Long-Term Multimodal Exercise Intervention for Patients with Frontotemporal Lobar Degeneration: Feasibility and Preliminary Outcomes

Frontotemporal lobar degeneration (FTLD) is the second most common form of early-onset dementia in individuals aged <65 years, following Alzheimer’s disease [1]. It is classified into three types: behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia [2, 3]. FTLD is a challenging form of dementia because of its unique clinical symptoms, such as disinhibition, apathy, and ritualistic behavior [4]. FTLD primarily affects patients with early-onset dementia, creating significant challenges for caregivers and imposing substantial economic and emotional burdens on both families and healthcare systems [5]. Nevertheless, no effective pharmacological or non-pharmacological treatments for FTLD have been established to date.

Non-pharmacological interventions for dementia appear promising, and exercise-based interventions are particularly effective [6‒9]. Exercise-induced expression of brain-derived neurotrophic factors is considered to promote neural regeneration, improve glucose tolerance and insulin resistance, and activate the frontal lobes, which are the mechanisms underlying dementia prevention [10].

Memory, motor function (excluding FTLD-motor neuron disease), and visuospatial cognitive function are preserved in patients with FTLD [11]; therefore, tasks based on motor function can be easily introduced [12]. Additionally, symptoms of heightened susceptibility to environmental influences may make exercise a habit and incorporate it into regular activities, a strategy known as routine-based therapy [13]. Despite reports of exercise-based interventions for Alzheimer’s disease [14], only a few case reports on such interventions for FTLD are available [15, 16]. Multimodal intervention is reportedly effective for dementia [17]. However, previous studies primarily involved short- to medium-term (12–24 weeks) interventions and unimodal training. Notably, the efficacy of long-term and multimodal interventions, specifically in FTLD, is largely unknown. Moreover, researchers have not indicated the outcomes, except for physical function, in multiple patients with FTLD. While certain types of exercise may help alleviate specific symptoms of FTLD, these benefits are often restricted to a limited range of symptoms. To address the full spectrum of FTLD manifestations, a multimodal approach is necessary. Unlike single exercise types, a multimodal regimen can engage and stimulate multiple brain regions, potentially offering broader and more comprehensive therapeutic benefits.

The present study aimed to investigate in clinical outcomes following a long-term multimodal exercise intervention for FTLD. Specifically, we sought to evaluate the feasibility of the program and assess preliminary effects on cognitive, psychological, physical, and behavioral functions. We hypothesized that the exercise intervention would be feasible and would lead to improvements across these domains. Regarding functional near-infrared spectroscopy (fNIRS), we anticipated that the intervention would increase activation in the prefrontal cortex, given its central role in cognitive control and physical coordination. As this was a preliminary study, the intervention was initially applied to a small sample.

This 48-week single-arm study was conducted at the University of Tsukuba Hospital in Tsukuba City, Ibaraki, Japan, from July 2017 to July 2018. The intervention involved physical exercise for patients with FTLD. A single-arm design without a control group was adopted because the study was preliminary. The study protocol followed the tenets of the Declaration of Helsinki was approved by the Ethics Committee of University of Tsukuba Hospital (approval number: H30-228) and was registered in the UMIN Clinical Trials Registry (No. UMIN000035097).

Patients with FTLD were recruited according to the FTLD criteria for bvFTD and SD [18, 19]. We did not limit recruitment to specific subtypes of FTLD; however, most participants who met the inclusion criteria were diagnosed with the bvFTD or SD, which is why these two subtypes were primarily represented in the study. The inclusion criteria were as follows: (i) age >60 years, (ii) ambulatory status with or without assistance, and (iii) ability to tolerate functional testing and exercise. The exclusion criteria were as follows: (i) terminal disease and (ii) major musculoskeletal conditions (e.g., severe joint disorders, fractures, or chronic pain syndromes), cardiovascular conditions (e.g., congestive heart failure, severe hypertension, or recent heart attacks), or other neurological conditions (e.g., stroke, epilepsy, or advanced Parkinson’s disease) precluding exercise. Table 1 presents the patients’ characteristics. Four male patients with FTLD met the eligibility criteria and were enrolled in the study. Among these, 3 patients had bvFTD, whereas 1 had SD.

The intervention program was provided under the following conditions: (i) participation with a partner (required but without specific guidance to partner), (ii) individualized exercise instructions, and (iii) a combination of regular hospital and home exercises. The patients engaged in a multimodal exercise program, which comprised cognitive training, moderate-intensity continuous training (MICT) [20], strength training, balance training, and flexibility and relaxation training. An exercise instructor provided the one-on-one program in a medically supervised university hospital for 60 min per day, once every 2 weeks, for 48 weeks.

The program included a 5-min warm-up, 10 min of dual task training, 10–30 min of MICT (on rowing ergometer; Technogym, Japan) at 40%–70% heart rate (HR)_peak, 10–30 min of strength training, 10 min of balance training, and 5-min flexibility and relaxation. Table 2 shows the details of the multimodal exercise program. All exercises were performed at a moderate intensity (rate of perceived exertion [21] of 11–13 and 40%–70% HR_peak by Polar A360 [Polar Electro., Kemple, Finland]). The patients were provided with home-based exercises (one type of exercise program per month: strength training, aerobic exercise, flexibility, and relaxation) tailored to their fitness level and instructed to perform them regularly.

The feasibility of the exercise program in the hospital used the dropout rate (proportion of patients who did not complete the post-intervention assessment), attendance rate (number of attendances/total number of sessions), diary review, and exercise persistence status (i.e., incorporation of exercise into daily life). The patients were instructed to record their daily exercises and impressions of the program in a printed diary. An exercise instructor reviewed each diary to assess the exercise routine at home and the patients’ impressions of the program. We evaluated the exercise persistence status with home exercise adherence rate from the diary (percentage of exercise days, divided by scheduled exercise date), action plans [22], recovery self-efficacy (Re-SE) [23], and exercise self-efficacy [24].

All outcome measures were assessed before and after the 48-week intervention by trained staff members, including a clinical psychologist. The following items were investigated: anthropometric variables, self-reported measures of physical function [25, 26], cognitive function [27‒29], psychological functions [30, 31], physical function tests [32‒35], behavioral function [23, 24, 36], and fNIRS. Details of outcome measures are described in the online supplementary materials (for all online suppl. material, see https://doi.org/10.1159/000542994). A description of fNIRS is provided in the next section.

fNIRS was used to assess frontal lobe function. fNIRS measurements were performed during a modified serial number task (Fig. 1). The patients performed subtraction drills (five questions, 20 s each) that appeared on the monitor. A 40 s rest interval was allowed between each task, during which patients were instructed to pronounce nonsense vowels (a, i, u, e, and o). fNIRS data were collected using a continuous three-wavelength fNIRS LABNIRS 67ch system with an entire head holder (Shimadzu, Japan). Subsequently, we arranged 54 channels to measure the dorsolateral prefrontal, parietal, somatosensory, and forehead regions [37]. We digitized each patient’s channel position using the Fastrak 3D digitizer (Polhemus, USA) and inputted the data into the standard brain model. Next, we obtained the Montreal Neurological Institute coordinate outputs using the NIRS-SPM software Ver. 4 (Department of Bio and Brain Engineering, KAIST, Korea) to extract brain anatomical information from measurement channels. The NIRS system measured oxyhemoglobin (HbO) and decreased deoxyhemoglobin levels following changes in their cortical concentration based on the modified Beer-Lambert law.

Values are expressed as means and standard deviations at baseline. The 48-week changes in all outcome measures are expressed as means, standard deviations, and effect sizes (Cohen’s d) to better interpret the intensity of within-group changes. Data were analyzed using IBM SPSS Statistics for Windows version 22 (IBM Corp., Armonk, NY, USA). fNIRS data analysis was conducted using the NIRS-SPM software operated in the MATLAB environment (MathWorks, Natick, MA, USA) [38]. In the analyzing process, after removing artifacts due to body movement, a predictive model of HbO and deoxyhemoglobin response was generated based on the general linear model to examine the transition of brain activity sites before and after exercise intervention. SPM t-statistic maps were created with significance for HbO set at p < 0.01.

After 48 weeks, all patients completed the post-intervention assessments, with a mean attendance rate of 93.6% (range, 88.2–100%). Based on a diary review, positive opinions included “exercise refreshes the mood,” “exercise has become a habit,” and “exercise is fun.” Negative opinions included “exercise makes me a little tired.” The program ended without injuries or other adverse events. The home exercise adherence rate based on the information in the diaries was 68.5% (range, 60.8–77.7%), and the diary collection rate (percentage of activity diaries successfully collected from participants) was 83.1% (range, 54.5–100.0%). Participants were instructed to submit their activity diaries on a monthly basis.

Table 1 presents the characteristics of the participants. The Barthel index scores were as follows: participants A and B both scored 85 points, participant C scored 95 points, and participant D achieved a perfect score of 100 points.

Table 3 presents the cognitive and psychological function values before and after the intervention. The changes in MMSE-J scores before and after the intervention showed improvement in two out of three cases of bvFTD, with scores increasing from 25 to 28 and from 23 to 25, respectively. However, in the third case of bvFTD, the score slightly decreased from 23 to 22. In contrast, the SD case exhibited a strongly decline, with the score dropping from 12 to 3. Overall, the MMSE-J scores reflected a small deterioration, indicating a small effect. Similarly, the FAB scores showed a slight overall decline. In the SCWT results, five items showed improvement, while one item showed deterioration. Despite these changes, most of the effect sizes were small, except for one improvement with a medium effect size of d = 0.52 in the mismatch condition (reaction time). The MCL-S.2 results showed three improvements, with two items – pleasantness and relaxation – exhibiting medium effect sizes of d = 0.68 and d = 0.71, respectively. Another item showed a small effect on anxiety. The GDS results indicated an improvement with a medium effect size of d = 0.68.

Table 4 presents the behavioral and physical function values before and after the intervention. All patients reported that the exercise regimen became an integrated part of their daily lives following the intervention. Both Re-SE and exercise efficacy showed significant improvements, with large effect sizes (d > 0.8). In the SRI results, overall stereotypical behaviors slightly decreased. However, specific increases were noted in areas such as eating, cooking, and speaking, while reductions were observed in roaming, movement, and daily rhythm (Cohen’s d = 0.56–0.71). For physical function, three items showed no effect, but one item demonstrated a positive effect on the TUG test (Cohen’s d = 0.68). Figure 2 shows the fNIRS results of patients. After the intervention, activation of the frontal lobe was observed in all patients.

The current study evaluated the feasibility of the exercise program and observed changes in the clinical outcomes of a long-term multimodal exercise intervention for FTLD. We hypothesized that the exercise program is feasible and may positively change the cognitive, psychological, physical, and behavioral functions of individuals with FTLD. Our preliminary findings largely supported the hypothesis, showing improvements in specific areas. However, declines were also observed in several functions, which may not necessarily be attributable to the intervention and could instead reflect the natural progression of FTLD.

The exercise program in the study might be feasible for the following reasons. The attendance and dropout rates were notably high at 93.6% and 0%, respectively, whereas the home exercise adherence rate was seemed moderately high (68.5%). Considering the characteristic regional atrophy of the frontal and temporal lobes in FTLD [39], patients usually experience difficulty while continuously participating in exercise programs. For example, atrophy of the anterior cingulate cortex is associated with apathy in FTLD, and dysfunction of the right temporal lobe is linked to disinhibition [40]. However, we obtained high attendance, low dropout rates, and home exercise adherence rates, which were established in daily life. All patients reported that they could integrate exercise into their daily lives and that their exercise time was regularly scheduled after the intervention. Furthermore, Re-SE and exercise self-efficacy showed positive changes. Patients’ feedback on the multimodal exercise intervention was generally positive. The exercise program in the study could be selected according to an individual’s level of fitness, and exercise at home was established according to individual characteristics. Additionally, the exercise instructor supported the exercise continuation at home, providing feedback on the diary (encouragement and praise). Therefore, this exercise program might have been more acceptable to the patients.

The presence of partners who provided support for the exercise intervention might have been important. For people with dementia, interventions with a partner have the potential to enhance well-being and satisfaction for both the partner and patient [41, 42]. For those with FTLD, activity-based interventions with a partner have also been suggested to alleviate behavioral symptoms [43]. Particularly in FTLD, it is crucial to provide fixed caregiver support owing to the symptoms of heightened susceptibility to environmental influences [44]. Participation in the exercise program with a partner would be considered to play an important role in this study.

FTLD is often challenging to manage due to its characteristic symptoms, such as stereotypic behavior and disinhibition. In this study, however, we implemented a 48-week exercise program for FTLD, which appeared feasible under the following conditions: (i) participation with a partner, (ii) individualized exercise instructions, and (iii) a combination of regular hospital and home exercises. Such feasibility may be attributed to the management of the symptom of heightened susceptibility to environmental influences.

In fNIRS, frontal lobe activation was visually observed before and after the exercise intervention. Previous fNIRS and MRI studies reported that an exercise intervention activated the frontal lobes in cognitively normal individuals and patients with MCI/AD [45, 46]. However, there are no reports on FTLD. This is the first report on FTLD to demonstrate that exercise may effectively activate the frontal lobes, even in FTLD cases in which the frontal lobes have degenerated and become atrophied. Furthermore, positive changes were observed in items related to the frontal lobe, such as cognitive function emotion. These findings suggest that the frontal lobe activation induced by the exercise intervention may be involved in the effects on cognitive, behavioral, psychological, and physical functions, as discussed in detail below.

The SCWT is a cognitive function test that assesses frontal lobe function [47]. While the SCWT results suggest that exercise may have a beneficial effect on frontal lobe function, the observed changes were not uniformly positive. Specifically, out of six cases, five showed improvements, but one case exhibited deterioration. The overall effects were small, with only one improvement reaching a medium effect size. The observed positive changes in SCWT scores before and after exercise intervention are noteworthy results in FTLD. Atrophy can be observed in the frontal and temporal lobes, with specific symptoms in FTLD [48]. There were also positive changes in global cognitive function. In patients with bvFTD, the MMSE-J scores after the intervention were either improved or remained slightly decreased. In contrast, in the patient with SD, a marked decrease was noted, possibly because of differences in the pathophysiology of both diseases. Specifically, in SD where semantic dysfunction is the primary symptom [49, 50], even mild disease progression may result in a greater loss of points on the MMSE-J, a test strongly influenced by the degree of language comprehension. While previous studies have reported the effects of exercise interventions on physical function, changes in cognitive function through exercise intervention have not been previously documented on FTLD [46].

Our findings suggest that multimodal exercise interventions positively influence psychological functions, particularly emotional functions. Previous studies have reported that physical activity and exercise may improve the psychological symptoms of dementia [51]. In this study, the positive changes in pleasant and relaxed emotions after the intervention may be attributed to exercise, even in patients with FTLD. Despite reports of changes in emotional expression (blunting of emotions) in FTLD, particularly in bvFTD and SD [52], changes in emotions before and after exercise intervention in FTLD remain unknown.

After the multimodal exercise intervention, changes in stereotypical behavior were observed in patients with FTLD. In SRI, we observed a positive change in roaming, movement, and daily rhythm, with a moderate effect size, particularly for movement. It should also be noted that two dimensions of stereotypical behavior – speaking and eating and cooking – worsened, and the overall sum score of SRI did not change significantly. Nevertheless, the beneficial changes in motion-related items (roaming, movement, and daily rhythm) are noteworthy and considered an outcome of the intervention. To our knowledge, changes in SRI through exercise intervention have not been previously reported in FTLD.

Based on our study findings, multimodal exercise intervention may positively affect physical function in patients with FTLD. Previous studies have shown that exercise intervention improves physical function in patients with bvFTD [15, 16]. In our study, a positive change was observed in the Timed Up and Go (TUG) test; however, the other three physical function measurements did not show any significant effects. While these preliminary findings are promising for TUG, they should be interpreted cautiously in the context of the overall physical function results. The effect of exercise intervention might have been easier to achieve as FTLD usually has an early-onset, and the patients report relatively well-preserved physical fitness.

The strength of this study lies in being the first long-term multimodal exercise intervention for FTLD globally. This is the first study to conduct a 48-week exercise intervention in multiple cases of FTLD, which is considered difficult to manage, and to evaluate the effect of exercise intervention from multiple perspectives. However, it is important to interpret the results cautiously because of the limited sample size and single-arm nature of the study. Despite these limitations, this study contributes to the emerging understanding of the potential benefits of exercise interventions for FTLD, warranting further research. This study was designed to observe changes specific to FTLD before and after the intervention by scientifically measuring various aspects of patients, including cognition, physical, psychological, and behavioral aspects. However, this study had some limitations. First, the single-arm design, limited sample size, and lack of a control group limit the ability to determine the effectiveness of the intervention. Specifically, the lack of a control group prevents comparison to confirm the effects of the intervention. Determining the certainty of the effects and causal relationships can be difficult. Furthermore, assessing how changes over time and other factors, such as learning effects, aging, and regression to the mean, may influence the outcomes is challenging. Second, we did not consider examination or evaluator blinding. A lack of blinding may lead to a biased evaluation and assessment. Therefore, these issues should be addressed in future studies. We intend to perform a small pilot randomized controlled trial to obtain a less biased effect size estimate. Specifically, the examination will introduce randomization and blinding of the assessors. Furthermore, we also aim to design a large-scale randomized controlled trial to test the effectiveness of this program on cognitive function.

This novel study reports the feasibility and changes in clinical outcomes of long-term multimodal exercise for FTLD. This multimodal exercise intervention is a feasible program for patients with FTLD. Additionally, this intervention might positively change clinical outcomes, such as frontal lobe, cognitive, psychological, behavioral, and physical functions in patients with FTLD. However, further studies should use a randomized design to assess the efficacy of multimodal exercise intervention on a larger scale.

We are grateful to the patients and staff involved in this study.

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of University of Tsukuba Hospital (approval No. H30-228). All participants provided written informed consent after receiving a thorough explanation of the study’s purpose, procedures, and potential risks. For all participants with cognitive impairments, consent was obtained in the presence of a family member, and the participant’s signature was still required, in accordance with ethical guidelines.

Shimadzu Corporation provided the fNIRS equipment used in this study and assisted with the technical aspects of data analysis related to the fNIRS measurements. This provision of equipment and assistance may be perceived as a potential conflict of interest due to the possibility of influencing the study’s outcomes. However, we want to emphasize that the study design, data collection, interpretation of results, and conclusions were conducted independently by the research team, ensuring the integrity and objectivity of the research.

This research was funded by JSPS KAKENHI (Grant No. JP17K13218) and supported by Shimadzu Corporation, which provided the fNIRS equipment for this study. The funder had no role in the design, data collection, data analysis, and reporting of this study.

M.N. made substantial contributions to the conceptualization and design of the study. M.N., S.H., and H.S. were responsible for the methodology and formal analysis, with all authors actively participating in the investigation. T.A. and K.N. provided essential resources, while M.N. and M.O. managed data curation. The original draft of the manuscript was prepared by M.N. and H.S., and all authors contributed to the critical review and revision of the manuscript for significant intellectual content. T.A. supervised the project, with project administration handled by M.N. and A.T. Funding acquisition was managed by M.N. and T.A. All authors have approved the final version of the manuscript and are committed to ensuring accountability for all aspects of the work, addressing any concerns regarding the accuracy or integrity of the study as needed.

The data presented in this study are available upon request from the corresponding author. The data are not publicly available owing to privacy concerns.