understand whether the relationship of NPS to functional impairment was direct or mediated by severity of cognitive dysfunction, i.e., Clinical dementia rating scale (CDR) score. Only agitation/aggression was mediated by the CDR score in affecting ADL status in VaD patients (OR: 1.12, 95% CI: 1.01-1.27). The NPI-Distress scores showed a significantly higher levels of distress in caregivers of AD than VaD. There were significant differences between AD and VaD patients with NPS, and these symptoms varied according to dementia subtype and severity and induced marked disability in ADL and IADL, increasing, prevalently, the distress of the caregivers of AD patients.

Apolipoprotein E genotypes and neuropsychiatric symptoms and syndromes in late-onset Alzheimer's disease

Neuropsychiatric symptoms (NPS) in dementia, previously denominated as behavioural and psychological symptoms of dementia, are often more distressing, impairing, and costly than cognitive symptoms, representing a major health burden for older adults. These symptoms are common features of Alzheimers disease (AD), and are one of the major risk factors for institutionalization. There is a high prevalence of neuropsychiatric disturbances in patients with AD, including depression, anxiety, apathy, psychosis, aggression, and agitation. At present, the role of the apolipoprotein E (APOE) genotypes in the development of NPS or neuropsychiatric syndromes/endophenotypes in AD patients is unclear. In this article, we summarized the findings of the studies of NPS and neuropsychiatric syndromes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between the APOE polymorphism and NPS in late-onset AD, other studies reported a significant association between the APOE ɛ4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. However, current cumulative evidence coming from the few existing longitudinal studies shows no association of APOE genotypes with NPS as a whole in AD. Some negative studies that focused on the distribution of APOE genotypes between AD patients with or without NPS further emphasized the importance of sub-grouping NPS in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, possible lack of statistical power to detect associations in the negative studies, and small sample sizes generating false positives that cannot be consistently replicated. Finally, many reviewed studies were cross-sectional, whereas it would be of paramount importance to evaluate the risk for incident NPS in relation to the APOE genotype in prospectively followed cohorts of AD patients. In fact, identifying predisposing genetic risk factors may allow us to understand the pathophysiological features of neuropsychiatric syndromes or symptoms in AD, so optimizing possible therapeutic options.

Phytochemicals in the Treatment of Alzheimer’s Disease: A Systematic Review

BACKGROUND Alzheimers disease (AD) is the most widespread age-related neurodegenerative disease. Recently, a growing body of evidence suggested the phytochemical use to slow down AD onset and progression. OBJECTIVE To review the phytochemical role potentially involved in AD treatment. METHOD A systematic review from existing literature on phytochemicals used in the treatment of AD patients was conducted. Selection criteria included: 1) age≥60 years; 2) AD diagnosis in agreement with the criteria of National Institute on Aging-Alzheimers Association (NIAAA), and 3) suitable measures to asses cognitive, functional and clinical status. RESULTS Ninety-seven articles were involved in the present study. Several phytochemicals seem to slow down AD onset, delay disease progression and let recovery through targeting multiple pathological causes by anti-cholinergic, antioxidant and anti-inflammatory features. CONCLUSION Deeper knowledge on phytochemicals and their specific molecular targets is essential to guarantee safe use of these compounds as an option for AD treatment.

Emerging biomarkers and screening for cognitive frailty

Physical frailty and cognitive frailty are two important targets of secondary intervention in aging research to narrow the gap between life and health span. The objective of the present narrative review was to examine clinical and epidemiological studies investigating the recently proposed construct of cognitive frailty and its subtypes, with a focus on operational definitions, clinical criteria, and emerging biomarkers potentially useful for the screening of this novel entity. Both physical frailty and frailty indexes with a multidimensional nature were associated with late-life cognitive impairment/decline, incident dementia, Alzheimer’s disease (AD), mild cognitive impairment, vascular dementia, non-AD dementias, and AD pathology proposing cognitive frailty as a clinical entity with cognitive impairment related to physical causes with a potential reversibility. The new clinical and research AD criteria established by the National Institute on Aging–Alzheimer’s Association and the American Psychiatric Association could improve the differential diagnosis of cognitive impairment within the cognitive frailty construct. The emerging biomarkers of sarcopenia, physical frailty, and cognitive impairment will provide the basis to establish more reliable clinical and research criteria for cognitive frailty, using different operational definitions for frailty and cognitive impairment and useful clinical, biological, and imaging markers for this novel clinical construct.

Polymorphism C in the serotonin transporter gene (SLC6A4) in questionable dementia and Alzheimer's disease.

The promoter region of the serotonin transporter gene (SLC6A4) shows a 22-bp tandem repeat polymorphism, indicated as polymorphism C, that has been associated to depression, obsessive-compulsive disorder, memory impairment, and anxiety. Less clear are data regarding its association with Alzheimers disease (AD). No data were reported regarding its association with questionable dementia (QD). In this study we investigate for polymorphism C in the SLC6A4 gene 302 elderly subjects with a clinical diagnosis of AD (n=105), QD (n=88) and no cognitive impairment (n=114) attending a geriatric ward. A community-dwelling sample of 390 healthy subjects was also included in the analysis. A significant higher prevalence of the C16/C16 genotype in AD than in QD was observed (37.14% vs. 3%; p=0.041, OR 2.001, 95%CI 1.018-4.024), while no differences in the C16/C14 and C14/C14 genotypes as well as in the estimated allele frequencies were found. No further differences among the three groups of subjects were found, also when they were compared with the community-dwelling sample. These findings suggest that SLC6A4 gene variation may have only a minor role, if any, in AD or QD.

Role of the serotonin transporter gene locus in the response to SSRI treatment of major depressive disorder in late life

It has been suggested that the serotonin or 5-hydroxytriptamine (5-HT) transporter (5-HTT) and its gene-linked polymorphic region (5-HTTLPR) are selective serotonin reuptake inhibitor (SSRI) response modulators in late-life depression (LLD), and particularly in late-life major depressive disorder (MDD). Previous studies differed in design and results. Our study aimed to investigate the solute carrier family 6 (neurotransmitter transporter and serotonin) member 4 (SLC6A4) gene locus, encoding 5-HTT and SSRI treatment response in late-life MDD. For a prospective cohort study, we enrolled 234 patients with late-life MDD to be treated with escitalopram, sertraline, paroxetine or citalopram for 6 months. The SLC6A4 polymorphisms rs4795541 (5-HTTLPR), rs140701 and rs3813034 genotypes spanning the SLC6A4 locus were investigated in blinded fashion. No placebo group was included. We assessed responder or non-responder phenotypes according to a reduction in the 21-item version of the Hamilton Depression Rating Scale (HDRS-21) score of ⩾ 50%. At follow-up, 30% of the late-life MDD patients were non-responders to SSRI treatment. No time-course of symptoms and responses was made. A poor response was associated with a higher baseline HDRS-21 score. We observed a significant over-representation of the rs4795541-S allele in the responder patients (0.436 versus 0.321; p = 0.023). The single S-allele dose-additive effect had OR = 1.74 (95% CI 1.12–2.69) in the additive regression model. Our findings suggested a possible influence of 5-HTTLPR on the SSRI response in patients with late-life MDD, which is potentially useful in identifying the subgroups of LLD patients whom need a different pharmacological approach.

Cognitive Home Rehabilitation in Alzheimer’s Disease Patients by a Virtual Personal Trainer

Alzheimer’s Disease is a problem of social and economic relevance as it involves both patients and their families/caregivers. Presently no cure is available. In the treatment of this disease, cognitive rehabilitation appears as an attractive choice for patients with a mild form. The aim of this work is the design and the development of a remote system, called “Virtual Personal Trainer”, integrating advanced Natural User Interface technologies to support the patients during the rehabilitation process at home. The system allows both the autonomous execution of the required exercises and the data reporting and storing of the daily performance for every exercise. In this scenario, the patient avoids to physically move to a specialized center and the physician can use the platform in order to verify the response to the therapy and the compliance to the treatment.

Daidzein and its Effects on Brain

Among naturally occurring isoflavones, soy isoflavones are an important class with various biological activities. Due to their phytoestrogenic structure, their effects on the brain are profound thus making the neurobiological effects of these compounds an active area of research. One such compound is daidzein, which has been reported to affect various neurobiological regulatory mechanisms such as behavior, cognition, growth, development and reproduction. These effects are mainly elicited through the interaction of daidzein with different signaling molecules and receptors, thereby offering neuroprotection. In addition, daidzein has also been reported to possess activities against various neuropathological conditions mainly by its interaction with the cerebrovascular system. This review focuses on providing a comprehensive account on the bioavailability and metabolism of daidzein in vivo, and discusses its activities and mechanisms of action in detail, in both physiological and pathological conditions. In addition, the effects of daidzein on other disorders have also been examined briefly in this article.

Erythrocyte Associated Amyloid-β as Potential Biomarker to Diagnose Dementia

BACKGROUND Although it is known that Alzheimers disease (AD) is associated with the progressive accumulation of amyloid β-peptide (Aβ) in the human brain, its pathogenic role has to be completely clarified. Aβ moves from the bloodbrain barrier to the plasma and an increased Aβ production in brain could be associated with higher Aβ concentrations in blood. A recent study has evaluated Aβ40 and Aβ42 levels in human red blood cells (RBCs) with evidence of agedependent higher Aβ concentration in RBCs. OBJECTIVE The aim of the study was to investigate if erythrocyte associated Aβ (iAβ) levels could be different in subjects affected by dementia in comparison with controls and according to the patients cognitive impairment or different dementia subtypes. METHOD To answer these questions we assessed iAβ40 and iAβ42 levels in 116 patients: 32 healthy controls, 39 with diagnosis of vascular dementia (VaD), 14 mild cognitive impairment (MCI) and 31 AD. RESULTS In this population we found significant differences in iAβ42 between controls and cognitive impaired patients. Moreover, iAβ42 significantly differed between dementia vs MCI. AD also showed different iAβ42 levels as compared to VaD. Conversely, no differences were found for iAβ40. All the analyses were adjusted for potential confounders like age, gender and Hb concentration. A direct correlation between increasing iAβ42 concentration and the progression of the cognitive decline using the MMSE score as continuous variable was also found. CONCLUSION Our findings support the evidence that iAβ42 could be an instrument to early recognize dementia and predict cognitive impairment.