The tailored activity program (TAP) to address behavioral disturbances in frontotemporal dementia: a feasibility and pilot study

Purpose: To explore the feasibility of implementing the Tailored Activity Program with a cohort of people with frontotemporal dementia and their carers (dyads). Methods: The Tailored Activity Program is an occupational therapy based intervention that involves working collaboratively with family carers and prescribes personalized activities for behavioral management in people with dementia. Twenty dyads randomized into the study (Tailored Activity Program: n = 9; Control: n = 11) were assessed at baseline and 4-months. Qualitative analyzes evaluated feasibility and acceptability of the program for the frontotemporal dementia cohort, and quantitative analyzes (linear mixed model analyzes, Spearman’s rho correlations) measured the impact of the program on the dyads. Results: The Tailored Activity Program was an acceptable intervention for the frontotemporal dementia dyads. Qualitative analyses identified five themes: “carer perceived benefits”, “carer readiness to change”, “strategies used by carer to engage person with dementia”, “barriers to the Tailored Activity Program uptake/implementation”, and “person with dementia engagement”. Quantitative outcomes showed an overall reduction of behavioral symptoms (F 18.34 = 8.073, p = 0.011) and maintenance of functional performance in the person with dementia (F 18.03 = 0.375, p = 0.548). Conclusions: This study demonstrates the potential for using an activity-based intervention such as the Tailored Activity Program in frontotemporal dementia. Service providers should recognize that while people with frontotemporal dementia present with challenging issues, tailored therapies may support their function and reduce their behavioral symptoms.Implications for rehabilitation The Tailored Activity Program is an occupational therapy based intervention that involves prescribing personalized activities for behavioral management in dementia. The Tailored Activity Program is an acceptable and feasible intervention approach to address some of the unique behavioral and functional impairments inherent in frontotemporal dementia

Longitudinal grey and white matter changes in frontotemporal dementia and Alzheimer's disease

Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct). Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD

Contrasting prefrontal cortex contributions to episodic memory dysfunction in behavioural variant frontotemporal dementia and alzheimer's disease

Recent evidence has questioned the integrity of episodic memory in behavioural variant frontotemporal dementia (bvFTD), where recall performance is impaired to the same extent as in Alzheimer's disease (AD). While these deficits appear to be mediated by divergent patterns of brain atrophy, there is evidence to suggest that certain prefrontal regions are implicated across both patient groups. In this study we sought to further elucidate the dorsolateral (DLPFC) and ventromedial (VMPFC) prefrontal contributions to episodic memory impairment in bvFTD and AD. Performance on episodic memory tasks and neuropsychological measures typically tapping into either DLPFC or VMPFC functions was assessed in 22 bvFTD, 32 AD patients and 35 age- and education-matched controls. Behaviourally, patient groups did not differ on measures of episodic memory recall or DLPFC-mediated executive functions. BvFTD patients were significantly more impaired on measures of VMPFC-mediated executive functions. Composite measures of the recall, DLPFC and VMPFC task scores were covaried against the T1 MRI scans of all participants to identify regions of atrophy correlating with performance on these tasks. Imaging analysis showed that impaired recall performance is associated with divergent patterns of PFC atrophy in bvFTD and AD. Whereas in bvFTD, PFC atrophy covariates for recall encompassed both DLPFC and VMPFC regions, only the DLPFC was implicated in AD. Our results suggest that episodic memory deficits in bvFTD and AD are underpinned by divergent prefrontal mechanisms. Moreover, we argue that these differences are not adequately captured by existing neuropsychological measures

IL1RN genetic variations and risk of IPF: a meta-analysis and mRNA expression study

Idiopathic pulmonary fibrosis (IPF) is a rare and devastating lung disease of unknown aetiology. Genetic variations in the IL1RN gene, encoding the interleukin-1 receptor antagonist (IL-1Ra), have been associated with IPF susceptibility. Several studies investigated the variable number tandem repeat (VNTR) or single nucleotide polymorphisms rs408392, rs419598 and rs2637988, with variable results. The aim of this study was to elucidate the influence of polymorphisms in IL1RN on IPF susceptibility and mRNA expression. We performed a meta-analysis of the five case–control studies that investigated an IL1RN polymorphism in IPF in a Caucasian population. In addition, we investigated whether IL1RN mRNA expression was influenced by IL1RN polymorphisms. The VNTR, rs408392 and rs419598 were in tight linkage disequilibrium, with D′ > 0.99. Furthermore, rs2637988 was in linkage disequilibrium with the VNTR (D′ = 0.90). A haploblock of VNTR*2 and the minor alleles of rs408392and rs419598 was constructed. Meta-analysis revealed that this VNTR*2 haploblock is associated with IPF susceptibility both with an allelic model (odds ratio = 1.42, p = 0.002) and a carriership model (odds ratio = 1.60, p = 0.002). IL1RN mRNA expression was significantly influenced by rs2637988, with lower levels found in carriers of the (minor) GG genotype (p < 0.001). From this meta-analysis, we conclude that the VNTR*2 haploblock is associated with susceptibility to IPF. In addition, polymorphisms in IL1RN influence IL-1Ra mRNA expression, suggesting that lower levels of IL-1Ra predispose to developing IPF. Together these findings demonstrate that the cytokine IL-1Ra plays a role in IPF pathogenesis

Simian virus 40 inhibits differentiation and maturation of rhesus macaque DC-SIGN+-dendritic cells

Dendritic cells (DC) are the initiators and modulators of the immune responses. Some species of pathogenic microorganisms have developed immune evasion strategies by controlling antigen presentation function of DC. Simian virus 40 (SV40) is a DNA tumor virus of rhesus monkey origin. It can induce cell transformation and tumorigenesis in many vertebrate species, but often causes no visible effects and persists as a latent infection in rhesus monkeys under natural conditions. To investigate the interaction between SV40 and rhesus monkey DC, rhesus monkey peripheral blood monocyte-derived DC were induced using recombinant human Interleukin-4 (rhIL-4) and infective SV40, the phenotype and function of DC-specific intracellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN)+ DC were analyzed by flow cytometry (FCM) and mixed lymphocyte reaction (MLR). Results showed that SV40 can down-regulate the expression of CD83 and CD86 on DC and impair DC-induced activation of T cell proliferation. These findings suggest that SV40 might also cause immune suppression by influencing differentiation and maturation of DC

Innate Immune Responses to Bacterial Ligands in the Peripheral Human Lung – Role of Alveolar Epithelial TLR Expression and Signalling

It is widely believed that the alveolar epithelium is unresponsive to LPS, in the absence of serum, due to low expression of TLR4 and CD14. Furthermore, the responsiveness of the epithelium to TLR-2 ligands is also poorly understood. We hypothesised that human alveolar type I (ATI) and type II (ATII) epithelial cells were responsive to TLR2 and TLR4 ligands (MALP-2 and LPS respectively), expressed the necessary TLRs and co-receptors (CD14 and MD2) and released distinct profiles of cytokines via differential activation of MAP kinases. Primary ATII cells and alveolar macrophages and an immortalised ATI cell line (TT1) elicited CD14 and MD2-dependent responses to LPS which did not require the addition of exogenous soluble CD14. TT1 and primary ATII cells expressed CD14 whereas A549 cells did not, as confirmed by flow cytometry. Following LPS and MALP-2 exposure, macrophages and ATII cells released significant amounts of TNFα, IL-8 and MCP-1 whereas TT1 cells only released IL-8 and MCP-1. P38, ERK and JNK were involved in MALP-2 and LPS-induced cytokine release from all three cell types. However, ERK and JNK were significantly more important than p38 in cytokine release from macrophages whereas all three were similarly involved in LPS-induced mediator release from TT1 cells. In ATII cells, JNK was significantly more important than p38 and ERK in LPS-induced MCP-1 release. MALP-2 and LPS exposure stimulated TLR4 protein expression in all three cell types; significantly more so in ATII cells than macrophages and TT1 cells. In conclusion, this is the first study describing the expression of CD14 on, and TLR2 and 4 signalling in, primary human ATII cells and ATI cells; suggesting that differential activation of MAP kinases, cytokine secretion and TLR4 expression by the alveolar epithelium and macrophages is important in orchestrating a co-ordinated response to inhaled pathogens

HIV-1 Efficient Entry in Inner Foreskin Is Mediated by Elevated CCL5/RANTES that Recruits T Cells and Fuels Conjugate Formation with Langerhans Cells

Male circumcision reduces acquisition of HIV-1 by 60%. Hence, the foreskin is an HIV-1 entry portal during sexual transmission. We recently reported that efficient HIV-1 transmission occurs following 1 h of polarized exposure of the inner, but not outer, foreskin to HIV-1-infected cells, but not to cell-free virus. At this early time point, Langerhans cells (LCs) and T-cells within the inner foreskin epidermis are the first cells targeted by the virus. To gain in-depth insight into the molecular mechanisms governing inner foreskin HIV-1 entry, foreskin explants were inoculated with HIV-1-infeceted cells for 4 h. The chemokine/cytokine milieu secreted by the foreskin tissue, and resulting modifications in density and spatial distribution of T-cells and LCs, were then investigated. Our studies show that in the inner foreskin, inoculation with HIV-1-infected cells induces increased CCL5/RANTES (1.63-fold) and decreased CCL20/MIP-3-alpha (0.62-fold) secretion. Elevated CCL5/RANTES mediates recruitment of T-cells from the dermis into the epidermis, which is blocked by a neutralizing CCL5/RANTES Ab. In parallel, HIV-1-infected cells mediate a bi-phasic modification in the spatial distribution of epidermal LCs: attraction to the apical surface at 1 h, followed by migration back towards the basement membrane later on at 4 h, in correlation with reduced CCL20/MIP-3-alpha at this time point. T-cell recruitment fuels the continuous formation of LC-T-cell conjugates, permitting the transfer of HIV-1 captured by LCs. Together, these results reveal that HIV-1 induces a dynamic process of immune cells relocation in the inner foreskin that is associated with specific chemokines secretion, which favors efficient HIV-1 entry at this site

Partial Regulatory T Cell Depletion Prior to Acute Feline Immunodeficiency Virus Infection Does Not Alter Disease Pathogenesis

Feline immunodeficiency virus (FIV) infection in cats follows a disease course similar to HIV-1, including a short acute phase characterized by high viremia, and a prolonged asymptomatic phase characterized by low viremia and generalized immune dysfunction. CD4+CD25hiFoxP3+ immunosuppressive regulatory T (Treg) cells have been implicated as a possible cause of immune dysfunction during FIV and HIV-1 infection, as they are capable of modulating virus-specific and inflammatory immune responses. Additionally, the immunosuppressive capacity of feline Treg cells has been shown to be increased during FIV infection. We have previously shown that transient in vivo Treg cell depletion during asymptomatic FIV infection reveals FIV-specific immune responses suppressed by Treg cells. In this study, we sought to determine the immunological influence of Treg cells during acute FIV infection. We asked whether Treg cell depletion prior to infection with the highly pathogenic molecular clone FIV-C36 in cats could alter FIV pathogenesis. We report here that partial Treg cell depletion prior to FIV infection does not significantly change provirus, viremia, or CD4+ T cell levels in blood and lymphoid tissues during the acute phase of disease. The effects of anti-CD25 mAb treatment are truncated in cats acutely infected with FIV-C36 as compared to chronically infected cats or FIV-naïve cats, as Treg cell levels were heightened in all treatment groups included in the study within two weeks post-FIV infection. Our findings suggest that the influence of Treg cell suppression during FIV pathogenesis is most prominent after Treg cells are activated in the environment of established FIV infection

Genome-wide analyses reveal a potential role for the <em>MAPT</em>, <em>MOBP</em>, and <em>APOE </em>loci in sporadic frontotemporal dementia

\ua9 2024 The Author(s)Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 7 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 7 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 7 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex