Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders

doi:10.1016/j.neulet.2012.02.083

Neuroscience Letters

Volume 514, Issue 2, 18 April 2012, Pages 169-172

https://doi.org/10.1016/j.neulet.2012.02.083 Get rights and content

Abstract

There are two major sources of cholinergic projections in the brain. The nucleus basalis of Meynert provides the principal cholinergic input of the cortical mantle and the pedunculopontine nucleus–laterodorsal tegmental complex (PPN–LDTC; hereafter referred to as PPN) provides the major cholinergic input to the thalamus. Cortical cholinergic denervation has previously been shown to be part of Alzheimer and parkinsonian dementia but there is less information about subcortical thalamic cholinergic denervation. We investigated thalamic cholinergic afferent integrity by measuring PPN–Thalamic (PPN–Thal) acetylcholinesterase (AChE) activity via PET imaging in Alzheimer (AD), Parkinson disease without dementia (PD), Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB). AD (n = 13; mean age 75.4 ± 5.5), PD (n = 11; age 71.4 ± 6.4), PDD (n = 6; age 70.8 ± 4.7), DLB (n = 6; age 68.0 ± 8.6) and normal controls (NC; n = 14; age 69.0 ± 7.5) subjects underwent AChE [¹¹C]-methyl-4-piperidinyl propionate (PMP) PET imaging. PPN–Thal PET data were analyzed using the Nagatsuka method. There were no significant differences in mean age between the groups (F = 1.86, p = 0.134). Kruskal–Wallis testing demonstrated a significant group effect for PPN–Thal AChE hydrolysis rates (F = 9.62, p < 0.0001). Compared to NC, reduced thalamic k3 hydrolysis rate was noted in subjects with PDD (−19.8%; AChE k3 hydrolysis rates 0.1072 ± 0.0143 min⁻¹), DLB (−17.4%; 0.1103 ± 0.0112 min⁻¹) and PD (−12.8%; 0.1165 ± 0.0114 min⁻¹). Each of these 3 subgroups was statistically different from AD subjects (−0.7%; 0.1326 ± 0.0095 min⁻¹) who showed relatively spared thalamic k3 hydrolysis rates which were comparable to NC (0.1336 ± 0.0142 min⁻¹). Thalamic cholinergic denervation is present in PD, PDD, and DLB but not in AD. Neurodegenerative involvement of thalamic cholinergic afferent projections may contribute to disease-specific motor and cognitive abnormalities.

Highlights

► The forebrain and subcortical systems are the principle brain cholinergic projection systems. ► AChE [¹¹C]-(PMP) PET estimates in vivo integrity of cholinergic terminals. ► Subcortical cholinergic denervation is relatively spared in Alzheimer disease compared to parkinsonian disorders. ► Subcortical cholinergic denervation may correlate with specific clinical features in parkinsonian disorders.

Introduction

Cortical cholinergic denervation is a well-established pathological hallmark of Alzheimer disease (AD) [7]. The two principle cholinergic projection systems of the brain include the basal forebrain system, in particular the nucleus basalis of Meynert (nBM), which supplies cholinergic projections throughout the cerebral cortex and the pontine projection system, including the pedunculopontine nucleus (PPN) and the lateral dorsal tegmental nucleus (LDTN), both of which provide cholinergic innervation to various subcortical structures including the basal ganglia, thalamus, brainstem and rostral spinal cord [10], [20]. While loss of nBM cholinergic neurons is a classic feature of feature of AD [26], less is known about the integrity of the pontine cholinergic projection system and its role in the pathogenesis of AD.

Though cortical cholinergic changes are recognized as a universal hallmark of late-stage AD, we have previously reported in vivo imaging findings suggesting that cortical cholinergic deficits in mild to moderate AD are less robust in comparison to those seen in Parkinson disease (PD) with dementia (PDD) of comparable severity of dementia [4]. Interestingly, thalamic cholinergic changes have also been described in PD without dementia and may associate with a propensity for falls and REM sleep behavior disorder [5], [15]. As the presence of REM sleep behavior disorder and falls is much more common in PD than in AD, it is possible that clinical phenotypic differences between these neurodegenerative disorders may reflect differences in the integrity of the cholinergic system.

In vivo [¹¹C]-methyl-4-piperidinyl propionate (PMP) positron emission tomography (PET) imaging assessment of acetylcholinesterase (AChE) activity in the human brain is a reliable marker for cholinergic terminal integrity [24] and also allows the differential assessment of cortical and subcortical (PPN–Thal) cholinergic systems in vivo. We performed [¹¹C]-PMP PET imaging in subjects with AD and various alpha-synuclein-related disorders (PD, PDD, and dementia with Lewy bodies – DLB) to assess the possible differential role of the pontine cholinergic projection system in these neurodegenerative diseases. We hypothesized that thalamic cholinergic denervation is present in these parkinsonian disorders but not in AD.

Section snippets

Subjects

This study involved 50 subjects: 13 with AD, 11 with PD, 6 with PDD, 6 with DLB, and 14 normal controls (NC). Results of the cortical AChE data from these subjects have been published previously [4]. There were no significant differences in mean (SD) age among the groups (Table 1): those with AD, 75.4 (5.5) years; those with PD, 71.4 (6.4) years; those with PDD, 70.8 (4.7) years; those with DLB, 68.0 (8.6) and NCs, 69.0 (7.5) years; F = 1.86, p = 0.134).

Mini-mental State Examination (MMSE) scores

Results

Mean thalamic AChE Activity [¹¹C]PMP k3 values for all subgroups are shown in Table 2. Kruskal–Wallis testing revealed significant differences between subgroups (χ² = 24.03, p < 0.001). AD subjects showed relatively preserved thalamic cholinergic innervation compared to subjects with PD, PDD and DLB. Relative to NCs, AD subjects showed only a 0.7% reduction in thalamic k3 hydrolysis rate. Comparatively, subjects with PD (12.8%), PDD (19.8%), and DLB (17.4%) showed significantly greater thalamic

Discussion

Our in vivo imaging findings suggest that patients with mild AD have similar thalamic cholinergic system integrity compared to normal controls and no significant thalamic cholinergic denervation compared to PD and parkinsonian dementia patients. These findings are consistent with the limited published post-mortem literature on the pontine cholinergic system in AD. Dugger et al. compared postmortem PPN/LDTN findings in subjects with Lewy-body-related disorders (LBD) (n = 19), AD (n = 19) and normal

Conclusion

Our findings suggest that the pontine cholinergic projection system may be relatively spared in early AD. Ongoing advances in the functional neuroimaging may allow for further correlative analyses amongst neurodegenerative diseases with shared cognitive symptoms.

Acknowledgements

Research support was provided by the Department of Veterans Affairs, and by NIH grants NIA AG05133, P01 NS015655, and R01 NS070856.

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¹: Functional Neuroimaging, Cognitive & Mobility Laboratory, Domino's farms, Lobby B-1000, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48105, United States.

²: 3129 POB CB 7025, Chapel Hill, NC 27517, United States.

³: Division of Nuclear Medicine, University of Michigan, 2276 Med Sci I, SPC 5610, 1301 Catherine Street, Ann Arbor, MI 48109-5610, United States.

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Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders

Abstract

Highlights

Introduction

Section snippets

Subjects

Results

Discussion

Conclusion

Acknowledgements

Neuroscience

Lancet

Nucl. Med. Biol.

Lancet Neurol.

Nucl. Med. Biol.

Neurosci. Lett.

Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis

Neurology

Gender and the Parkinson's disease phenotype

J. Neurol.

Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study

Arch. Neurol.

History of falls in Parkinson disease is associated with reduced cholinergic activity

Neurology

Neuropathological analysis of brainstem cholinergic and catecholaminergic nuclei in relation to REM sleep behaviour disorder

Neuropathol. Appl. Neurobiol.

Systematic regional variations in the loss of cortical cholinergic fibers in Alzheimer's disease

Cereb. Cortex