Accelerated atrophy in dopaminergic targets and medial temporo-parietal regions precedes the onset of delusions in patients with Alzheimer’s disease

Abstract

People with Alzheimer’s disease (AD) and delusions have worse quality of life and prognosis. However, early markers of delusions have not been identified yet. The present study investigated whether there are any detectable differences in grey matter (GM) volume and cognitive changes in the year before symptom onset between patients with AD who did and did not develop delusions. Two matched samples of AD patients, 63 who did (PT-D) and 63 who did not develop delusions (PT-ND) over 1 year, were identified from the Alzheimer’s Disease Neuroimaging Initiative database. The Neuropsychiatric Inventory (NPI) was used to assess the presence of delusions. Sixty-three additional matched healthy controls (HC) were selected. Repeated-measures ANCOVA models were used to investigate group-by-time effects on the volume of selected GM regions of interest and on cognitive performance. No neurocognitive differences were observed between patient groups prior to symptom onset. Greater episodic memory decline and GM loss in bilateral caudate nuclei, medio-temporal and midline cingulo-parietal regions were found in the PT-D compared with the PT-ND group. A pattern of faster GM loss in brain areas typically affected by AD and in cortical and subcortical targets of dopaminergic pathways, paralleled by worsening of episodic memory and behavioural symptoms, may explain the emergence of delusions in patients with AD.

Dopaminergic deficits along the spectrum of Alzheimer’s Disease

“…Thus, the evidence presented, here, showing ventral striatum and the dorsal caudate de cits since the MCI-AD phase are important tools for early diagnosis. This is perfectly in line with previous works pinpointing dopaminergic de cits as predictive hallmarks of the pathology and of early conversion from MCI to AD-DEM [12,34,35].…”

The VTA dopaminergic system as diagnostic and therapeutical target for Alzheimer's disease

“…Of note, these studies also confirmed that the extend of gray matter atrophy in mesocorticolimbic dopaminergic targets since the MCI stage was associated with greater severity of NPS, in particular depression linked to the meso-cortical route, anxiety linked to the mesolimbic route, and apathy linked to the mesohippocampal/meso-amygdaloid route ( 136 ). Indeed, stronger loss of gray matter in dopaminergic pathways was also paralleled by a worsening not only of episodic memory but also of behavioral alterations, related to the emergence of psychiatric symptoms and delusions in patients with AD ( 137 ). Given the link between the mesocorticolimbic dopamine and NPS, and the fact that these symptoms speed up the disease progression, it is not surprising that functional disconnection of the VTA with mesocorticolimbic targets can accelerate the conversion from the MCI stage to clinical AD ( 137 , 141 , 142 ).…”

“…Indeed, stronger loss of gray matter in dopaminergic pathways was also paralleled by a worsening not only of episodic memory but also of behavioral alterations, related to the emergence of psychiatric symptoms and delusions in patients with AD ( 137 ). Given the link between the mesocorticolimbic dopamine and NPS, and the fact that these symptoms speed up the disease progression, it is not surprising that functional disconnection of the VTA with mesocorticolimbic targets can accelerate the conversion from the MCI stage to clinical AD ( 137 , 141 , 142 ).…”