Cortical Acetylcholinesterase Activity Research Articles

Progression of brain cholinergic dysfunction in patients with isolated rapid eye movement sleep behavior disorder.

Reduced cortical acetylcholinesterase activity, as measured by 11 C-donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship between longitudinal changes in brain acetylcholinesterase activity and cognitive function in iRBD. Twelve iRBD patients underwent 11 C-donepezil PET at baseline and after 3 years. PET images were interrogated with statistical parametric mapping (SPM) and a regions of interest (ROI) approach. Clinical progression was assessed with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). Cognitive function was rated using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). From baseline to follow-up, the mean 11 C-donepezil distribution volume ratio (DVR) decreased in the cortex (p = 0.006), thalamus (p = 0.013), and caudate (p = 0.013) ROI. Despite no significant changes in the group mean MMSE or MoCA scores being observed, individually, seven patients showed a decline in their scores on these cognitive tests. Subgroup analysis showed that only the subgroup of patients with a decline in cognitive scores had a significant reduction in mean cortical 11 C-donepezil DVR. Our results show that severity of brain cholinergic dysfunction in iRBD patients increases significantly over 3 years, and those changes are more severe in those with a decline in cognitive test scores.

Structural and molecular cholinergic imaging markers of cognitive decline in Parkinson's disease.

Cognitive decline in Parkinson's disease is related to cholinergic system degeneration, which can be assessed in vivo using structural MRI markers of basal forebrain volume and PET measures of cortical cholinergic activity. In the present study we aimed to examine the interrelation between basal forebrain degeneration and PET-measured depletion of cortical acetylcholinesterase activity as well as their relative contribution to cognitive impairment in Parkinson's disease. This cross-sectional study included 143 Parkinson's disease participants without dementia and 52 healthy control participants who underwent structural MRI, PET scanning with 11C-methyl-4-piperidinyl propionate (PMP) as a measure of cortical acetylcholinesterase activity, and a detailed cognitive assessment. Based on the fifth percentile of the overall cortical PMP PET signal from the control group, people with Parkinson's disease were subdivided into a normo-cholinergic (n = 94) and a hypo-cholinergic group (n = 49). Volumes of functionally defined posterior and anterior basal forebrain subregions were extracted using an established automated MRI volumetry approach based on a stereotactic atlas of cholinergic basal forebrain nuclei. We used Bayesian t-tests to compare basal forebrain volumes between controls, and normo- and hypo-cholinergic Parkinson's participants after covarying out age, sex and years of education. Associations between the two cholinergic imaging measures were assessed across all people with Parkinson's disease using Bayesian correlations and their respective relations with performance in different cognitive domains were assessed with Bayesian ANCOVAs. As a specificity analysis, hippocampal volume was added to the analysis. We found evidence for a reduction of posterior basal forebrain volume in the hypo-cholinergic compared to both normo-cholinergic Parkinson's disease [Bayes factor against the null model (BF10) = 8.2] and control participants (BF10 = 6.0), while for the anterior basal forebrain the evidence was inconclusive (BF10 < 3). In continuous association analyses, posterior basal forebrain volume was significantly associated with cortical PMP PET signal in a temporo-posterior distribution. The combined models for the prediction of cognitive scores showed that both cholinergic markers (posterior basal forebrain volume and cortical PMP PET signal) were independently related to multi-domain cognitive deficits, and were more important predictors for all cognitive scores, including memory scores, than hippocampal volume. We conclude that degeneration of the posterior basal forebrain in Parkinson's disease is accompanied by functional cortical changes in acetylcholinesterase activity and that both PET and MRI cholinergic imaging markers are independently associated with multi-domain cognitive deficits in Parkinson's disease without dementia. Comparatively, hippocampal atrophy only seems to have minimal involvement in the development of early cognitive impairment in Parkinson's disease.

Progression of regional cortical cholinergic denervation in Parkinson's disease.

Cortical cholinergic deficits contribute to cognitive decline and other deficits in Parkinson's disease. Cross-sectional imaging studies suggest a stereotyped pattern of posterior-to-anterior cortical cholinergic denervation accompanying disease progression in Parkinson's disease. We used serial acetylcholinesterase PET ligand imaging to characterize the trajectory of regional cholinergic synapse deficits in Parkinson's disease, testing the hypothesis of posterior-to-anterior progression of cortical cholinergic deficits. The 16 Parkinson's disease subjects (4 females/12 males; mean age: 64.4 ± 6.7 years; disease duration: 5.5 ± 4.2 years; Hoehn & Yahr stage: 2.3 ± 0.6 at entry) completed serial 11C-methyl-4-piperidinyl propionate acetylcholinesterase PET scans over a 4-8 year period (median 5 years). Three-dimensional stereotactic cortical surface projections and volume-of-interest analyses were performed. Cholinergic synapse integrity was assessed by the magnitude, k 3, of acetylcholinesterase hydrolysis of 11C-methyl-4-piperidinyl propionate. Based on normative data, we generated Z-score maps for both the k 3 and the k 1 parameters, the latter as a proxy for regional cerebral blood flow. Compared with control subjects, baseline scans showed predominantly posterior cortical k 3 deficits in Parkinson's disease subjects. Interval change analyses showed evidence of posterior-to-anterior progression of cholinergic cortical deficits in the posterior cortices. In frontal cortices, an opposite gradient of anterior-to-posterior progression of cholinergic deficits was found. The topography of k 3 changes exhibited regionally specific disconnection from k 1 changes. Interval-change analysis based on k 3/k 1 ratio images (k 3 adjustment for regional cerebral blood flow changes) showed interval reductions (up to 20%) in ventral frontal, anterior cingulate and Brodmann area 6 cortices. In contrast, interval k 3 reductions in the posterior cortices, especially Brodmann areas 17-19, were largely proportional to k 1 changes. Our results partially support the hypothesis of progressive posterior-to-cortical cholinergic denervation in Parkinson's disease. This pattern appears characteristic of posterior cortices. In frontal cortices, an opposite pattern of anterior-to-posterior progression of cholinergic deficits was found. The progressive decline of posterior cortical acetylcholinesterase activity was largely proportional to declining regional cerebral blood flow, suggesting that posterior cortical cholinergic synapse deficits are part of a generalized loss of synapses. The disproportionate decline in regional frontal cortical acetylcholinesterase activity relative to regional cerebral blood flow suggests preferential loss or dysregulation of cholinergic synapses in these regions. Our observations suggest that cortical cholinergic synapse vulnerability in Parkinson's disease is mediated by both diffuse processes affecting cortical synapses and processes specific to subpopulations of cortical cholinergic afferents.

Age and Anterior Basal Forebrain Volume Predict the Cholinergic Deficit in Patients with Mild Cognitive Impairment due to Alzheimer's Disease.

Early and severe neuronal loss in the cholinergic basal forebrain is observed in Alzheimer's disease (AD). To date, cholinomimetics play a central role in the symptomatic treatment of AD dementia. Although basic research indicates that a cholinergic deficit is present in AD before dementia, the efficacy of cholinomimetics in mild cognitive impairment (MCI) remains controversial. Predictors of cholinergic impairment could guide individualized therapy. To investigate if the extent of the cholinergic deficit, measured using positron emission tomography (PET) and the tracer 11C-N-methyl-4-piperidyl acetate (MP4A), could be predicted from the volume of cholinergic basal forebrain nuclei in non-demented AD patients. Seventeen patients with a high likelihood of MCI due to AD and 18 age-matched cognitively healthy adults underwent MRI-scanning. Basal forebrain volume was assessed using voxel-based morphometry and a cytoarchitectonic atlas of cholinergic nuclei. Cortical acetylcholinesterase (AChE) activity was measured using MP4A-PET. Cortical AChE activity and nucleus basalis of Meynert (Ch4 area) volume were significantly decreased in MCI. The extent of the cholinergic deficit varied considerably across patients. Greater volumes of anterior basal forebrain nuclei (Ch1/2 area) and younger age (Spearman's rho(17) = -0.596, 95% -CI [-0.905, -0.119] and 0.593, 95% -CI [0.092, 0.863])) were associated with a greater cholinergic deficit. Data suggest that less atrophy of the Ch1/2 area and younger age are associated with a more significant cholinergic deficit in MCI due to AD. Further investigations are warranted to determine if the individual response to cholinomimetics can be inferred from these measures.

Chronic Administration of Combined Oral Contraceptive Pill Causes Prefrontal Cortical Oxidative Stress in Female Wistar Rats

Combined oral contraceptive pill (COCP) is used by women to prevent ovulation. This study investigated toxicological effects of COCP on the brain of female rats. Fifteen rats were divided at random into three groups (n=5): Normal control, and first and second cycles treated orally with COCP (0.04 μg/kg bwt of ethinyl oestradiol and 2 μg/kg bwt levonorgestrel) daily for 21 and 42 days respectively. Toxicological effect of treatment on the brain was assessed in the prefrontal cortical acetylcholinesterase, sodium/potassium-ATPase (Na+/K+-ATPase), superoxide dismutase and catalase activities, lipid peroxidation and reduced glutathione levels. Histomorphological examination of the prefrontal cortex of the rats in all the groups was carried out. Activities of cortical Na+/K+-ATPase, acetylcholinesterase, superoxide dismutase and catalase were significantly (p&lt;0.05) reduced following chronic administration of COCP. Histomorphological study of the pre-frontal cortex showed large pyramidal neurons, pyknotic pyramidal neurons, condensed nuclei and increased perineural spaces. Results showed that chronic administration of oral contraceptive caused prefrontal cortical oxidative stress by repressing activities of antioxidant enzymes, Na+/K+-ATPase and acetylcholinesterase.

Cortical cholinergic dysfunction correlates with microglial activation in the substantia innominata in REM sleep behavior disorder

IntroductionIn vivo PET studies in patients with isolated REM sleep behavior disorder (iRBD) have shown presence of neuroinflammation (microglial activation) in the substantia nigra, and reduced cortical acetylcholinesterase activity, suggestive of cholinergic dysfunction, that was more widespread in patients with poorer cognitive performances. This study aimed to explore whether reduced cortical acetylcholinesterase activity in iRBD is linked to microglial activation in the substantia innominata (SI), the major source of cholinergic input to the cortex. MethodsWe used 11C(R)-PK11195 and 11C-Donepezil PET to assess levels of activated microglia and cholinergic function, respectively, in 19 iRBD patients. 11C(R)-PK11195 binding potential (BPND) and 11C-Donepezil distribution volume ratio (DVR) values were correlated using the Pearson statistic. ResultsWe found that a lower cortical 11C-Donepezil DVR correlated with a higher 11C(R)-PK11195 BPND in the SI (r = −0.48, p = 0.04). At a voxel level, the strongest negative correlations were found in the frontal and temporal lobes. ConclusionOur results suggest that reduced cortical acetylcholinesterase activity observed in our iRBD patients could be linked to the occurrence of neuroinflammation in the SI. Early modulation of microglial activation might therefore preserve cortical cholinergic functions in these patients.

Amelioration of diabetes-induced cognitive impairment by Transient Receptor Potential Vanilloid 2 (TRPV2) channel inhibitor: Behavioral and mechanistic study

Transient receptor potential (TRP) channels are Ca2+ permeable non-selective cation channels which play a pivotal role in diabetes and diabetic complications. Among diabetic complications, diabetes-induced cognitive impairment is a major CNS complication. The role of several TRP channels has been investigated extensively for their diverse Ca2+ regulating mechanism, and recently their role has been postulated in the progression of neurodegenerative disorders. However, the role of TRPV2 has not been investigated yet. Therefore, in the present study, the involvement of TRPV2 channels was investigated in diabetes-induced cognitive impairment using TRPV2 inhibitor, tranilast. High glucose exposure in rat C6 glial cells enhances the Ca2+-entry through TRPV2 channels. In our in-vivo study, diabetic rats showed increased gene and protein expression of TRPV2 in the hippocampus. Subsequent increase in the acetylcholinesterase activity in the cortex, as well as decrease in the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (p-CaMKII-Thr-286), p-GSK-3β (Ser-9), p-CREB (Ser-133) and postsynaptic density protein 95 (PSD-95) in the hippocampus were also observed this led to the impairment in the learning and memory as evident from behavioral parameters such as Morris water maze test, passive avoidance and Y-maze test paradigm. Three-week treatment with tranilast (30 and 100 mg/kg, p.o.) showed improvement in learning and memory associated behaviours (Morris water maze test, passive avoidance, and Y-maze test) by increasing the p-CaMKII (Thr-286), p-GSK-3β (Ser-9), p-CREB (Ser-133) and PSD-95 in the hippocampus. Cortical acetylcholinesterase activity was also reduced by the tranilast. These findings depicted that TRPV2 inhibition may be an effective treatment strategy in diabetes-induced cognitive deficits.

Antidepressant-like effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one in rats exposed to malathion: Involvement of BDNF-Trkβ pathway and AChE

BackgroundOrganophosphorus pesticides exert their toxic effects mainly by the inhibition of acetylcholinesterase (AChE), which is related to emotional disorders, such as depression. Atropine-oximes therapy is commonly used; however, the efficacy of oximes in the reactivation of AChE has been inconsistent. The objective of this study was to investigate the possible neuroprotective effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cℓ-HIN), a compound that combines the isatin and oxime functional groups, in rats exposed to malathion. The effect of Cℓ-HIN on the AChE activity and the BDNF-Trkβ pathway in the prefrontal cortex of malathion-exposed rats were tested. MethodsWistar male rats were co-treated with Cℓ-HIN [50 mg/kg (p.o.) (3 mL/kg)] and/or malathion [250 mg/kg (i.p.) (5 mL/kg)] and performed behavioral tests twelve hours after these exposures. ResultsThe Cℓ-HIN reversed the increased immobility time in the forced swimming test and the decreased grooming time in the splash test induced by malathion, but any significant difference was observed in locomotion analysis. These results demonstrate the antidepressant-like effect of Cℓ-HIN. The cortical AChE activity was reactivated by Cℓ-HIN in rats exposed to malathion. Malathion induced an increase in Trkβ and a decrease in BDNF levels in the prefrontal cortex of rats, which were avoided by Cℓ-HIN. ConclusionThese findings support the hypothesis that Cℓ-HIN is an AChE reactivator with antidepressant-like properties, which is related to the improvement of BDNF-Trkβ signaling after acute exposure to malathion in rats. Thus, the results allow suggesting the potential use of Cℓ-HIN as an oxime-based therapy against the neurotoxic effects of malathion.

Protocatechuic acid mitigates cadmium-induced neurotoxicity in rats: Role of oxidative stress, inflammation and apoptosis

Environmental and occupational exposure to heavy metals, including cadmium (Cd), is associated with extremely adverse impacts to living systems. Antioxidant agents are suggested to eliminate Cd intoxication. In this paper, we investigated the potential neuroprotective effect of protocatechuic acid (PCA) against Cd-induced neuronal damage in rats. Adult male Wistar rats were randomly divided into control, PCA (100 mg/kg)-treated, CdCl2 (6.5 mg/kg)-treated, and PCA and Cd treatment groups. Pre-treatment with PCA significantly reduced Cd concentrations and increased cortical acetylcholinesterase activity and brain derived neurotrophic factor. Additionally, PCA also prevented CdCl2-induced oxidative stress in the cortical tissue by preventing lipid peroxidation and the formation of nitric oxide (NO), and significantly enhancing antioxidant enzymes. Molecularly, PCA significantly up-regulated the antioxidant gene expression (Sod2, Cat, Gpx1, and Gsr) that was down-regulated by Cd. It should be noted that this effect was achieved by targeting the nuclear-related factor 2 (Nfe2l2) mRNA expression. PCA also prevented the Cd-induced inflammation by reducing the pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β. Moreover, PCA supplementation relieved the Cd-induced neuronal death by increasing Bcl-2 and decreasing Bax and Cas-3 levels in the cortical tissue. The improvement of the cortical tissue histopathology by PCA confirmed the biochemical and molecular data. Collectively, our findings indicate that PCA can counteract Cd-induced cortical toxicity by enhancing the antioxidant defense system and suppressing inflammation and apoptosis.

Red Beetroot Extract Abrogates Chlorpyrifos-Induced Cortical Damage in Rats.

Organophosphorus insecticides including chlorpyrifos (CPF) are mainly used for agriculture, household, and military purposes; their application is associated with various adverse reactions in animals and humans. This study was conducted to evaluate the potential neuroprotective effect of red beetroot methanolic extract (RBR) against CPF-induced cortical damage. Twenty-eight adult male Wistar albino rats were divided into 4 groups (n = 7 in each group): the control group was administered physiological saline (0.9% NaCl), the CPF group was administered CPF (10 mg/kg), the RBR group was administered RBR (300 mg/kg), and the RBR+CPF group was treated with RBR (300 mg/kg) 1 hr before CPF (10 mg/kg) supplementation. All groups were treated for 28 days. Rats exposed to CPF exhibited a significant decrease in cortical acetylcholinesterase activity and brain-derived neurotrophic factor and a decrease in glial fibrillary acidic protein. CPF intoxication increased lipid peroxidation, inducible nitric oxide synthase expression, and nitric oxide production. This was accompanied by a decrease in glutathione content and in the activities of glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase in the cortical tissue. Additionally, CPF enhanced inflammatory response, indicated by increased levels and expression of interleukin-1β and tumor necrosis factor-α. CPF triggered neuronal apoptosis by upregulating Bax and caspase-3 and downregulating Bcl-2. However, RBR reversed the induced neuronal alterations following CPF intoxication. Our findings suggest that RBR can minimize and prevent CPF neurotoxicity through its antioxidant, anti-inflammatory, and antiapoptotic activities.

Effect of cholinergic treatment depends on cholinergic integrity in early Alzheimer's disease.

In early Alzheimer's disease, which initially presents with progressive loss of short-term memory, neurodegeneration especially affects cholinergic neurons of the basal forebrain. Pharmacotherapy of Alzheimer's disease therefore often targets the cholinergic system. In contrast, cholinergic pharmacotherapy of mild cognitive impairment is debated since its efficacy to date remains controversial. We here investigated the relationship between cholinergic treatment effects and the integrity of the cholinergic system in mild cognitive impairment due to Alzheimer's disease. Fourteen patients with high likelihood of mild cognitive impairment due to Alzheimer's disease and 16 age-matched cognitively normal adults performed an episodic memory task during functional magnetic resonance imaging under three conditions: (i) without pharmacotherapy; (ii) with placebo; and (iii) with a single dose of rivastigmine (3 mg). Cortical acetylcholinesterase activity was measured using PET with the tracer 11C-N-methyl-4-piperidyl acetate (MP4A). Cortical acetylcholinesterase activity was significantly decreased in patients relative to controls, especially in the lateral temporal lobes. Without pharmacotherapy, mild cognitive impairment was associated with less memory-related neural activation in the fusiform gyrus and impaired deactivation in the posterior cingulate cortex, relative to controls. These differences were attenuated under cholinergic stimulation with rivastigmine: patients showed increased neural activation in the right fusiform gyrus but enhanced deactivation of the posterior cingulate cortex under rivastigmine, compared to placebo. Conversely, controls showed reduced activation of the fusiform gyrus and reduced deactivation of the posterior cingulate under rivastigmine, compared to placebo. In both groups, the change in neural activation in response to rivastigmine was negatively associated with local acetylcholinesterase activity. At the behavioural level, an analysis of covariance revealed a significant group × treatment interaction in episodic memory performance when accounting for hippocampal grey matter atrophy and function. Our results indicate that rivastigmine differentially affects memory-related neural activity in patients with mild cognitive impairment and cognitively normal, age-matched adults, depending on acetylcholinesterase activity as a marker for the integrity of the cortical cholinergic system. Furthermore, hippocampal integrity showed an independent association with the response of memory performance to acetylcholinesterase inhibition.

Effect of khat extract on young rat's memory

Consumption of khat is still pressing issue in Jazan region. The present study was imperative to know the effect of khat use on memory of young rats. The current study used rats in age comparable to adult humans that mimic the stages of education and grouped in four groups. 1-control normal, 2-scopolamine, 3-khat extract administered group for four weeks, 4- khat withdrawal group administered khat extract for four weeks then left for one week without khat administration. All groups of rats were trained using Morris water maze task before treatment then the behavioral test was performed after treatments and cortex acetylcholinesterase (AChE) enzyme activities were determined in all groups. The body weights were detected weekly. The study showed that khat extract impaired performance in the water maze test, increased cortical AChE activity and reduced the body weight in a time related manner, meanwhile khat withdrawals showed partial retention of the maze performance, reduction in AChE activity and body weight gain. The study knocks alarm on cognitive impairment due to khat consumption especially on youth.

Effect of canagliflozin and metformin on cortical neurotransmitters in a diabetic rat model

BackgroundThe rapid economic development in the Arabian Gulf has resulted in lifestyle changes that have increased the prevalence of obesity and type 2 diabetes, with the greatest increases observed in Kuwait. Dyslipidemia and diabetes are risk factors for disruptions in cortical neurotransmitter homeostasis. This study investigated the effect of the antidiabetic medications canagliflozin (CAN) and metformin (MET) on the levels of cortical neurotransmitters in a diabetic rat model. Materials and methodsThe rats were assigned to the control (C) group, the diabetic group that did not receive treatment (D) or the diabetic group treated with either CAN (10 mg/kg) or MET (100 mg/kg) for 2 or 4 weeks. Blood and urine glucose levels and cortical acetylcholinesterase (AChE) activity were assayed, and amino acid and monoamine levels were measured using HPLC. ResultsThe diabetic group exhibited a significant increase in AChE activity and a decrease in monoamine and amino acid neurotransmitter levels. In the CAN group, AChE was significantly lower than that in the D and D + MET groups after 2 weeks of treatment. In addition, a significant increase in some cortical monoamines and amino acids was observed in the D + MET and D + CAN groups compared with the D group. Histopathological analysis revealed the presence of severe focal hemorrhage, neuronal degeneration, and cerebral blood vessel congestion, with gliosis in the cerebrum of rats in the D group. The CAN-treated group exhibited severe cerebral blood vessel congestion after 2 weeks of treatment and focal gliosis in the cerebrum after 4 weeks of treatment. Focal gliosis in the cerebrum of rats in the MET-treated group was observed after 2 and 4 weeks of treatment. ConclusionsWe conclude that the effect of CAN and MET on neurotransmitters is potentially mediated by their antihyperglycemic and antihyperlipidemic effects. In addition, the effects of CAN on neurotransmitters might be associated with its receptor activity, and the effect of MET on neurotransmitters might be associated with cerebral metabolism.

Dopaminergic and Cholinergic Brain Activity and Performance on MMSE and MoCA in Parkinson's Disease (P03.127)

Objective: To investigate the relationship between performance on the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Exam (MMSE) and PET measures (dopaminergic/cholinergic) of brain activity. Background Executive dysfunction seen in early Parkinson9s disease (PD) is believed to result from striatal dopaminergic denervation, while the degree of cognitive impairment in PD dementia is thought to correlate with cortical cholinergic activity. Because it contains tasks that evaluate executive function, performance on the MoCA may correlate more strongly with striatal dopaminergic activity, while performance on the MMSE may better correlate with cortical cholinergic activity. Design/Methods: 19 non-demented men with PD (mean age 66.4 ± 7.5; mean disease duration 5.7 ± 3.5 years) underwent (+)-[ 11 C] dihydrotetrabenazine (DTBZ) vesicular monoamine transporter 2 and [ 11 C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging as well as the Unified PD Rating Scale (UPDRS), MoCA and MMSE. Results: Stepwise regression analysis was performed, with MoCA or MMSE as the dependent variable and the PET measures (cortical PMP, basal ganglia, putamen and caudate DTBZ) as regressors. Results for the MOCA show that cortical PMP was the only variable that met entry criteria in the model (F=6.12, P=0.024). The DTBZ measures did not meet entry criteria. Similar results were seen for the MMSE, with the cortical PMP variable as the only significant variable in the model (F=5.76, P=0.028). Conclusions: Both MoCA and MMSE performance were associated with cortical AChE activity in PD patients. Surprisingly, we did not find a significant relationship between the MoCA and striatal dopaminergic denervation, but we may not have had the power to detect such a relationship. Nevertheless, these findings suggest that both the MoCA and the MMSE may be reliable measures of the cognitive decline attributable to cortical cholinergic denervation seen in early PD. Supported by: NIH P01 NS15655, NIH R01 NS070856 (PI), and a grant from the Department of Veterans Affairs. Disclosure: Dr. Lenhart has nothing to disclose. Dr. Bohnen has nothing to disclose. Dr. Koeppe has nothing to disclose. Dr. Chou has received personal compensation for activities with Medtronic, Inc. and Merz Pharma.

Cerebral acetylcholinesterase activity is not decreased in MS patients with cognitive impairment

Background: Neuropsychological studies have extensively described the presence of cognitive dysfunction in MS patients. One possible pharmacological treatment of the impairment could be based on acetylcholinesterase inhibitors (AChEIs), which have shown efficacy in alleviating cognitive impairment in many other disorders. The findings on the efficacy of AChEI medication in MS associated cognitive symptoms are preliminary and no studies concerning cerebral acetylcholinesterase (AChE) activity in these patients have been published. Objective: The objective of the study was to examine cerebral AChE activity in cognitively deteriorated MS patients. Cerebral AChE activity of 10 MS patients with secondary progressive disease and marked cognitive impairment, and 10 healthy controls, was studied with positron emission tomography using tracer 11C-MP4A. Methods: The cognitive profile of the patients was assessed with CERAD (Consortium to Establish a Registry for Alzheimer’s Disease). Results: No differences in cortical AChE activity between MS patients and controls were seen. Conclusions: In the patient group regional AChE activities had inverse correlations with Word learning and MMSE (Mini-Mental State Examination) scores. In the group of cognitively deteriorated MS patients no change in cerebral AChE activity, compared with controls, was observed, but within the patient group more pronounced cognitive symptoms were associated with higher cerebral AChE activity.

Cholinergic system function and cognition in mild cognitive impairment

Evidence for cholinergic dysfunction in very early stages of neurodegeneration like mild cognitive impairment (MCI) is inconclusive. Previous positron emission tomography (PET) studies based on small samples investigated if it is related to memory impairment. We examined whether cortical acetylcholine esterase (AChE) activity is reduced at this stage and correlated with cognitive function. N-[11C]-methyl-4-piperidyl acetate ([11C]MP4A), a positron emission tomography tracer for measuring cerebral AChE activity in vivo, was applied in 21 controls and 17 MCI patients. Parametric images of AChE activity were analyzed using standard atlas regions. Principal components analysis (PCA) of regional values of AChE activity and correlation analysis with neuropsychological test results was performed. Cortical AChE activity showed a significant decline in MCI patients compared with controls which was most pronounced in temporal regions. They formed the main part of a principal component that was related significantly to verbal and nonverbal memory, language comprehension and executive function. Cholinergic dysfunction is an early hallmark even before onset of dementia at the clinical stage of MCI. Its impact especially on temporal neocortex is associated with impaired neuropsychological function.

Lewy Body Disease With Dementia can be Well-Differentiated from Alzheimer's Disease By Measurement of Cerebral Cortical Acetylcholinesterase Activity by PET

Lewy Body Disease With Dementia can be Well-Differentiated from Alzheimer's Disease By Measurement of Cerebral Cortical Acetylcholinesterase Activity by PET

Lewy body disease with dementia can be well-differentiated from Alzheimer's disease by measurement of cerebral cortical acetylcholinesterase activity by PET

IC-P-017 LEWY BODY DISEASE WITH DEMENTIA CAN BE WELL-DIFFERENTIATED FROM ALZHEIMER’S DISEASE BY MEASUREMENT OF CEREBRAL CORTICAL ACETYLCHOLINESTERASE ACTIVITY BY PET Hitoshi Shimada, Hitoshi Shinotoh, Shigeki Hirano, Michie Miyoshi, Koichi Sato, Noriko Tanaka, Tsuneyoshi Ota, Masato Asahina, Akiyo Aotsuka, Kiyoshi Fukushi, Hiroshi Ito, Satoshi Kuwabara, Toshiaki Irie, Tetsuya Suhara, Molecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Section for Human Neurophysiology, Research Center for Frontier Medical Engineering, Chiba University, Chiba, Japan; Asahi Hospital for Neurological Diseases and Rehabilitation, Chiba, Japan; Department of Neurology, JR Tokyo General Hospital, Tokyo, Japan; Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Hiroshima, Japan; Department of Psychiatry, Ichihara Hospital, Teikyo University School of Medicine, Chiba, Japan; Department of Neurosurgery, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan; Department of Psychiatry, Juntendo University School of Medicine, Tokyo, Japan; Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan; Molecular Probe Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Department of Rehabilitation Medicine, Chiba Aoba Municipal Hospital, Chiba, Japan. Contact e-mail: shim@alpha.ocn.ne.jp

Cholinergic imaging in corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia

Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders. We measured brain acetylcholinesterase activity by [11C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6+/-5.9 years), 12 with progressive supranuclear palsy (68.5+/-4.1 years), eight with frontotemporal dementia (59.8+/-6.9 years) and 16 healthy controls (61.2+/-8.5 years). Two-tissue compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k3 value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k3 images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k3 images. The corticobasal syndrome group showed decreased acetylcholinesterase activity (k3 values) in the paracentral region, frontal, parietal and occipital cortices (P<0.05, cluster corrected). The group with progressive supranuclear palsy had reduced acetylcholinesterase activity in the paracentral region and thalamus (P<0.05, cluster corrected). The frontotemporal dementia group showed no significant differences in acetylcholinesterase activity. Volume of interest analysis showed mean cortical acetylcholinesterase activity to be reduced by 17.5% in corticobasal syndrome (P<0.001), 9.4% in progressive supranuclear palsy (P<0.05) and 4.4% in frontotemporal dementia (non-significant), when compared with the control group. Thalamic acetylcholinesterase activity was reduced by 6.4% in corticobasal syndrome (non-significant), 24.0% in progressive supranuclear palsy (P<0.03) and increased by 3.3% in frontotemporal dementia (non-significant). Both corticobasal syndrome and progressive supranuclear palsy showed brain cholinergic deficits, but their distribution differed somewhat. Significant brain cholinergic deficits were not seen in frontotemporal dementia, which may explain the unresponsiveness of this condition to cholinergic modulation therapy.

Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson's disease

Olfactory dysfunction is common in subjects with Parkinson’s disease. The pathophysiology of such dysfunction, however, remains poorly understood. Neurodegeneration within central regions involved in odour perception may contribute to olfactory dysfunction in Parkinson’s disease. Central cholinergic deficits occur in Parkinson’s disease and cholinergic neurons innervate regions, such as the limbic archicortex, involved in odour perception. We investigated the relationship between performance on an odour identification task and forebrain cholinergic denervation in Parkinson’s disease subjects without dementia. Fifty-eight patients with Parkinson’s disease (mean Hoehn and Yahr stage 2.5 ± 0.5) without dementia (mean Mini-Mental State Examination, 29.0 ± 1.4) underwent a clinical assessment, [11C]methyl-4-piperidinyl propionate acetylcholinesterase brain positron emission tomography and olfactory testing with the University of Pennsylvania Smell Identification Test. The diagnosis of Parkinson’s disease was confirmed by [11C]dihydrotetrabenazine vesicular monoamine transporter type 2 positron emission tomography. We found that odour identification test scores correlated positively with acetylcholinesterase activity in the hippocampal formation (r = 0.56, P < 0.0001), amygdala (r = 0.50, P < 0.0001) and neocortex (r = 0.46, P = 0.0003). Striatal monoaminergic activity correlated positively with odour identification scores (r = 0.30, P < 0.05). Multiple regression analysis including limbic (hippocampal and amygdala) and neocortical acetylcholinesterase activity as well as striatal monoaminergic activity, using odour identification scores as the dependent variable, demonstrated a significant regressor effect for limbic acetylcholinesterase activity (F = 10.1, P < 0.0001), borderline for striatal monoaminergic activity (F = 1.6, P = 0.13), but not significant for cortical acetylcholinesterase activity (F = 0.3, P = 0.75). Odour identification scores correlated positively with scores on cognitive measures of episodic verbal learning (r = 0.30, P < 0.05). These findings indicate that cholinergic denervation of the limbic archicortex is a more robust determinant of hyposmia than nigrostriatal dopaminergic denervation in subjects with moderately severe Parkinson's disease. Greater deficits in odour identification may identify patients with Parkinson's disease at risk for clinically significant cognitive impairment.