Cholinergic imaging in dementia spectrum disorders

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 [(11)C]MP4A and [(11)C]PMP PET for acetylcholinesterase (AChE), [(123)I]5IA SPECT for the α(4)β(2) nicotinic acetylcholine receptor and [(123)I]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

Nicotinic Acetylcholine Receptor Signaling in Neuroprotection

Alzheimer’s disease; Neurodegenerative diseases; Nicotine; Transporter; Gli

Nicotinic Acetylcholine Receptor Signaling in Neuroprotection

Alzheimer’s disease; Neurodegenerative diseases; Nicotine; Transporter; Gli

Cholinergic system changes in Parkinson's disease: emerging therapeutic approaches

In patients with Parkinson's disease, heterogeneous cholinergic system changes can occur in different brain regions. These changes correlate with a range of clinical features, both motor and non-motor, that are refractory to dopaminergic therapy, and can be conceptualised within a systems-level framework in which nodal deficits can produce circuit dysfunctions. The topographies of cholinergic changes overlap with neural circuitries involved in sleep and cognitive, motor, visuo-auditory perceptual, and autonomic functions. Cholinergic deficits within cognition network hubs predict cognitive deficits better than do total brain cholinergic changes. Postural instability and gait difficulties are associated with cholinergic system changes in thalamic, caudate, limbic, neocortical, and cerebellar nodes. Cholinergic system deficits can involve also peripheral organs. Hypercholinergic activity of mesopontine cholinergic neurons in people with isolated rapid eye movement (REM) sleep behaviour disorder, as well as in the hippocampi of cognitively normal patients with Parkinson's disease, suggests early compensation during the prodromal and early stages of Parkinson's disease. Novel pharmacological and neurostimulation approaches could target the cholinergic system to treat motor and non-motor features of Parkinson's disease

The pharmacology of visual hallucinations in synucleinopathies

Visual hallucinations (VH) are commonly found in the course of synucleinopathies like Parkinson's disease and dementia with Lewy bodies. The incidence of VH in these conditions is so high that the absence of VH in the course of the disease should raise questions about the diagnosis. VH may take the form of early and simple phenomena or appear with late and complex presentations that include hallucinatory production and delusions. VH are an unmet treatment need. The review analyzes the past and recent hypotheses that are related to the underlying mechanisms of VH and then discusses their pharmacological modulation. Recent models for VH have been centered on the role played by the decoupling of the default mode network (DMN) when is released from the control of the fronto-parietal and salience networks. According to the proposed model, the process results in the perception of priors that are stored in the unconscious memory and the uncontrolled emergence of intrinsic narrative produced by the DMN. This DMN activity is triggered by the altered functioning of the thalamus and involves the dysregulated activity of the brain neurotransmitters. Historically, dopamine has been indicated as a major driver for the production of VH in synucleinopathies. In that context, nigrostriatal dysfunctions have been associated with the VH onset. The efficacy of antipsychotic compounds in VH treatment has further supported the notion of major involvement of dopamine in the production of the hallucinatory phenomena. However, more recent studies and growing evidence are also pointing toward an important role played by serotonergic and cholinergic dysfunctions. In that respect, in vivo and post-mortem studies have now proved that serotonergic impairment is often an early event in synucleinopathies. The prominent cholinergic impairment in DLB is also well established. Finally, glutamatergic and gamma aminobutyric acid (GABA)ergic modulations and changes in the overall balance between excitatory and inhibitory signaling are also contributing factors. The review provides an extensive overview of the pharmacology of VH and offers an up to date analysis of treatment options

Clinicopathological investigations of the cholinergic basal forebrain in Lewy body disorders and ageing

Cholinergic dysfunction has long been associated with cognitive impairment in Alzheimer’s disease (AD). However, neuropathological and functional imaging studies have also found significant cortical cholinergic deficit in Lewy body disorders (LBD), but in a different pattern from that in AD. There is topographical cholinerigic innervation to the cortex and the hippocampus from the basal forebrain. In light of differences in cognitive deficits seen in LBD and AD, I hypothesised that cholinergic basal forebrain subregions are differentially affected in these disorders. In this thesis, novel tissue techniques have been developed for the visualisation of pathology in human post-mortem brain tissue in three-dimensions. Based on a thorough review of the literature and my personal observations, I have established a simplified subdivisional scheme of the nucleus basalis of Meynert (nbM) in the human brain. Using this scheme, a quantification of nbM cholinergic neurons and assessment of neuropathological burden were performed in a large cohort of LBD and AD cases. Severe neuronal depletion across the entire nbM was observed in LBD with cognitive impairment and relative sparing of the anterior nbM was found in AD, supporting findings from previous neuropathological and imaging studies. Further investigation was carried out in the more rostral, hippocampal-projecting cholinergic group in the vertical limb of the nucleus of the diagonal band of Broca. Significant neurodegeneration in this area was identified in LBD with cognitive impairment, but not AD, suggesting its possible role in retrieval memory function via projection to the hippocampal CA2 subfield. In the final section, it was demonstrated that lactacystin injection into the rat nbM can replicate certain pathological and clinical features of LBD with dementia and this may be a useful model for the disease. Results from these studies support my initial hypothesis regarding differential susceptibility of the basal forebrain subregions in LBD and AD.Open Acces

Assessment of the visual thalamic circuitry in hallucinations in dementia with Lewy bodies

PhD ThesisBackground Visual hallucinations occur in 70-90% of patients with dementia with Lewy bodies (DLB) and are related to decreased quality of life for patients. However, the underlying neuropathological changes that promote the manifestation of visual hallucinations in DLB are not known. Several hypotheses of visual hallucinations in DLB have either directly implicated the lateral geniculate nucleus (LGN), pulvinar and superior colliculus or suggested impairments in their putative functions. Methods Post-mortem LGN, pulvinar and superior colliculus tissue was obtained from DLB cases with a clinical history of visual hallucinations and compared to cognitively normal control and Alzheimer’s disease (AD) cases without visual hallucinations. Neuropathological lesions were quantified in individual cases using densitometry and neuronal and glial cell populations were quantified with stereology. RNA sequencing and subsequent bioinformatics analysis of biological pathway alterations was performed by a collaborator on pulvinar tissue from DLB and non-hallucinating control cases. The bioinformatics data was used to identify protein targets based on pathway alterations, which were then investigated using western blot analysis. Results Lewy body pathology and neuronal loss was specifically found in the pulvinar and superior colliculus of DLB cases, particularly in regions implicated in visual attention and target selection. In contrast, AD cases had more widespread degenerative changes. Molecular analysis of the pulvinar demonstrated reduced expression of several synaptic markers, concomitant with elevated expression of several astrocytic markers in DLB. Conclusion ii The relative specificity of changes in visual thalamic regions may contribute to the occurrence of visual hallucinations in DLB. Synaptic degeneration in the pulvinar likely further impedes visual attentional function in DLB. The present results may indicate DLB patients have impairments in directing visual attention to external stimuli, thus facilitating visual hallucinations by an over-reliance upon expectations and experience rather than stimulus-driven perception.Yvonne Emily Mairy, whose generous donation to the National Institute for Health Research Biomedical Research Unit in Lewy body dementia at Newcastle University funded this project. I a

Nicotinic α4β2 receptor binding in dementia with Lewy bodies using 123I-5IA-85380 SPECT demonstrates a link between occipital changes and visual hallucinations

<p>Introduction To investigate in vivo differences in the distribution of α4β2 subtypes of nAChR using the ligand <sup>123</sup>I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) and single photon emission computed tomography (SPECT) in DLB and similarly aged controls.</p> <p>Methods Thirty-one subjects (15 DLB and 16 controls) underwent <sup>123</sup>I-5IA-85380 and perfusion (<sup>99m</sup>Tc-exametazime) SPECT scanning. Patient scans were compared to scans of control subjects on a voxel-by-voxel basis using SPM2.</p> <p>Results Compared to controls, significant reductions in relative <sup>123</sup>I-5IA-85380 uptake were identified in frontal, striatal, temporal and cingulate regions in DLB. Elevation of scaled <sup>123</sup>I-5IA-85380 uptake in occipital cortex was observed in DLB relative to controls, as well as being associated with DLB subjects with a recent history of visual hallucinations. Changes in <sup>123</sup>I-5IA-85380 SPECT in DLB were different from perfusion.</p> <p>Conclusion: Reductions in normalised <sup>123</sup>I-5IA-85380 uptake in DLB were distinct from their perfusion deficits. Significant increase in occipital lobe uptake was present in DLB, a change most pronounced in subjects with a recent history of visual hallucinations. The findings directly link cholinergic changes in occipital lobe to visual hallucinations in DLB.</p&gt