Time to Diagnosis and Its Predictors in Syndromes Associated With Frontotemporal Lobar Degeneration.

OBJECTIVES: Frontotemporal Lobar Degeneration (FTLD) causes a heterogeneous group of neurodegenerative disorders with a wide range of clinical features. This might delay time to diagnosis. The aim of the present study is to establish time to diagnosis and its predictors in patients with FTLD-associated syndromes. DESIGN: Retrospective study. SETTING: Tertiary referral center. PARTICIPANTS: A total of 1029 patients with FTLD-associated syndromes (age: 68 [61-73] years, females: 46%) from 1999 to 2023 were included in the present study. MEASUREMENTS: Time to diagnosis was operationalized as the time between symptom onset and the diagnosis of a FTLD-associated syndrome. The associations between time to diagnosis and possible predictors (demographic and clinical variables) were investigated through univariate and multivariate linear models. RESULTS: Median time to diagnosis was 2 [1-3] years. We observed that younger age at onset (ß = -0.03, p <0.001), having worked as a professional rather than as a blue (ß = 0.52, p = 0.024) or a white (ß = 0.46, p = 0.050) collar, and having progressive supranuclear palsy (p <0.05) or the semantic variant of primary progressive aphasia (p <0.05) phenotypes were significantly associated with increased time to diagnosis. No significant changes of time to diagnosis have been observed over 20 years. CONCLUSIONS: The identification of predictors of time to diagnosis might improve current diagnostic algorithms, resulting in a timely initiation of symptomatic treatments, early involvement in clinical trials, and more adequate public health policies for patients and their families.

Clinical and imaging correlates of hyperorality in syndromes associated with frontotemporal lobar degeneration.

AIM: Empirical research investigating hyperorality in syndromes associated with frontotemporal lobar degeneration (FTLD) is limited. The present study aims to assess and describe hyperorality and its clinical and imaging correlates in patients with FTLD-associated syndromes. METHODS: This retrospective longitudinal study included consecutive patients with FTLD who underwent a clinical, cognitive, and behavioral assessment. The presence and severity of hyperorality was assessed using the Frontal Behavior Inventory. RESULTS: A total of 712 patients with FTLD were included in the study. Hyperorality was reported by 29% (204 of 712 [95% CI: 25-32%]) of patients; was more frequent in those with severe dementia than in those with prodromal or mild to moderate dementia (P < 0.05); was associated with younger age (odds ratio [OR] = 0.96 [95% CI: 0.94-0.99]), (P = 0.003) and positive family history for dementia (OR = 2.03 [95% CI: 1.18-3.49], P = 0.010); was overall more probable in the behavioral variant of frontotemporal dementia (bvFTD) and frontotemporal dementia with amyotrophic lateral sclerosis phenotypes, and less probable in other language or motor phenotypes; and was associated with higher severity of neuropsychiatric symptoms (OR = 1.08 [95% CI: 1.06-1.10], P < 0.001) and with the presence of several behavioral symptoms (P < 0.05). Moreover, hyperorality severity increased over time only in patients with bvFTD (ß = +0.15, P = 0.011) or semantic variant of primary progressive aphasia (ß = +0.34, P = 0.010). Finally, the presence of hyperorality was significantly associated with greater atrophy in the right anterior insula and right orbitofrontal region (false discovery rate-corrected P < 0.05). CONCLUSION: Hyperorality is common in certain FTLD-associated syndromes. Understanding its correlates can help clinicians define pharmacological and educational interventions and clarify related anatomical circuits.

Neurophysiological correlates of altered time awareness in Alzheimer's disease and frontotemporal dementia.

BACKGROUND: Alterations in time awareness have been reported in dementia, particularly in Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, the neurophysiological correlates underlying these alterations remain largely unexplored. This study aimed to investigate the neurophysiological correlates of altered time awareness in AD and FTD patients. METHODS: A total of 150 participants (50 AD patients, 50 FTD patients, and 50 healthy controls [HC]) underwent a standardized neuropsychological assessment, an altered time awareness survey, and transcranial magnetic stimulation (TMS) to assess cholinergic (short latency afferent inhibition-SAI), GABAergic (short interval intracortical inhibition-SICI), and glutamatergic (intracortical facilitation-ICF) circuits. RESULTS: In AD patients, the most frequent symptom was difficulty in ordering past events (52.0%), while FTD patients primarily struggled with estimating temporal intervals between events (40.0%). Significant differences were observed between HC and both patient groups, as well as between AD and FTD patients in their tendency to re-live past events. Binomial logistic regression analysis revealed that impairments in glutamatergic and cholinergic circuits significantly predicted the likelihood of participants manifesting altered time awareness symptoms. CONCLUSIONS: This study provides novel insights into the neurophysiological correlates of altered time awareness in AD and FTD patients, highlighting the involvement of specific neurotransmitter circuits, particularly glutamatergic and cholinergic circuits. Further research is needed to explore the potential clinical implications and therapeutic targets arising from these findings.