Neuromodulation for Apathy in Alzheimer’s Disease: A Double-Blind, Randomized, Sham-Controlled Pilot Study

Abstract

Background: Apathy, a profound loss of motivation, initiation, and goal directed cognition, is a common comorbidity of Alzheimer’s disease (AD). The presence of apathy is associated with rapid progression of AD, long-term impairment, disability, and higher mortality. Pharmacological treatments of apathy are limited. Objective: The primary objective was to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) for apathy in AD. Methods: A randomized, double-blind, parallel-arm, sham-controlled pilot study was conducted in subjects with AD and apathy (N = 20). Subjects were randomized to rTMS or sham treatment (5 days/week) for four weeks. Primary outcome, apathy evaluation scale-clinician version (AES-C), and secondary outcome measures, modified-Mini Mental State Examination (3MS), instrumental activities of daily living (IADL), and clinical global impression (CGI), were assessed at baseline and four weeks. Follow-up visits were conducted at 8 and 12 weeks to test the durability of effects of intervention. Results: Mean age was 77.3 (±7.2) years, 80% were Caucasians and 10% were females. After adjusting for baseline, there was a significantly greater improvement in the AES-C with rTMS compared to sham treatment (–10.1 (–15.9 to –4.3); t (16) = –3.69; p = 0.002) at 4 weeks. There was also significantly greater improvement in 3MS (6.9 (1.7 to 12.0); t (15) = 2.85; p = 0.012), IADL (3.4 (1.0 to 5.9); χ21 = 7.72; p = 0.006), CGI-S (1.4 (0.5 to 2.3), t (16) = 3.29; p = 0.005), and CGI-I (–2.56 (–3.5 to –1.6), t (17) = –5.72; p < 0.001) for rTMS compared to the sham at 4 weeks. The effects of rTMS were durable at 12 weeks. Conclusion: rTMS may be safely used in subjects with AD and may improve apathy, function, and some aspects of cognition.

The therapeutic efficacy of transcranial magnetic stimulation in managing Alzheimer’s disease: A systemic review and meta-analysis

“…A study by Turriziani et al (2019) used 1 Hz, and the other 6 studies used 10 Hz ( Rabey et al, 2013 ; Leocani et al, 2020 ; Padala et al, 2020 ; Jia et al, 2021 ; Vecchio et al, 2022 ). The dorsolateral prefrontal cortex (DLPFC) was selected as the stimulation site in the majority of studies (10/14) ( Cotelli et al, 2011 ; Ahmed et al, 2012 ; Rabey et al, 2013 ; Wu et al, 2015 ; Turriziani et al, 2019 ; Zhang et al, 2019 ; Bagattini et al, 2020 ; Padala et al, 2020 ; Li et al, 2021 ; Vecchio et al, 2022 ). Rabey et al (2013) and Vecchio et al (2022) stimulated Broca, Wernicke, L/R-DLPFC, and L/R pSAC.…”

Apathy as a Treatment Target in Alzheimer's Disease: Implications for Clinical Trials

“…175 Another double-blind, sham-controlled, parallel arm, randomized study of rTMS in older subjects with Alzheimer's dementia and apathy (N=20) showed significant improvement in motivation for rTMS compared to sham treatment after twenty treatments. 176 Additionally, there was also significantly greater improvement…”

“…Am J Geriatr Psychiatry 30:2, February 2022 in cognition, function and clinical global improvement. 176 Another RCT is evaluating the efficacy of a 20-session Cognitive-Behavioral-Treatment program compared to treatment as usual on depression and other NPS (apathy is a secondary outcome) in patients with mild AD, mixed AD and vascular dementia. 177 Further research is also emerging which demonstrates the efficacy of information and communication technology (ICT) approaches such as serious games to improve apathy.…”

Revisiting Apathy in Alzheimer’s Disease: From Conceptualization to Therapeutic Approaches

“…There is preliminary evidence to suggest that rTMS might be effective for attenuating their severity [ 94 ]. A very recent preliminary study of apathy in AD found that stimulation to the left dorsolateral prefrontal cortex was associated with greater improvement in AES-C relative to sham treatment [ 95 ].…”