Alzheimer's Disease Pharmacotherapy Research Articles

Monoaminergic neurotransmitters, their precursors and metabolites in brains of Alzheimer patients

The catecholamines dopamine (DA), noradrenaline (NA) and adrenaline (A), their aminoacid precursors tyrosine (Tyr), l-3,4-dihydroxyphenylalanine ( l-DOPA), two of their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxy phenyl glycol (MHPG), serotonin (5-HT) and its precursor tryptophan (Trp), were measured by high pressure liquid chromatography (HPLC) with electrochemical detection in seven regions (globus pallidus, putamen, nucleus amygdalae, nucleus caudatus, substantia nigra, gyrus cinguli and raphe) of postmortem brains from eight histologically verified cases with Alzheimer's disease (AD) and six histologically normal controls. Concentrations of l-DOPA, DA, DOPAC, NA and 5-HT were significantly reduced, while Tyr and MHPG concentrations were significantly increased in AD versus control patients. The concentrations of Trp and A in AD patients were not significantly different from controls. Furthermore, for most brain regions examined, significant negative correlations between Tyr and DA as well as between NA and MHPG levels were found. These data confirm and extend findings of monoaminergic systems disturbances in AD, emphasize the significance of dopaminergic deficit for AD and suggest that in pharmacotherapy of AD, attempts to restore deficits of the transmitter systems should be directed to the monoaminergic, in particular the dopaminergic system.

Chapter 55: Pharmacotherapy of Alzheimer disease: new drugs and novel strategies

Publisher Summary Four major and distinct therapeutic interventions for the treatment of Alzheimer disease (AD) have been envisioned in order to: (1) achieve a symptomatic improvement without attenuation of the pathology by acting on one or several neurotransmitter systems; (2) slow down the progression of amyloid formation in individuals with a diagnosed Alzheimer condition; this might also slow down the disease course; (3) prevent, slow down or reverse the accumulation of the P-amyloid protein in cerebral blood vessels and/or neuritic plaques in individuals genetically at risk for the disease; this group of patients is relatively small (0.7%–5 %) ; (4) develop a curative therapy by means of a causal approach. Approach (1) is discussed in detail in this chapter. Approaches (2) and (3) are important, although P-amyloid deposition is probably not the primary cause of the disease. Approach (4) is theoretical since the etiology of the disease is unknown. With regard to approach (1), one should keep in mind that AD is not a “mono-neurotransmitter disease.” In younger patients, a deficiency of norepinephrine (NE) in the central nervous system (CNS) seems to be frequent. There is also evidence that the concentration of other neurotransmitters, besides acetylcholine (ACh) and NE, is lower than normal. Glutamate and serotonin are also reduced in cerebral cortex.

Pharmacotherapy of Alzheimer disease. New drugs and novel strategies: Ezio Giacobini. Dept. Pharmacology, Southern Illinois Univ. Sch. Med., P.O. Box 19230, Springfield, IL 62794-9230 USA

Pharmacotherapy of Alzheimer disease. New drugs and novel strategies: Ezio Giacobini. Dept. Pharmacology, Southern Illinois Univ. Sch. Med., P.O. Box 19230, Springfield, IL 62794-9230 USA

Neurotransmitter changes in alzheimer's disease: Implications to diagnostics and therapy

Changes in the cholinergic, serotonergic, noradrenergic, dopaminergic, GABAergic and somatostatinergic neurons were investigated to determine their roles in Alzheimer's disease (AD). Markers for these systems were analyzed in postmortem brain samples from 20 patients with AD and 14 controls. In the CSF study, markers for the cholinergic neurons (choline esterase, ChE) and for the somatostatinergic neurons (somatostatin-like immunoreactivity, SLI) were assayed for 93 and 75 probable AD patients and 29 and 19 controls, respectively. Activity of choline acetyltransferase (CAT) was decreased by 50-85% in four cortical areas and hippocampus in patients with AD, but not in other areas of the brain, indicating a profound deficit in the function of cholinergic projections ascending from the nucleus basalis to the cerebral cortex and hippocampus in AD. Muscarinic receptor binding was reduced by 18% in the frontal cortex but not in other areas of the brain in AD. Serotonin (5HT) concentrations were reduced (by 21-37%) in hippocampal cortex, hippocampus and striatum; and 5HT metabolite levels were lowered (by 39-54%) in three cortical areas, thalamus and putamen in AD patients. Concentrations of noradrenaline (NA) were reduced (18-36%) in frontal and temporal cortex and putamen. These data imply that serotonergic and noradrenergic projections are also affected in AD but less than the cholinergic neurons. Dopamine (DA) concentrations in AD patients were reduced by 18-27% in temporal and hippocampal cortex and hippocampus, while HVA, the metabolite of DA, was unaltered. Glutamic acid decarboxylase activity was not altered in AD. SLI was decreased (28-42%) in frontal, temporal and parietal cortex, but not in thalamus and putamen in patients with AD. Frontal tangle scores correlated most strongly with cortical CAT activity reduction and less so with decreases of 5HT, NA and DA, indicating a closer correlation with the cholinergic changes and severity of AD than with other neurotransmitter deficiencies. ChE activity and SLI were reduced by 20% and 35%, respectively, in CSF of the whole group of AD patients as compared to the controls. Comparison of CSF findings between four subgroups of dementia severity indicated that the SLI was already reduced in the group of mildest AD (-31%), while ChE activity was not. Although ChE activity in CSF declined in relation to dementia severity, however, the maximal reduction was only modest (-30%). On the other hand, SLI in CSF showed only a slight further reduction (up to -41%) as the dementia become more severe.(ABSTRACT TRUNCATED AT 400 WORDS)