Cholinergic imaging in dementia spectrum disorders

Abstract

The multifaceted nature of the pathology of dementia spectrum disorders has complicated their management and the development of effective treatments. This is despite the fact that they are far from uncommon, with Alzheimer’s disease (AD) alone affecting 35 million people worldwide. The cholinergic system has been found to be crucially involved in cognitive function, with cholinergic dysfunction playing a pivotal role in the pathophysiology of dementia. The use of molecular imaging such as SPECT and PET for tagging targets within the cholinergic system has shown promise for elucidating key aspects of underlying pathology in dementia spectrum disorders, including AD or parkinsonian dementias. SPECT and PET studies using selective radioligands for cholinergic markers, such as [11C]MP4A and [11C]PMP PET for acetylcholinesterase (AChE), [123I]5IA SPECT for the α4β2 nicotinic acetylcholine receptor and [123I]IBVM SPECT for the vesicular acetylcholine transporter, have been developed in an attempt to clarify those aspects of the diseases that remain unclear. This has led to a variety of findings, such as cortical AChE being significantly reduced in Parkinson’s disease (PD), PD with dementia (PDD) and AD, as well as correlating with certain aspects of cognitive function such as attention and working memory. Thalamic AChE is significantly reduced in progressive supranuclear palsy (PSP) and multiple system atrophy, whilst it is not affected in PD. Some of these findings have brought about suggestions for the improvement of clinical practice, such as the use of a thalamic/cortical AChE ratio to differentiate between PD and PSP, two diseases that could overlap in terms of initial clinical presentation. Here, we review the findings from molecular imaging studies that have investigated the role of the cholinergic system in dementia spectrum disorders.

Cognitive decline in Parkinson disease

“…Cholinergic PET might also be sensitive to subclinical dementia. In PD patients without a diagnosis of cognitive impairment, lower cortical AChE PET activity was associated with reduced cognitive performance scores for attention, memory and executive functions 145,148,151 . A number of molecular targets related to the cholinergic system can be evaluated with PET, and further studies are needed to understand cholinergic system involvement in the development of cognitive impairment in PD.…”

“…The cholinergic system has a key role in functional and structural remodelling of the cortical circuits that underlie cognitive processing 145 . Cholinergic PET imaging studies seem to be consistent with postmortem evidence suggesting that loss of cholinergic function, in the forebrain, is associated with the manifestation of PDD 36,146–148 .…”

Magnetic resonance imaging in Alzheimer’s disease and mild cognitive impairment

“…Frontal, parietal, and temporal brain areas experience volumetric reductions, and so do the putamen and basal forebrain cholinergic system [15, 16, 19, 20]. Cholinergic abnormalities in AD have been further highlighted through the use of molecular imaging technologies [21]. Atrophy is also found in the primary olfactory cortex [22], in addition to lower-level brain areas including the cerebellum and brainstem [23, 24].…”

Impaired connectivity within neuromodulatory networks in multiple sclerosis and clinical implications

“…Network impairment in such neurodegenerative disorders has been selectively associated with neurological symptoms such as cognitive, motor, Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s0041 5-020-09806 -3) contains supplementary material, which is available to authorized users. and non-motor symptoms [4][5][6][7][8]. Tools to measure impaired neurotransmitter networks integrity require either the application of PET or complex MRI methodology with contrast injection.…”