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Distinct Involvement of Neurotransmitter Systems in Early- And Late-Onset Alzheimer’s Disease

Poster No:

237

Submission Type:

Abstract Submission

Authors:

Ersin Ersözlü¹, Amir Dehsarvi², Nicolai Franzmeier², Boris Rauchmann³

Institutions:

¹Department of Psychiatry and Psychotherapy, Campus Benjamin Franklin, Charité-Universitaetsmedizin, Berlin, Germany, ²Institute for Stroke and Dementia Research, University Hospital LMU Munich, Munich, Germany, ³Department of Radiology, University Hospital LMU Munich, Munich, Germany

First Author:

Ersin Ersözlü
Department of Psychiatry and Psychotherapy, Campus Benjamin Franklin, Charité-Universitaetsmedizin
Berlin, Germany

Co-Author(s):

Amir Dehsarvi
Institute for Stroke and Dementia Research, University Hospital LMU Munich
Munich, Germany

Nicolai Franzmeier
Institute for Stroke and Dementia Research, University Hospital LMU Munich
Munich, Germany

Boris Rauchmann
Department of Radiology, University Hospital LMU Munich
Munich, Germany

Introduction:

Alzheimer's disease (AD) induces pathological changes in a heterogeneous fashion. Early onset of symptoms is associated with atypical patterns of pathology, such as increased involvement of neocortical regions, asymmetry, and non-amnestic manifestations in AD (Lu et al. 2023; Schöll et al. 2017). The role of alterations in neurotransmitter (NT) systems in heterogeneity in AD is highly unknown, while the current symptomatic treatments of mild-to-moderate AD dementia affect acetylcholine or N-methyl-D-aspartate (NMDA) receptor activities with highly variable response rates. We aimed to examine the group differences between early- and late-onset AD (EOAD and LOAD, respectively) and spatial associations between tau positron emission tomography (PET) uptake and mean neurotransmitter receptor/transporter maps in an explorative manner.

Methods:

We included n=276 cognitively normal participants without abnormal Amyloid-beta (Aβ) in PET as healthy controls and n=181 patients with mild cognitive impairment or AD dementia and abnormal Aβ (n=48 EOAD, n=133 LOAD) as the patient group. We derived individual cortical [18F]AV-1451 (tau PET) uptake and used the previously published data mean NT receptor and transporter maps (Hansen et al. 2022) for cortical regions (Fig. 1) according to the Schaefer Atlas (parcellation resolution of 200). Next, we calculated tau PET abnormality in patients with AD, defined as z-scores using means and standard deviations of healthy controls in each atlas region. We then obtained the individual correlation coefficients between tau PET z-scores and mean NT maps independently for each receptor/transporter (NTxTau). We compared NTxTau between EOAD and LOAD and tested the mediation effects of NT on the relationship between tau PET uptake in temporal meta region and memory cognitive composite score.

Results:

Mean differences in NTxTau revealed slightly stronger positive correlations in LOAD compared to EOAD for serotonin transporter (HTT, estimated-Δmean=0.02, p=0.03) and NMDA receptor (estimated-Δmean=0.03, p=0.002), while EOAD had slightly stronger negative correlations for vesicular acetylcholine transporter (VAChT, estimated-Δmean=0.03, p=0.046) than LOAD (Fig. 1A). The three NT with significant group differences between EOAD and LOAD were further studied in a mediation analysis. The individual correlations between tau PET uptake and HTT density mediated partially the association between tau PET uptake in meta region and memory performance that was moderated by the age at symptom onset (Index of moderated mediation: -0.033, lowest and highest bootstrap confidence intervals: -0.077 and -0.002, number of bootstrap samples: 5000). The moderation suggested that a higher regional HTT density and tau PET uptake correlation was related to a stronger association between tau PET and memory in patients with LOAD (Fig. 1B).

·Figure 1

Conclusions:

The results of the present study suggest a distinguishable relationship, i.e., spatial correlation, between three of the nineteen NT receptors or transporters (Serotonin, Glutamat, and Acetylcholine) and neurofibrillary tau pathology. More, the mediation of HTT on the relationship between tau and memory was dependent on the age at symptom onset. Our approach can potentially be utilized in further imaging modalities, while studying the role of NT systems in neurodegenerative diseases.

Disorders of the Nervous System:

Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) ¹

Neuroanatomy, Physiology, Metabolism and Neurotransmission:

Transmitter Receptors

Transmitter Systems ²

Keywords:

Cognition

Data analysis

Degenerative Disease

Memory

Neurotransmitter

Positron Emission Tomography (PET)

^1|2Indicates the priority used for review

Provide references using author date format

Hansen JY, Shafiei G, Markello RD, Smart K, Cox SML, et al. 2022. Mapping neurotransmitter systems to the structural and functional organization of the human neocortex. Nat. Neurosci. 25(11):1569–81
Lu J, Zhang Z, Wu P, Liang X, Zhang H, et al. 2023. The heterogeneity of asymmetric tau distribution is associated with an early age at onset and poor prognosis in Alzheimer’s disease. Neuroimage Clin. 38:103416
Schöll M, Ossenkoppele R, Strandberg O, Palmqvist S, Swedish BioFINDER study, et al. 2017. Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer’s disease. Brain. 140(9):2286–94