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At least 649 records · Page 36Linked to original sources
PubMed2003

What causes mental dysfunction in Parkinson's disease?

Parkinson's disease (PD) is frequently associated with mental dysfunction. Domain-specific cognitive deficits are ubiquitous, and although they may not be clinically apparent in all patients, they are demonstrable by neuropsychological testing. Dementia is less frequent but is present significantly more in PD patients than in controls, with a cumulative prevalence rate up to 40% and up to six-fold increased incidence. Cognitive impairment mainly involves executive and visuospatial functions; memory is secondarily impaired with relatively preserved recognition. Qualitatively, the neuropsychological profile of dementia encompasses the same type of deficits found in nondemented PD patients. The dementia seen in PD, therefore, can be described as a dysexecutive syndrome combined with visuospatial dysfunction and behavioural symptoms. Dopaminergic, noradrenergic, serotoninergic, and cholinergic deficits have all been described as the underlying neurochemical impairment, but the strongest evidence exists for a cholinergic dysfunction. Involvement of brainstem nuclei, limbic structures, and cerebral cortex have been suggested as the site, and Lewy body (LB) degeneration and Alzheimer-type changes as the type of pathology underlying the mental dysfunction in PD. Although there is still some controversy as to the site and type of pathology, recent evidence suggests that LB-type degeneration in limbic structures and cerebral cortex, with consequent synaptic and cell loss, is the main pathological state associated with dementia in PD.

Brain↗
PubMed2005

Post-lesion transcommissural olivocerebellar reinnervation improves motor function following unilateral pedunculotomy in the neonatal rat.

In the adult mammalian central nervous system, reinnervation and recovery from trauma are limited. During development, however, post-lesion plasticity may generate alternate paths providing models to investigate reinnervation and repair. Sometimes, these paths are maladaptive, although the relationship between dysfunction and anatomical abnormality remains unknown. After unilateral transection of the neonatal rat olivocerebellar path (pedunculotomy), axons from the remaining inferior olive reinnervate Purkinje cells in the denervated hemicerebellum with appropriate topography and synaptic function. However, whether this new pathway confers beneficial behavioural effects remains unknown. We studied the behavioural sequelae in rats with and without transcommissural reinnervation using righting and vestibular-drop reflexes, simple locomotion (bridge), complex locomotion (wire) and motor coordination (rotarod) tests. In animals pedunculotomised on day 3 (Px3), which develop olivocerebellar reinnervation, dynamic postural adjustments and complex motor skills develop normally, whereas simple gait is broad-based and slightly delayed. In contrast, Px11 animals, which do not develop reinnervation, have delayed maturation of postural reflexes, gait and complex locomotor skills. In addition, when compared to control animals, their performance in locomotory tasks was slower and the complex task impaired. On the rotarod, control and Px3 animals learned to coordinate their gait and walked for longer at 10 and 20 rpm than Px11 animals. These results show that transcommissural olivocerebellar reinnervation is associated with almost normal motor development and the ability to synchronise gait at slow and moderate speeds, i.e. this reinnervation confers significant behavioural function and is therefore truly compensatory.

Age Factors↗
PubMed2006

Phasic dopaminergic transmission increases NO efflux in the rat dorsal striatum via a neuronal NOS and a dopamine D(1/5) receptor-dependent mechanism.

Dysfunctional neurotransmission within striatal networks is believed to underlie the pathophysiology of several neurological and psychiatric disorders. Nitric oxide (NO)-producing interneurons have been shown to play a critical role in modulating striatal synaptic transmission. These interneurons receive synaptic contacts from midbrain dopamine (DA) neurons and may be regulated by DA receptor activation. In the current study, striatal NO efflux was measured in anesthetized male rats using an NO-selective electrochemical microsensor and the role of DA in modulating NO synthase (NOS) activity was assessed during electrical or chemical (bicuculline) stimulation of the substantia nigra (SN). Electrical stimuli were patterned to approximate the natural single spike or burst firing activity of midbrain DA neurons. Electrical stimulation of the SN at low frequencies induced modest increases in striatal NO efflux. In contrast, train stimulation of the SN robustly increased NO efflux in a stimulus intensity-dependent manner. NO efflux evoked by SN stimulation was similar in chloral hydrate- and urethane-anesthetized rats. The facilitatory effect of train stimulation on striatal NO efflux was transient and attenuated by systemic administration of the neuronal NOS inhibitor 7-nitroindazole and the nonselective NOS inhibitor methylene blue. Moreover, the increase in NO efflux observed during chemical and train stimulation of the SN was attenuated following systemic administration of the DA D(1/5) receptor antagonist SCH 23390. SCH 23390 also blocked NO efflux induced by systemic administration of the D(1/5) agonist SKF 81297. These results indicate that neuronal NOS is activated in vivo by nigrostriatal DA cell burst firing via a DA D(1/5)-like receptor-dependent mechanism.

Anesthesia↗
PubMed2001

Alzheimer disease therapeutics.

Alzheimer disease (AD) is characterized pathologically by cholinergic deficits, amyloid plaques, neurofibrillary tangles, gliosis, and neuronal and synaptic loss. The primary therapeutic approach that has arisen from the pathological analysis of AD brain has been cholinergic augmentation by cholinesterase inhibitors, which modestly improve cognitive function. Research on the underlying pathophysiological dysfunction have focussed on AD-specific processes such as amyloid precursor protein, tau, and cerebral apolipoprotein E metabolism, and more general neurodegenerative processes such as inflammation, oxidation, excitotoxicity, and apoptosis. Rational neuroprotective approaches have led to recent trials of estrogen, antioxidant and anti-inflammatory medications in AD, and to the development of anti-amyloid strategies for delaying progression or preventing development of AD.

Alzheimer Disease↗
PubMedDate not supplied

The pharmacology of auditory and vestibular systems.

Pharmacologists are among the most recent basic medical scientists to apply themselves to the auditory and vestibular systems. They bring to the subject a fresh perspective and, uniquely, the ability to control biological processes through drugs. Interest in the auditory and vestibular systems among pharmacologists has focussed on: the drug-sensitive processes (primarily but not exclusively neuro-transmission); toxicology, and pharmacotherapy. Pharmacology holds the promise of shedding further light on auditory and vestibular function and ameliorating auditory and vestibular dysfunction.

Auditory Cortex↗
PubMed2005

Targeting prefrontal cortical dopamine D1 and N-methyl-D-aspartate receptor interactions in schizophrenia treatment.

The prefrontal cortex plays a principal role in higher cognition and particularly in the fast online manipulation of appropriate information to guide forthcoming behavior. Dysfunction of this process represents a main feature in the pathophysiology of schizophrenia. Both dopamine D1 and N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex play a critical role in synaptic plasticity, memory mechanisms, and cognition. Recent data have shown that D1 and NMDA receptors interact bidirectionally and may greatly influence the output of the prefrontal cortex. Hypofunction of these receptor systems in the prefrontal cortex is found in schizophrenia. This review attempts to summarize some of the latest findings on the cellular mechanisms that underlie D1-NMDA receptor interactions. These findings have provided potential therapeutic strategies that aim to functionally up-regulate D1 and/or NMDA receptor safely via selective activation of D1 receptors or coagonist activation of NMDA receptors through blockade of the glycine transporter-1.

Animals↗
PubMed1996

Respiratory muscles and weaning failure.

Weaning failure is, unfortunately, a rather common phenomenon for mechanically-ventilated patients (especially those with chronic obstructive pulmonary disease (COPD)), and the respiratory muscles play a pivotal role in its development. Weaning fails whenever an imbalance exists between the ventilatory needs and the neurocardiorespiratory capacity. This can happen if there is an increase in the energy demands of the respiratory muscles, a decrease in the energy available, a decrease in neuromuscular competence, or if the respiratory muscles pose an impediment to the heart and blood flow. The imbalance created will lead to weaning failure through the development of respiratory muscle fatigue, hypercapnia, dyspnoea, anxiety and organ dysfunction.

Anxiety↗
PubMed1998

Nefazodone and depression.

Nefazodone is a fourth-generation antidepressant with novel serotonergic actions. It is a potent antagonist of synaptic 5-HT(2) receptors and a moderate blocker of synaptic 5-HT reuptake. Its mild synaptic blockade of norepinephrine is of little clinical importance. Besides its effectiveness in depression, nefazodone is effective in depression-related anxiety. Of all the antidepressants, nefazodone is least likely to induce sexual dysfunction. This drug increases sleep efficiency and reduces the number of nighttime awakenings. Nefazodone, compared with many other antidepressants, is unlikely to induce a withdrawal syndrome if abruptly stopped.

Journal Article↗
PubMed1981

[Clinicoelectroneuromyographic characteristics of neuralgic amyotrophy].

Clinical and genealogical examinations of 155 patients with neural amyotrophies were carried out. Use was made of general and local electromyography, determinations of the speed of impulse transmission along the efferent fibres of the peripheral nerves, and examinations of the H-reflex. The examinations revealed a great diversity of the clinical forms of the neural amyotrophies, each forms having a definite clinical picture, type of hereditary transmission, and characteristic electrophysiological changes. The electroneuromyographic examinations showed that in cases of Charcot-Marie-Tooth's classical neural amyotrophy neuritic changes were prevailing in rapidly-progressing autosomo-dominant neural amyotrophies and autosomo-recessive infantile neural amyotrophy the peripheral efferent neuron was affected over its entire length. A complex examination of Roussy-Levy's syndrome revealed a pronounced dissociation between the relatively unimpaired motor function and the considerable delay of the impulse transmission along the efferent fibres of the peripheral nerves. In heterozygotic carries signs of mononeuron dysfunction were determined.

Adult↗
PubMed1997

Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity.

BACKGROUND: Multiple lines of evidence indicate that the prefrontal cortex is a site of dysfunction in schizophrenia. However, the apparent absence of gross structural abnormalities in this area suggests that the pathophysiological characteristics of schizophrenia may involve more subtle disturbances in prefrontal cortical circuitry, such as alterations in synaptic connectivity and transmission. In this study, immunoreactivity for synaptophysin, an integral membrane protein of small synaptic vesicles, was used to assess the integrity of cortical synaptic circuitry in schizophrenia. METHODS: Using immunocytochemical techniques and adjusted optical density measurements, we examined synaptophysin immunoreactivity in prefrontal cortical areas 9 and 46 and in area 17 (the primary visual cortex) from 10 pairs of case subjects with schizophrenia and control subjects. matched on a pairwise basis for age, sex, race, and postmortem interval, and in 5 matched pairs of nonschizophrenic psychiatric case subjects and normal control subjects. RESULTS: Compared with levels found in matched control subjects, synaptophysin immunoreactivity in areas 46 and 9 was significantly decreased (P < .001 and P < .008, respectively) across all cortical layers in the case subjects with schizophrenia. In contrast, no differences were observed in area 17. In addition, levels of synaptophysin immunoreactivity in areas 46, 9, and 17 did not differ between 5 nonschizophrenic psychiatric case subjects and their matched controls, suggesting that decreased synaptophysin levels in the prefrontal cortex of patients with schizophrenia may be specific to that disorder. CONCLUSION: Additional studies are required to determine if the decrease in levels of synaptophysin immunoreactivity is caused by a decrease in the number or size of presynaptic terminals, a decrease in the number of synaptic vesicle per terminal, or a decrease in the expression of synaptophysin. However, all of these potential explanations are consistent with a disturbance in synaptic transmission in the prefrontal cortex of patients with schizophrenia.

Adult↗
PubMed1997

Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity.

BACKGROUND: Multiple lines of evidence indicate that the prefrontal cortex is a site of dysfunction in schizophrenia. However, the apparent absence of gross structural abnormalities in this area suggests that the pathophysiological characteristics of schizophrenia may involve more subtle disturbances in prefrontal cortical circuitry, such as alterations in synaptic connectivity and transmission. In this study, immunoreactivity for synaptophysin, an integral membrane protein of small synaptic vesicles, was used to assess the integrity of cortical synaptic circuitry in schizophrenia. METHODS: Using immunocytochemical techniques and adjusted optical density measurements, we examined synaptophysin immunoreactivity in prefrontal cortical areas 9 and 46 and in area 17 (the primary visual cortex) from 10 pairs of case subjects with schizophrenia and control subjects matched on a pairwise basis for age, sex, race, and postmortem interval, and in 5 matched pairs of nonschizophrenic psychiatric case subjects and normal control subjects. RESULTS: Compared with levels found in matched control subjects, synaptophysin immunoreactivity in areas 46 and 9 was significantly decreased (P < .001 and P < .008, respectively) across all cortical layers in the case subjects with schizophrenia. In contrast, no differences were observed in area 17. In addition, levels of synaptophysin immunoreactivity in areas 46, 9, and 17 did not differ between 5 nonschizophrenic psychiatric case subjects and their matched controls, suggesting that decreased synaptophysin levels in the prefrontal cortex of patients with schizophrenia may be specific to that disorder. CONCLUSIONS: Additional studies are required to determine if the decrease in levels of synaptophysin immunoreactivity is caused by a decrease in the number or size of presynaptic terminals, a decrease in the number of synaptic vesicles per terminal, or a decrease in the expression of synaptophysin. However, all of these potential explanations are consistent with a disturbance in synaptic transmission in the prefrontal cortex of patients with schizophrenia.

Adult↗
PubMed1998

Cortical acetylcholine, reality distortion, schizophrenia, and Lewy Body Dementia: too much or too little cortical acetylcholine?

Aberrations in cortical cholinergic transmission have been hypothesized to mediate the development and manifestation of psychotic cognition. Based primarily on hypotheses about mesolimbic dopaminergic hyperactivity in schizophrenia, the actions of antipsychotic drugs, the trans-synaptic regulation of the excitability of basal forebrain corticopetal cholinergic neurons, and the role of cortical cholinergic inputs in attentional functions, we hypothesized that persistent disinhibition of cortical cholinergic inputs mediates the fundamental cognitive dysfunctions which form the basis for the development of positive symptoms in schizophrenia. In contrast to this hypothesis, Perry and Perry (1995), based on evidence from hallucinating patients with Lewy Body Dementia (LBD), concluded that the extensive loss of cortical acetylcholine allows irrelevant information to enter "conscious awareness" and thus hallucinations to emerge. The discussion of these contrasting hypotheses highlights the need for more dynamic and precise theories describing the cognitive variables and neuronal processes which contribute to the development and manifestation of psychotic cognition. While the hypothesis that a disinhibited cholinergic system mediates the evolution of psychotic symptoms corresponds more convincingly with current theories about the cognitive functions of cortical cholinergic inputs, both hypotheses stress the critical role of cortical acetylcholine in the highest levels of cognitive functioning.

Acetylcholine↗
PubMed2001

Is anti-cholinesterase therapy of Alzheimer's disease delaying progression?

During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer's disease (AD) resulted in three drugs being registered for the first time in the US and Europe. All three compounds are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a stable level during a 6-month to 1-year period of treatment, as compared to placebo. Additional drug effects are to slow down cognitive deterioration and improve behavioral and daily living activity. Recent studies show that in many patients the cognitive stabilization effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic, and directly cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and amyloid precursor protein (APP) metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and cholinergic synaptic function; the effect of such lesions can be reversed by ChEI treatment. A reduction in cholinergic neurotransmission, experimental or pathological, leads to amyloidogenic metabolism and contributes to the development of neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, for which evidence is available on an experimental as well as clinical level, a mechanism based on beta-amyloid metabolism is postulated. The question whether cholinergic stabilization implies simply slowing down progression of disability or also involves delay of disease progression is discussed.

Aged↗
PubMed2006

Altered expression of hippocampal dentate granule neuron genes in a mouse model of human 22q11 deletion syndrome.

Hemizygous deletion of a 3 Mb region of 22q11.2 is found in 1/4000 humans and produces 22q11 deletion syndrome (22q11DS). Up to 35% of 22q11DS patients develop schizophrenia, making it the second highest risk factor for schizophrenia. A mouse model for 22q11DS, the Df1/+ mouse, carries a hemizygous deletion in a region syntenic with the human deletion. Df1/+ mice are mostly viable but display deficits in prepulse inhibition and learning and memory, two common traits of schizophrenia thought to result, at least in part, from defects in hippocampal neurons. We used oligonucleotide microarrays and QRT-PCR to evaluate gene expression changes in hippocampal dentate granule neurons of Df1/+ mice versus wild-type littermates (n=12/group). The expression of only 287 genes changed with p value significance below 0.05 by microarray, yet 12 of the 21 Df1 region genes represented on the array showed highly significantly reduced expression compared to wild-type controls (33% on average, p values from 10(-3) to 10(-7)). Variants in two of these genes, COMT and PRODH, have been linked with schizophrenia. Overlap of the 287 genes with the reportedly reduced expression of mitochondrial, ubiquitin/proteasome, and synaptic plasticity genes in schizophrenia dentate granule neurons, was not significant. However, modest increases in expression of mitochondrial electron transport genes were observed in the Df1/+ mice. This perhaps indicates a compensation for mitochondrial dysfunction caused by the strongly reduced expression of the Df1 region-encoded mitochondrial enzymes proline dehydrogenase (Prodh) and thioredoxin reductase 2 (Txnrd2).

Animals↗
PubMed2005

Prenatal ethanol exposure in rats decreases levels of complexin proteins in the frontal cortex.

BACKGROUND: Rodents that are prenatally exposed to ethanol have been shown to exhibit a wide range of cognitive deficits, including impairments in memory, attention and executive function. To determine a potential molecular substrate for cognitive dysfunction in adulthood, we measured regional levels of the presynaptic proteins complexin I and II in a rat model of prenatal ethanol exposure, as levels of these proteins are altered in cognitive-related synaptic plasticity. METHODS: Pregnant female rats received either a liquid ethanol diet (36% ethanol-derived calories) or a liquid control diet (maltose-dextrin isocalorically substituted for ethanol, matched in amount [g/kg body wt/day of gestation] to an ethanol-consuming partner), or were given ad libitum-fed access to standard laboratory chow and water. Levels of complexin I, II and the ubiquitous presynaptic marker synaptophysin were measured in the frontal cortex and hippocampus of adult male offspring, using ELISA. RESULTS: Prenatal exposure to ethanol did not alter levels of presynaptic proteins in the hippocampus or levels of synaptophysin in the prefrontal cortex. However, rats prenatally exposed to ethanol displayed significantly lower levels of both complexin I and II in the prefrontal cortex compared to control animals. CONCLUSIONS: These data indicate that prenatal exposure to ethanol is associated with a selective loss of complexin proteins in the frontal cortex. These proteins are known to be important for activity-dependent neurotransmission, and have previously been shown to mediate synaptic plasticity and cognition. These combined findings suggest that further study of complexin proteins as a substrate for cognitive impairment related to prenatal exposure to ethanol is warranted.

Adaptor Proteins, Vesicular Transport↗
PubMedDate not supplied

Synaptogenesis and myopathy under acetylcholinesterase overexpression.

Environmental, congenital, and acquired immunological insults perturbing neuromuscular junction (NMJ) activity may induce a variety of debilitating neuromuscular pathologies. However, the molecular elements linking NMJ dysfunction to long-term myopathies are unknown. Here, we report dramatically elevated levels of mRNA encoding c-Fos and the "readthrough" (R) variant of acetylcholinesterase (AChE) in muscles of transgenic mice overexpressing synaptic (S) AChE in motoneurons and in control mice treated with the irreversible cholinesterase inhibitor diisopropylfluorophosphonate (DFP). Tongue muscles from DFP-treated and AChE-S transgenic mice displayed exaggerated neurite branching and disorganized, wasting fibers. Moreover, diaphragm muscles from both transgenic and DFP-treated mice exhibited NMJ proliferation. 2'-O-methyl-protected antisense oligonucleotides targeted to AChE mRNA suppressed feedback upregulation of AChE and ameliorated DFP-induced NMJ proliferation. Our findings demonstrate common transcriptional responses to cholinergic NMJ stress of diverse origin, and implicate deregulated AChE expression in excessive neurite outgrowth, uncontrolled synaptogenesis, and myopathology.

Acetylcholinesterase↗
PubMed2002

Impaired prefrontal inhibition in schizophrenia: relevance for cognitive dysfunction.

In schizophrenia, critical deficits in cognitive functions appear to reflect altered neural processing in the prefrontal cortex (PFC). Given the essential role of inhibitory neurotransmission in mediating these cognitive functions, we sought to determine whether abnormalities in the inhibitory circuitry of the PFC may contribute to the cognitive deficits of schizophrenia. In situ hybridization analyses in postmortem brain tissue from subjects with schizophrenia revealed that a subset of GABA neurons in PFC layers 1-5 do not express detectable levels of the mRNAs encoding glutamate decarboxylase (GAD(67)), a synthesizing enzyme for GABA, or the GABA membrane transporter (GAT-1), which is responsible for the reuptake of GABA into the nerve terminal. Furthermore, the affected GABA neurons appear to include chandelier cells, since decreased expression of GAT-1 mRNA is associated with decreased GAT-1 protein immunoreactivity in chandelier neuron axon terminals. Finally, immunocytochemical studies revealed that decreased GAT-1 immunoreactivity in chandelier neuron axon terminals is associated with an increase in a marker of GABA(A) receptors at the postsynaptic targets of chandelier neuron axons, the axon initial segment (AIS) of pyramidal neurons. These findings suggest that schizophrenia is associated with an up-regulation of GABA(A) receptors at pyramidal neuron AIS in response to deficient GABAergic input from chandelier neurons. Selective disruptions in inhibitory neurotransmission are likely to distort aspects of pyramidal neuron function important for working memory tasks, and thus may contribute to cognitive dysfunction in schizophrenia.

Cognition Disorders↗