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.

Parkinson's disease CA2-CA3 hippocampal atrophy is accompanied by increased cholinergic innervation in patients with normal cognition but not in patients with mild cognitive impairment.

Although brain cholinergic denervation has been largely associated with cognitive decline in patients with Parkinson's disease (PD), new evidence suggests that cholinergic upregulation occurs in the hippocampus of PD patients without cognitive deficits. The specific hippocampal sectors and potential mechanisms of this cholinergic compensatory process have been further studied here, using MRI volumetry and morphometry coupled with molecular imaging using the PET radiotracer [18F]-Fluoroethoxybenzovesamicol ([18F]-FEOBV). Following a thorough screening procedure, 18 participants were selected and evenly distributed in three groups, including cognitively normal PD patients (PD-CN), PD patients with mild cognitive impairment (PD-MCI), and healthy volunteers (HV). Participants underwent a detailed neuropsychological assessment, structural MRI, and PET imaging with [18F]-FEOBV. Basal forebrain Ch1-Ch2 volumes were measured using stereotaxic mapping. Hippocampal subfields were automatically defined using the MAGeT-Brain segmentation algorithm. Cholinergic innervation density was quantified using [18F]-FEOBV uptake. Compared with HV, both PD-CN and PD-MCI displayed significantly reduced volumes in CA2-CA3 bilaterally. We found no other hippocampal subfield nor Ch1-Ch2 volume differences between the three groups. PET imaging revealed higher [18F]-FEOBV uptake in CA2-CA3 of the PD-CN compared with HV or PD-MCI. A positive correlation was observed between cognitive performances and [18F]-FEOBV uptake in the right CA2-CA3 subfield. Reduced volume, together with increased [18F]-FEOBV uptake, were observed specifically in the CA2-CA3 hippocampal subfields. However, while the volume change was observed in both PD-CN and PD-MCI, increased [18F]-FEOBV uptake was present only in the PD-CN group. This suggests that a cholinergic compensatory process takes place in the atrophied CA2-CA3 hippocampal subfields and might underlie normal cognition in PD.

Hippocampal subfield associations with memory depend on stimulus modality and retrieval mode.

Hippocampal atrophy is a well-known feature of age-related memory decline, and hippocampal subfields may contribute differently to this decline. In this cross-sectional study, we investigated the associations between hippocampal subfield volumes and performance in free recall and recognition memory tasks in both verbal and visual modalities in older adults without dementia. We collected MRIs from 97 (41 males) right-handed participants aged over 60. We segmented the right and left hippocampi into (i) dentate gyrus and cornu ammonis 4 (DG/CA4); (ii) CA2 and CA3 (CA2/CA3); (iii) CA1; (iv) strata radiatum, lacunosum and moleculare; and (v) subiculum. Memory was assessed with verbal free recall and recognition tasks, as well as visual free recall and recognition tasks. Amyloid-ß and hippocampal tau positivity were assessed using [18F]AZD4694 and [18F]MK6240 PET tracers, respectively. The verbal free recall and verbal recognition performances were positively associated with CA1 and strata radiatum, lacunosum and moleculare volumes. The verbal free recall and visual free recall were positively correlated with the right DG/CA4. The visual free recall, but not verbal free recall, was also associated with the right CA2/CA3. The visual recognition was not significantly associated with any subfield volume. Hippocampal tau positivity, but not amyloid-ß positivity, was associated with reduced DG/CA4, CA2/CA3 and strata radiatum, lacunosum and moleculare volumes. Our results suggest that memory performances are linked to specific subfields. CA1 appears to contribute to the verbal modality, irrespective of the free recall or recognition mode of retrieval. In contrast, DG/CA4 seems to be involved in the free recall mode, irrespective of verbal or visual modalities. These results are concordant with the view that DG/CA4 plays a primary role in encoding a stimulus' distinctive attributes, and that CA2/CA3 could be instrumental in recollecting a visual memory from one of its fragments. Overall, we show that hippocampal subfield segmentation can be useful for detecting early volume changes and improve our understanding of the hippocampal subfields' roles in memory.

PET imaging of cholinergic deficits in rats using [18F]fluoroethoxybenzovesamicol ([18F]FEOBV).

[(18)F]fluoroethoxybenzovesamicol ([(18)F]FEOBV) is one of the most promising radioligands for imaging the vesicular ACh transporter (VAChT) with positron emission tomography (PET). We report here that this method can detect subtle cholinergic terminals losses such as those associated with aging, or those following a partial lesion of the nucleus basalis magnocellularis (NBM). Twenty-one adult rats were evenly distributed in three groups including 1) aged rats (18 months); 2) young rats (3 months); and 3) rats with unilateral lesion of the NBM, following a local stereotaxic infusion of 192 IgG-saporin. In both normal and lesioned rats, our results revealed the highest [(18)F]FEOBV binding to be in the striatum, followed by similar values in both frontal cortex and thalamus, while lower values were observed in both hippocampus and temporo-parietal cortex. This binding distribution is consistent with the known anatomy of brain cholinergic systems. In the lesioned rats, [(18)F]FEOBV binding was found to be reduced mostly in the ventral frontal cortex on the side of the lesion, but some reductions were also observed in the homologous region of the contralateral hemisphere. Aging was found to be associated with a [(18)F]FEOBV binding reduction limited to the hippocampus of both hemispheres. [(18)F]FEOBV appears to be a very promising marker for the in vivo quantification of the brain VAChT; PET imaging of this agent allows in vivo detection of both physiological and pathological reductions of cholinergic terminals density.

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.

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex.

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.

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.

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.

Movement chunking during sequence learning is a dopamine-dependant process: a study conducted in Parkinson's disease.

Chunking of single movements into integrated sequences has been described during motor learning, and we have recently demonstrated that this process involves a dopamine-dependant mechanism in animal (Levesque et al. in Exp Brain Res 182:499-508, 2007; Tremblay et al. in Behav Brain Res 198:231-239, 2009). However, there is no such evidence in human. The aim of the present study was to assess this question in Parkinson's disease (PD), a neurological condition known for its dopamine depletion in the striatum. Eleven PD patients were tested under their usual levodopa medication (ON state), and following a 12-h levodopa withdrawal (OFF state). Patients were compared with 12 healthy participants on a motor learning sequencing task, requiring pressing fourteen buttons in the correct order, which was determined by visual stimuli presented on a computer screen. Learning was assessed from three blocks of 20 trials administered successively. Chunks of movements were intrinsically created by each participant during this learning period. Then, the sequence was shuffled according to the participant's own chunks, generating two new sequences, with either preserved or broken chunks. Those new motor sequences had to be performed separately in a fourth and fifth blocks of 20 trials. Results showed that execution time improved in every group during the learning period (from blocks 1 to 3). However, while motor chunking occurred in healthy controls and ON-PD patients, it did not in OFF-PD patients. In the shuffling conditions, a significant difference was seen between the preserved and the broken chunks conditions for both healthy participants and ON-PD patients, but not for OFF-PD patients. These results suggest that movement chunking during motor sequence learning is a dopamine-dependent process in human.

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.

Over facilitation of unadapted cognitive processes in obsessive compulsive disorder as assessed with the computerized mirror pointing task.

Response inhibition has been suggested to be dysfunctional in obsessive-compulsive disorder (OCD). However, this process involves intentional cognitive control, which does not correspond to the automatic emergence of stereotyped thoughts and behaviours usually reported by patients with OCD. In the present study, the excessive facilitation of unintentional processes was assessed in OCD by using the Computerized Mirror Pointing Task (CMPT). Seventy-six volunteers participated in this study, including 39 patients with OCD and 37 healthy controls. The CMPT was administered to all participants, and a score of appropriateness of the sensorimotor adaptation to the mirror inversion was computed from the initial deviation angle (IDA), that precedes the intentional readjustment of movement. Results showed that throughout the 40 trials of the CMPT, the IDA score remained significantly abnormal in patients with OCD in comparison with control participants. Further analyses of IDA scores in OCD revealed a clear tendency to keep a natural visuomotor processing that is rigid and unadapted to the mirror condition. Irrespective of the physical requirements of the environment, patients with OCD showed a strong tendency to initiate movements as per a previously consolidated - although unadapted - sensorimotor mapping. This suggests a tendency for an excessive facilitation of unintentional stereotyped processes. Further studies should be conducted on this question by using tasks sensitive to cognitive processes other than visuo-spatial abilities.

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.

Assessment of executive dysfunction during activities of daily living in schizophrenia.

Many neuropsychological studies have described deficits of memory and executive functions in patients with schizophrenia, and the severity of these deficits seems to be determinant in predicting the community outcome of these patients [Schizophr. Bull. 26 (2000) 119]. However, neuropsychological evaluation does not provide valuable information about how the cognitive deficits directly affect daily living, that is, which cognitive deficit affects which behavior. The present study aimed at determining whether executive dysfunction in schizophrenia could be directly measured by analyzing three activities of daily living (ADL), in addition to assessing the ecological validity of commonly used neuropsychological tests. Within specific ADL (choosing a menu, shopping the ingredients, cooking a meal), the sequences of behaviors that have been performed by 27 control subjects and 27 patients with schizophrenia were both analyzed by using a preset optimal sequence of behavior. When compared with control subjects, patients with schizophrenia showed more omissions when choosing the menu, more sequencing and repetitions errors during the shopping task, and more planning, sequencing, repetition and omission errors during the cooking task. These behavioral errors correlated significantly with negative, but not with positive symptoms of the patients. Furthermore, they also correlated with the poor performances on executive neuropsychological tests, especially those sensitive to shifting and sequencing abilities, but not with memory tests. These results suggest that executive deficits in schizophrenia may specifically affect ADL and that such deficits can be quantitatively assessed with a behavioral scale of action sequences.

Lack of efficacy of a nicotine transdermal treatment on motor and cognitive deficits in Parkinson's disease.

UNLABELLED: Studies assessing the efficacy of nicotine in Parkinson's disease (PD) have generated contradictory results. The controversy seems to stem from uncontrolled factors including the lack of objective measures, the practice effect in a test-retest design, and the absence of plasmatic dosage. This study aimed at further controlling these factors using transdermal nicotine in PD. METHODS: Twenty-two nonsmoking PD patients received a transdermal nicotine treatment over 25 days in increasing titrated doses. Motor and cognitive assessments were carried out on days 11 and 25 (low-dose and high-dose assessments, respectively) and after a 14-day washout period. RESULTS: Patients tolerated nicotine poorly. Thirteen (59%) withdrew, mostly because of acute side effects. In the remaining nine patients, nicotine neither improved nor worsened motor or cognitive functioning in comparison with 10 age, gender and education matched controls. CONCLUSIONS: Transdermal nicotine is not effective in treating motor and cognitive deficits in PD. The results obtained with our objective measures confirm a recent double-blind, placebo-controlled study that used clinical measures. It is possible that nicotine lacks specificity in targeting critical nicotinic receptors that might be involved in PD pathophysiology. The low tolerability may be related to such a lack of specificity of nicotine, which would directly stimulate the autonomic nervous system.

Poor tolerability of a transdermal nicotine treatment in Parkinson's disease.

Studies assessing the effect of transdermal nicotine in Parkinson's disease (PD) have generated mixed results regarding its efficacy to treat motor and cognitive deficits. These studies generally reported good tolerability in nonsmoking PD patients. The authors report the tolerability data of an open trial with transdermal nicotine in PD. Twenty-two therapeutically well-controlled nonsmoking PD patients received a transdermal nicotine treatment over 25 days according to the following fixed titration schedule: 7 mg for the first 11 days, 14 mg for the next 11 days, and 21 mg for the last 3 days. Fourteen PD patients (64%) had side effects such as nausea, vomiting, and dizziness, and 10 of them withdrew from the study. Factors such as age, body mass index, disease duration, and motor disability were not related to this intolerance. Transdermal nicotine can produce unpleasant adverse effects in patients with PD. Given that similar doses of nicotine were better tolerated in previous studies, the authors suspect the pharmacokinetic profile of the transdermal delivery system to be a determining factor in the effect of nicotine treatment in PD.

Cognitive deficits and striatal dopaminergic denervation in Parkinson's disease: a single photon emission computed tomography study using 123iodine-beta-CIT in patients on and off levodopa.

Cognitive deficits affecting executive (frontal) functions have been widely described in Parkinson's disease (PD). However, dopa therapies are generally ineffective at reversing these deficits, except for tasks involving a sharing of attention such as working memory or simultaneous processing tasks. The aim of this study was to assess the relation between the nigrostriatal dopaminergic denervation in PD, as measured by SPECT with (123)Iodine-beta-CIT and the cognitive deficits, as measured by a simultaneous processing task, which had already been shown to be sensitive to dopa treatment. Ten patients with PD and ten control subjects were selected and matched for age, sex, and education. All subjects were assessed using computed visuo-auditory tasks which allow for the measurement of three cognitive processing conditions: 1) a Selective Processing Time; 2) a Competitive Processing Time; and 3) a Simultaneous Processing Time. Patients with PD were assessed both with (ON) and without (OFF) their usual dopaminergic treatment. The simultaneous processing condition but not the selective or the competitive conditions took significantly more time for patients with PD OFF than for either the control subjects or the patients with PD ON. In addition, when patients with PD were OFF, the simultaneous processing condition was correlated with the (123)Iodine-beta-CIT binding, but not when they were ON. These results suggest that nigrostriatal DA denervation may be involved in the specific impairment that patients with PD experience with simultaneous cognitive processing.

[Benzodiazepines: Consequences on memory in the elderly]. / Benzodiazépines: conséquences sur le fonctionnement mnésique des personnes âgées.

Studies conducted with a healthy voluntary population with a unique medication indicate that benzodiazepines (BZD) are known to induce memory deficits. However, this group does not correspond to the population usually using these medication on a regular basis, knowingly the elderly people. Few studies have been conducted with this target population to determine the impact of BZD on their memory. However, some findings suggest that there are important consequences on the functioning of memory of the elderly people taking BZD. The current data go as far as suggesting that BZD exacerbate memory deficits in the elderly. This could even constitute a risk factor that could hasten cognitive decline and thus increase development of dementia.

PET imaging with [¹8F]fluoroethoxybenzovesamicol ([¹8F]FEOBV) following selective lesion of cholinergic pedunculopontine tegmental neurons in rat.

INTRODUCTION: [(18)F]fluoroethoxybenzovesamicol ([(18)F]FEOBV) is a PET radiotracer with high selectivity and specificity to the vesicular acetylcholine transporter (VAChT). It has been shown to be a sensitive in vivo measurement of changes of cholinergic innervation densities following lesion of the nucleus basalis of Meynert (NBM) in rat. The current study used [(18)F]FEOBV with PET imaging to detect the effect of a highly selective lesion of the pedunculopontine (PPTg) nucleus in rat. METHODS: After bilateral and selective lesions of the PPTg cholinergic neurons, rats were scanned using [(18)F]FEOBV, then sacrificed, and their brain tissues collected for immunostaining and quantification of the VAChT. RESULTS: Comparisons with control rats revealed that cholinergic losses can be detected in the brainstem, lateral thalamus, and pallidum by using both in vivo imaging methods with [(18)F]FEOBV, and ex vivo measurements. In the brainstem PPTg area, significant correlations were observed between in vivo and ex vivo measurements, while this was not the case in the thalamic and pallidal projection sites. CONCLUSIONS: These findings support PET imaging with [(18)F]FEOBV as a reliable in vivo method for the detection of neuronal terminal losses resulting from lesion of the PPTg. Useful applications can be found in the study of neurodegenerative diseases in human, such as Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, or dementia with Lewy bodies.