Aims

It is critical to identify effective interventions that can help maintain or enhance cognitive functioning in patients with mild cognitive impairment due to Alzheimer disease (MCI-AD). Recent studies have shown that stimulation at gamma frequency can entrain brain oscillatory activity in a mouse model of AD, improving memory functions and lowering amyloid and tau burden. The objective of this study was to assess whether findings in murine models can be translated to humans and generate early insights on whether non-invasive brain stimulation with transcranial alternating current stimulation at gamma frequency (gamma-tACS) can improve memory and modulate cholinergic transmission in MCI-AD.

Methods

Patients were randomly assigned to a 60 min treatment with gamma-tACS targeting the precuneus or sham tACS in a randomized, double-blind, sham-controlled study. Subjects underwent a clinical evaluation including assessment of episodic memory pre- and post-gamma-tACS or sham stimulation. Indirect measures of cholinergic neurotransmission were also evaluated.

Results

We observed a significant improvement at the Rey auditory verbal learning test (RAVLT) immediate recall (5.7 [95% CI, 4.0-7.4], p<0.001) and delayed recall scores (1.3 [0.4-2.1], p=0.007) after gamma-tACS but not after sham tACS. Face-name associations scores improved during gamma-tACS (4.3 [2.8-5.8], p<0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission evaluated with TMS, increased only after gamma-tACS (0.31 [0.24-0.38], p<0.001) but not after sham tACS.

Conclusions

Gamma-tACS targeting the precuneus showed a significant improvement of memory performances, along with restoration of intracortical connectivity measures of cholinergic neurotransmission, compared to sham tACS.

Aims

We and collaborators discovered that flickering lights and sound at gamma frequency (40Hz) reduces Alzheimer’s Disease (AD) pathology and alters immune cells and signaling in mice. To determine the feasibility of this intervention in humans we tested the safety, tolerability, and daily adherence of extended audiovisual gamma Flicker stimulation and explored biological effects.

Methods

Ten patients with mild cognitive impairment due to underlying AD received 1-hour daily gamma Flicker using audiovisual stimulation for 4 or 8 weeks at home with a delayed start design. Primary outcomes were safety, tolerance, and daily adherence to gamma Flicker stimulation. Exploratory biological outcomes were also assessed including neural entrainment, amyloid beta and tau pathology, cytokines and immune factors, and default mode network functional connectivity at baseline and after 4 and 8 weeks.

Results

Gamma sensory stimulation resulted in no severe adverse events related to treatment. Of 17 screened and enrolled subjects, 16 found the stimulation tolerable even at high intensities. Average adherence rates during the study were 95.5% with all subjects having adherence rates greater than 88%. All participants’ neural activity entrained to stimulation. While this study was not powered to conclusively assess biological changes following gamma Flicker, we found preliminary evidence that gamma Flicker strengthened functional connectivity between nodes in the default mode network and altered cytokines and immune factors in the cerebral spinal fluid.

Conclusions

These findings show that prolonged gamma sensory Flicker is safe, tolerable, and feasible with preliminary indications of immune and network effects, supporting further study of gamma stimulation in AD.

Aims

We aim to develop a gene therapy platform for the non-invasive delivery of transgenes efficiently targeting pathologies in brain areas affected by Alzheimer’s and Parkinson’s diseases. Therapies based on recombinant proteins, such as antibodies, have shown promises for the treatment of neurodegenerative disorders. To overcome the blood-brain barrier, current delivery strategies require repeated injections of proteins at high dosage. Gene therapy holds the potential of a one-time administration, resulting in the long-term expression of recombinant proteins for sustained therapeutic effects. The safe, low-dose, and non-invasive delivery to the brain of a gene carrier, such as adeno-associated virus (AAV), still represents an unmet need in the field of gene therapy.

Methods

We use focused ultrasound and intravenously injected microbubbles to temporarily increase the permeability of the blood-brain barrier and deliver intravenous AAVs non-invasively to the brain.

Results

AAVs of different serotypes were delivered to the hippocampus, cortex, striatum and other brain regions relevant to neurodegenerative disorders. We established the impact of ultrasound parameters, promoters, and AAV capsids on AAV delivery to specific cell types, to restricted–or to large and diffuse–brain areas.

Conclusions

This systematic and thorough investigation of the use of focused ultrasound and microbubbles for delivery of intravenous AAVs to the brain provides the foundation of a gene therapy platform. This approach can be tailored for cell-type specificity and the required volume of brain area(s) to be treated, thereby enabling efficient delivery of therapeutic genes were they are most needed in cases of Alzheimer’s and Parkinson’s diseases.

Aims

In recent years, repetitive transcranial magnetic stimulation (rTMS) has received increasing attention as a potential treatment for Alzheimer’s disease (AD). Combining neurostimulation techniques with neuroimaging allows designing personalized protocols that take into account the functional organization of the brain. AD is associated with alterations of specific large-scale networks, such as the Default Mode (DMN) and Fronto-Parietal (FPN) networks, which might represent targets for rTMS interventions. Here, we propose a novel tailored approach in which functional MRI (fMRI) is used to identify individual network targets for rTMS stimulation.

Methods

Single-subject resting-state fMRI independent component analysis was used to extract individual coordinates of two hubs: the inferior parietal cortex node of the DMN and the dorsolateral prefrontal cortex (DLPFC) node of the FPN in 8 mild AD patients (age [IQR]: 75 [69-80] years; MMSE: 22 [18-25]). The localization of these targets was compared to that of group-level targets defined according to traditional anatomical approaches, assuming different levels of spatial extent of rTMS-induced activation (12mm vs. 20mm).

Results

Both DMN and FPN fMRI-derived hub coordinates showed a large variability between subjects (distance in mm [IQR]: DMN=19 [15-26]; FPN=21 [14-26]) and were significantly distant from traditionally-defined targets when assuming a rTMS focality of 12mm (p<0.05) but not of 20mm (p>0.08).

Conclusions

Our results show the feasibility of tailored network-based fMRI-guided rTMS targeting. This approach may enhance the spatial selectivity of rTMS compared to traditional anatomical approaches. Clinical trials testing the efficacy and the advantage of this approach in AD are needed.

Aims

Physiological and pathological ageing (e.g. Alzheimer’s disease) both lead to a progressive cognitive decline (Götz et al., Nat Rev Neurosci 2018). Whether this can be slowed or even reversed remains to be determined.

Here, we explored whether therapeutic ultrasound together with intravenously injected microbubbles (which transiently opens the blood-brain barrier, SUS^+MB) or without (SUS^only) improves cognition in senescent mice. We were guided by our finding that SUS^+MB effectively clears amyloid and restores memory in APP transgenic APP23 mice (Leinenga & Götz, Science Transl Med 2015), and partially clears tau and ameliorates memory impairments in either tau transgenic pR5 (Nisbet et al., Brain 2017) or K3 mice (Pandit et al., Theranostics 2019). We also demonstrated in wild-type mice that SUS^+MB is safe (Blackmore et al., Theranostics 2018).

Methods

We treated 20 month-old wild-type mice weekly over 1, 3, and 6 weeks using the SUS^only and SUS^+MB paradigms, with sham-treated and naïve mice as control, followed by an extensive behavioural, electrophysiological, biochemical and histological analysis.

Results

We will discuss data generated by our comprehensive analysis (which also includes SWATH quantitative proteomic) to reveal pleiotropic effects of either the SUS^only or SUS^+MB treatment in improving cognitive functions at an age when wild-type mice are severely impaired. We will put these findings into perspective by discussing them side-by-side with findings obtained in Alzheimer’s models.

Conclusions

We conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may not only be a treatment for Alzheimer’s disease, but also enhance cognition in physiological ageing.

Aims

Evaluation of the safety and efficacy of the RGn530 photobiomodulation device on cognitive performances in mild-to-moderate AD patients.

Methods

This double-blind, randomized, monocenter, placebo-controlled clinical trial started in 2018, prematurely ended in 2020 due to Covid-19 pandemic. Only 53 patients were randomized into 2 groups: 27 patients treated and 26 patients not treated (placebo-sham group). Each patient received five 25-min sessions per week for 8 weeks and total study duration was 12 weeks. The primary efficacy endpoint was the evolution of the ADAS-Cog total score between inclusion and W8.

Results

RGn530 device appeared safe, as only 4.0% of patients reported possibly medical device-related adverse events (AEs) without significant difference in both groups and no serious AEs have been reported. The compliance with treatment sessions was very good for 92% of patients, confirming the good tolerance of the device. The primary efficacy endpoint was not met but a significant decrease in the ADAS-Cog comprehension subscore in the treated group compared to placebo was observed (mean change at W8 was -0.4±0.9 and 0.3±0.9, respectively; p=0.029). First efficacy results suggested a role in executive functions, as showed by TMT-B completion time significantly lower in patients treated compared to placebo (mean change at W8 was -45.8±88.0 sec and 53.1±83.8 sec, respectively; p=0.012), indicating better performances.

Conclusions

The results of this pilot study showed that the REGEnLIFE device is safe and well tolerated by patients. These very encouraging safety and efficacy results need to be confirmed in a pivotal phase III clinical trial.

Aims

Parkinson’s disease (PD) is characterized by motor deficits and brain alterations that have a detrimental impact on balance and gait. Therapies based on challenging and cognitively demanding physical exercise can induce neuroplasticity, potentially inhibiting degenerative processes underlying PD.

Methods

We investigated neuroplasticity effects of a highly challenging balance, gait and cognitively demanding training program (HiBalance) in participants with PD using a randomized controlled trial design (Franzén,2019). Participants were assigned to the HiBalance training or an active control group performing speech/communication training. Each group trained twice a week for 10 weeks with additional home exercises. Participants underwent a comprehensive assessment of balance/gait, motor functions, and speech/communication in addition to magnetic resonance imaging (MRI) before and after the interventions. The structural MRI data of 34 HiBalance (70.26±5.82yrs,MDS-UPDRSIII 31.55±12.91) and 31 control participants (70.45±6.11yrs,MDS-UPDRSIII 28.03±10.00) were analyzed using CAT12. Whole-brain and regions of interest (ROI) analyses were performed.

Results

After training, a main effect of time was observed in whole-brain cortical thickness in the left precuneus. The ROI analyses showed decreased cortical thickness in the left medial orbitofrontal gyrus and posterior cingulate in the HiBalance group. Higher whole-brain gray matter volume was revealed in the left putamen after HiBalance program training(Fig.1), which correlated with higher post-training gait speed.

Conclusions

Our results did not show an interaction effect between the HiBalance and active control training. However, the HiBalance training was associated with higher putamen volume, which also correlated with gait speed. Further investigation of the neural mechanisms underlying the effect of gait and balance exercise is needed.

Aims

In Alzheimer’s disease, higher cognitive reserve has been linked to a more rapid cognitive decline from the point of diagnosis. Whether similar trajectories exist concerning motor reserve (MR) in Parkinson's disease (PD) remains unclear. Here, we investigated the longitudinal decline in motor function by considering different levels of MR.

Methods

Data of 151 PD patients (M_age=58.7±4.5) were included, for whom a baseline DaT-SPECT and longitudinal clinical information were available at the PPMI database. Based on the residuals derived from the association between DaT signal loss and UPDRS-III score, we defined a group of high (n=50, M_{years_follow-up}=6.2) and low (n=45, M_{years_follow-up}=5.4) MR. To assess the trajectories of motor decline, we performed linear mixed-effects models with SPSS26 (p<.05), comparing the decline of high and low MR group over time. The model comprised an interaction term between time and reserve groups additionally to several covariates as fixed plus subjects and time as random effects, allowing individually varying slopes and intercepts. The model was corrected by an unstructured covariance matrix.

Results

At baseline, high MR was associated with significantly lower UPDRS-III scores compared to low MR. While this difference remained over 7 years (p=.029), no difference in group-average decline rate (p=.252) was observed. However, a positive covariance (cov_{Intercept-Slope}= .082, p=.018) between intercept and slope was found indicating that individual motor decline depends on baseline symptom severity.

Conclusions

Higher initial MR may be associated with slower disease progression and generally less severe symptoms over time, which has major implications for disease prognosis and the development of interventional strategies.