Per Wester

Transmitter deficits in Alzheimer's disease

The pattern of neurotransmitter pathway losses in Alzheimers disease are reviewed. Deficits of the cholinergic pathway from the nucleus basalis, the noradrenergic pathway from the locus coeruleus and the serotoninergic pathway from the raphe nuclei are established. Cortical somatostatin interneurons are affected and dopaminergic neurons may be affected although these may be late or secondary phenomena in the disease process. Other neuronal systems, particularly in the hippocampus and temporal cortex, are also damaged. However, the disease is not one of generalised neuronal atrophy since some neurons are selectively spared. The established pathway-specific losses are discussed in relation to the clinical symptomatology and the pathology of the disorder. The biochemical and histological findings are compared with similar measurements made on tissues from other dementing disorders in an attempt to trace features common to dementias. Finally, as an addendum, a hypothesis is briefly outlined which attempts to explain the common features of the affected neurons and the pathogenesis of the disorder.

Cortical Neurogenesis in Adult Rats After Transient Middle Cerebral Artery Occlusion

Background and Purpose This study explored the possible occurrence of newly generated nerve cells in the ischemic cortex of adult rats after middle cerebral artery occlusion and reperfusion. Methods Nine- to 10-week-old male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion by the monofilament method. Rats received repeated intraperitoneal injections of the cell proliferation-specific marker 5-bromodeoxyuridine (BrdU) after stroke induction. Brain sections were processed for immunohistochemistry with an avidin-biotin complex-alkaline phosphatase and/or -peroxidase method. Brain sections processed with double-immunofluorescent staining were further scanned by confocal microscopy. Results Interspersed among the predominantly newly formed glial cells, some cells were double labeled by BrdU and 1 of the neuron-specific markers, Map-2, &bgr;-tubulin III, and Neu N, at 30 and 60 days after stroke onset. These cells were randomly distributed throughout cortical layers II through VI, occurring with highest density in the ischemic boundary zone. Three-dimensional confocal analyses of BrdU and the neuron-specific marker Neu N confirmed their colocalization within the same cortical cells. Conclusions This study suggests that new neurons can be generated in the cerebral cortex of adult rats after transient focal cerebral ischemia. Cortical neurogenesis may be a potential pathway for brain repair after stroke.

Cortical Neurogenesis in Adult Rats after Reversible Photothrombotic Stroke

Neurogenesis occurs throughout life in the dentate gyrus of hippocampus and subventricular zone, but this phenomenon has rarely been observed in other brain regions of adult mammals. The aim of the current study was to investigate the cell proliferation process in the ischemically challenged region-at-risk after focal cerebral ischemia in the adult rat brain. A reversible photothrombotic ring stroke model was used, which features sustained hypoperfusion followed by late spontaneous reperfusion and a remarkable morphologic tissue recovery in the anatomically well defined somatosensory cortical region-at-risk. Twelve-week-old male Wistar rats received repeated intraperitoneal injections of the cell proliferation specific marker 5-bromodeoxyuridine (BrdU) after stroke induction. Immunocytochemistry of coronal brain sections revealed that the majority of BrdU-positive cells were of glial, macrophage, and endothelial origin, whereas 3% to 6% of the BrdU-positive cells were double-labeled by BrdU and the neuron-specific marker Map-2 at 7 and 100 days after stroke onset in the region-at-risk. They were distributed randomly in cortical layers II-VI. Three-dimensional confocal analyses of BrdU and the neuronal-specific marker Neu N by double immunofluorescence confirmed their colocalization within the same cells at 72 hours and 30 days after stroke induction. This study suggests that, as a potential pathway for brain repair, new neurons can be generated in the cerebral cortex of adult rats after sublethal focal cerebral ischemia.

The patients dying after long terminal phase have acidotic brains; implications for biochemical measurements on autopsy tissue.

Measurement of the frontal cortex and the medulla oblongata pH at autopsy revealed that those brains from individuals who died after long terminal phase had lower pHs than those who died quickly. These low pHs (pH 6.0–6.5) corresponded to lactic acid concentrations (20–25 mM) which are known to be neurotoxic. The cerebrospinal fluid pH and blood pH correlated with the cortical pH. The significance of these observations to the study of the biochemistry and histology on post-mortem human brain tissue and their possible clinical relevance are discussed.

Region-specific loss of glutamate innervation in Alzheimer's disease

Synaptosomal D-aspartate has been used as a marker for glutamate neurons in control and in postmortem Alzheimers disease brains. This technique shows a marked (60%) decrease of the glutamate uptake site in cortical and hippocampal regions. There were no significant changes in subcortical regions. We interpret these results as indicating loss of, or damage to, cortical glutamatergic innervation. These losses probably represent the biochemical correlate of pyramidal neuron damage in Alzheimers disease.

Physostigmine restores 3H-acetylcholine efflux from Alzheimer brain slices to normal level.

A technique was developed, which made it possible to study thein vitro release of3H-acetylcholine (3H-ACh) from human post mortem brain tissue, collected with short post-mortem delay (2,5–22 hours), both from controls and patients with Alzheimers disease (AD/SDAT). The tritium (3H) release was investigated during potassium stimulation, and AD/SDAT cortical slices were found to release a decreased amount of3H compared to control brain slices. Physostigmine, 10−5 and 10−4 M, has no significant effect on the release of3H from control slices, while physostigmine 10−4 M increased the evoked release from AD/SDAT brain slices over threefold, nearly to the control level.

A disorder of cortical GABAergic innervation in Alzheimer's disease

Synaptosomal gamma-aminobutyric acid (GABA) uptake has been used as a biochemical marker for GABAergic terminals in controls and Alzheimer disease brains. Use of this marker suggests a large (ca. 70%) loss of cortical and hippocampal GABA terminals in Alzheimer brain. To explain this observation we suggest that neuron loss in this disorder occurs via a process of cortical retrograde degeneration. This scheme reconciles our findings with previous neurochemical measurements on Alzheimer disease brains and also better reconciles the biochemistry with the histology of the disorder.

Ventricular Cerebrospinal Fluid Monoamine Transmitter and Metabolite Concentrations Reflect Human Brain Neurochemistry in Autopsy Cases

Concentrations of dopamine (DA), its metabolites 3‐methoxytyramine and homovanillic acid (HVA), noradrenaline (NA), its metabolites normetanephrine (NM) and 3‐methoxy‐4‐hydroxyphenylglycol (MHPG), 5‐hydroxytryptamine (5‐HT, serotonin), and its metabolite 5‐hy‐droxyindoleacetic acid (5‐HIAA) were measured in 14 brain regions and in CSF from the third ventricle of 27 human autopsy cases. In addition, in six cases, lumbar CSF was obtained. Monoamine concentrations were determined by reversed‐phase liquid chromatography with electrochemical detection. Ventricular/lumbar CSF ratios indicated persistence of rostrocaudal gradients for HVA and 5‐HIAA post mortem. Ventricular CSF concentrations of DA and HVA correlated positively with striatal DA and HVA. CSF NA correlated positively with NA in hypothalamus, and CSF MHPG with levels of MHPG in hypothalamus, temporal cortex, and pons, whereas CSF NM concentration showed positive correlations with NM in striatum, pons, cingulate cortex, and olfactory tubercle. CSF 5‐HT concentrations correlated positively with 5‐HT in caudate nucleus, whereas the concentration of CSF 5‐HIAA correlated to 5‐HIAA levels in thalamus, hypothalamus, and the cortical areas. These data suggest a specific topographic origin for monoamine neurotransmitters and their metabolites in human ventricular CSF and support the contention that CSF measurements are useful indices of central monoaminergic activity in man.

Divergent changes in D-1 and D-2 dopamine binding sites in human brain during aging

The density of D-1 and D-2 dopamine receptors in human caudate nucleus and putamen, obtained postmortem, were studied throughout the adult lifespan using [3H]fluphenazine as the dopamine receptor ligand. The D-1 subtype increased progressively with age in both regions, while the D-2 subtype declined in caudate nucleus. The ratio of D-1/D-2 Bmax in both regions increased from approximately 1 at age 20 to 2 by age 75. The dopamine content in putamen declined with age and was inversely correlated with D-1 receptor density. We suggest that D-1 receptor density is up-regulated by loss of dopamine during aging. The D-2 receptor density in caudate nucleus was positively correlated with choline acetyltransferase activity, suggesting that loss of intrastriatal neurons with age may contribute to the decrease in D-2 sites. These divergent changes in dopamine receptor subtypes with age result in an altered complement of dopamine receptors in older humans and may provide a basis for selective pharmacotherapy in disorders of the basal ganglia.

Coronary and carotid atherosclerosis: Similarities and differences

Although a relationship is commonly accepted between coronary and carotid arterial disease, suggesting that atherosclerosis is a systemic condition, the extent of this association and correspondence has not been fully elucidated. This review discusses recent research in this field and highlights areas for future study. The prevalence of severe carotid stenosis increases with prevalence of coronary stenosis, with the latter being found in a significant number of stroke patients, while those with carotid stenosis may be at higher risk of myocardial infarction than stroke. There also appear to be common risk factors (age, diabetes, hypertension, smoking and dyslipidemia), although the effects in both vascular systems may not be identical. Furthermore, while the degree of stenosis in the coronary artery has little ability to predict acute coronary syndrome, which is caused by local thrombosis from a ruptured or eroded plaque, severe carotid stenosis causing hypoperfusion is highly predictive of stroke, although this effect may be time-limited. This apparent difference in event mechanism in the two arteries is interesting as is the difference in the rate of development of collaterals. Overall, the evidence shows that a clear relationship exists between disease in the coronary and carotid arteries, since conventional risk factors and the extent of stenosis and/or previous events emanating from one artery have a strong bearing on the prevalence of events in the other artery. Nevertheless, the exact correspondence between the two arteries is unclear, with sometimes contradictory study results. More research is needed to identify the full extent of risk factors for severe stenosis and cardio- or cerebral vascular events, among which, inflammatory biomarkers such as hs-CRP and prior vascular events are likely to play a key role.