Behavioral, neuropsychiatric disturbances differ by frontotemporal dementia type

The common frontotemporal dementia gene variations have different behavioral and neuropsychiatric disturbances and different trajectories through the course of the disease, according to study results published in JAMA Network Open.

“Several studies have investigated the development of behavioral disturbances in sporadic [frontotemporal dementia], with a recent study showing that the progression and severity of behavioral symptoms may change during the course of the disease,” Alberto Benussi, MD, of the department of clinical and experimental sciences at the University of Brescia in Italy, and colleagues wrote. “Negative symptoms, such as apathy and loss of empathy, steadily increase throughout the course of disease, whereas positive symptoms, such as disinhibition and perseverative behavior, tend to worsen until the intermediate stages and then decrease in severity in the more advanced phases.”

The researchers noted that this progression has yet to be addressed systematically within and across the symptomatic phases of genetic frontotemporal dementia. Further, it remains unclear how neuropsychiatric and behavioral symptoms change during the course of the disease, as well as whether distinct patterns of symptom progression exist among different gene variants.

To address these research gaps, Benussi and colleagues conducted the current longitudinal study, the international Genetic FTD Initiative, to evaluate behavioral symptom severity and frequency, and their evolution and progression, among different genetic frontotemporal dementia forms. They analyzed data of 232 patients with frontotemporal dementia at 23 multicenter specialist tertiary frontotemporal dementia research clinics in 11 countries. A total of 115 participants had variations in C9orf72, 78 in GRN and 39 in MAPT, and 101 carriers had one or more follow-up evaluation for a total of 400 assessments. The researchers included gene variations only if considered pathogenetic. They assessed behavioral and neuropsychiatric symptoms across disease duration and evaluated from onset of symptoms, and they modeled behavioral and neuropsychiatric measures as a function of disease duration and variation using hierarchical generalized linear mixed models.

Results showed a high expression among all gene variant carriers for all core behavioral symptoms, including apathy, disinhibition, hyperorality, loss of empathy and perseverative behavior, with apathy among the most common and severe symptoms throughout the disease course. Those with MAPT variants had the highest frequency and severity of most behavioral symptoms, especially disinhibition and compulsive behavior, vs. C9orf72 carriers and GRN carriers. Neuropsychiatric symptoms were also very frequently reported among patients with genetic frontotemporal dementia, with anxiety and depression most common among GRN carriers and MAPT carriers, whereas hallucinations, especially auditory and visual, were most common among C9orf72 carriers. In the early-intermediate phases, most behavioral and neuropsychiatric symptoms increase and then plateaued in the late stages of disease, aside from depression, which steadily declined among C9orf72 carriers, and depression and anxiety, which increased only in the late stages among GRN carriers.

“[These results have] crucial implications for counseling patients and caregivers and [are] very important for the design of disease-modifying treatment trials in genetic [frontotemporal dementia],” the researchers wrote.