Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of illnesses which can be difficult to diagnose. Modern diagnostic criteria require the presence of imaging abnormalities, but these are not always seen in the early stages of the illness. Hence there is a need to consider the use of more advanced MR techniques. This thesis reports the results of a multimodal MRI study of patients with FTLD, and considers two things: how well data from the different modalities can classify patients, and how well the different modalities can identify affected tissue. FTLD is thought to involve alterations in cerebral blood flow, but it is possible that microvascular changes will alter additional perfusion parameters, such as the time taken for blood to reach the tissue (the arrival time). Multi-time point arterial spin labelling (ASL) measurements have the ability to extract the relevant parameters. I consider the parameters involved in modelling these data, and report the accuracy of cerebral blood flow (CBF) measurement achievable in a clinically acceptable time. FTLD patients have atrophy in the frontal and temporal lobes, regions problematic for MRI because of susceptibility artefacts caused by adjacent air spaces. I consider two ASL MR read-out sequences (gradient-echo and spin-echo)and show that spin-echo images give higher signal in frontal and temporal regions than gradient-echo. ASL, T1-weighted and diffusion-weighted images were collected for a group of 17 FTLD patients and 18 controls. I found decreased CBF in highly atrophied regions of cortical grey matter in patients, but this deficit was not seen when corrected for atrophy. An increased arrival time was seen in regions adjacent to the atrophied regions, but a decreased arrival time was seen in the atrophied regions; this is a novel finding. The diffusion metrics of fractional anisotropy (FA) and particularly mean diffusivity (MD) are found to be highly sensitive to differences in FTLD patients. I speculate that this is an increased sensitivity to atrophy because of the increased signal from cerebrospinal fluid. I combine the regional values of all the modalities in a classification method to distinguish patients from controls, and establish a combination of region and modality that classified 21/22 subjects correctly. This exploratory study is the first time all three modalities have been combined in a study of FTLD patients; it shows that combining MR modalities may lead to improved classification of FTLD patients and better identification of affected tissue.

We present a 56-year-old patient suffering from frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The history included a three-generation pedigree and the patient was found to be a mutation carrier. The diagnosis was hindered by late appearance of the hypokinetic movement disorder. For clinicians, it is important to consider rare neurodegenerative disease variants in early-onset familial dementia syndromes with behavioral, cognitive, and motor symptoms

The global population with dementia is rapidly increasing around the world.The major risk factor for dementia is aging. There is currently no treatmentavailable and the cost of symptomatic treatment is high. There is a growinginterest in possible clinical applications of non-invasive methods that are safeand easy-to-perform in diagnosis of dementia. The purpose of this paper is toinvestigate the usage of transcranial magnetic stimulation (TMS) withelectroencephalography (EEG) to diagnose dementia in early stages of thedisease. Early diagnosis is needed to reduce the costs of symptomatic care.When investigating the usage of TMS-EEG technology, we will look at how wecan distinguish dementia in different neurodegenerative diseases between eachother. More research is needed to suggest an accurate parameters fordiagnosis of dementia with this type of technology.

No description available.

In this article we address how relatives of people with frontal-variant frontotemporal dementia (fvFTD) experience the illness and how it impacts their lives. We interviewed 6 participants and carried out interpretative phenomenological analysis. We report on 11 themes that reflect distinctive challenges. Five themes relate to witnessing bizarre and strange changes: changed appetites and drives, loss of planning ability, loss of inhibition leading to social embarrassment, risky behavior, and communication problems. Four relate to managing these changes and two to the impact on the person and his or her relationships. Relatives must live with unusual changes in the person with fvFTD and the stigma this carries in social settings. They learn to act assertively for their relatives and put effort into promoting quality of life, using strategies adapted for fvFTD. Relatives grieve the loss of the person with fvFTD and their mutual relationship, but nonetheless find sources of solace and hope.

Yes / Objectives: Young onset dementia is associated with distinctive support needs but existing research on service provision has been largely small scale and qualitative. Our objective was to explore service use, cost and satisfaction across the UK. Methods: Information about socio‐demographic characteristics, service use and satisfaction were gathered from people with young onset dementia (YOD) and/or a family member/supporter via a national survey. Results: Two hundred and thirty‐three responses were analysed. Diagnosis was most commonly received through a Memory Clinic or Neurology. The type of service delivering diagnosis impacted on post‐diagnostic care. Those diagnosed in specialist YOD services were more likely to receive support within the first 6 weeks and receive ongoing care in the service where they were diagnosed. Ongoing care management arrangements varied but generally care was lacking. Around 42% reported no follow‐up during 6‐weeks after diagnosis; over a third reported seeing no health professional within the previous 3 months; just over a third had a key worker and just under a third had a care plan. Satisfaction and quality of care were highest in specialist services. Almost 60% of family members spent over 5 h per day caring; median costs of health and social care, 3 months, 2018, were £394 (interquartile range £389 to 640). Conclusions: Variation across diagnostic and post‐diagnostic care pathways for YOD leads to disparate experiences, with specialist young onset services being associated with better continuity, quality and satisfaction. More specialist services are needed so all with YOD can access age‐appropriate care. / Alzheimer's Society. Grant Number: 278 AS-PG-15b-034

Aggregations of fused in sarcoma (FUS), a multifunctional RNA processing protein, define a pathological subtype of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), whilst mutations in the FUS gene are causative for ALS. To model the impact of FUS mutations, expression vectors containing the entire genomic sequence of FUS, up and downstream regions, and native promoter sequences have been generated. The constructs have been tagged with an mCherry fluorescent tag, and three separate pathological mutations (R244C, R521C, and P525L) have been separately inserted. Transgenic mice have been generated using the WT and P525L FUS vectors to provide a highly physiological model of FUS in disease. Within transfected HEK293 cells, insertion of the P525L and R521C FUS mutations leads to relocalisation of FUS from the nucleus to the cytoplasm. R521C and P525L mutant FUS incorporates into cytoplasmic aggregations of untranslated mRNA and RNA binding proteins known as stress granules. The strong relocalisation seen with P525L-FUS is associated with a gain of cytotoxicity. Reversal of this cytoplasmic relocalisation by demethylation of FUS rescues this cytotoxicity, suggesting a toxic gain of cytoplasmic function in the majority of FUS mutations. By contrast, insertion of the R244C mutation leads to neither relocalisation, stress granule association, nor cytotoxicity. Notably the R244C mutation, located away from the nuclear localization domain in which the majority of FUS mutations are found, leads to the presence of smaller FUS fragments in western blot analyses. These fragments appear not to be due to splicing defects in FUS but rather are due to post-translational modifications or aberrant protein cleavage. These data suggest an alternative pathway for FUS toxicity based upon a nuclear loss of function.

Les dégénérescences lobaires frontotemporales (DLFT) représentent la deuxième étiologie neurodégénérative chez l’adulte de moins de 65 ans. Les DLFT sont constituées d’un ensemble hétérogène de phénotypes cliniques et sont fréquemment héréditaires. Leurs particularités neuropathologiques communes reposent sur une atrophie des lobes frontaux et/ou temporaux associée à la présence d’inclusions de protéines agrégées parmi lesquelles la protéine TAR DNA binding protein 43 (TDP43). Actuellement, aucun marqueur protéique n’est validé pour diagnostiquer les DLFT du vivant du patient.Une cohorte de cas certains DLFT-TDP43 a été constituée grâce au développement d’outils spécifiques de diagnostic moléculaire. Une analyse des concentrations pondérales de protéine TDP43 dans le liquide cérébrospinal (LCS) a été réalisée dans cette cohorte, puis comparée à des cohortes bien caractérisées sur le plan clinique et neuropathologique. Finalement, les profils qualitatifs de la protéine TDP43 ont été étudiés dans différents compartiments accessibles du vivant du patient : les profils des formes solubles (LCS et plasma) et des formes intracellulaires (éléments figurés du sang) de la protéine TDP43 ont été comparés aux profils protéiques obtenus sur des tissus cérébraux présentant des inclusions de protéine TDP43. Les profils protéiques des culots plaquettaires présentent des similitudes avec le tissu cérébral et pourraient devenir un marqueur candidat pour le diagnostic probabiliste des DLFT / Frontotemporal lobar degeneration (FTLD) syndrome is the second most common of presenile dementia. FTLD is a clinically heterogeneous syndrome and comprises many hereditary cases. Common neuropathological features rely on a degeneration of the frontal and/or anterior temporal lobes, associated to specific inclusions of aggregated proteins including TAR DNA binding protein 43 (TDP43). Unfortunately, no practical protein marker is currently validated to improve FTLD diagnosis in living patients.A cohort of FTLD patients with definite TDP43 pathology was defined with the development of specific genetic testing. An analysis of TDP43 concentrations in cerebrospinal fluid (CSF) was performed in this cohort and then compared to other cohorts well-characterized on clinical and neuropathological features. Finally, qualitative patterns of TDP43 were studied in compartments accessible from the patient’s living: profiles of soluble TDP43 protein (in CSF or in plasma) and intracellular TDP43 protein (in the formed elements of blood) were compared to protein patterns observed in brain tissues with TDP43 protein inclusions. Platelet samples exhibit similar characteristics to brain tissue and could become a candidate biomarker for FTLD probabilistic diagnosis

Doctor of Clinical Psychology / Obsessive-compulsive (OC) symptoms occur in a variety of clinical conditions, but the underlying pathogenesis of these symptoms remains elusive. Few neuropsychological investigations have compared idiopathic Obsessive-Compulsive Disorder (OCD) with patient groups where OC symptoms are acquired. The present study investigated the neuropsychological correlates of OC symptoms in OCD and frontotemporal dementia (FTD), a neurodegenerative illness in which OC symptoms are often acquired. Neuroimaging in OCD has consistently implicated the frontal-striatal-thalamic circuit, particularly the orbitofrontal cortex and basal ganglia. These areas overlap considerably with the sites of cerebral pathology found in FTD. OCD has been associated with a number of neuropsychological deficits, with most consistent findings pointing towards impaired executive function (EF), and less commonly reported deficits in visual memory and visuospatial ability. The neuropsychological hallmark of FTD is deficits in EF. However in both OCD and FTD, the relationship between cognitive deficits and OC symptoms remains unclear. Further, the extent to which OC symptoms are comparable between the groups is ambiguous. Part I of the present study compared 19 OCD subjects to 20 age, education and IQ-matched healthy controls on a battery of neuropsychological tests of all major cognitive domains with emphasis on EF. A measure of Theory of Mind (ToM) thought to be sensitive to orbitofrontal function was also administered. OCD subjects performed worse than controls on a measure of visual memory, visuospatial reasoning and on only one measure of EF. OCD symptom subtypes, as measured by the Obsessive-Compulsive Inventory (OCI), were not correlated with any cognitive deficits. No group differences in ToM were found. It is suggested that prior research has overestimated the severity and significance of EF deficits in OCD. Part II of the study compared 9 FTD participants with 10 matched healthy controls on the same neuropsychological test battery and OC symptom measures. In addition, a measure of compulsive behaviours used in neurological populations was administered to carers. While the incidence of OC symptoms was comparable to reports in previous studies (78%), the OCI was not sensitive in the detection of OC symptoms in FTD. The similarities and differences in OC symptoms between the two patient groups are discussed.

Progression and pattern of changes in different biomarkers of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) like [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI) have been carefully investigated over the past decades. However, there have been substantially less studies investigating the potential of combining these imaging modalities to make use of multimodal information to further improve understanding, detection and differentiation of various dementia syndromes. Further the role of preprocessing has been rarely addressed in previous research although different preprocessing algorithms have been shown to substantially affect diagnostic accuracy of dementia. In the present work common preprocessing procedures used to scale FDG-PET data were compared to each other. Further, FDG-PET and MRI information were jointly analyzed using univariate and multivariate techniques. The results suggest a highly differential effect of different scaling procedures of FDG-PET data onto detection and differentiation of various dementia syndromes. Additionally, it has been shown that combining multimodal information does further improve automatic detection and differentiation of AD and FTLD.