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.

Functional neurological disorder is a feminist issue.

Functional neurological disorder (FND) is a common and disabling disorder, often misunderstood by clinicians. Although viewed sceptically by some, FND is a diagnosis that can be made accurately, based on positive clinical signs, with clinical features that have remained stable for over 100 years. Despite some progress in the last decade, people with FND continue to suffer subtle and overt forms of discrimination by clinicians, researchers and the public. There is abundant evidence that disorders perceived as primarily affecting women are neglected in healthcare and medical research, and the course of FND mirrors this neglect. We outline the reasons why FND is a feminist issue, incorporating historical and contemporary clinical, research and social perspectives. We call for parity for FND in medical education, research and clinical service development so that people affected by FND can receive the care they need.

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 cell-secreted superoxide dismutase promotes cerebellar neuronal survival.

It has been postulated that bone marrow-derived mesenchymal stem cells (MSCs) might be effective treatments for neurodegenerative disorders either by replacement of lost cells by differentiation into functional neural tissue; modulation of the immune system to prevent further neurodegeneration; and/or provision of trophic support for the diseased nervous system. Here we have performed a series of experiments showing that human bone marrow-derived MSCs are able to protect cultured rodent cerebellar neurons, and specifically cells expressing Purkinje cell markers, against either nitric oxide exposure or withdrawal of trophic support via cell-cell contact and/or secretion of soluble factors, or through secretion of soluble factors alone. We have demonstrated that MSCs protect cerebellar neurons against toxic insults via modulation of both the phosphatidylinositol 3-kinase/Akt and MAPK pathways and defined superoxide dismutase 3 as a secreted active antioxidant biomolecule by which MSCs modulate, at least in part, their neuroprotective effect on cerebellar cells in vitro. Together, the results demonstrate new and specific mechanisms by which MSCs promote cerebellar neuronal survival and add further evidence to the concept that MSCs may be potential therapeutic agents for neurological disorders involving the cerebellum.

Characterization of in vitro expanded bone marrow-derived mesenchymal stem cells from patients with multiple sclerosis.

Recent studies have investigated the potential of autologous bone marrow-derived mesenchymal stem cells (MSCs) as a therapy for multiple sclerosis. Whether MSCs from individuals with multiple sclerosis are functionally and/or phenotypically abnormal has received less attention. Through our Phase I clinical trial, SIAMMS, we were able to isolate and characterize MSCs from individuals with multiple sclerosis. The objective of the study was to demonstrate that MSCs from individuals with multiple sclerosis show no significant differences from MSCs derived from individuals without multiple sclerosis. MSCs were isolated from bone marrow aspirates from four SIAMMS participants. We were also able to isolate MSCs from bone marrow obtained during a total hip replacement operation on an individual with multiple sclerosis. Control MSCs were isolated from bone marrow acquired during total hip replacement operations on five individuals without MS. MSCs were characterized using standard criteria: plastic adherence, differentiation along adipogenic/osteogenic/chondrogenic lineages, and expression of specific cell surface antigens. We also determined their proliferation potential. MSCs from individuals with multiple sclerosis and individuals without multiple sclerosis were similar in proliferation, differentiation potential and cell surface antigen expression. This has relevance to scientific studies investigating the therapeutic potential of autologous MSCs which primarily utilize MSCs from individuals without multiple sclerosis, and relevance to clinical studies extrapolating from these scientific findings.

Chemotherapy-induced mesenchymal stem cell damage in patients with hematological malignancy.

Hematopoietic recovery after high-dose chemotherapy (HDC) in the treatment of hematological diseases may be slow and/or incomplete. This is generally attributed to progressive hematopoietic stem cell failure, although defective hematopoiesis may be in part due to poor stromal function. Chemotherapy is known to damage mature bone marrow stromal cells in vitro, but the extent to which marrow mesenchymal stem cells (MSCs) are damaged by HDC in vivo is largely unknown. To address this question, the phenotype and functional properties of marrow MSCs derived from untreated and chemotherapeutically treated patients with hematological malignancy were compared. This study demonstrates a significant reduction in MSC expansion and MSC CD44 expression by MSCs derived from patients receiving HDC regimens, thus implicating potential disadvantages in the use of autologous MSCs in chemotherapeutically pretreated patients for future therapeutic strategies. The clinical importance of these HDC-induced defects we have observed could be determined through prospective randomized trials of the effects of MSC cotransplantation on hematopoietic recovery in the setting of HDC with and without hematopoietic stem cell rescue.

Characterization of a novel TYMP splice site mutation associated with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).

Mitochondrial neurogastrointestinal encephalomyopathy is an autosomal recessive disorder caused by loss-of-function mutations in the thymidine phosphorylase gene (TYMP). We report here a patient compound heterozygous for two TYMP mutations: a novel g.4009G>A transition affecting the consensus splice donor site of intron 9, and a previously reported g.675G>C splice site mutation. The novel mutation causes exon 9 skipping but leaves the reading frame intact; however, TYMP protein was not detected by immunoblot analysis, suggesting that neither mutant allele is expressed as protein. The patient's fibroblasts showed gradual loss of the mitochondrial DNA-encoded subunit I of cytochrome-c oxidase, suggesting a progressive mitochondrial DNA defect in culture.

Changes in expression of the antioxidant enzyme SOD3 occur upon differentiation of human bone marrow-derived mesenchymal stem cells in vitro.

The discovery that mesenchymal stem cells (MSCs) secrete SOD3 may help explain studies in which MSCs have direct antioxidant activities both in vivo and in vitro. SOD3 is an antioxidant enzyme that dismutes toxic free radicals produced during inflammatory processes. Therefore, MSC production and secretion of active and therapeutically significant levels of SOD3 would further support the use of MSCs as a cellular based antioxidant therapy. The aim of this study was therefore to investigate in vitro if MSC differentiation down the adipogenic, chondrogenic, and osteogenic lineages influences the expression of the antioxidant molecule SOD3. Human bone marrow MSCs and their differentiated progeny were cultured under standard conditions and both the SOD3 gene and protein expression examined. Following adipogenesis, cultures demonstrated that both SOD3 protein and gene expression are significantly increased, and conversely, following chondrogenesis SOD3 protein and gene expression is significantly decreased. Following osteogenesis there were no significant changes in SOD3 protein or gene expression. This in vitro study describes the initial characterization of SOD3 expression and secretion by differentiated MSCs. This should help guide further in vivo work establishing the therapeutic and antioxidative potential of MSC and their differentiated progeny.

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.

Stem cells in genetic myelin disorders.

The genetic myelin disorders are a range of diseases that manifest with severe neurological problems, often from infancy. It has been postulated for some time that stem cells might be an effective treatment for these disorders, primarily as agents to restore dysfunctional or lost myelin. Stem cells, however, may offer a wider range of therapeutic potential, for instance as vehicles to replace abnormal enzymes or genes, or to provide trophic support for residual CNS tissue. This article will review several of the more common genetic myelin disorders and currently available therapies, including bone marrow transplantation for adrenoleukodystrophy. Specific stem cell subtypes and their relevance to potential therapeutic use will be discussed and stem cell transplantation in animal model studies will also be reviewed.

Inflammatory cytokine induced regulation of superoxide dismutase 3 expression by human mesenchymal stem cells.

Increasing evidence suggests that bone marrow derived-mesenchymal stem cells (MSCs) have neuroprotective properties and a major mechanism of action is through their capacity to secrete a diverse range of potentially neurotrophic or anti-oxidant factors. The recent discovery that MSCs secrete superoxide dismutase 3 (SOD3) may help explain studies in which MSCs have a direct anti-oxidant activity that is conducive to neuroprotection in both in vivo and in vitro. SOD3 attenuates tissue damage and reduces inflammation and may confer neuroprotective effects against nitric oxide-mediated stress to cerebellar neurons; but, its role in relation to central nervous system inflammation and neurodegeneration has not been extensively investigated. Here we have performed a series of experiments showing that SOD3 secretion by human bone marrow-derived MSCs is regulated synergistically by the inflammatory cytokines TNF-alpha and IFN-gamma, rather than through direct exposure to reactive oxygen species. Furthermore, we have shown SOD3 secretion by MSCs is increased by activated microglial cells. We have also shown that MSCs and recombinant SOD are able to increase both neuronal and axonal survival in vitro against nitric oxide or microglial induced damage, with an increased MSC-induced neuroprotective effect evident in the presence of inflammatory cytokines TNF-alpha and IFN-gamma. We have shown MSCs are able to convey these neuroprotective effects through secretion of soluble factors alone and furthermore demonstrated that SOD3 secretion by MSCs is, at least, partially responsible for this phenomenon. SOD3 secretion by MSCs maybe of relevance to treatment strategies for inflammatory disease of the central nervous system.

Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro.

Bone marrow-derived mesenchymal stem cells (MSCs) are of therapeutic interest in a variety of neurological diseases. In this study, we wished to determine whether human MSCs secrete factors which protect cultured rodent cortical neurons from death by trophic factor withdrawal or nitric oxide (NO) exposure. Medium conditioned by MSCs attenuated neuronal death under these conditions, a process which was dependent on intact PI(3)kinase/Akt pathway signaling. Trophic withdrawal and NO exposure in cultured cortical neurons led to reduction in Akt signaling pathways, whereas NO administration activated p38 MAPkinase in neuronal cultures. Addition of MSC-conditioned medium significantly activated the PI3kinase/Akt pathway and in neurons exposed to NO, MSC-conditioned medium reduced p38 signaling. We show that MSCs secrete brain-derived neurotrophic factor (BDNF) and addition of anti-BDNF neutralising antibodies to MSC-conditioned medium attenuated its neuroprotective effect. Exposure of neurons to BDNF increased activation of Akt pathways and protected neurons from trophic factor withdrawal. These observations determine the mechanisms of neuroprotection offered by MSC-derived factors and suggest an important role for BDNF in neuronal protection.