Welcome to the AD/PD™ 2022 Interactive Program
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NON-REM SLEEP HYPERTONIA IN PARKINSONIAN-SPECTRUM DISORDERS
Abstract
Aims
Non-REM sleep with hypertonia (NRH) is independently associated with synucleinopathy-mediated Parkinson-spectrum disorders (PSD), including dementia with Lewy Bodies/Parkinson’s Disease Dementia (DLB/PDD), Parkinson’s Disease (PD), and isolated REM sleep behavior disorder (iRBD). We sought to evaluate NRH in PSDs mediated by progressive supranuclear palsy (PSP) which is instead caused by tau pathology.
Methods
In this multicenter study, NRH in Parkinsonian-spectrum disorders DLB/PDD (n=15), PD (n=14), iRBD(n=19), and PSP (n=13) was compared to similar age-sex subjects with Alzheimer’s Disease (AD, n=22), mild cognitive impairment (MCI, n=35), and normal cognition (NC, n=61). In-home Sleep Profiler studies were attempted in all participants except iRBD patients, who had a single-night, in-laboratory SP recording. NRH was weighted-averaged in the 84% of in-home studies with two-nights of data. Statistical analyses included multiple logistic regression, receiver-operating-characteristic curves (ROC), and inter-class correlations (ICC).
Results
Abnormal NRH was detected in PSD with PSP=92%, DLB/PDD=80%, iRBD=74%, and PD=64%, compared to AD=14%, MCI=23%, and NC=16% (P<0.0001). Abnormal NRH differentiated the two groups with an area under the curve of 0.79 (95%CI: 0.73-0.85), a sensitivity of 0.76 (95%CI: 0.64-0.85) and a specificity of 0.82 (85%CI: 0.74-0.88). NRH demonstrated strong between-night (ICC=0.83, n=125) and >360-day test-retest (ICC=0.87, n=29) reliabilities.
Conclusions
NRH independently discriminated PSDs from age-sex similar non-PSD patients, suggesting that NRH is a common sleep motor signature across clinical PSD phenotypes. We speculate that NRH could be related to pathological changes within the substantia nigra (SNr) given common involvement of this key non-REM sleep motor modulating center in synucleinopathies and PSP.
SLOW-WAVE SLEEP IMPACTS SYNUCLEINOPATHY AND REGULATES PROTEOSTATIC PROCESSES IN MICE MODELS OF PARKINSON’S DISEASE
Abstract
Aims
In Parkinson’s disease (PD), SWS appears to be closely linked with disease symptoms and progression. PD is characterized by damaging intracellular α-synuclein (αSyn) deposition that propagates extracellularly, contributing to disease spread. Intracellular αSyn is sensitive to degradation, whereas extracellular αSyn may be eliminated by glymphatic clearance, a process increased during SWS. Here, we explored whether long-term slow-wave modulation in murine models of PD presenting αSyn aggregation alters pathological protein burden and, thus, might constitute a valuable therapeutic target.
Methods
Slow-waves enhancement in VMAT2-deficient and A53T mouse models of PD was achieved by twice daily adminsitration of sodium oxybate (200mg/kg, p.o.) 5 days/week for 4 months. Slow-waves deprivation in VMAT2-deficient mice consisted of 16h/day sleep deprivation using the platform-over-water method. Multiple histopathological, immunofluorescence, biochemical, and molecular analyses were performed over brain samples from sleep-modulated healthy and PD mice.
Results
Sleep-modulating treatments showed that enhancing slow waves in both VMAT2-deficient and A53T mouse models of PD reduced pathological αSyn accumulation compared to control animals. Non-pharmacological sleep deprivation had the opposite effect in VMAT2-deficient mice, severely increasing the pathological burden. Additionally, we found that SWS enhancement was associated with increased recruitment of aquaporin-4 to perivascular sites, suggesting a possible increase of glymphatic function. Furthermore, mass spectrometry data revealed differential and specific upregulation of functional protein clusters linked to proteostasis upon slow-wave-enhancing interventions.
Conclusions
Overall, the beneficial effect of SWS enhancement on neuropathological outcome in murine synucleinopathy models mirrors findings in models of Alzheimer. Modulating SWS might constitute an effective strategy for modulating PD pathology in patients.
PRECLINICAL ASSESSMENT OF DRUG TREATMENT OPTIONS FOR SLEEP-RELATED EPILEPTIC SPIKING IN ALZHEIMER'S DISEASE
Abstract
Aims
Epileptic spiking without motor manifestations can be found in 30-40% patients with early AD. This number may still be an underestimate as this spiking occurs almost exclusively during sleep and may limit to the deep temporal lobe. Further, AD patients with subclinical epileptiform
activity have about twice faster cognitive decline during a follow-up of 3-5 years (Vossel K Ann. Neurol. 2016; Horvath A EEG Clin Neurophys. 2021). Treating epileptic spiking during sleep may thus offer a way to slow down AD progression, but so far there is no published clinical study on the topic, calling for preclinical testing to guide the choice of optimal drug treatments.
Methods
Ten male APP/PS1 mice (3-5 months) were implanted with EEG screw electrodes and hippocampal triple wire electrodes to record local field potentials. Sleep was monitored by video-recording and neck EMG. We tested the standard AD-drugs donepezil and memantine as well as anti-epileptic drugs levetiracetam and lamotrigine recommended for AD patients with epilepsy. In addition, we administered the gamma-secretase inhibitor semagacestat to acutely reduce amyloid-beta levels and the anti-inflammatory tetracycline derivative minocycline to suppress neuroinflammation. The analysis focused on hippocampally generated giant spikes and cortical spike-wave dischanges and was done within-subject in reference to a repeated vehicle injection.
Results
Levetiracetam decreased while lamotrigine unexpectedly increased sleep-related giant spikes in APP/PS1 mice. Both reduced cortical spike-wave discharges, whereas memantine increased their prevalence. Other drugs had no significant effects.
Conclusions
Levetiracetam proved to be an effective treatment for sleep-related epileptic spiking while lamotrigine should be used with caution.
THE CB2-FACED RECEPTORS: IMPROVEMENT OF SLEEP OR MEMORY IN PARKINSON’S DISEASE.
Abstract
Aims
The main objective was to investigate the potential of nigrostriatal cannabinoid receptor 2 (CB2) in reverse sleep alterations observed in the animal model of Parkinson’s disease induced by rotenone. We also evaluated whether such modulation would decrease the rotenone-induced desynchronization between left and right cortical hemispheres and consequently reverse its detrimental effects on memory consolidation.
Methods
Male Wistar rats received a bilateral infusion of rotenone (12 ug/ul) or dimethylsulfoxide (DMSO, 10% v/v) within the Substantia nigra pars compacta. Seven days later, striatal infusions of CB2 agonist GW405833 (10 ug/ul), antagonist AM630 (3 ug/ul), or vehicle (DMSO 10% v/v) were performed. One set of animals was submitted to a period of 6h of sleep-wake recording and the other to a memory evaluation.
Results
CB2 antagonist AM630 reversed the rotenone effects on sleep macrostructure, establishing the values of sleep efficiency and NREM sleep duration to that observed in the control group. In the same way, the rotenone-induced desynchronization between left and right cortical hemispheres was reversed by CB2 blockade. However, AM630 did not present an effect on memory consolidation. Instead, the activation of CB2 by GW405833 was able to reverse the memory impairment induced by rotenone.
Conclusions
These findings suggest a role for nigrostriatal CB2 in sleep regulation in the context of Parkinson’s disease. Its effect on memory consolidation appears to be independent of sleep and cortical synchronization.
PHOSPHATASE ACTIVITY DURING SLEEP/WAKE CYCLES REGULATES APP PROCESSING AND BRAIN ISF AMYLOID-BETA LEVELS
Abstract
Aims
Evidence in both APP transgenic animal models and in humans demonstrate that brain Abeta levels fluctuate with the diurnal cycle; Abeta within the brain extracellular fluids are high during wakefulness and low during sleep. In mice and in humans, sleep deprivation increases Abeta levels acutely. Chronic alterations in sleep have a similar impact on amyloid plaque accumulation in these mice. We hypothesized that sleep is altering an intracellular signaling pathway that ultimately regulates Abeta generation and secretion into the brain ISF.
Methods
We used in vivo microdialysis to measure brain ISF Abeta levels every hour over several days in living APP transgenic mice while manipulating orexin receptor signaling and downstream intracellular signaling pathways, such as the extracellular regulated kinase (ERK) and phosphatases such as SHP2 and PP2A.
Results
Similar to previous studies, we detected a diurnal fluctuation in ISF Abeta levels during the sleep/wake cycle. Inhibiting Extracellular Regulated Kinase (ERK), increased ISF Abeta levels by 50% and blocked the fluctuation in ISF Abeta, suggesting that ERK plays a role in the diurnal rhythm of Abeta. SHP-2 is a phosphatase that dephosphorylates phospho-ERK to deactivate it. Inhibition of SHP-2 reduces ISF Abeta levels and also blocks the diurnal fluctuation.
Conclusions
Our data suggest that there is an inverse relationship between the amount of phospho-ERK and the activity of SHP-2 which determines how much Abeta is produced in response to the physiological fluctuation in sleep/wake.
MELANIN CONCENTRATING HORMONE- AND SLEEP-DEPENDENT SYNAPTIC DOWNSCALING IS IMPAIRED IN ALZHEIMER’S DISEASE
Abstract
Aims
In Alzheimer’s disease (AD), pathophysiological changes in the hippocampus cause deficits in episodic memory formation, leading to cognitive impairment. Neuronal hyperactivity and increased risk for seizure is observed early in AD, and occurs many years before cognitive decline onset. This period is characterized by a complex interplay of molecular events that lead to cellular alterations in all brain cell types, and over many years, result in chronic inflammation, neuronal death and cognitive impairment
Methods
Using electrophysiology recordings and neuronal activity monitoring we find that homeostatic mechanisms transiently counteract increased neuronal activity in the hippocampal CA1 region of the AppNL-G-F humanized knock-in mouse model for AD, but ultimately fail to maintain neuronal activity at set-point. Spatial transcriptomic analysis in CA1 during the homeostatic response identifies the Melanin-Concentrating Hormone (MCH)-encoding gene.
Results
MCH is expressed in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH regulates synaptic plasticity genes and synaptic downscaling in hippocampal neurons. Furthermore, MCH-neuron activity is impaired in AppNL-G-F mice, disrupting sleep-dependent homeostatic plasticity and stability of neuronal activity in CA1. Finally, we find perturbed MCH-axon morphology in CA1 early in AppNL-G-F mice and in AD patients.
Conclusions
Our work identifies the MCH-system as a key player maintaining synapse homeostasis in early stages of AD. Dysregulation of this system can underlie aberrant neuronal activity and modulate the risk for seizure through different molecular candidates in the early stages of AD.
EEG FINDINGS IN A PHASE 2 STUDY OF THE ORAL P38Α KINASE INHIBITOR NEFLAMAPIMOD IN PATIENTS WITH MILD-TO-MODERATE DEMENTIA WITH LEWY BODIES (DLB)
Abstract
Aims
Neflamapimod targets pathogenic mechanisms considered to underlie basal forebrain cholinergic (BFC) neurodegeneration, a major driver of dementia in DLB. In a recent phase 2 study in mild-to-moderate DLB (“AscenD-LB”), neflamapimod demonstrated clinically meaningful improvement in cognition (DLB-specific Neuropsychological Test Battery) and function (Timed-Up-and-Go Test). Here, we provide the EEG results from this study.
Methods
Neflamapimod (40 mg) or placebo was administered BID or TID for 16 weeks. Task-free, eyes-closed EEG was performed at baseline and week 16. Due to COVID-19, week 16 EEG assessments were only available in 29 of 91 patients. Quantitative EEG analysis involved functional connectivity analysis in canonical frequency bands, more specifically the corrected Amplitude Envelope Correlation (AECc). 2-sided Wilcoxon Rank Sum Test p-values are reported.
Results
Overall, a consistent trend towards improved functional connectivity was found in the treated group. Mean AECc in the beta band (13-30 Hz) significantly increased with neflamapimod TID vs all placebo (p=0.033) and vs placebo TID (p=0.01). The effect was most prominent in the frontal region (p=0.009 for placebo TID vs neflamapimod TID), and in the lower beta range (13-20 Hz).
Conclusions
In this modest cohort size, neflamapimod shows a positive effect on beta band functional connectivity. The effect is dose-dependent and most pronounced in the 40mg TID dose group, which previously also showed the clinical effects. Since impaired functional connectivity in the beta band is a known and relatively specific DLB finding, these results imply functional recovery. A follow-up clinical study will explore the observed treatment effects on EEG in a larger cohort.