Understanding the Impact of Urinary Incontinence in Persons with Dementia:Development of an Interdisciplinary Service Model

Introduction. Prevalence of urinary symptoms such as incontinence (UI) in patients with dementia is estimated to exceed 50%. The resultant psychological and socio-economic burden can be substantial. Our aim was to develop a dedicated urology service within a cognitive impairment clinic in order to treat and better understand the bothersome urinary symptoms suffered by persons with dementia. Methods. Patients attending this clinic were invited to be assessed and interviewed by urologist, together with their family and/or carer. In addition, formal history, examination and relevant investigations, themes of importance such as quality of life, and select question items were drawn from validated questionnaires. Multidisciplinary team (MDT) meeting was carried out on the same day. Outcomes of the first 75 patients with UI and dementia have been reported. Results. Average age was 70 years (range 58–98). Majority of persons had a diagnosis of Alzheimer’s disease (n = 43, 57%). Average score for how much urine leakage interferes with everyday life was 7.7/10 (range 2–10). 58.7% (n = 44) revealed some degree of sleep disturbance due to UI. 83% (n = 62) stated daily activities were limited due to UI. Two-thirds of persons with dementia (n = 50) stated their bladder problem makes them feel anxious. 88% (n = 67) felt the topic was socially embarrassing. All carers stated that the person’s continence issues affect the care they provide. Less than one-third of carers (30.7%, n = 23) were aware of or had been in contact with any bladder and bowel community service. More than half of the carers (n = 46, 65%) were concerned incontinence may be a principal reason for future nursing home admission. Conclusion. UI can be distressing for persons with dementia. Care partners were concerned about loss of independence and early nursing home admission. Awareness of bladder and bowel services should be increased

Mesenchymal Stem Cells Restore Frataxin Expression and Increase Hydrogen Peroxide Scavenging Enzymes in Friedreich Ataxia Fibroblasts

Dramatic advances in recent decades in understanding the genetics of Friedreich ataxia (FRDA)—a GAA triplet expansion causing greatly reduced expression of the mitochondrial protein frataxin—have thus far yielded no therapeutic dividend, since there remain no effective treatments that prevent or even slow the inevitable progressive disability in affected individuals. Clinical interventions that restore frataxin expression are attractive therapeutic approaches, as, in theory, it may be possible to re-establish normal function in frataxin deficient cells if frataxin levels are increased above a specific threshold. With this in mind several drugs and cytokines have been tested for their ability to increase frataxin levels. Cell transplantation strategies may provide an alternative approach to this therapeutic aim, and may also offer more widespread cellular protective roles in FRDA. Here we show a direct link between frataxin expression in fibroblasts derived from FRDA patients with both decreased expression of hydrogen peroxide scavenging enzymes and increased sensitivity to hydrogen peroxide-mediated toxicity. We demonstrate that normal human mesenchymal stem cells (MSCs) induce both an increase in frataxin gene and protein expression in FRDA fibroblasts via secretion of soluble factors. Finally, we show that exposure to factors produced by human MSCs increases resistance to hydrogen peroxide-mediated toxicity in FRDA fibroblasts through, at least in part, restoring the expression of the hydrogen peroxide scavenging enzymes catalase and glutathione peroxidase 1. These findings suggest, for the first time, that stem cells may increase frataxin levels in FRDA and transplantation of MSCs may offer an effective treatment for these patients

Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study

Background: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. Methods: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. Results: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%–88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%–92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. Conclusions: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions

Mesenchymal stem cell conditioned medium increases frataxin protein expression.

<p>Immunoblotting of human frataxin in (A) FRDA fibroblasts and (B) control fibroblasts after exposure to minimal medium (MIN) or MSC conditioned medium (MSC CM) for 24 hours. Upper panels correspond to frataxin (FXN); lower panel corresponds to the loading control GAPDH. Western blot densitometic analysis of frataxin expression in fibroblasts derived from patients with Friedreich ataxia at (C) 24 hours and (D) over a 72 hour period. (E) Western blot densitometic analysis of frataxin expression in fibroblasts derived from healthy controls. (F) The dipstick immunoassay of human frataxin in FRDA fibroblasts (or MSC CM alone) after exposure to minimal medium (MIN) or MSC CM for 24 hours. Upper panels correspond to internal control; lower panel corresponds to human frataxin (FXN). (G) The dipstick immunoassay densitometic analysis of frataxin expression in fibroblasts derived from patients with Friedreich ataxia. Data are given using arbitrary units of integrated density. Results are expressed as the mean +/− (SEM). (*p<0.05, comparing test condition to control; n = 3 independent experiments).</p

Fibroblasts derived from patients with Friedreich ataxia have low frataxin expression.

<p>(A) Immunoblotting of human frataxin in FRDA and control (CON) fibroblasts. Upper panels correspond to frataxin (FXN); lower panel corresponds to the loading control GAPDH. (B) Densitometic analysis of frataxin expression of western blot bands. Data are given using arbitrary units of integrated density. (C) The relative frataxin mRNA expression in control and FRDA fibroblasts . Results are expressed as the mean +/− (SEM). (*p<0.05, comparing test condition to control; n = 3 independent experiments).</p

Enhanced frataxin expression in <i>FXN</i>-transfected FRDA fibroblasts increases catalase expression.

<p>(A) FRDA fibroblast culture transfected with a GFP-tagged <i>FXN</i> gene. (B) Immunoblotting of human frataxin in GFP-tagged frataxin transfected (right) and untransfected (left) FRDA fibroblasts. Upper panels correspond to frataxin; lower panel corresponds to the loading control GAPDH. Immunoblotting of human catalase, glutathione peroxidase 1 (GPX1) and loading control GAPDH in (C) FRDA fibroblasts and (E) control fibroblasts after transfection with the GFP-tagged <i>FXN</i> gene. Western blot densitometic analysis of catalase and GPX1expression in fibroblasts derived from (D) patients with FRDA and (F) control fibroblasts at 24 hours. Data are given using arbitrary units of integrated density. Results are expressed as the mean +/− (SEM). (*p<0.05, comparing test condition to control; n = 3 independent experiments).</p

Mesenchymal stem cell conditioned medium increases both catalase and glutathione peroxidase 1 expression in fibroblasts-derived from FRDA patients.

<p>Immunoblotting of human catalase, glutathione peroxidase 1 (GPX1) and loading control GAPDH in (A) FRDA/control fibroblasts and (C) control fibroblasts after exposure to minimal medium (MIN) or MSC conditioned medium (MSC CM) for 24 hours. Western blot densitometic analysis of catalase and GPX1expression in fibroblasts derived from (B) patients with FRDA/controls and (D) control fibroblasts at 24 hours. Data are given using arbitrary units of integrated density. Results are expressed as the mean +/− (SEM). (*p<0.05, comparing test condition to control; n = 3 independent experiments).</p

Mesenchymal stem cell conditioned medium increases frataxin gene expression.

<p>The relative frataxin mRNA expression in (A) FRDA and (B) control fibroblasts after exposure to minimal medium (MIN) or MSC conditioned medium (MSC CM) for 2, 6 and 24 hours. The mean maximal relative frataxin mRNA expression in (C) FRDA and (D) control fibroblasts evident throughout the 24 hour exposure to minimal medium (MIN) or MSC CM. Results are expressed as the mean +/− (SEM). (*p<0.05, comparing test condition to control; n = 3 independent experiments).</p

Mesenchymal stem cell conditioned medium or <i>FXN</i>-transfection increases resistance to hydrogen peroxide mediated toxicity in fibroblasts derived from FRDA patients.

<p>The effect of hydrogen peroxide (600 µM) on FRDA and control fibroblast cell survival <i>in vitro</i> post exposure to minimal medium (MIN) or MSC-conditioned medium (MSC CM) for 24hours, with/without the addition of the catalase inhibitor 3-AminoTriazole (CATIN), catalase (CAT) and glutathione peroxidase (GPX1). FXN indicates fibroblasts have been transfected with the GFP-tagged <i>FXN</i> gene. Cell survival was assesed using the MTT cell viability assay (MTT). Cell survival is expressed as a percentage of cell survival compared to cells grown in minimal medium alone. Results are expressed as the mean +/− (SEM). (*p<0.05, comparing test condition to control; n = 3 independent experiments).</p