Welcome to the AD/PD™ 2024 Interactive Program
The conference will officially run on Western European Standard Time (Lisbon, UTC+0)
To convert the conference times to your local time Click Here
MOLECULAR, FUNCTIONAL AND STRUCTURAL IMAGING OF THE HUMAN BASAL FOREBRAIN PROJECTIONS: IMPLICATIONS FOR ALZHEIMER’S DISEASE
Abstract
Abstract Body
The basal forebrain (BF) is a collection of subcortical nuclei which provide the major sources of acetylcholine to the neocortex, hippocampus, and amygdala via long-range axonal projections. Although recent work in non-human animal models has provided insight on the organizing principles of the BF cholinergic projectome, it remains unknown to what extent these principles are conserved in the human brain. In this talk, I will present new work from our lab which uses high resolution 7T diffusion MRI, resting state fMRI data and a PET radiotracer targeting the vesicular acetylcholine transporter (VAChT) to investigate the organization of BF cholinergic neurons and their projections in the human brain. We also use cross-species translational strategies to determine whether our findings in humans are supported by cell-type specific axonal tracing using optogenetic techniques in mice. Our findings reveal that BF cholinergic neurons vary in their branch complexity. Certain subpopulations of BF cholinergic neurons exhibit many axonal branches per cell while others exhibit relatively fewer branches per cell. These projection patterns differ depending on the neuron’s location within the BF nuclei and the intrinsic properties of its cortical targets. The properties include the target’s position in the cortical hierarchy (unimodal versus transmodal), its membership within cortical-cortical networks (ventral versus dorsal attention networks), and its physical proximity to the BF. These organizing principles are conserved across the mouse and human brain. A diversity of branch complexity in BF cholinergic neurons may also account for differences in their vulnerability to aging and disease. I will discuss how our findings inform parallel lines of work examining the cortical cholinergic innervation in age-related neurodegenerative conditions such as Alzheimer’s disease.THE CHOLINERGIC PROJECTOME AS A BIOMARKER FOR CHOLINERGIC DYSFUNCTION ACROSS THE AD CONTINUUM
Abstract
Aims
The cholinergic neurons of the basal forebrain (BF) innervate the brain through large axonal projections known as the cholinergic projectome. Longitudinal structural MRI studies of individuals with pre-symptomatic Alzheimer’s disease (AD) indicate loss of BF grey matter volume, consistent with degeneration of BF cell bodies. However, degeneration may manifest in the cholinergic projectome prior to degeneration of the cell bodies in the BF. Therefore, we investigated the temporal progression of grey matter loss in the cholinergic projectome relative to the BF in individuals at multiple stages of AD.
Methods
[18]F-FEOBV binds to VAChT, a protein selectively expressed on cholinergic nerve terminals. Using [18F]-FEOBV PET data in cognitively normal (CN) participants (N = 60), we defined a region of interest (ROI) mask of cortical locations most densely innervated by the cholinergic projectome. Using longitudinal structural MRI data (mean interval = 2.9 years), we examined whether temporal relationships between grey matter loss in the cholinergic projectome and the BF were moderated by CSF amyloid beta and phosphorylated tau in two independent CN cohorts (ADNI N = 387; PREVENT-AD N = 220). Lastly, we investigated grey matter loss within the cholinergic projectome and BF in AD participants (N = 242) using longitudinal structural MRI data from a 26-week clinical trial of the p75 neurotrophin receptor modulator LM11A-31.
Results
Longitudinal relationships between grey matter degeneration within the cholinergic projectome and BF in pre-symptomatic and clinical stages of AD will be discussed.
Conclusions
Our study provides the first in vivo test of the hypothesis that cholinergic projectome damage precedes BF grey matter degeneration. As a clinical application, we utilize this ROI to optimize clinical trial analysis for a therapeutic targeting a receptor highly expressed on BF cholinergic neurons.
IMMUNO AND CHOLINERGIC THERAPY: ARE THEY COMPLEMENTARY IN AD TREATMENT?
Abstract
Aims
The recent registration in the USA of three new selective anti-a-beta antibodies (aducanumab, lecanumab, and donanemab) raises the question whether their use could be associated to the well established cholinergic therapy of AD, such as cholinesterase (ChE) inhibition.
Methods
The two therapeutic approaches differ substantially from one another both in aims and in targets. However, since the clinical outcomes used in clinical trials have been similar with both approaches (CDR-SB, MMSE, ADAS-cog and ADCS-ADL ) they can be directly compared
Results
Inhibition of ChE aims to compensate for the progressive reduction of synaptic acetylcholine (ACh), due to the unrelenting disease progression, by enhancing cholinergic neurotransmission. Thus, the target is ACh itself. The aim of immunization with monoclonal antibodies against a-beta is to reduce the presence of a-beta in the brain which is presumed to be correlated to disease progression. The target is the a-beta molecule itself. Although targets and mechanisms of action are quite different, the final goal is similar i.e., a significant and long-lasting improvement of the patients’ clinical conditions. A difference between the two approaches is the stage of the disease. Immunotherapy has been applied to MCI individuals while ChE inhibition to mild -moderate or severe AD patients. Another important difference is their effect on brain volume shrinkage and side effects.
Conclusions
Given both differences and similarities of the e therapeutical approaches, an interesting question and consideration is if the combination of monoclonal immunization with ChEI treatment, would complement each other in effect and therefore represent a therapeutical advantage.
LONG-TERM EFFECTS OF CHOLINESTERASE INHIBITORS AND MEMANTINE ON COGNITIVE DECLINE, MAJOR CARDIOVASCULAR EVENTS, AND MORTALITY IN DEMENTIA WITH LEWY BODIES: A 10-YEAR FOLLOW-UP STUDY
Abstract
Aims
Cholinesterase inhibitors (ChEIs) and memantine are frequently prescribed for dementia with Lewy bodies (DLB). However, there is limited knowledge regarding their long-term effects on cognition and adverse outcomes in patients with DLB. The aim of this study is to investigate the impact of ChEIs and memantine on cognition, major cardiovascular events, and mortality in patients with DLB.
Methods
Data from the Swedish Registry on cognitive/dementia disorders (SveDem) was linked with the National patient-, the Prescribed drug-, and the Cause of death registries. We compared patients with DLB starting on ChEI or memantine within 90 days of the DLB diagnosis to patients not receiving these medications. In an inverse probability of treatment weighting cohort, the association between ChEIs/memantine and MMSE trajectories were examined with mixed models and the risks of major cardiovascular events or death with flexible parametric survival models.
Results
We included 1,095 patients with incident DLB (76.7±7.0years, 38% women), of whom 814 received ChEI, 133 memantine, and 148 did not receive these medications within 90 days of diagnosis. At baseline, treatment groups did not differ in MMSE (21.9±4.4 points). During a median follow-up time of 3 years (interquartile 1.5-4.1, range 0.2-10), ChEI-users showed slower cognitive decline compared to memantine-users and non-users. During follow-up, 106 (10%) major cardiovascular events occurred, along with 610 (56%) deaths. Major cardiovascular events did not differ between treatment groups. In comparison to memantine-users and non-users, ChEI use was associated with a lower incidence of death in the first 3 years of follow-up (p=0.02) but not at longer follow-up periods.
Conclusions
In patients with DLB, the use of ChEI (vs. no-use) was associated with slower cognitive decline and lower mortality in the first 3 years after diagnosis.
CHOLINERGIC DYSFUNCTION IN THE PARIETAL CORTEX PREDICTS DISEASE PROGRESSION TO LEWY BODY DISEASES IN ISOLATED REM SLEEP BEHAVIOUR DISORDER
Abstract
Aims
Isolated REM sleep behaviour disorder (iRBD) represents a prodromal phase of synucleinopathies, with the majority of patients with iRBD progressing to develop a Lewy body disorder (Parkinson’s disease, Dementia with Lewy bodies) or Multiple System Atrophy. However, no biomarkers are currently available to predict the disease course. The cholinergic system is affected early in the cortex of patients with iRBD and can be assessed in vivo with 11C-donepezil positron emission tomography (PET). The aim of this study was to determine whether baseline cortical cholinergic dysfunction in iRBD patients is a predictor of an impending progression to a parkinsonian disorder.
Methods
A cohort of 21 polysomnography-confirmed iRBD patients had 11C-donepezil PET at baseline. Subsequently, an eight-year follow-up was conducted to detect potential phenoconversion to a parkinsonian disorder and baseline imaging was re-evaluated according to the patients’ final diagnosis using a linear regression model.
Results
Successful follow-up and determination of their current diagnosis status was accomplished in 15 iRBD patients with a baseline 11C-donepezil PET scan. Patients who phenoconverted to Parkinson’s disease or Dementia with Lewy Bodies within three years following the scan (n=5) had significantly lower tracer uptake in the cortical regions (parietal; p=0.013, frontal; p=0.048, and temporal; p=0.048) at baseline compared to patients who maintained their iRBD diagnosis throughout the same three-year interval. After correcting for iRBD disease duration at baseline, the mean difference in the parietal cortex 11C-donepezil PET uptake remained significant (p=0.020). No differences in subcortical cholinergic function were found.
Conclusions
By examining cholinergic dysfunction using 11C-donepezil PET in iRBD patients, our study suggests its presence, particularly within the parietal cortex, predicts which patients are closest to phenoconversion.
RECOVERY OF REM SLEEP FRAGMENTATION, HIPPOCAMPAL OSCILLATORY ACTIVITY AND ALTERED CHOLINERGIC SIGNALLING AT PRESYMPTOMATIC STAGES OF AD
Abstract
Aims
The current study aimed to evaluate how circadian rhythm, sleep macro-architecture and hippocampal oscillations are altered at pre-plaque and early-plaque stages of AD in TgF344-AD rats.
Methods
We performed 24-hour hippocampal electrophysiological measurements in TgF344-AD rats and wildtype littermates at pre- and early-plaque stages of AD, combined with histological analysis to evaluate synaptic density.
Results
We observed a differential impact of AD on rapid eye movement (REM) and non-REM (NREM) sleep. Circadian rhythmicity was intact and TgF344-AD rats did not show signs of NREM sleep fragmentation. We observed a significantly increased probability for shorter REM bouts, suggestive of REM sleep fragmentation, in TgF344-AD rats at the pre-plaque stage, which recovered at the early-plaque stage (Fig.1A). In addition, we observed a significantly decreased theta-gamma coupling, a measure for task-related information ordering, at the pre-plaque stage, which was partially restored at the early-plaque stage (Fig.1B,C). Moreover, theta-gamma coupling in the slow gamma range was significantly increased during the pre-plaque stage in TgF344-AD rats but returned to WT levels at the early-plaque stage (Fig1B,D). Interestingly, the partial compensation of hippocampal activity and REM sleep behavior coincided with an increased number of cholinergic synapses in the hippocampus during the early-plaque stage in TgF344-AD rats (Fig 2).
Conclusions
The results from this study reveal early changes in sleep architecture and hippocampal function prior to Aß plaque deposition in AD. In addition, the current findings highlight the important role of the basal forebrain cholinergic system to compensate for AD-related network alterations. Network disturbances and sleep alterations are known to drive disease progression. Modulation of cholinergic signalling in early, presymptomatic AD might be a promising therapeutic strategy to alter disease progression by restoring network function and sleep architecture.
CORTICAL HYPOMETABOLISM ASSOCIATED WITH BASAL FOREBRAIN ATROPHY CORRESPONDS TO AREAS OF CHOLINERGIC DENERVATION IN PARKINSON’S DISEASE
Abstract
Aims
To assess whether the pattern of cortical hypometabolism associated with cholinergic basal forebrain (cBF) degeneration in Parkinson's disease (PD) corresponds to areas of cortical cholinergic denervation as measured by [18F]-FEOBV-PET.
Methods
95 PD patients (65±9 years; 75% males) with varying degrees of cognitive impairment (MoCA: 21.1±6.0) underwent high-resolution structural MRI and FDG-PET scans (cohort-1), and 15 PD patients (70±7 years; 60% males) and 15 healthy controls (HC:75±6 years; 67% males) underwent cholinergic [18F]-FEOBV-PET imaging (cohort-2). Cortical hypometabolism associated with cBF atrophy was calculated in cohort-1 using voxel-wise linear regression of cBF volume on FDG-PET maps controlled for age, sex, education, degree of cognitive impairment, and intracranial volume. The pattern of cortical cholinergic denervation was calculated in cohort-2 using a voxel-wise t-test of [18F]-FEOBV-PET maps between PD and HC participants. The spatial correspondence between the respective patterns was quantified using Spearman correlation across cortical regions as parcellated in a functional anatomy atlas (‘Schaefer-100’).
Results
Lower cBF volume was significantly associated with extensive cortical hypometabolism, most prominently in fronto-parietal, lateral temporal, and occipital areas [r(max,inferior-parietal)=0.39, p(FDR)<0.05] (Figure1-a). Cortical cholinergic depletion as measured by [18F]-FEOBV-PET showed a similar pattern and was most pronounced in posterior parieto-temporo-occipital areas and the superior frontal lobe [t-value(max,cuneus)=5.09, p<0.05] (Figure1-b). Formal topographic correspondence analysis revealed a strong spatial correlation between cBF-associated cortical hypometabolism and the pattern of regional [18F]-FEOBV depletion [Spearman’s r=0.57, p<0.001] (Figure1-c).
Conclusions
Atrophy of the cBF in PD associates with hypometabolism in cortical areas that also show most pronounced reductions in [18F]-FEOVB uptake, suggesting that this cortical hypometabolism may represent a functional consequence of cholinergic denervation. Combined FDG- and [18F]-FEOVB-PET studies are needed to substantiate these data using individual-level analyses.
CHOLINERGIC MODULATION OF GLUTAMINYL CYCLASE EXPRESSION AND CONTRIBUTION TO NEUROINFLAMMATION IN A RAT MODEL OF ALZHEIMER ‘S DISEASE
Abstract
Aims
Despite soaring patient numbers, there is still no satisfying treatment of AD. In this study, we assess therapeutic effects of co-treatment using cotinine, a positive allosteric modulator of alpha7-nicotinic acetylcholine receptors, plus galantamine, an acetylcholine-esterase inhibitor, on molecular AD pathology. In the hippocampus, we assume that the expression of glutaminyl cyclases and their substrates, the chemokines CCL2 and CX3CL1, may be reduced upon activation of alpha7-nicotinergic acetylcholine receptors. Such reduced glutaminyl cyclase expression may lead to diminished pyroglutamate modification of amyloid beta as well as CCL2 and CX3CL1, which potentially reduces their pro-inflammatory and neurotoxic effects. As the cholinergic afference from the basal forebrain to the hippocampus degenerates in AD, thereby promoting neuroinflammation and neurodegeneration, we hypothesize that boosting the cholinergic system may restore its anti-inflammatory effects. Thus here, we evaluated the preclinical therapeutic efficacy of the suggested combination therapy in hAPP-transgenic rats analyzing the levels of glutaminyl cyclases, CCL2 and CX3CL1 as well as pyroglutaminylated amyloid beta deposition.
Methods
Early-symptomatic 6-month-old McGill-R-Thy1-APP rats and wildtype rats received galantamine (3 mg/kg/24h) plus cotinine (2 mg/kg/24h) via drinking water for 13 weeks. The levels of glutaminyl cyclases, CCL2, CX3CL1, amyloid beta and its pyroglutamate-modified form, astrocyte and microglia activation markers were analyzed in the hippocampus using immunohistochemistry and qPCR.
Results
Cholinergic intervention yielded decreased expression of glutaminyl cyclases and their substrates CCL2 and CX3CL1. This was associated with reduced pE-Amyloid beta levels and signs of attenuated neuroinflammation illustrated by astrocyte and microglia activation.
Conclusions
Our study suggests a potential beneficial effect of combined cholinergic therapy in early AD. This preclinical beneficial effect is achieved by attenuating neuroinflammation in the hippocampus via reduced expression of glutaminyl cyclases and corresponding AD-relevant substrates.