Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, with around 30% of patients having a strong family history. The majority of that heritability is accounted ...for by autosomal dominant mutations in the chromosome 9 open reading frame 72 (
C9orf72
), progranulin (
GRN
), and microtubule-associated protein tau (
MAPT
) genes, with mutations more rarely seen in a number of other genes. This review will discuss the recent updates in the field of genetic FTD. Age at symptom onset in genetic FTD is variable with recently identified genetic modifiers including
TMEM106B
(in
GRN
carriers particularly) and a polymorphism at a locus containing two overlapping genes
LOC101929163
and
C6orf10
(in
C9orf72
carriers). Behavioural variant FTD (bvFTD) is the most common diagnosis in each of the genetic groups, although in
C9orf72
carriers amyotrophic lateral sclerosis either alone, or with bvFTD, is also common. An atypical neuropsychiatric presentation is also seen in
C9orf72
carriers and family members of carriers are at greater risk of psychiatric disorders including schizophrenia and autistic spectrum disorders. Large natural history studies of presymptomatic genetic FTD are now underway both in Europe/Canada (GENFI—the Genetic FTD Initiative) and in the US (ARTFL/LEFFTDS study), collaborating together under the banner of the FTD Prevention Initiative (FPI). These studies are taking forward the validation of cognitive, imaging and fluid biomarkers that aim to robustly measure disease onset, staging and progression in genetic FTD. Grey matter changes on MRI and hypometabolism on FDG-PET are seen at least 10 years before symptom onset with white matter abnormalities seen earlier, but the pattern and exact timing of changes differ between different genetic groups. In contrast, tau PET has yet to show promise in genetic FTD. Three key fluid biomarkers have been identified so far that are likely to be helpful in clinical trials—CSF or blood neurofilament light chain levels (in all groups), CSF or blood progranulin levels (in
GRN
carriers) and CSF poly(GP) dipeptide repeat protein levels (in
C9orf72
carriers). Increased knowledge about genetic FTD has led to more clinical presymptomatic genetic testing but this has not yet been mirrored in the development of either an accepted FTD-specific testing protocol or provision of appropriate psychological support mechanisms for those living through the at-risk phase. This will become even more relevant as disease-modifying therapy trials start in each of the genetic groups over the next few years.
Carers of people with frontotemporal dementia (FTD) experience greater challenges than carers of people with other dementias due to the younger age of onset and the challenging presentation of ...symptoms. The aim of the present study was to explore experiences of spousal carers of people with bvFTD, including those with the familial form of the disease (fFTD).
Fourteen qualitative interviews were analysed using an inductive approach to Thematic Analysis to understand experiences of spousal carers of people with bvFTD including those with fFTD.
Five main themes were identified including: a) The "Constant Battle" - A journey toward an FTD diagnosis, b) Shock, Relief and Fear - Challenges persist post diagnosis, c) The "Life Altering" impact - The loss of the spousal relationship and shifting roles, d) Adapting, Managing Symptoms and Receiving Carer Support, e) Lack of General Knowledge - Barriers to support.
Healthcare professionals should be educated on the initial presentations of FTD, to enable carers and families receive timely diagnosis and appropriate support. Future research should investigate the impact of fFTD on carers and families, to explore positive or meaningful experiences in caring, as well as theory-driven research to identify helpful coping strategies for carers of people with FTD.
Background
Frontotemporal dementia (FTD) is genetic in around 30% of people. The aim of the study was to develop a consensus protocol for genetic testing in FTD.
Methods
A Delphi methodology was used ...to achieve consensus recommendations from an international consortium of FTD and neurogenetics specialists. Participants were presented with a number of scenarios involving an asymptomatic individual from a family with a history of FTD but no known genetic mutation, who is requesting predictive testing. Consensus was defined as a recommendation being selected by >80% of respondents.
Results
1) If an affected relative is alive and able to consent for diagnostic testing, a sample should be taken to ascertain whether there is a genetic form of FTD in the family before the asymptomatic individual can pursue predictive testing. 2) In the case where the affected relative is alive but unable to consent to diagnostic testing, experts decided that a blood or saliva sample could be taken if possible, and with the family’s agreement diagnostic testing could be performed to ascertain whether a mutation is present prior to predictive testing. 3) When there is no living affected relative but a sample of DNA or tissue has been stored, experts agreed that diagnostic testing should be performed on the sample, independent of family history, prior to offering predictive testing. 4) In the case where there is no living relative and no stored DNA or tissue but there is known pathology in a deceased family member that is pathognomonic for a specific genetic form of FTD, the consensus was to perform predictive testing based on that pathology. 5) Where there is no stored sample available, experts were in agreement that predictive testing should not be offered.
Conclusions
This revised protocol will provide guidance to clinicians for FTD‐specific genetic testing.
Background
Frontotemporal dementia is the second most common form of dementia in those under 65 years of age and is found to be genetic in around a third of cases. Familial FTD has an autosomal ...dominant pattern of inheritance meaning that the offspring of a mutation carrier has a 50% chance of carrying the mutation themselves. For those at risk of FTD, there are a number of issues that can cause distress including the high penetrance of the most common FTD‐causing genes, heterogeneity of symptoms and unpredictable age of symptom onset. Despite this, there have been no studies looking at the experiences of this group, particularly those who do not pursue predictive testing.
Method
Sixteen qualitative interviews were analysed using an inductive approach to thematic analysis. Participants were asked about their experience finding out about their risk, how they felt throughout different parts of their journey, their experience of genetic testing if this was performed, as well as the support they had or feel they would have benefited from.
Result
Key themes identified included: 1) Depression, uncertainty and survivor guilt – the ups and downs of living at‐risk, 2) Worries about the wider family, 3) Lack of support ‐ “You need people who really understand”, 4) Coping mechanisms ‐ Living like a gene carrier and 5) Seeing at risk status as a positive thing. Almost all participants expressed a need for tailored psychological support facilitated by “someone who understands” the unique issues they face.
Conclusion
Living at risk of familial FTD is a psychologically challenging experience, independent of the challenges presented by predictive testing. Those who choose not to undergo predictive testing may also, at times, require specific support. Future research should explore tailored support strategies to assist people in coping with these challenges.
ObjectiveFrontotemporal dementia (FTD) is typically associated with changes in behaviour, language and movement. However, recent studies have shown that patients can also develop an abnormal response ...to pain, either heightened or diminished. We aimed to investigate this symptom in mutation carriers within the Genetic FTD Initiative (GENFI).MethodsAbnormal responsiveness to pain was measured in 462 GENFI participants: 281 mutation carriers and 181 mutation-negative controls. Changes in responsiveness to pain were scored as absent (0), questionable or very mild (0.5), mild (1), moderate (2) or severe (3). Mutation carriers were classified into C9orf72 (104), GRN (128) and MAPT (49) groups, and into presymptomatic and symptomatic stages. An ordinal logistic regression model was used to compare groups, adjusting for age and sex. Voxel-based morphometry was performed to identify neuroanatomical correlates of abnormal pain perception.ResultsAltered responsiveness to pain was present to a significantly greater extent in symptomatic C9orf72 expansion carriers than in controls: mean score 0.40 (SD 0.71) vs 0.00 (0.04), reported in 29% vs 1%. No significant differences were seen between the other symptomatic groups and controls, or any of the presymptomatic mutation carriers and controls. Neural correlates of altered pain perception in C9orf72 expansion carriers were the bilateral thalamus and striatum as well as a predominantly right-sided network of regions involving the orbitofrontal cortex, inferomedial temporal lobe and cerebellum.ConclusionChanges in pain perception are a feature of C9orf72 expansion carriers, likely representing a disruption in somatosensory, homeostatic and semantic processing, underpinned by atrophy in a thalamo-cortico-striatal network.
Introduction
Frontotemporal dementia (FTD) is one of the most common types of dementia in persons younger than 65 years of age. Diagnosis is often delayed due to slow, gradual decline and ...misinterpretation of ‘non-typical’ dementia symptoms. Informal carers of people with FTD experience greater levels of overall burden than carers of people with other forms of dementia. The aim of this systematic review was to describe the subjective experience of being an informal carer of a person with FTD and to identify the specific needs, coping strategies and helpful support resources of this carer population.
Methods
Four electronic databases were used to search for published literature presenting experiences of carers of people with FTD between January 2003 and July 2019. Search strategy followed PRISMA guidelines. Findings were analysed using framework analysis, employing five stages of analysis to develop a coding index and thematic framework that included key aspects of the carer experience, which were grouped into themes and presented in a narrative format.
Results
1213 articles were identified in total. Twelve studies were included in the final synthesis of the review. Six themes were identified: ‘Challenging road to and receipt of diagnosis’, ‘relationship change and loss’, ‘challenging experiences in caring’, ‘positive experiences and resilience’, ‘coping’ and ‘support needs’.
Discussion
Findings highlight an increased need for carers of people with FTD to receive support during the pre-diagnostic stage, including support to manage symptoms. Further research should explore relationship changes and loss amongst carers to inform approaches for carer support. In conclusion, the lack of knowledge and unique needs of carers highlight the importance of public awareness campaigns and healthcare professional education to support carers with FTD symptom impact.
Semantic variant of primary progressive aphasia (svPPA) is a subtype of frontotemporal dementia characterized by asymmetric temporal atrophy.
We investigated the pattern of medial temporal lobe ...atrophy in 24 svPPA patients compared to 72 controls using novel approaches to segment the hippocampal and amygdalar subregions on MRIs. Based on semantic knowledge scores, we split the svPPA group into 3 subgroups of early, middle and late disease stage.
Early stage: all left amygdalar and hippocampal subregions (except the tail) were affected in svPPA (21-35% smaller than controls), together with the following amygdalar nuclei in the right hemisphere: lateral, accessory basal and superficial (15-23%). On the right, only the temporal pole was affected among the cortical regions. Middle stage: the left hippocampal tail became affected (28%), together with the other amygdalar nuclei (22-26%), and CA4 (15%) on the right, with orbitofrontal cortex and subcortical structures involvement on the left, and more posterior temporal lobe on the right. Late stage: the remaining right hippocampal regions (except the tail) (19-24%) became affected, with more posterior left cortical and right extra-temporal anterior cortical involvement.
With advanced subregions segmentation, it is possible to detect early involvement of the right medial temporal lobe in svPPA that is not detectable by measuring the amygdala or hippocampus as a whole.
Current tasks measuring social cognition are usually 'pen and paper' tasks, have ceiling effects and include complicated test instructions that may be difficult to understand for those with cognitive ...impairment. We therefore aimed to develop a set of simple, instructionless, quantitative, tasks of emotion recognition using the methodology of eye tracking, with the subsequent aim of assessing their utility in individuals with behavioural variant frontotemporal dementia (bvFTD).
Using the Eyelink 1000 Plus eye tracker, 18 bvFTD and 22 controls completed tasks of simple and complex emotion recognition that involved viewing four images (one target face (simple) or pair of eyes (complex) and the others non-target) followed by a target emotion word and lastly the original four images alongside the emotion word. A dwell time change score was then calculated as the main outcome measure by subtracting the percentage dwell time for the target image before the emotion word appeared away from the percentage dwell time for the target image after the emotion word appeared. All participants also underwent a standard cognitive battery and volumetric T1-weighted magnetic resonance imaging.
Analysis using a mixed effects model showed that the average (standard deviation) mean dwell time change score in the target interest area was 35 (27)% for the control group compared with only 4 (18)% for the bvFTD group (p < 0.05) for the simple emotion recognition task, and 15 (26)% for the control group compared with only 2 (18)% for the bvFTD group (p < 0.05) for the complex emotion recognition task. Worse performance in the bvFTD group correlated with atrophy in the right ventromedial prefrontal and orbitofrontal cortices, brain regions previously implicated in social cognition.
In summary, eye tracking is a viable tool for assessing social cognition in individuals with bvFTD, being well-tolerated and able to overcome some of the problems associated with standard psychometric tasks.
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