Welcome to the AD/PD™ 2022 Interactive Program
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CORTICAL MAPPING OF TAU AGGREGATION AND CHOLINERGIC DENERVATION WITH MULTIMODAL POSITRON EMISSION TOMOGRAPHY
CHANGES IN VESICULAR ACETYLCHOLINE TRANSPORTER (VACHT) LEVELS HAVE A CAUSAL EFFECT ON AMYLOID PATHOLOGY, COGNITIVE FUNCTION AND NEURODEGENERATION
Abstract
Abstract Body
Cholinergic deficiency is a hallmark of many neurodegenerative disorders including Alzheimer’s disease (AD). Decreased levels of the vesicular acetylcholine transporter (VAChT) have been detected in AD and imaging data suggest that VAChT levels can predict human pathology. Decreased forebrain VAChT levels cause cognitive dysfunction, however, whether changes in VAChT levels are causally associated with plaque formation is unknown. We tested this by generating humanized APP knock-in (KI) mice lacking VAChT in cholinergic forebrain neurons and humanized APP knock-in (KI) mice overexpressing VAChT. In males, elimination of forebrain VAChT led to increased plaque area and Ab levels compared to AD mice expressing normal levels of VAChT. In contrast, male mice with VAChT overexpression showed decreased Ab levels. Surprisingly, this causal relationship was not found in intact female mice. In contrast, in female mice submitted to ovariectomy, to reduce a major source of sex hormones, the causal relationship between VAChT levels and amyloid pathology was restored. Interestingly, a similar sexual dimorphism was observed when analyzing glial cells association to plaques, suggesting the possibility that sexual dimorphic glial responses are modulated by cholinergic signaling. In humans, VAChT levels have been associated to AD pathology in both males and females. Our experiments suggest that cholinergic regulation of plaque pathology is not observed in intact female mice, pointing to an important effect of sexual hormones for cholinergic regulation of plaque pathology. These results suggest that VAChT has a causal relationship with AD pathology and that ovariectomized mice may better mimic AD pathological changes in post-menopausal women.
LONGITUDINAL CHOLINERGIC BASAL FOREBRAIN DEGENERATION IN EARLY-STAGE PD LINKS WITH PARALLEL ATROPHY OF COGNITION-RELEVANT CORTICAL AREAS.
Abstract
Aims
Degeneration of the cortically-projecting cholinergic basal forebrain (cBF) is an early pathologic feature of both Alzheimer’s disease (AD) and Parkinson’s disease (PD). In AD, in-vivo cBF degeneration on MRI was shown to be associated with parallel atrophy of its cortical projection areas. We examined whether longitudinal cBF degeneration in early-stage PD is linked with regional cortical atrophy, and whether this link depends on the presence of AD co-pathology as assessed by a CSF amyloid-β biomarker.
Methods
The study included a total of 167 de novo PD patients that underwent serial 3T MRI scanning within the Parkinson’s Progression Markers Initiative (average follow-up: 2.3±1.5 years). Gray matter volumes of the cBF and 34 cortical regions per hemisphere were automatically extracted using established procedures within SPM12. Individual slopes of regional volume changes were estimated from the serial measurements using linear-mixed models, controlled for intracranial volume, age, and sex. Associations between longitudinal cBF degeneration and cortical atrophy were assessed using Pearson correlations. Complementary analyses assessed these correlations separately for amyloid-β-positive (N=58) and –negative (N=105) patient groups.
Results
Longitudinal cBF degeneration was highly correlated with longitudinal degeneration of specific cortical limbic and association areas, most notably the insular, medial temporal, and posterior medial cortices (Fig-1a). Interestingly, significant associations were observed independent of amyloid-β status (Fig-1b,c), although associations with posterior cortical areas were significantly more pronounced in amyloid-β-positive patients.
Conclusions
These findings establish a link between longitudinal atrophy of the cBF and cognition-relevant cortical areas in early-stage PD, which is enhanced by AD co-pathology.
DIFFERENTIAL RESPONSE TO DONEPEZIL ACROSS BIOLOGICAL SUBTYPES IN PRODROMAL ALZHEIMER´S DISEASE
Abstract
Aims
Donepezil (acetylcholinesterase inhibitor) is an approved drug for the symptomatic treatment of Alzheimer’s disease (AD). However, inconsistent results have been reported across clinical trials, which might be explained by the biological heterogeneity in AD. A new model describing biological subtypes has opened an opportunity to understand this heterogeneity by combining two dimensions, severity and typicality [1]. Here, we investigated the impact of this subtyping model on the response to donepezil in patients with suspected prodromal AD.
Methods
The effects of donepezil were investigated in 173 MCI individuals (donepezil=83; placebo=90) with structural MRI data at both baseline and follow-up (6-12-month). Efficacy outcomes were the annualized percentage change (APC) of the volumes in the hippocampus, ventricles, total grey matter, and the AD cortical thickness signature. Patients were classified as typical-AD, limbic-predominant, hippocampal-sparing, or minimal atrophy, based on visual ratings. Complementary, the two core dimensions for subtyping were analyzed as continuums using an index of global brain atrophy for severity and the hippocampus-to-cortex ratio for typicality.
Results
Among patients classified as minimal atrophy or hippocampal sparing, those treated with donepezil showed a slower atrophy rate than their subtype-specific placebo group.
Both the severity and typicality dimensions independently modulated donepezil efficacy, especially in AD-related regions. In general, patients showing a lower degree of atrophy and/or hippocampal atrophy responded better to treatment.
Conclusions
Biologically defined subtypes are useful to target patients more accurately for the treatment with donepezil. Positioning patients along subtyping dimensions could provide meaningful information regarding their prognosis and response to treatment.
M1 MUSCARINIC STIMULATION OF POST-SYNAPTIC RECEPTORS FOR THE POTENTIAL TREATMENT AND PREVENTION OF COGNITIVE DECLINE
Abstract
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Activation of the M1 muscarinic receptor (M1 mAChR) is a rational therapeutic strategy for the treatment of schizophrenia and Alzheimer's disease (AD) as this receptor has a pivotal role in modulating cognitive deficits and the pathology of the disease. Such activation can be achieved through M1 allosteric and bitopic muscarinic agonists, M1 PAMs, and direct-acting M1 muscarinic orthosteric agonists. The efficacy of M1 PAMs depends upon the presence of acetylcholine, which declines as post-synaptic neurons lose cholinergic input from the basal forebrain in AD. On the other hand, the activity of M1 muscarinic orthosteric agonists is independent of the functional or anatomical integrity of presynaptic cholinergic terminals and would likely retain efficacy as the disease progresses even after pre-synaptic degeneration of cholinergic fibers. The preferred compound should have: i) a high safety profile and selectivity for M1 mAChR, in vivo and a brain/plasma ratio greater than 1; ii) the potential to improve cognition and behavior; and iii) the potential to prevent, delay or halt disease progression. In this context, rigid analogs of acetylcholine from the AF series are relatively selective M1 orthosteric partial agonists including AF102B (prescribed for the treatment of dry mouth in Sjogren’s disease), AF150(S), AF267B, and AF292. AF267B, which fulfills the criteria mentioned above, improved cognitive deficits in many animal models and chronic treatment decreased both Aβ and tau pathologies in the hippocampus and cortex and reversed cognitive deficits in 3xTg-AD mice. Chronic treatment with AF267B and AF102B also decreased alpha-synuclein aggregates in human alpha-synuclein transgenic mice. Positive effects on some of the neuropathological hallmarks of AD were also reported in preclinical studies with EUK1001, VU0364572, a bitopic M1 agonist, VU0486846, an M1 PAM, and AF710B, a mixed M1 allosteric/sigma-1 agonist. Chronic treatment with AF102B and Talsaclidine, decreased significantly CSF Aβ in AD patients whereas AChEIs had no effects on Aβ. Translating these findings to AD patients may extend the classical cholinergic hypothesis initially limited to symptomatic treatment. Few of the reported M1 muscarinic agonists (preferable M1 partial orthosteric) may fulfill the above-mentioned criteria as the next generation of therapies in AD, schizophrenia, and related diseases. Ref: E. Giacobini, AC Cuello and A. Fisher. REIMAGINING CHOLINERGIC THERAPY FOR ALZHEIMER DISEASE, Brain, in press.BRAIN SYNCHRONIZATION AT GAMMA FREQUENCY INCREASES EPISODIC MEMORY AND RESTORES CHOLINERGIC DYSFUNCTION IN ALZHEIMER’S DISEASE
Abstract
Aims
To assess whether exposure to non-invasive brain stimulation with transcranial alternating current stimulation at gamma-frequency (γ-tACS) applied over the precuneus can improve memory and modulate cholinergic transmission by entraining cerebral rhythms in mild cognitive impairment due to Alzheimer’s disease (MCI-AD).
Methods
In this randomized, double-blind, sham controlled, crossover study, participants were assigned to a 60 min treatment with precuneus γ-tACS or sham tACS. Each subject underwent a clinical and neurophysiological evaluation including assessment of episodic memory and cholinergic transmission pre- and post- γ-tACS or sham stimulation. In a subset of patients, EEG analysis and individualized modelling of electric field distribution were carried out.
Results
Sixty MCI-AD participants completed the study. We observed a significant improvement at the Rey auditory verbal learning (RAVL) test immediate (p<0.001) and delayed recall scores (p<0.001) after γ-tACS but not after sham tACS. Face-name associations scores improved during γ-tACS (p<0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission, increased only after γ-tACS (p<0.001). Clinical improvement correlated with the increase in gamma frequencies in posterior regions and with the amount of predicted electric field distribution in the precuneus.
Conclusions
Precuneus γ-tACS showed a significant improvement of memory performances, along with restoration of intracortical connectivity measures of cholinergic transmission, compared to sham tACS. Response to γ-tACS was dependent on genetic factors and on the amount of predicted stimulation in the precuneus.
CHOLINERGIC MARKERS AS A PREDICTIVE TOOL OF THE THERAPEUTIC RESPONSE IN ALZHEIMER’S DISEASE
Abstract
Aims
Acetylcholinesterase (AchE) inhibitors efficacy in Alzheimer’s disease (AD) is variable between patients, with only 20-30% being clinically responders. However, this efficacy has never been evaluated in regards to the therapeutic target engagement (acetylcholine [Ach] deficit). We aimed to determine if cerebrospinal fluid (CSF) Ach level and AchE activity measurements could predict the therapeutical response in AD patients using recent AD diagnosis criteria.
Methods
Non-randomized single-center prospective non-placebo-controlled phase 4 study, including AD patients diagnosed according to recent criteria. AchE activity was measured using an enzymatic reaction, and Ach level using a mass spectrometry technique.
Clinical response to AChEI was evaluated at 6 months using the ADAS-Cog (Alzheimer’s Disease Assessment Scale [cognitive part]) scale. Our primary outcome was to compare the mean value of CSF Ach level and AchE activity between responders (≥4 points improvement in the ADAS-Cog scale at 6 months) and non-responders AD patients.
Results
100 patients were included from 2017 to 2020, comprised of 64 women and 36 men. Mean age was 72.9 years old (SD 7.9) and mean ADAS-Cog at inclusion 18.8/70 (SD 9.8). Responders had significant lower mean Ch levels than non-responders (p = 0.04). We did not observe any other significant difference between responders and non-responders patients.
Conclusions
AChEI responders had a significant lower Ch concentration than non-responders however CSF Ach level or AchE activity were not predictive of AChEI therapeutical response.
The clinical-biological approach we used was innovative and could be extended to other treatments targeting neurotransmitters, in a personalized medicine approach (with benefit-risks balance improvement).
PRE-RECORDED: NGF METABOLISM, ALZHEIMER’S PATHOLOGY AND PRECLINICAL BIOMARKERS
Abstract
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AIM: To study NGF trophic support in Health and Disease.
METHODS: Neurochemical and pharmacological procedures.
RESULTS: We have shown that this brain NGF Metabolic pathway
-Sustains the cholinergic phenotype of basal forebrain (BF) neurons.
-In Alzheimer’s disease (AD) pathology there is diminished proNGF to mNGF conversion and increased mNGF degradation
-In AD, the normal NGF synthesis and the failed pro-to-mature NGF conversion provokes a brain build-up of proNGF
-The above NGF metabolic deregulation is found in non-cognitively impaired (NCI) individuals with preclinical Aβ-amyloid pathology and remains physiologically normal in NCI brain samples lacking significant Aβ amyloidosis, proNGF levels correlating with cognitive scores.
-The NGF pathway is deregulated in Down Syndrome (DS) brains at clinical and preclinical AD stages.
-In DS body fluids, proNGF levels are increasingly elevated in their transition from DS without clinical AD to DS with clinical AD and predict subsequent cognitive decline.
CONCLUSIONS The failure of the NGF metabolic pathway, even at preclinical AD stages, would explain the early loss of trophic support to the NGF-dependent cholinergic neurons of the basal forebrain. The correction of this brain metabolic dysfunction at stages preclinical AD should prevent their neuronal atrophy and synaptic loses. The investigation of levels of key molecules of NGF metabolic pathway in blood and cerebrospinal fluids offers an opportunity to reveal the ongoing, silent, preclinical AD pathology.