Cerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from phenocopy non-progressors

Background: Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non-neurodegenerative non-progressor, phenocopy mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay. Methods: Cerebrospinal fluid (CSF) NfL, amyloid beta 1-42 (AB42), total and phosphorylated tau (T-tau, P-tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow up information, patients were categorised as Progressors. Non-Progressors were subtyped in to Phenocopy Non-Progressors (non-neurological/neurodegenerative final diagnosis), and Static Non-Progressors (static deficits, not fully explained by non-neurological/neurodegenerative causes). Results: Forty-three patients were included: 20 Progressors, 23 Non-Progressors (15 Phenocopy, 8 Static), 20 controls. NfL concentrations were lower in Non-Progressors (Non-Progressors Mean, M=554pg/mL, 95%CI:[461, 675], Phenocopy Non-Progressors M=459pg/mL, 95%CI:[385, 539], Static Non-Progressors M=730pg/mL, 95%CI:[516, 940]), compared to bvFTD Progressors (M=2397pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non-Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Static Non-Progressors tended to have higher T-tau and P-tau levels compared to Phenocopy Non-Progressors. Conclusion: This study demonstrated strong diagnostic utility of CSF NfL to distinguish bvFTD from phenocopy non-progressor variants, at baseline, with high accuracy, in a real-world clinical setting. This has important clinical implications, to improve outcomes for patients and clinicians facing this challenging clinical dilemma, as well as for healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non-progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL

Antisense oligonucleotide-based therapeutic strategy for progranulin-deficient frontotemporal dementia

Loss-of-function GRN mutations result in progranulin haploinsufficiency and are a common cause of frontotemporal dementia (FTD). Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but ASO-based strategies for increasing target protein levels are still relatively limited. Here, we report the use of ASOs to increase progranulin protein levels by targeting the miR-29b binding site in the 3′ UTR of the GRN mRNA, resulting in increased translation.

Apathy, Executive Function, and Emotion Recognition Are the Main Drivers of Functional Impairment in Behavioral Variant of Frontotemporal Dementia

Background: The cognitive and neuropsychiatric deficits present in patients with behavioral variant frontotemporal dementia (bvFTD) are associated with loss of functionality in the activities of daily living (ADLs). The main purpose of this study was to examine and explore the association between the cognitive and neuropsychiatric features that might prompt functional impairment of basic, instrumental, and advanced ADL domains in patients with bvFTD.Methods: A retrospective cross-sectional study was conducted with 27 patients with bvFTD in its early stage (<2 years of evolution) and 32 healthy control subjects. A neuropsychological assessment was carried out wherein measures of cognitive function and neuropsychiatric symptoms were obtained. The informant-report Technology–Activities of Daily Living Questionnaire was used to assess the percentage of functional impairment in the different ADL domains. To identify the best determinants, three separate multiple regression analyses were performed, considering each functional impairment as the dependent variable and executive function, emotion recognition, disinhibition, and apathy as independent variables.Results: For the basic ADLs, a model that explains 28.2% of the variability was found, in which the presence of apathy (β = 0.33, p = 0.02) and disinhibition (β = 0.29, p = 0.04) were significant factors. Concerning instrumental ADLs, the model produced accounted for 63.7% of the functional variability, with the presence of apathy (β = 0.71, p < 0.001), deficits in executive function (β = −0.36, p = 0.002), and lack of emotion recognition (β = 0.28, p = 0.017) as the main contributors. Finally, in terms of advanced ADLs, the model found explained 52.6% of the variance, wherein only the presence of apathy acted as a significant factor (β = 0.59, p < 0.001).Conclusions: The results of this study show the prominent and transverse effect of apathy in the loss of functionality throughout all the ADL domains. Apart from that, this is the first study that shows that the factors associated with loss of functionality differ according to the functional domain in patients with bvFTD in its early stage. Finally, no other study has analyzed the impact of the lack of emotion recognition in the functionality of ADLs. These results could guide the planning of tailored interventions that might enhance everyday activities and the improvement of quality of life.

Knowledge and Attitudes for the Management of Behavioral Variant of Frontotemporal Dementia

Background: The diagnosis of the behavioral variant of frontotemporal dementia (bvFTD) can be especially challenging and is relatively underdiagnosed. There is scarce information on training and attitudes from care providers facing bvFTD in settings with limited resources. We aim to describe clinical knowledge and attitudes facing bvFTD from neurologists, psychiatrists, and residents in Peru.Methods: Potential participants received invitations by email to complete an online questionnaire. In addition, we reviewed 21 curricula from undergraduate medical schools' programs offered by the main schools of medicine in Peru during 2020 and 2021.Results: A total of 145 participants completed the survey. The responders were neurologists (51%), psychiatrists (25%), and residents in neurology or psychiatry (24%). Only 26% of the respondents acknowledged receiving at least one class on bvFTD in undergraduate medical training, but 66.6% received at least some training during postgraduate study. Participants identified isolated supportive symptoms for bvFTD; however, only 25% identified the possible criteria and 18% the probable bvFTD criteria. They identified MoCA in 44% and Frontal Assessment Battery (39%) as the most frequently used screening test to assess bvFTD patients. Memantine and Acetylcholinesterase inhibitors were incorrectly indicated by 40.8% of participants. Seventy six percentage of participants indicated that they did not provide education and support to the caregiver. The dementia topic was available on 95.2%, but FTD in only 19%.Conclusion: Neuropsychiatry medical specialists in Peru receive limited training in FTD. Their clinical attitudes for treating bvFTD require appropriate training focused on diagnostic criteria, assessment tools, and pharmacological and non-pharmacological management.