Search

BackgroundBehavioral and psychological symptoms of dementia (BPSD) have a high prevalence, and their presence is associated with a severe impact in terms of social costs. However, dedicated clinical tools or biomarkers to detect these symptoms are lacking. Thus, BPSD management in clinical settings is challenging. The aim of this study was to investigate the perception and the treatment strategies for BPSD in Italian centers working in the dementia field.MethodsA multicenter, national survey was developed by BPSD Study Group of the Italian Neurological Society for Dementia (SINDEM). The survey consisted of a semi-structured questionnaire that was e-mailed to SINDEM members, dementia centers part of the national network of memory clinics (Centers for Cognitive Deterioration and Dementia [CDCD]), and clinicians working in dementia care settings. The questions were focused on (1) perceived global frequency and relevance of BPSD; (2) tools used to assess BPSD; (3) pharmacological treatment for psychosis, apathy, agitation, aggression, depression, anxiety, sleep, and nutrition disturbances; (4) non-pharmacological treatments; (5) drugs side effects.ResultsOne-hundred and thirty-six clinicians participated in this study. Seventy-nine participants worked in a CDCD and 57 in other settings. The perceived frequency of BPSD was 74%. BPSD are detected by means of a clinical assessment for 96.3% or a caregiver interview for 97%. For psychosis treatment the first choice was atypical antipsychotics (83.3%), followed by typical antipsychotic (8.9%) and antidepressants (4.8%). For agitation, atypical antipsychotics were the first-choice treatment in 64% of cases and antidepressants in 16.1%. For aggression, the most used drugs were atypical antipsychotics (82.9%). For anxiety, 55.2% use antidepressants, 17.9% use atypical antipsychotics, and 16.9% use benzodiazepines. Interestingly, most of the centers apply non-pharmacological treatments for BPSD. Some differences emerged comparing the responses from CDCD and other care settings.ConclusionThe survey results revealed many differences in BPSD perception, treatment options, and observed side effect according to the clinical setting. This variability can be explained by the absence of clear guidelines, by differences in patients' characteristics, and by clinical practice based on subjective experience. These results suggest that producing guidelines for the pharmacological treatment of BPSD is a major need.

Amnestic mild cognitive impairment (aMCI) conversion to Alzheimer’s disease (AD) is seen in a sizable portion of aMCI patients; correlates predicting such conversion are poorly defined but neuroinflammation and the reactivation of chronic viral infections are suspected to play a role in this phenomenon. We analyzed these aspects in two homogeneous groups of aMCI who did or did not convert to AD over a 24-months period. Results showed that at baseline in those aMCI individuals who did not convert to AD: 1) Aβ1-42 stimulated production of the pro-inflammatory cytokines IL6 and IL1β by CD14+ cells was significantly reduced (p = 0.01), 2) CD14+/IL-33+ cells were increased (p = 0.0004); 3) MFI of TLR8 and TLR9 was significantly increased, and 4) better preserved hippocampus volumes were observed and correlated with IL33+/CD14+ cells. Notably, Aβ1-42 stimulated production of the antiviral cytokine IFN-λ was increased as well in non-AD converters, although with a borderline statistical significance (p = 0.05). Data herein indicating that proinflammatory cytokines are reduced, whereas IFN-λ production and TLR8 and 9 MFI are augmented in those aMCI in whom AD conversion is not observed suggest that the ability to mount stronger antiviral response within an antiiflammatory milieu associates with lack of AD conversion.

Background. Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disorder. Rate of decline and functional restoration in AD greatly depend on the capacity for neural plasticity within residual neural tissues; this is at least partially influenced by polymorphisms in genes that determine neural plasticity, including Apolipoprotein E4 ( ApoE4) and synaptosomal-associated protein of 25 kDa ( SNAP-25). Objective. We investigated whether correlations could be detected between polymorphisms of ApoE4 and SNAP-25 and the outcome of a multidimensional rehabilitative approach, based on cognitive stimulation, behavioral, and functional therapy (multidimensional stimulation therapy [MST]). Methods. Fifty-eight individuals with mild-to-moderate AD underwent MST for 10 weeks. Neuro-psychological functional and behavioral evaluations were performed blindly by a neuropsychologist at baseline and after 10 weeks of therapy using Mini-Mental State Examination (MMSE), Functional Living Skill Assessment (FLSA), and Neuropsychiatric Inventory (NPI) scales. Molecular genotyping of ApoE4 and SNAP-25 rs363050, rs363039, rs363043 was performed. Results were correlated with ΔMMSE, ΔNPI and ΔFLSA scores by multinomial logistic regression analysis. Results. Polymorphisms in both genes correlated with the outcome of MST for MMSE and NPI scores. Thus, higher overall MMSE scores after rehabilitation were detected in ApoE4 negative compared to ApoE4 positive patients, whereas the SNAP-25 rs363050(G) and rs363039(A) alleles correlated with significant improvements in behavioural parameters. Conclusions. Polymorphisms in genes known to modulate neural plasticity might predict the outcome of a multistructured rehabilitation protocol in patients with AD. These data, although needing confirmation on larger case studies, could help optimizing the clinical management of individuals with AD, for example defining a more intensive treatment in those subjects with a lower likelihood of success.

To investigate the signs of inflammatory processes in Alzheimer's disease (AD), we examined peripheral blood mononuclear cells (PBMC) from 51 AD patients (29 with mild and 22 with moderately severe dementia) and 51 age-matched healthy controls (HC), using flow cytometry to analyse the absolute number and the percentage of T, B and NK cells. We also studied the surface expression of CD25, CD28, CD57, CD71, CD45RA and CD45RO markers on cells CD4+ and CD8+. In 30 AD patients and 20 HC the production of IL-2, IFN-gamma, IL-10 and TNF-alpha by PBMC after stimulation with [25-35], [1-40] and [1-16] beta-amyloid (betaA) fragments was also evaluated. A significant decrease in circulating B and CD8+CD28- cells, as well as an increase in CD8+ cells expressing CD71+ and CD28+, was observed in AD patients. A significant decrease in IL-10 production was also found after stimulation of PMBC with betaA [1-40]. The decreased IL-10 production was not related to disease severity. The observed imbalance of immune peripheral cell subpopulations and decreased IL-10 production point to a reduction of suppressor cell function in AD patients.

The modulation of CD44, VCAM-1 and CD71 expression was analysed by flow cytometry in the 1321N1 astrocytoma cell line in the presence of interleukin-1β (IL1β), tumour necrosis factor-α (TNFα) and 1–40 or 25–35 β-amyloid (Aβ) fragments. The percentage of 1321N1 astrocytoma cell line expressing these markers increased significantly after treatment with TNFα or IL1β. The presence of Aβ 1–40 fragment, alone or in combination with IL1β, induced an increase in the percentage of cells expressing CD44, but not VCAM-1. However, the concomitant presence of Aβ 1–40 fragment and of IL1β or TNFα caused an increase in the percentage of CD71 positive cells. In contrast, the shorter Aβ 25–35 fragment was always inactive. These results indicates that Aβ 1–40 fragment, in association with cytokines, can activate this astrocyte-derived cell line and add further elements in favour of the hypothesis that β-amyloid can act as immunological mediator. © 2003 Wiley-Liss, Inc.

Synaptosomal-associated protein of 25 kDa (SNAP-25) is an age-regulated vesicular SNARE protein involved in the exocytosis of neurotransmitters from synapses, a process that is altered in Alzheimer's disease (AD). Changes in SNAP-25 levels are suggested to contribute to age-related decline of cognitive function, and single nucleotide polymorphisms (SNPs) in the SNAP-25 gene are present in neuropsychiatric conditions and play a role in determining IQ phenotypes. To verify a possible role of SNAP-25 in AD, we analyzed five gene polymorphisms in patients with AD (n = 607), replicating the study in subjects with amnestic mild cognitive impairment (aMCI) (n = 148) and in two groups of age-matched healthy controls (HC1: n = 615 and HC2: n = 310). Results showed that the intronic rs363050 (A) and rs363043 (T) alleles, as well as the rs363050/rs363043 A-T haplotype are significantly more frequent in AD and aMCI and are associated with pathological scores of categorical fluency in AD. Notably, functional MRI analyses indicated that SNAP-25 genotypes correlate with a significantly decreased brain activity in the cingulate cortex and in the frontal (middle and superior gyri) and the temporo-parietal (angular gyrus) area. SNAP-25 polymorphisms may be associated with AD and correlate with alterations in categorical fluency and a reduced localized brain activity. SNAP-25 polymorphisms could be used as surrogate markers for the diagnosis of AD and of cognitive deficit; these SNPs might also have a possible predictive role in the natural history of AD.

Neuroinflammation and brain functional disconnection result from β-amyloid (Aβ) accumulation and play fundamental roles in the pathogenesis of Alzheimer's disease (AD). We investigated possible correlations between these two AD-associated phenomena using DTI-based tractography and immunologic analyses in people with amnestic mild cognitive impairment (aMCI) and AD. DTI-Analyses focused on corpus callosum (CC). We found that frontal CC regions were preserved with respect to the posterior ones in aMCI; in these individuals significant correlations were seen between DTI-derived metrics in frontal-parietal CC areas and Aβ42-stimulated BDNF-producing CD4+ T lymphocytes and PDL-1-expressing CD14+ cells. These associations were lost in AD where DTI data involving the same CC areas correlated instead with Aβ42-stimulated interleukin (IL)-21 producing CD4+ T lymphocytes. Higher susceptibility to PDL-1-mediated apoptosis of Aβ42-specific lymphocytes and BDNF-associated survival of existing neurons could contribute to the relative CC structure preservation seen in aMCI. These potentially protective mechanisms are lost in frank AD, when severe alterations in the CC are mirrored in peripheral blood by proinflammatory cytokines-producing T cells. Monitoring of immune cells in peripheral blood could have a prognostic value in AD.

Cagliani, Rachele et al., The THBS4 gene encodes a glycoprotein involved in inflammatory responses and synaptogenesis. THBS4 is expressed at higher levels in the brain of humans compared with nonhuman primates, and the protein accumulates in β-amyloid plaques. We analyzed THBS4 genetic variability in humans and show that two haplotypes (hap1 and hap2) are maintained by balancing selection and modulate THBS4 expression in lymphocytes. Indeed, the balancing selection region covers a predicted transcriptional enhancer. In humans, but not in macaques and chimpanzees, THBS4 brain expression increases with age, and variants in the balancing selection region interact with sex in influencing THBS4 expression (pinteraction = 0.038), with hap1 homozygous females showing lowest expression. In Alzheimer disease (AD) patients, significant interactions between sex and THBS4 genotype were detected for peripheral gray matter (pinteraction = 0.014) and total gray matter (pinteraction = 0.012) volumes. Similarly to the gene expression results, the interaction is mainly mediated by hap1 homozygous AD females, who show reduced volumes. Thus, the balancing selection target in THBS4 is likely represented by one or more variants that regulate tissue-specific and sex-specific gene expression. The selection signature associated with THBS4 might not be related to AD pathogenesis, but rather to inflammatory responses. © 2013 Wiley Periodicals, Inc.

In this study, the distribution of HLA-A alleles was analyzed in Italian Alzheimer's Disease (AD) patients. Interaction between HLA alleles, APOE genotypes, age of onset, and gender were also analyzed. The results were compared to those obtained in healthy controls (HC). One hundred-seventy-three AD patients and 258 age-and-sex-matched healthy controls were enrolled in the study. AD patients were classified according to age at the onset of disease using quartiles of the distribution. HLA-A genotyping was performed by PCR-SSP; APOE genotyping was performed by RFLP. A correlation between late disease onset and HLA-A*01 was observed. Thus, HLA-A*01, calculated as number of alleles, was significantly more present in patients with age of onset > 74 years than in HC (20% vs 10.5%; p=0.014); the distribution of this allele was skewed also in patients 68.1–74.0 years of age (16.3%), even if the difference did not reach statistical significance. The relative risk ratio (RRR) of AD onset calculated by a multinomial logistic regression adjusted for sex and presence of APOE-4 confirmed a significant association of HLA-A*01 with AD onset > 74.0 years of age (RRR=2.2; 95%CI: 1.1 – 4.6; p=0.033). A high RRR (2.04) was also present in patients 68.1 – 74 years (p=0.064). Lower age of disease onset did not correlate with HLA-A*01. Data herein suggest that the presence of HLA-A*01 results in delayed AD development, even in patients carrying APOE-4. These results could offer new insights into the etiopathogenesis of Alzheimer's disease.

Background Interleukin-1 beta (IL-1β) and its key regulator, the inflammasome, are suspected to play a role in the neuroinflammation observed in Alzheimer’s disease (AD); no conclusive data are nevertheless available in AD patients. Results mRNA for inflammasome components (NLRP1, NLRP3, PYCARD, caspase 1, 5 and 8) and downstream effectors (IL-1β, IL-18) was up-regulated in severe and MILD AD. Monocytes co-expressing NLRP3 with caspase 1 or caspase 8 were significantly increased in severe AD alone, whereas those co-expressing NLRP1 and NLRP3 with PYCARD were augmented in both severe and MILD AD. Activation of the NLRP1 and NLRP3 inflammasomes in AD was confirmed by confocal microscopy proteins co-localization and by the significantly higher amounts of the pro-inflammatory cytokines IL-1β and IL-18 being produced by monocytes. In MCI, the expression of NLRP3, but not the one of PYCARD or caspase 1 was increased, indicating that functional inflammasomes are not assembled in these individuals: this was confirmed by lack of co-localization and of proinflammatory cytokines production. Conclusions The activation of at least two different inflammasome complexes explains AD-associated neuroinflammation. Strategies targeting inflammasome activation could be useful in the therapy of AD.