Neural correlates of apathy : a transdiagnostic systematic review

Introduction

Apathy is increasingly recognised as a clinically relevant transdiagnostic syndrome across psychiatric and neurological disorders. Its high prevalence, daily functional impact, and occurrence prior to the onset of major cognitive disorders justify further investigation.

Aims

This systematic review aimed to summerise the neural correlates of apathy across neurological and psychiatric disorders to better understand its pathophysiology.

Methods

This review followed PRISMA guidelines and was registered in PROSPERO (CRD42024532662). Searches were conducted in PubMed/MEDLINE, Embase, and Web of Science, with the last search performed in January 2024. Studies were included if they used validated apathy scales, including the Neuropsychiatric Inventory (NPI), Apathy Evaluation Scale (AES), Apathy Scale (AS), and Lille Apathy Rating Scale (LARS), and performed structural, functional, or molecular neuroimaging. Task-based functional MRI paradigms were excluded due to their high methodological heterogeneity. No meta-analysis was conducted due to substantial heterogeneity in imaging modalities, apathy scales, and population characteristics. Data synthesis relied on a structured narrative approach : brain regions were harmonised into a consensual neuroanatomical taxonomy and, for functional imaging studies, mapped onto established functional networks. Results were then stratified by diagnostic and imaging modality.

Results

A total of 174 studies published between 1996 and 2024 were included. Methodological quality ranged from 7.5 to 14/14 (mean : 11.1) using an adapted Newcastle-Ottawa Scale. The most represented conditions were Alzheimer’s disease (n=37), Parkinson’s disease (n=29), stroke (n=17), major depressive disorder (n=15), cognitive impairment (n=14), frontotemporal dementia (n=13), amyotrophic lateral sclerosis (n=5), and small vessel disease (n=4). Early work, mostly conducted in Alzheimer’s disease, relied on the NPI in combination with structural MRI and SPECT, from which the anterior cingulate cortex (ACC) and prefrontal regions (including the orbitofrontal cortex), emerged as key neural correlates of apathy.Since the 2010s, methodological advances have enabled the identification of additional regions associated with apathy. Multidimensional apathy scales, improved control of confounders, higher-resolution imaging and broader inclusion of clinical conditions highlighted the involvment of the thalamus (n=20), inferior parietal cortex (n=17), cerebellum (n=15), hippocampus (n=14), and precuneus (n=10). White matter alterations, particularly within the cingulum and corpus callosum, supported a network disconnection model, especially in vascular conditions. Cortical atrophy predominated in neurodegenerative disorders, and connectivity disruptions in psychiatric populations. Molecular PET studies using dopaminergic and serotonergic tracers provided limited and heterogeneous evidence for neurochemical contributions to apathy. Only three studies reported significant findings, including reduced dopamine synthesis or altered serotonergic binding within striatal and limbic regions, whereas four others found no significant associations.

Conclusions

New neural correlates of apathy have emerged, extending beyond classical fronto-striatal circuits. These include limbic, parietal, thalamic, and cerebellar regions. Methodological improvements and multimodal imaging have provided new insights into the pathophysiology. However, the neurochemical basis of apathy remains poorly characterised. Few studies have combined pharmacological and neuroimaging approaches, and the effects of treatments on underlying neurobiological mechanisms remain largely unreported.

References

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