Early-onset mild cognitive impairment in Parkinson's disease: Altered corticopetal cholinergic network.

Degeneration of the substantia innominata (SI) is significantly correlated with cognitive performance in Parkinson's disease (PD). We examined functional and structural patterns of SI degeneration in drug-naïve PD patients according to the duration of parkinsonism before mild cognitive impairment (MCI) diagnosis. Twenty PD patients with a shorter duration (PD-MCI-SD, <1 year), 18 patients with a longer duration (PD-MCI-LD, ≥1 year), and 29 patients with intact cognition (PD-IC) were included. Seed-based resting-state functional connectivity (rsFC) analysis using bilateral SI seed and region-of-interest-based volumetric analysis were performed. Compared to PD-IC, the collapsed PD-MCI group showed altered rsFC in the right frontal and bilateral parietal areas. PD-MCI-SD showed rsFC alteration in broader frontal and parietal areas compared to the other groups. Decreased rsFC in the right frontal area was also significantly correlated with shorter disease duration. No significant SI volume change was found between the groups. Altered rsFC between the SI and the frontal and parietal areas might be relevant to cognitive dysfunction in PD. Decreased rsFC between the SI and frontal area might be associated with early-onset MCI, suggesting that cholinergic deficits in the frontal brain areas might play an important role in the acceleration of cognitive decline in PD.

Effect of nucleus basalis magnocellularis cholinergic lesions on fear-like and anxiety-like behavior.

Previous research has suggested that cholinergic neurons in the nucleus basalis magnocellularis and substantia innominata (NBM/SI) may be important in mediating aversive states. The authors investigated the effect of NBM/SI cholinergic lesions, induced with 192 IgG saporin, on behavioral measures of aversive states in rats. Behavior in the elevated plus maze and behavioral suppression induced by 2 fear-conditioned stimuli, a tone and a light, were evaluated. Lesions had no effect on any measures in the elevated plus maze but attenuated operant suppression induced by the light and attenuated freezing induced by the tone, though this last effect was not statistically significant. The results of the study suggest that NBM/SI cholinergic neurons may be important in mediating selective aspects of aversive states.

Increased brain levels of 4-hydroxy-2-nonenal glutathione conjugates in severe Alzheimer's disease.

In the last decade an important role for the progression of neuronal cell death in Alzheimer's disease (AD) has been ascribed to oxidative stress. trans-4-Hydroxy-2-nonenal, a product of lipid peroxidation, forms conjugates with a variety of nucleophilic groups such as thiols or amino moieties. Here we report for the first time the quantitation of glutathione conjugates of trans-4-hydroxy-2-nonenal (HNEGSH) in the human postmortem brain using the specific and very sensitive method of electrospray ionization triple quadrupole mass spectrometry (ESI-MS-MS). Levels of HNEGSH conjugates calculated as the sum of three chromatographically separated diastereomers were determined in hippocampus, entorhinal cortex, substantia innominata, frontal and temporal cortex, as well as cerebellum from patients with AD and controls matched for age, gender, postmortem delay and storage time. Neither age, nor postmortem delay, nor storage time did correlate with levels of HNEGSH conjugates which ranged between 1 and 500 pmol/g fresh weight in the brain areas examined. The brain specimen from patients with clinically and neuropathologically probable AD diagnosed according to criteria of the consortium to establish a registry for AD (CERAD) show increased levels of HNEGSH in the temporal and frontal cortex, as well as in the substantia innominata. Classification of disease severity according to Braak and Braak, which takes into consideration the amount of neurofibrillary tangles and neuritic plaques, revealed highest levels of HNEGSH in the substantia innominata and the hippocampus, two brain regions known to be preferentially affected in AD. These results substantiate the link between conjugates of glutathione with a product of lipid peroxidation and Alzheimer's disease and justify further studies to evaluate the role of HNE metabolites as potential biomarkers for disease progression in AD.

Cu, Zn- and Mn-superoxide dismutase levels in brains of patients with schizophrenic psychosis.

Impaired oxidative stress defense has been reported in blood of both drug-naïve and antipsychotic-treated patients suffering from schizophrenic psychosis, indicating the involvement of free radical metabolism in the pathogenetic processes of schizophrenia. In this study, the concentrations of two isoenzymes of superoxide dismutase (SOD), Cu, Zn- and MnSOD, were determined with ELISA in various cortical (frontal, parietal, temporal and occipital cortex) and subcortical areas (putamen, caudate nucleus, thalamus, and substantia innominata) of post-mortem brain tissue from patients diagnosed with a schizophrenia spectrum disorder and compared with those of controls. Post-mortem brain tissue from individuals without neuropsychiatric disorders served for control. Cu, Zn- and MnSOD levels were significantly increased in frontal cortex and substantia innominata of the index group, respectively. In all other areas both types of SOD remained virtually unchanged. Detection of SOD changes in the brain supports previous reports of alterations of antioxidant indices in blood cells of patients with schizophrenia and suggests a specific neuroanatomical distribution pattern of oxidative stress processes possibly related to the pathophysiology of schizophrenia.

Neuron loss in key cholinergic and aminergic nuclei in Alzheimer disease: a meta-analysis.

Cell counts in the cholinergic nucleus basalis (NB), noradrenergic locus coeruleus (LC), dopaminergic substantia nigra (SN), and the serotonergic dorsal raphe nucleus (DRN) were assessed from primary-level reports in patients with Alzheimer disease (AD) and in controls. Sixty-seven studies that covered about 20 years were included in the meta-analysis. Effect sizes were computed as a standardized mean difference (d) in cell counts between AD and controls. Effect sizes were largest in magnitude for the NB (mean d=2.48, 33 studies, N=585), and the LC (d=2.28, 24 studies, N=545), then the DRN (d=1.79, 11 studies, N=234), and were smallest for the SN (d=0.61, 14 studies, N=440). In general, the overall effect size estimates for the four cell areas were reliable. Using effect size magnitude in the SN as a referent, cell loss was about three times greater in the DRN and four times greater in the NB and LC. Symptomatic drug treatment for AD might be beneficially directed toward ameliorating multiple neurotransmitter deficiencies, particularly cholinergic and noradrenergic.

Atrophy of the substantia innominata on magnetic resonance imaging and response to donepezil treatment in Alzheimer's disease.

Atrophy of the substantia innominata on magnetic resonance imaging (MRI), reflecting degeneration of cholinergic neurons in the nucleus basalis of Meynert, may be an in vivo marker of cholinergic damage. We attempted to investigate whether the MRI features of the substantia innominata predict response to donepezil treatment in Alzheimer's patients. The thickness of the substantia innominata was measured on the coronal T2-weighted MRI through the anterior commissure. Seventy-two patients treated with donepezil were divided into the two groups (responders and non-responders) based on changes in Mini-Mental State Examination (MMSE) scores from baseline to study endpoint. Atrophy of the substantia innominata was more pronounced in responders than non-responders. There was a significant inverse correlation between thickness of the substantia innominata and MMSE changes. MRI analysis of the substantia innominata may be a simple and practical method for the selection of possible treatment responders.

A possible selective impairment of magnocellular function in compression of the anterior visual pathways.

Two parallel visual systems, the magnocellular (M) and parvocellular (P) pathways, originate from different types of retinal ganglion cells, and are known to be segregated in different portions of the pregeniculate visual pathways. Their relative contribution to two main cortical streams, dorsal and ventral, is still under discussion, but it is reasonable to suppose that selective damage to the M or P subcortical system might interfere with specific aspects of processing within one or the other cortical system. Using two different apparent-motion tasks, we compared the performance of patients affected by compression of the ventral part of the pregeniculate visual pathways with that of normal controls. In the first task, observers detected small displacements of a low-contrast vertical bar, while in the second task they estimated the visible persistence of moving dots. In the first task, patients were impaired with parafoveal displays, especially in the temporal portion of the visual field. In the second task, patients showed reduced suppression of visible persistence at long, but not at short, exposure durations. Three considerations support the hypothesis that these results represent a selective impairment of the M system. First, M axons are more likely to suffer from compression, particularly in the case of a mass growing from below since they are known to occupy a ventral subpial position in the optic chiasm and tract. Second, the performance of patients with a ventral compression is consistent with the characteristics of the response properties of P ganglion cells, which have previously been shown to exhibit elevated and unmodulated thresholds for displacement detection in the macaque monkey. Third, such patients are less sensitive to the inhibitory signals that suppress visible persistence, which probably originate in the M system.

The effect of sequential lesioning in the basal forebrain on cerebral cortical glucose metabolism in rats. An animal positron emission tomography study.

We studied the effect of the cortical projection from the basal forebrain on the cerebral cortical metabolism using positron emission tomography (PET) with [(18)F] fluorodeoxyglucose. Unilateral damage of the nucleus basalis magnocellularis (NBM) did not cause a permanent reduction of cortical metabolism: recovery was observed 4 weeks after the operation. Destruction of the contralateral side after recovery from unilateral damage produced persistent bilateral suppression of glucose metabolism, with partial recovery. We speculate that recovery from the unilateral NBM lesions is partly ascribable to the cholinergic projection from the contralateral NBM, and partly due to non-cholinergic systems, and conclude that bilateral damage might be responsible for persistent cortical glucose metabolism suppression.

Impaired visual search in dyslexia relates to the role of the magnocellular pathway in attention.

We tested the hypothesis that in a cluttered visual scene, the magnocellular (M) pathway is crucial for focusing attention serially on the objects in the field. Since developmental dyslexia is commonly associated with an M pathway deficit, we compared reading impaired children and age-matched normal readers in a search task that required the detection of a target defined by the conjunction of two features, namely form and colour, that are processed by the parvocellular dominated ventral neocortical stream. The dyslexic group's performance was significantly poorer than the controls when there were a large number of distractor items. The scheme of selective attention proposed from these results provides a neural mechanism that underlies reading and explains the pathophysiology of dyslexia.

N-Methyl-D-aspartate receptor antagonist MK-801 and radical scavengers protect cholinergic nucleus basalis neurons against beta-amyloid neurotoxicity.

Previous experimental data indicate the involvement of Ca(2+)-related excitotoxic processes, possibly mediated by N-Methyl-D-Aspartate (NMDA) receptors, in beta-amyloid (beta A) neurotoxicity. On the other hand, other lines of evidence support the view that free radical generation is a critical step in the beta A-induced neurodegenerative cascade. In the present study, therefore, a neuroprotective strategy was applied to explore the contributions of each of these pathways in beta A toxicity. beta A(1-42) was injected into the magnocellular nucleus basalis of rats, while neuroprotection was achieved by either single or combined administration of the NMDA receptor antagonist MK-801 (2.5 mg/kg) and/or a vitamin E and C complex (150 mg/kg). The degree of neurodegeneration was determined by testing the animals in consecutive series of behavioral tasks, including elevated plus maze, passive avoidance learning, small open-field and open-field paradigms, followed by acetylcholinesterase (AChE), choline-acetyltransferase (ChAT), and superoxide dismutase (SOD) biochemistry. beta A injected in the nucleus basalis elicited significant anxiety in the elevated plus maze, derangement of passive avoidance learning, and altered spontaneous behaviors in both open-field tasks. A significant decrease in both AChE and ChAT accompanied by a similar decrement of MnSOD, but not of Cu/ZnSOD provided neurochemical substrates for the behavioral changes. Each of the single drug administrations protected against the neurotoxic events, whereas the combined treatment failed to ameliorate beta A toxicity.

Anxiolytic-like action of neurokinin substance P administered systemically or into the nucleus basalis magnocellularis region.

There is evidence that the neurokinin substance P plays a role in neural mechanisms governing learning and reinforcement. Reinforcing and memory-promoting effects of substance P were found after it was injected into several parts of the brain and intraperitoneally. With regard to the close link between anxiety and memory processes for negative reinforcement learning, the aim of the present study was to gauge the effect of substance P on anxiety-related behaviors in the rat elevated plus-maze and social interaction test. Substance P was tested at injection sites where the neurokinin has been shown to promote learning and to serve as a reinforcer, namely in the periphery (after i.p. administration) and after injection into the nucleus basalis magnocellularis region. When administered i.p., substance P had a biphasic dose-response effect on behavior in the plus-maze with an anxiolytic-like action at 50 microg/kg and an anxiogenic-like one at 500 microg/kg. After unilateral microinjection into the nucleus basalis magnocellularis region, substance P (1 ng) was found to exert anxiolytic-like effects, because substance P-treated rats spent more time on the open arms of the plus-maze and showed an increase in time spent in social interaction. Furthermore, the anxiolytic effects of intrabasalis substance P were sequence-specific since injection of a compound with the inverse amino acid sequence of substance P (0.1 to 100 ng) did not influence anxiety parameters. These results show that substance P has anxiolytic-like properties in addition to its known promnestic and reinforcing effects, supporting the hypothesis of a close relationship between anxiety, memory and reinforcement processes.

The cholinergic deficit in Alzheimer's disease.

The history of the discovery of cholinergic deficit in Alzheimer's disease is briefly reviewed, focusing on the cholinergic basal forebrain. The anatomy of the structure is discussed, and the clinical implications of pathology in this population of nerve cells are presented.

Effects of lesions of the Substantia Innominata/Ventral Pallidum, globus pallidus and medial septum on rat's performance in object-recognition and radial-maze tasks: physostigmine and amphetamine treatments.

The present study examined the effects of electrolytic lesions of the Medial Septum/Vertical Diagonal Band of Broca (MS/VDBB), the Globus Pallidus (GP) and the Substantia- Innominata/Ventral Pallidum (SI/VP) on the performance of rats in object-recognition memory and radial-maze learning tests. In the latter test, subgroups of sham-operated, MS/VDBB, SI/VP and GP rats were treated with saline, amphetamine or physostigmine. (1) In the object recognition task, the level of discrimination wa s significantly lower in GP compared to SI/VP and in both GP and SI/VP compared to Control and MS/VDBB groups, however, only GP did not discriminate between new and familiar objects; (2) in the radial-maze task, GP and SI/VP lesions produced weak and tran sient impairment whereas MS/VDBB lesions produced a large deficit; (3) in the radial-maze task, performance of normal rats was improved with physostigmine and impaired with amphetamine. The effect of amphetamine was significant on non-memory measures only; (4) neither amphetamine nor physostigmine improved memory performances of lesioned rats. These results suggest that the septo-hippocampal projections are involved in spatial memory but not in object recognition whereas the integrity of Substantia Inno minata/Ventral Pallidum does not seem critical for either task. The cholinergic nature of the deficit produced by the medial septal lesion remains in question because of improvements seen in sham-operated rats but not in lesioned rats.

Aggravated decrease in the activity of nucleus basalis neurons in Alzheimer's disease is apolipoprotein E-type dependent.

As reported before, the metabolic activity of nucleus basalis neurons is reduced significantly in Alzheimer patients. Because the apolipoprotein E (ApoE) epsilon4 genotype is a major risk factor for Alzheimer's disease (AD), we determined whether the decrease in metabolic activity in nucleus basalis neurons in AD is ApoE-type dependent. The size of the Golgi apparatus (GA) was determined as a measure of neuronal metabolic activity in 30 controls and 41 AD patients with a known ApoE genotype by using an image analysis system in the nucleus basalis of Meynert. A polyclonal antibody directed against MG-160, a sialoglycoprotein of the GA, was used to visualize this organelle. There was a very strong reduction in the size of the GA in the nucleus basalis of AD patients. Furthermore, a strong and significant extra reduction in the size of the GA was found in the nucleus basalis neurons of AD patients with either one or two ApoE epsilon4 alleles compared with Alzheimer patients without ApoE epsilon4 alleles. Our data show that the decreased activity of nucleus basalis neurons in AD is ApoE epsilon4 dependent and suggest that ApoE epsilon4 participates in the pathogenesis of AD by decreasing neuronal metabolism.

Learning and memory in nucleus basalis magnocellularis-lesioned rats after transplantation of fetal frontal cortex.

The effect of fetal frontal cortex transplantation on behaviour performance was examined in adult male Wistar rats with lesions of the nucleus basalis magnocellularis (NBM). Compared to intact and sham-operated controls, the rats tested ten or twenty days after bilateral electrolytic lesions of NBM exhibited the significant learning and memory impairments (acquisition and performance of two-way active avoidance) whereas spontaneous motor activity was not significantly altered. The animals which received allotransplants of fetal frontal cortex (from 18-day gestational rat fetuses) into NBM, two ("early" transplantation-NBM-ET) or ten ("delayed" transplantation-NBM-DT) days after lesioning, respectively, manifested the complete amelioration of noticed impairments when tested ten days after transplantation procedure. Corresponding sham-transplants groups (NBM-SET and NBM-SDT) showed only slightly improvement of acquisition but not performance of two-way active avoidance. The ability of the transplants to restore learning and memory in the NBM lesioned rats suggests that graft of fetal frontal cortex can functionally influence neuronal activity of the lesioned host brain.

Open field behavior in nucleus basalis magnocellularis-lesioned rats treated with physostigmine and verapamil.

The present study was done to investigate and compare the effect of acetylcholinesterase inhibitor, physostigmine (0.030, 0.045, 0.060 and 0.075 mg/kg sc) and Ca-antagonist, verapamil (1.0, 2.5, 5.0 and 10.0 mg/kg sc) on open field behavior in male Wistar rats with bilateral electrolytic lesions of nucleus basalis magnocellularis (NBM). NBM-lesions produced a significant increase and decrease of ambulation and number of inner squares entered, and defecation, respectively, with no influence on grooming in rats exposed to novel environment. Physostigmine and verapamil in all tested doses, given 30 min before the test did not affect the open field behavior in control animals. In contrast to that, physostigmine (0.045, 0.060 and 0.075 mg/kg) and verapamil (2.5 and 5.0 mg/kg) significantly reduced ambulation and number of inner squares entered in NBM-lesioned rats. Also, physostigmine in a dose of 0.060 mg/kg significantly decreased defecation and in doses of 0.060 and 0.075 mg/kg the grooming, as well. On the other hand, verapamil only in a dose of 2.5 mg/kg significantly increased defecation. It could be concluded that lesions of NBM in rats induced disturbances in the open field behavior, which might be successfully ameliorate by physostigmine and verapamil treatment.

Expression of Bcl-2 in adult human brain regions with special reference to neurodegenerative disorders.

The expression of the protooncogene bcl-2, an inhibitor of apoptosis in various cells, was examined in the adult human brain. Several experimental criteria were used to verify its presence; mRNA was analyzed by northern blot with parallel experiments in mouse tissues, by RNase protection, and by in situ hybridization histochemistry. Bcl-2 protein was detected by western blot analysis and immunohistochemistry. Two bcl-2 mRNA species were identified in the human brain. The pattern of distribution of bcl-2 mRNA at the cellular level showed labeling in neurons but not glia. The in situ hybridization signal was stronger in the pyramidal neurons of the cerebral cortex and in the cholinergic neurons of the nucleus basalis of Meynert than in the Purkinje neurons of the cerebellum. Both melanized and nonmelanized neurons were labeled in the substantia nigra. In the striatum, bcl-2 mRNA was detected in some but not all neurons. In the regions examined for Bcl-2 protein, the expression pattern correlated with the mRNA results. In patients with Alzheimer's and Parkinson's diseases, quantification of bcl-2 mRNA in the nucleus basalis of Meynert and substantia nigra, respectively, showed that the expression was unaltered compared with controls, raising the possibility that the expression of other components of apoptosis is modulated.

GTS-21, a nicotinic agonist, protects against neocortical neuronal cell loss induced by the nucleus basalis magnocellularis lesion in rats.

Effect of subchronically administered GTS-21 [3-(2,4-dimethoxybenzylidene)-anabaseine dihydrochloride], a selective nicotinic agonist, on neuronal cell loss caused by nucleus basalis magnocellularis (nBM) lesion was studied in rats. After 2 weeks of bilateral nBM excitotoxic lesion, GTS-21 was orally administered once daily for 20 weeks. Neuronal cell loss was observed in layers II-III of the parietal cortex in the lesioned control rats. GTS-21 significantly attenuated the neuron loss in these layers. These results suggest that GTS-21 exhibits a protective action against the neuronal cell death in the parietal cortex and may have a beneficial effect on neurodegenerative disorders such as an Alzheimer-type disease.