Alan M. Palmer

The cholinergic hypothesis of Alzheimer’s disease: a review of progress

Alzheimer’s disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer’s disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer’s disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer’s disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no “cure” for Alzheimer’s disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer’s disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer’s disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.

Treatment of Traumatic Brain Injury with Moderate Hypothermia

Background Traumatic brain injury initiates several metabolic processes that can exacerbate the injury. There is evidence that hypothermia may limit some of these deleterious metabolic responses. Methods In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in 82 patients with severe closed head injuries (a score of 3 to 7 on the Glasgow Coma Scale). The patients assigned to hypothermia were cooled to 33°C a mean of 10 hours after injury, kept at 32 to 33°C for 24 hours, and then rewarmed. A specialist in physical medicine and rehabilitation who was unaware of the treatment assignments evaluated the patients 3, 6, and 12 months later with the use of the Glasgow Outcome Scale. Results The demographic characteristics and causes and severity of injury were similar in the hypothermia and normothermia groups. At 12 months, 62 percent of the patients in the hypothermia group and 38 percent of those in the normothermia group had good outcomes (moderate, mild, or no d...

Drug Metabolism and Pharmacokinetics, the Blood-Brain Barrier, and Central Nervous System Drug Discovery

SummaryThe worldwide market for therapies for CNS disorders is worth more than

Presynaptic Serotonergic Dysfunction in Patients with Alzheimer's Disease

50 billion and is set to grow substantially in the years ahead. This is because: 1) the incidence of many CNS disorders (e.g., Alzheimer’s disease, stroke, and Parkinson’s disease) increase exponentially after age 65 and 2) the number of people in the world over 65 is about to increase sharply because of a marked rise in fertility after World War II. However, CNS research and development are associated with significant challenges: it takes longer to get a CNS drug to market (12–16 years) compared with a non-CNS drug (10–12 years) and there is a higher attrition rate for CNS drug candidates than for non-CNS drug candidates. This is attributable to a variety of factors, including the complexity of the brain, the liability of CNS drugs to cause CNS side effects, and the requirement of CNS drugs to cross the blood-brain barrier (BBB). This review focuses on BBB penetration, along with pharmacokinetics and drug metabolism, in the process of the discovery and development of safe and effective medicines for CNS disorders.

Evidence of Glutamatergic Denervation and Possible Abnormal Metabolism in Alzheimer's Disease

Abstract: Indices of presynaptic serotonergic nerve endings were assayed in neocortical biopsy samples from patients with histologically verified Alzheimers disease. The concentrations of 5‐hydroxytryptamine (serotonin) and 5‐hydroxyindoleacetic acid, serotonin uptake, and K+‐stimulated release of endogenous serotonin were all found to be reduced below control values. Changes occurred in samples from both the frontal and temporal lobes, but they were most severe (at least a 55% reduction) in the temporal lobe. This is indicative of substantial serotonergic denervation. Values for serotonergic markers in Alzheimers disease samples did not show correlations with rating of the severity of dementia, indices of cholinergic innervation, or senile plaque and cortical pyramidal neurone loss. However, neuronbrillary tangle count and an index of glucose oxidation (both probably reflecting pyramidal cells) correlated with the concentration of 5‐hydroxyindoleacetic acid.

Monoaminergic innervation of the frontal and temporal lobes in Alzheimer's disease

Excitatory dicarboxylic amino acids previously have been ascribed several functions in the brain. Here their total concentration and proposed neurochemical markers of neurotransmitter function have been measured in brain from patients with Alzheimers disease (AD) and controls. Specimens were obtained antemortem (biopsy) approximately 3 years after emergence of symptoms and promptly (<3 h) postmortem some 10 years after onset. Early in the disease a slight elevation in aspartic acid concentration of cerebral cortex was observed in the patients with AD. A reduction in glutamic acid concentration of a similar magnitude was found. It is argued that this, together with a decrease in CSF glutamine content and lack of change in the phosphate‐activated brain glutaminase activity of tissue, reflects an early metabolic abnormality. Later in the disease evidence of glutamatergic neurone loss is provided by the finding that in many regions of the cerebral cortex the Na+‐dependent uptake of D‐[3H]aspartic acid was almost always lowest in AD subjects compared with control when assessed by a method designed to minimise artifacts and epiphenomena. Release of endogenous neuro‐transmitters from human brain tissue postmortem did not appear to have the characteristics of that from human tissue antemortem and rat brain.

Mild Posttraumatic Hypothermia Reduces Mortality after Severe Controlled Cortical Impact in Rats

Seven markers of ascending (corticopetal) dopaminergic, noradrenergic and serotonergic neurones and choline acetyltransferase activity have been studied postmortem in frontal and temporal cortex from subjects with Alzheimers disease and compared with a matched group of controls. Dopaminergic neurones (concentrations of dopamine, dihydroxyphenylacetic acid and homovanillic acid) were not deficient but some markers of the other neurones were affected. Noradrenaline and serotonin concentrations were reduced whereas the concentrations of their metabolites were either unaltered (5-hydroxyindoleacetic acid) or increased (3-methoxy-4-hydroxyphenylglycol). All deficits were most pronounced in the temporal cortex. Severely demented subjects had evidence of generalized neuronal loss, whereas those with moderate dementia showed significant loss of only choline acetyltransferase activity. In Alzheimer subjects, a significant relationship (inverse) was found between 5-hydroxyindoleacetic acid concentration and the number of neurofibrillary tangles.

Topographical distribution of neurochemical changes in Alzheimer's disease

The effect of posttraumatic hypothermia (brain temperature controlled at 32°C for 4 h) on mortality after severe controlled cortical impact (CCI) was studied in rats. Four posttraumatic brain temperatures were compared: 37°C (n = 10), 36°C (n = 4), 32°C (n = 10), and uncontrolled (UC; n = 6). Rats were anesthetized and subjected to severe CCI (4.0-m/s velocity, 3.0-mm depth) to the exposed left parietal cortex. At 10 min posttrauma the rats were cooled or maintained at their target brain temperature, using external cooling or warming. Brain temperature in the UC group was recorded but not regulated, and rectal temperature was maintained at 37 ± 0.5°C. After 4 h, rats were rewarmed over a 1-h period to 37°C, extubated, and observed for 24 h. In the 37 and 36°C groups, 24-h mortality was 50% (37°C = 5/10, 36°C = 2/4). In the 32°C group, 24-h mortality was 10% (1/10). In the UC group, brain temperature was 35.4 ± 0.6°C during the 4-h treatment period and 24-h mortality was 0% (0/6). Mortality was higher in groups with brain temperatures ≥36°C versus those with brain temperatures <36°C (50 vs. 6%, respectively; p < 0.05). Additionally, electroencephalograms (EEG) were recorded in subsets of each temperature group and the percentage of time that the EEG was suppressed (isoelectric) was determined. Percentage of EEG suppression was greater in the hypothermic (32°C, n = 6; UC, n = 4) groups than in the normothermic(36°C, n = 3; 37°C, n = 6) groups (23.3 ± 14.3 vs. 1.2 ± 3.1%, respectively; p < 0.05). Posttraumatic hypothermia suppressed EEG during treatment and reduced mortality after severe CCI. The threshold for this protective effect appears to be a brain temperature <36°C. Thus, even mild hypothermia may be beneficial after severe brain trauma.

Increased transmitter amino acid concentration in human ventricular CSF after brain trauma

Biochemical indices of cortical nerve cells affected in Alzheimers disease have been proposed (excitatory dicarboxylic amino acid, EDAA, sodium-dependent carrier; phosphate-activated glutaminase activity; serotonin type 2 recognition site; somatostatin-like immunoreactivity). These and the content of EDAAs and two related amino acids, and choline acetyltransferase (ChAT) activity have been measured in up to 13 areas of cerebral cortex and the cerebellar cortex from 16 patients with Alzheimers disease and 17 controls. Reduction of the index of the serotonin recognition site, somatostatin content and another biochemical index of interneurones coincide and indicate a rather unexpected focal loss of such neurones from the parietal lobe. No unequivocal measure of the integrity of pyramidal neurones could be established as the content of no amino acid was reduced, the index of the EDAA carrier showed evidence of change in few brain regions and glutaminase activity was subject to unexplained variability. ChAT activity alone closely paralleled a previous report of the distribution of morphological degeneration. The results are discussed in relation to therapy and positron emission tomography.

Catecholaminergic neurones assessed ante-mortem in Alzheimer's disease.

THE concentrations of L-aspartate, L-glutamate, L-serine, glycine, and γ-aminobutyric acid (GABA) were determined in repeated samples of ventricular CSF from five patients with severe closed head injury. The values were compared with those obtained from five subjects undergoing surgical treatment for intractable depression. In the head-injured patients, the concentrations of aspartate, glutamate, and glycine were 2− to 8-fold higher, and the concentration of GABA 56− to 317-fold higher than control values; the concentration of serine was unaffected. Spearman correlation analysis indicated that the concentration of glutamate significantly increased after injury (Rs = 0.60, p < 0.0001, n = 42), reaching an average concentration of about 7 μM 3 days after the injury. This is probably sufficient to cause further excitotoxicity, which suggests the use of excitatory amino acid receptor antagonists as a treatment following severe head injury may require prolonged administration for maximum therapeutic benefit.