Normal cognition in Parkinson's disease may involve hippocampal cholinergic compensation: An exploratory PET imaging study with [18F]-FEOBV.

BACKGROUND: Severe cholinergic degeneration is known to occur in Parkinson's disease (PD) and is thought to play a primary role in the cognitive decline associated with this disease. Although cholinergic losses occur in all patients with PD, cognitive performance remains normal for many of them, suggesting compensatory mechanisms in those. OBJECTIVES: This exploratory study aimed at verifying if normal cognition in PD may involve distinctive features of the brain cholinergic systems. METHODS: Following extensive neuropsychological screening in 25 patients with PD, 12 were selected and evenly distributed between a cognitively normal (PD-CN) group, and a mild cognitive impairment (PD-MCI) group. Each group was compared with matched healthy volunteers (HV) on standardized cognitive scales (MoCA, PDCRS), and PET imaging with [18F]-FEOBV, a sensitive measurement of brain cholinergic innervation density. RESULTS: [18F]-FEOBV uptake reductions were observed in PD-CN as well as in PD-MCI, with the lowest values located in the posterior cortical areas. However, in PD-CN but not in PD-MCI, there was a significant and bilateral increase of [18F]-FEOBV uptake, exclusively located in the hippocampus. Significant correlations were observed between cognitive performance and hippocampal [18F]-FEOBV uptake. CONCLUSION: These findings suggest a compensatory upregulation of the hippocampal cholinergic innervation in PD-CN, which might underly normal cognitive performances in spite of cortical cholinergic denervation in other regions.

Molecular Imaging of the Cholinergic System in Alzheimer and Lewy Body Dementias: Expanding Views.

PURPOSE OF REVIEW: Brain cholinergic denervation is a major feature of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We reviewed the topography assessed by a cholinergic molecular imaging study in these two major types of dementia. A small meta-analysis directly comparing vesicular acetylcholine transporter (VAChT) PET scans of AD vs. DLB patients is presented. RECENT FINDINGS: VAChT PET studies showed evidence of extensive cortical cholinergic denervation in both forms of dementia, while multiple subcortical structures were also in DLB. Novel analysis revealed evidence of metathalamic denervation in AD, and epithalamus, premotor/sensorimotor cortical, and striatal losses in DLB. Topographically distinct cortical and subcortical cholinergic lesions can distinguish AD and DLB, and new structures have been highlighted here. Differential vulnerability of specific cholinergic projections is likely associated with specific clinical features of these disorders. Improved understanding of the mechanisms and roles of cholinergic neurotransmission in regions with cholinergic deficits may lead to symptomatic therapies.

FEOBV-PET to quantify cortical cholinergic denervation in AD: Relationship to basal forebrain volumetry.

BACKGROUND AND PURPOSE: Fluorine-18-fluoroethoxybenzovesamicol([18 F]-FEOBV) is a PET radiotracer previously used in neurodegenerative diseases to quantify brain cholinergic denervation. The current exploratory study aimed at verifying the reliability of such an approach in Alzheimer's disease (AD) by demonstrating its concordance with MRI volumetry of the cholinergic basal forebrain (ChBF). METHODS: The sample included 12 participants evenly divided between healthy volunteers and patients with AD. All participants underwent MRI ChBF volumetry and PET imaging with [18 F]-FEOBV. Comparisons were made between the two groups, and partial correlations were performed in the AD patients between [18 F]-FEOBV uptake in specific cortical regions of interest (ROIs) and volumetry of the corresponding ChBF subareas, which include the nucleus basalis of Meynert (Ch4), and the medial septum/vertical limb of the diagonal band of Broca (Ch1/2). RESULTS: Patients with AD showed both lower ChBF-Ch4 volumetric values and lower [18 F]-FEOBV cortical uptake than healthy volunteers. Volumes of the Ch4 subdivision were significantly correlated with the [18 F]-FEOBV uptake values observed in the relevant ROIs. Volumes of the Ch1/2, which remains relatively unaffected in AD, did not correlate with [18 F]-FEOBV uptake in the hippocampus, nor in any cortical area. CONCLUSION: These results suggest that cortical cholinergic denervation as measured with [18 F]-FEOBV PET is proportional to ChBF atrophy measured by MRI-based volumetry, further supporting the reliability and validity of [18 F]-FEOBV PET to quantify cholinergic degeneration in AD.

Brain cholinergic alterations in idiopathic REM sleep behaviour disorder: a PET imaging study with 18F-FEOBV.

BACKGROUND: REM sleep behaviour disorder (RBD) occurs frequently in patients with synucleinopathies such as Parkinson's disease, dementia with Lewy body, or multiple system atrophy, but may also occur as a prodromal stage of those diseases; and is termed idiopathic RBD (iRBD) when not accompanied by other symptoms. Cholinergic degeneration of the mesopontine nuclei have been described in synucleinopathies with or without RBD, but this has not yet been explored in iRBD. We sought to assess cholinergic neuronal integrity in iRBD using PET neuroimaging with the 18F-fluoroethoxybenzovesamicol (FEOBV). METHODS: The sample included 10 participants evenly divided between healthy subjects and patients with iRBD. Polysomnography and PET imaging with FEOBV were performed in all participants. Standardized uptake value ratios (SUVRs) were compared between the two groups using voxel wise t-tests. Non-parametric correlations were also computed in patients with iRBD between FEOBV uptake and muscle tonic and phasic activity during REM sleep. RESULTS: Compared with healthy participants, significantly higher FEOBV uptakes were observed in patients with iRBD. The largest differences were observed in specific brainstem areas corresponding to the bulbar reticular formation, pontine coeruleus/subcoeruleus complex, tegmental periacqueductal grey, and mesopontine cholinergic nuclei. FEOBV uptake in iRBD was also higher than in controls in the ventromedial area of the thalamus, deep cerebellar nuclei, and some cortical territories (including the paracentral lobule, anterior cingulate, and orbitofrontal cortex). Significant correlation was found between muscle activity during REM sleep, and SUVR increases in both the mesopontine area and paracentral cortex. CONCLUSION: We showed here for the first time the brain cholinergic alterations in patients with iRBD. As opposed to the cholinergic depletion described previously in RBD associated with clinical Parkinson's disease, increased cholinergic innervation was found in multiple areas in iRBD. The most significant changes were observed in brainstem areas containing structures involved in the promotion of REM sleep and muscle atonia. This suggests that iRBD might be a clinical condition in which compensatory cholinergic upregulation in those areas occurs in association with the initial phases of a neurodegenerative process leading to a clinically observable synucleinopathy.

Longitudinal Alzheimer's Degeneration Reflects the Spatial Topography of Cholinergic Basal Forebrain Projections.

The cholinergic neurons of the basal forebrain (BF) provide virtually all of the brain's cortical and amygdalar cholinergic input. They are particularly vulnerable to neuropathology in early Alzheimer's disease (AD) and may trigger the emergence of neuropathology in their cortico-amygdalar projection system through cholinergic denervation and trans-synaptic spreading of misfolded proteins. We examined whether longitudinal degeneration within the BF can explain longitudinal cortico-amygdalar degeneration in older human adults with abnormal cerebrospinal fluid biomarkers of AD neuropathology. We focused on two BF subregions, which are known to innervate cortico-amygdalar regions via two distinct macroscopic cholinergic projections. To further assess whether structural degeneration of these regions in AD reflects cholinergic denervation, we used the [18F] FEOBV radiotracer, which binds to cortico-amygdalar cholinergic terminals. We found that the two BF subregions explain spatially distinct patterns of cortico-amygdalar degeneration, which closely reflect their cholinergic projections, and overlap with [18F] FEOBV indices of cholinergic denervation.

Deficit in sustained attention following selective cholinergic lesion of the pedunculopontine tegmental nucleus in rat, as measured with both post-mortem immunocytochemistry and in vivo PET imaging with [¹8F]fluoroethoxybenzovesamicol.

Cholinergic neurons of the pedunculopontine tegmental nucleus (PPTg) are thought to be involved in cognitive functions such as sustained attention, and lesions of these cells have been documented in patients showing fluctuations of attention such as in Parkinson's disease or dementia with Lewy Body. Animal studies have been conducted to support the role of these cells in attention, but the lesions induced in these animals were not specific to the cholinergic PPTg system, and were assessed by post-mortem methods remotely performed from the in vivo behavioral assessments. Moreover, sustained attention have not been directly assessed in these studies, but rather deduced from indirect measurements. In the present study, rats were assessed on the 5-Choice Serial Reaction Time Task (5-CSRTT), and a specific measure of variability in response latency was created. Animals were observed both before and after selective lesion of the PPTg cholinergic neurons. Brain cholinergic denervation was assessed both in vivo and ex vivo, using PET imaging with [(18)F]fluoroethoxybenzovesamicol ([(18)F]FEOBV) and immunocytochemistry respectively. Results showed that the number of correct responses and variability in response latency in the 5-CSRTT were the only behavioral measures affected following the lesions. These measures were found to correlate significantly with the number of PPTg cholinergic cells, as measured with both [(18)F]FEOBV and immunocytochemistry. This suggests the primary role of the PPTg cholinergic cells in sustained attention. It also allows to reliably use the PET imaging with [(18)F]FEOBV for the purpose of assessing the relationship between behavior and cholinergic innervation in living animals.

Pyrithiamine-induced thiamine deficiency alters proliferation and neurogenesis in both neurogenic and vulnerable areas of the rat brain.

Thiamine deficiency (TD) leads to Wernicke's encephalopathy (WE), in which focal histological lesions occur in periventricular areas of the brain. Recently, impaired neurogenesis has been reported in the hippocampus during the dietary form of TD, and in pyrithiamine-induced TD (PTD), a well-characterized model of WE. To further characterize the consequences of PTD on neural stem/progenitor cell (NSPC) activity, we have examined the effect of this treatment in the rat on both the subventricular zone (SVZ) of the rostral lateral ventricle and subgranular layer (SGL) of the hippocampus, and in the thalamus and inferior colliculus, two vulnerable brain regions in this disorder. In both the SVZ and SGL, PTD led to a decrease in the numbers of bromodeoxyuridine-stained cells, indicating that proliferation of NSPCs destined for neurogenesis in these areas was reduced. Doublecortin (DCX) immunostaining in the SGL was decreased, indicating a reduction in neuroblast formation, consistent with impaired NSPC activity. DCX labeling was not apparent in focal areas of vulnerability. In the thalamus, proliferation of cells was absent while in the inferior colliculus, numerous actively dividing cells were apparent, indicative of a differential response between these two brain regions. Exposure of cultured neurospheres to PTD resulted in decreased proliferation of NSPCs, consistent with our in vivo findings. Together, these results indicate that PTD considerably affects cell proliferation and neurogenesis activity in both neurogenic areas and parts of the brain known to display structural and functional vulnerability, confirming and extending recent findings on the effects of TD on neurogenesis. Future use of NSPCs in vitro may allow a closer and more detailed examination of the mechanism(s) underlying inhibition of these cells during TD.

Loss of astrocytic glutamate transporters in Wernicke encephalopathy.

Wernicke encephalopathy (WE), a neurological disorder caused by thiamine deficiency (TD), is characterized by structural damage in brain regions that include the thalamus and cerebral cortex. The basis for these lesions is unclear, but may involve a disturbance of glutamatergic neurotransmission. We have therefore investigated levels of the astrocytic glutamate transporters EAAT1 and EAAT2 in order to evaluate their role in the pathophysiology of this disorder. Histological assessment of the frontal cortex revealed a significant loss of neurons in neuropathologically confirmed cases of WE compared with age-matched controls, concomitant with decreases in alpha-internexin and synaptophysin protein content of 67 and 52% by immunoblotting. EAAT2 levels were diminished by 71% in WE, with levels of EAAT1 also reduced by 62%. Loss of both transporter sites was confirmed by immunohistochemical methods. Development of TD in rats caused a profound loss of EAAT1 and EAAT2 in the thalamus accompanied by decreases in other astrocyte-specific proteins. Treatment of TD rats with N-acetylcysteine prevented the downregulation of EAAT2 in the medial thalamus, and ameliorated the loss of several other astrocyte proteins, concomitant with increased neuronal survival. Our results suggest that (1) loss of EAAT1 and EAAT2 glutamate transporters is associated with structural damage to the frontal cortex in patients with WE, (2) oxidative stress plays an important role in this process, and (3) TD has a profound effect on the functional integrity of astrocytes. Based on these findings, we recommend that early treatment using a combination of thiamine AND antioxidant approaches should be an important consideration in cases of WE.