External validity of randomized controlled trials on Alzheimer's disease: the biases of frailty and biological aging

To date, the external validity of randomized controlled trials (RCTs) on Alzheimer's disease (AD) has been assessed only considering monodimensional variables. Nevertheless, looking at isolated and single characteristics cannot guarantee a sufficient level of appreciation of the AD patients' complexity. The only way to understand whether the two worlds (i.e., research and clinics) deal with the same type of patients is to adopt multidimensional approaches more holistically reflecting the biological age of the individual. In the present study, we compared measures of frailty/biological aging [assessed by a Frailty Index (FI)] of a sample of patients with AD resulted eligible and subsequently included in phase III RCTs compared to patients referring to the same clinical service, but not considered for inclusion. The "RCT sample" and the "real world sample" were found to be statistically similar for all the considered sociodemographic and clinical variables. Nevertheless, the "real world sample" was found to be significantly frailer compared to the "RCT sample," as indicated by higher FI scores [0.28 (SD 0.1) vs. 0.17 (SD 0.1);p < 0.001, respectively]. Moreover, when assessing the relationship between FI and age, we found that the correlation was almost null in the "RCT sample" (Spearman'sr = 0.01;p = 0.98), while it was statistically significant in the "real world sample" (r = 0.49;p = 0.02). The application of too rigid designs may result in the poor representativeness of RCT samples. It may even imply the study of a condition biologically different from that observed in the "real world." The adoption of multidimensional measures capable to capture the individual's biological age may facilitate evaluating the external validity of clinical studies, implicitly improving the interpretation of the results and their translation in the clinical arena

Modulation of the cannabinoid system. a new perspective for the treatment of the Alzheimer's disease

Abstract: The pathogenesis of Alzheimer’s disease (AD) is somewhat complex and has yet to be fully understood. As the effectiveness of the therapy currently available for AD has proved to be limited, the need for new drugs has become increasingly urgent. The modulation of the endogenous cannabinoid system (ECBS) is one of the potential therapeutic approaches that is attracting a grow- ing amount of interest. The ECBS consists of endogenous compounds and receptors. The receptors CB1 and CB2 have already been well characterized: CB1 receptors, which are abundant in the brain, particularly in the hippocampus, basal ganglia and cerebellum, regulate memory function and cognition. It has been suggested that the activation of CB1 receptors reduces intracellular Ca con- centrations, inhibits glutamate release and enhances neurotrophin expression and neurogenesis. CB2 receptors are expressed, though to a lesser extent, in the central nervous system, particularly in the microglia and immune system cells involved in the release of cytokines. CB2 receptors have been shown to be upregulated in neuritic plaque-associated microglia in the hippocampus and entorhinal cortex of patients, which suggests that these receptors play a role in the inflammatory pathology of AD. The role of the ECBS in AD is supported by cellular and animal models. By contrast, few clinical studies designed to investigate therapies aimed at reducing behaviour disturbances, espe- cially night-time agitation, eating behaviour and aggressiveness, have yielded positive results. In this review, we will describe how the manipulation of the ECBS offers a potential approach to the treatment of AD

Repetitive Deep Transcranial Magnetic Stimulation Improves Verbal Fluency and Written Language in a Patient with Primary Progressive Aphasia-Logopenic Variant (LPPA)

Background: To date, no therapies are available for the logopenic variant of primary progressive aphasia (LPPA). Even though deep repetitive transcranial magnetic stimulation (rTMS) may improve cognitive functions in some neurodegenerative disorders, no previous studies investigated its effects in patients with LPPA. Objective: Our aim was to investigate the effects on cognitive function of high frequency rTMS (hf-rTMS) delivered over the left dorso-lateral prefrontal cortex (DLPFC) through a coil designed for deep rTMS, compared to a SHAM stimulation, in a right-handed patient with LPPA. Methods: The patient presented a progressive language impairment (phonological errors in speech and naming, impaired single word retrieval and sentences repetition) and predominant left perisylvian atrophy and hypoperfusion. He received four stimulation cycles (two REAL and two SHAM) each of whom lasted 20 min for 5 consecutive days. Patient's performances in frontal, visuo-spatial and linguistic tasks were evaluated before and after each stimulation session. Test scores after REAL were compared with those obtained at baseline and after SHAM. Results: We found a temporary and highly significant improvement in the linguistic skills (both oral and written tasks) but not in the other cognitive domains tested, after REAL, but not SHAM stimulations. Discussion: Hf-rTMS delivered over the DLPFC could improve language in LPPA by enhancing long-term potentiation and synaptic plasticity within the stimulated and interconnected areas involved in language network. Our findings might prompt future researches into the feasibility and efficacy of deep hf-rTMS as a therapeutic tool in progressive aphasia syndromes and other neurodegenerative disorders. (C) 2013 Elsevier Inc. All rights reserved

Diffusion tensor imaging (DTI) study of a trigeminal neuralgia due to large venous angioma

[No abstract available

Beta-Amyloid Peptide in Tears: An Early Diagnostic Marker of Alzheimer’s Disease Correlated with Choroidal Thickness

We aimed to evaluate the diagnostic role of Alzheimer’s disease (AD) biomarkers in tears as well as their association with retinal and choroidal microstructures. In a cross-sectional study, 35 subjects (age 71.7 ± 6.9 years) were included: 11 with prodromal AD (MCI), 10 with mild-to-moderate AD, and 14 healthy controls. The diagnosis of AD and MCI was confirmed according to a complete neuropsychological evaluation and PET or MRI imaging. After tear sample collection, β-amyloid peptide Aβ1-42 concentration was analyzed using ELISA, whereas C-terminal fragments of the amyloid precursor protein (APP-CTF) and phosphorylated tau (p-tau) were assessed by Western blot. Retinal layers and choroidal thickness (CT) were acquired by spectral-domain optical coherence tomography (SD-OCT). Aβ1-42 levels in tears were able to detect both MCI and AD patients with a specificity of 93% and a sensitivity of 81% (AUC = 0.91). Tear levels of Aβ1-42 were lower, both in the MCI (p < 0.01) and in the AD group (p < 0.001) when compared to healthy controls. Further, Aβ1-42 was correlated with psychometric scores (p < 0.001) and CT (p < 0.01). CT was thinner in the affected patients (p = 0.035). No differences were observed for APP-CTF and p-tau relative abundance in tears. Testing Aβ1-42 levels in tears seems to be a minimally invasive, cost-saving method for early detection and diagnosis of AD

Beta-Amyloid Peptide in Tears: An Early Diagnostic Marker of Alzheimer’s Disease Correlated with Choroidal Thickness

We aimed to evaluate the diagnostic role of Alzheimer’s disease (AD) biomarkers in tears as well as their association with retinal and choroidal microstructures. In a cross-sectional study, 35 subjects (age 71.7 ± 6.9 years) were included: 11 with prodromal AD (MCI), 10 with mild-to-moderate AD, and 14 healthy controls. The diagnosis of AD and MCI was confirmed according to a complete neuropsychological evaluation and PET or MRI imaging. After tear sample collection, β-amyloid peptide Aβ1-42 concentration was analyzed using ELISA, whereas C-terminal fragments of the amyloid precursor protein (APP-CTF) and phosphorylated tau (p-tau) were assessed by Western blot. Retinal layers and choroidal thickness (CT) were acquired by spectral-domain optical coherence tomography (SD-OCT). Aβ1-42 levels in tears were able to detect both MCI and AD patients with a specificity of 93% and a sensitivity of 81% (AUC = 0.91). Tear levels of Aβ1-42 were lower, both in the MCI (p p p p p = 0.035). No differences were observed for APP-CTF and p-tau relative abundance in tears. Testing Aβ1-42 levels in tears seems to be a minimally invasive, cost-saving method for early detection and diagnosis of AD