Frontotemporal Dementia: A systematic review

Background: Frontotemporal dementia is a common type of dementia and is a group of progressive neurodegenerative syndromes usually caused by the accumulation of pathological tau or TDP-43 proteins. The review is identifying the clinical measures including neuropsychological scores and functional measures. Methods: A systematic review was conducted covering the clinical trials done to investigate the Frontotemporal Dementia. The sample was taken from Pubmed library. 28 results were found in a range of time from 2016 to 2021. The excluded papers were 17. A total of 10,349 articles were identied at the rst stage of selecting. All records were screened in and exclude by and then based on full After excluding articles by and type of a total of 28 articles were identied through the databases. Following this, the irrelevant papers from databases were removed from original articles, and nally 11 articles were included based on their title/abstract. Full articles were then sourced for about 600 references. It included 732 patients and 195 controls as a total.


Introduction
Frontotemporal Dementia (FTD) tends to start at a younger age than 65 in the contrary to general Dementia. Most cases are diagnosed in people aging 45-65, although it can also affect younger or older people [1]. Frontal and temporal lobes are affected in case of frontotemporal dementia with progressive syndromes caused by the accumulation of TDP-43 proteins [2]. Symptoms of FTD includes personal and behavioral changes as impulsivity and loss of motivation, language problems as speaking slowly, and mental abilities and memory problems [1].
FTD was studied in a longitudinal multimodal imaging and clinical endpoints clinical trials. Most imaging studies in frontotemporal dementia have been cross-sectional, and few have compared longitudinal changes in cortical volume with changes in other measures such as perfusion and white matter integrity.
The goal of the study was to study stated longitudinal changes in 161 patients with three frontotemporal dementia syndromes: behavioral variant frontotemporal dementia (n = 77) and the semantic (n = 45) and non-uent (n = 39) variants of primary progressive aphasia. Visits included comprehensive neuropsychological and functional assessment, structural MRI (3 T), diffusion tensor imaging, and arterial spin labelled perfusion imaging. identify measures that are appropriate as clinical trial outcomes for each group, as well as those that might be appropriate for trials that would include more than one of these groups [2].
Imaging changes were signi cantly correlated with the change in most clinical measures. Perfusion and diffusion tensor imaging accounted for variation in clinical decline beyond volume alone. Corpus callosal fractional anisotropy led to the least sample size estimates for all three syndromes. These ndings provide further guidance on selection of trial endpoints for studies in frontotemporal dementia and support the use of neuroimaging, particularly structural and diffusion weighted imaging, as biomarkers. Diffusion and perfusion imaging appear to offer additional utility for explaining clinical change beyond the variance explained by volume alone, arguing for considering multimodal imaging in treatment trials [2].
A study was conducted using blood uids of FTD patients as they have been analyzed using conventional lipid assays based on enzymes, and these have shown that triglyceride (TG) levels are increased in FTD compared to controls. Global lipid analysis has also shown that TG levels are increased in FTD compared to controls, along with changes in other lipids. The study undertook lipidomics analysis of FTD serum to investigate three key aspects of FTD pathophysiology relevant to neurodegeneration: mitochondrial dysfunction, in ammation, and oxidative stress. It analyzed cardiolipin and acylcarnitine, both of which are involved in mitochondrial energy production. Individuals diagnosed with bvFTD (N = 40) and healthy controls (N = 22) were recruited at Neuroscience Research Australia in Sydney from FRONTIER, the frontotemporal dementia clinical research group, and from a panel of healthy study volunteers [3].
Frozen post-mortem brain tissue samples were obtained from Sydney Brain Bank and NSW Brain Tissue Resource Centre following appropriate ethical approvals (University of New South Wales Human Research Ethics approval number: HC15789). Frozen samples from the superior frontal cortex from 10 FTD cases, 10 AD cases and 11 controls without neurological, psychiatric or neuropathological diagnoses were used in this study. The mean age of the three groups were 72.9 ± 13.0, 73.7 ± 7.5 and 79.5 ± 12.1 years, respectively [3].
Statistical analyses were performed using SPSS Statistics software (IBM, Chicago, Illinois). For comparisons between FTD and control groups, either univariate analysis (general linear model) or Student's t-test was used and statistical signi cance set at p < 0.05. When univariate analysis was performed, age and gender were included as covariates. Pearson's correlations were used to determine if changes in lipid levels were associated with each other with statistical signi cance set at p < 0.05. Graphs were generated using GraphPad Prism 7 [3].
The Tailored Activity Program is an occupational therapy based intervention that involves working collaboratively with family carers (dyads) 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 [4]. 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 [4].
Previous research has proved that odor identi cation is impaired in the frontal variant of FTD. According to the Spanish Law 14/2007 of Biomedical Research, inform written consent forms of the Neurological Tissue Bank of Navarra Health Service, Brain Bank of IDIBELL, and Neurological Tissue Bank of IDIBAPS-Hospital Clinic (Barcelona, Spain) was obtained for research purposes from relatives of patients included in this study. The study was conducted in accordance with the Declaration of Helsinki and all assessments, post-mortem evaluations, and procedures were previously approved by the Clinical Ethics Committee of Navarra Health Service. For the proteomic phase, 4 FTLD-TDP43 and 4 FTLD-Tau (PSP) cases were analyzed. Four cases from elderly subjects with no histological ndings of any neurological disease were used as a non-FTD group. All human brains considered in the proteomic study had a postmortem interval (PMI) lower than 16 h. Proteomics was complemented with a follow-up phase in which protein changes and activation dynamics where checked by Western-blotting across all samples included in the study (n = 27 OB samples) [6].
Another study was conducted to determine whether intranasal oxytocin, alone or in combination with instructed mimicry of facial expressions, would augment neural activity in patients with frontotemporal dementia (FTD) in brain regions associated with empathy, emotion processing, and the simulation network, as indexed by blood oxygen-level dependent (BOLD) signal during fMRI [7].
A study was done to determine the effect of tolcapone, a speci c inhibitor of Catechol-O-Methyltransferase (COMT), in patients with bvFTD. The most frequent treatment-related adverse event during tolcapone treatment was elevated liver enzymes (21%). There were no signi cant differences between tolcapone treatment and placebo in the primary or imaging outcomes [5].
Another study was conducted to compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD. A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug [8].
Behavioural variant frontotemporal dementia (bvFTD) is a form of frontotemporal degeneration characterized by early changes in personality, emotional blunting, and/or loss of empathy. Recent research has highlighted that these features may be at least partially explained by impairments in the theory of mind.
A study applied anodal tDCS over the MFC (Fpz site, with the cathode between Oz and Inion) to modulate ToM performance in bvFTD patients. We used an adapted version of a ToM task, measuring the ability to represent other people's private and communicative intentions from the observation of their daily actions. Three out of the 16 patients had monogenic FTD [10].
In order to study the brain networks oscillations in bvFTD, some collaborators used a promising new connectivity measure called Weighted Symbolic Mutual Information (wSMI). In particular, this method proves more sensitive than previous approaches to EEG connectivity (phase-locking value, phase-lag index, and power spectral densities) used to evaluate network abnormalities in other pathological samples. Moreover, wSMI has already proven sensitive to detect aberrant networks in other neurodegenerative conditions. Instead of measuring basic oscillatory correlations, wSMI assesses the non-linear coupling of information sharing among distant networks [9].
The last study describes a novel adaptive proof-of-concept, phase 2, placebo-controlled, randomized crossover trial repurposing the hormone and neuropeptide oxytocin as a potential symptomatic treatment for apathy/indifference and related empathy de cits in patients with FTD. The objectives of the study design are to (1) e ciently identify the most promising dose schedule of oxytocin, given potential habituation to daily dosing, and (2) permit e cacy analysis of the most promising dose compared with placebo to determine whether progression to a phase 3 trial is warranted. We propose that this approach may inform the design and conduct of other RCTs, particularly of symptomatic medications in FTD and related neuropsychiatric disorders [11].

Methods
The methodology to perform this systematic review was developed according to recommendations from the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. A systematic review was conducted covering the clinical trials done to investigate the Frontotemporal Dementia. The sample was taken from Pubmed library. 28 results were found in a range of time from 2016 to 2021. The excluded papers were 17.

Inclusion criteria:
The review included only clinical trials and randomized controlled trials.
Exclusion criteria: The review excluded systematic reviews, meta-analysis, books and documents.
The following data were extracted: The outcome of the review is covering the clinical trials about FTD updated on the widest range databased library Pubmed in the last ve years. It allows the reader to collect the required data for the research about FTD and its concerns in the latest research done the last half decade.

Data Synthesis:
As there were no RCT or quasi-experimental observational studies available in this area, a meta-analysis was not conducted, nor was it possible to examine measures of treatment effects, as all the studies reviewed were case studies. Data were synthesized by a narrative approach. PRISMA Flow Chart: ( Fig. 1

Results
A total of 10,349 articles were identi ed at the rst stage of papers selecting. All records were screened in order to include and exclude by title/abstract and then based on full text. After excluding articles by year and type of papers, a total of 28 articles were identi ed through the databases. Following this, the irrelevant papers from databases were removed from original articles, and nally 11 articles were included based on their title/abstract. Full articles were then sourced for about 600 references. It included 732 patients and 195 controls as a total.

Conclusions
This is the rst systematic review that covers the clinical trials and the randomized controlled trials in the last ve years on Pubmed library. The review describes the clinical and RCT trials for FTD in the last ve years so it can be very updated information for the researchers to cover information required for their researches in the future ones.
Declarations I declare that the review has been composed by myself and that the work has not be submitted for any other degree or professional quali cation or journal.
Competing interests: the author declares no competing interests