Cholinergic deficit

Parkinson s disease (PD) patients may suffer cognitive and behavioural impairments including apathy, personality changes and visual hallucinations, with no currently recommended treatment. Their significant cholinergic deficits led to recommendation of ChEI therapeutics. 

Vascular dementia (VD) accounts for 20-30% of dementia cases, with clinical and pathological overlap with AD. Reductions in cholinergic markers suggest cholinergic deficits in VD, and ChEIs increase ACh availability and improve their cerebral blood flow. 

Poirier J, Delisle MC, Quirion R et al. Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc Natl Acad Sci USA 1995 92[26] 12260-12264. 

Poirier, J., et al., "Apolipoprotein E4 Allele as a Predictor of Cholinergic Deficits and Treatment Outcome in Alzheimer Disease," Proc. Natl. Acad. Sci. U.S.A., 92,... 

Fujimoto, Y., K. Maruno, and S. Made. Antitumor sesquiterpene extraction from ginger roots. Patent-Japan Kokai Tokkyo Koho-01 221,344 1989 6 pp. Yabe, T., K. Toriizuka, and H. Yamada. Kami-untan-to (Kut) improves cholinergic deficits in aged rats. Phytomedicine 1996 2(3) 253-258. Nishimura, K., Y. Kitada, and T. Fukuda. Phenols for moisture-increas-... 

Kami-Untan-To (KUT) improves cholinergic deficits in aged rats. Phytomedicine 1996 2(3) 253-258. 

Correlations of Cholinergic Deficits With Clinical and Pathological Findings... 

The consistent findings of cholinergic deficits in AD and their correlations with both pathological and clinical features have suggested cholinergic maintenance and replacement therapies similar to the dopaminergic treatment of patients with Parkinson s disease. Theoretically, an enhancement of cholinergic neurotransmission can be achieved in various ways [Davies 1981) ... 

Perry EK The chohnergic hypothesis— ten years on. Br Med Bull 42(l) 63-69, 1986 Perry EK, Perry RH, Blessed G, et al Necropsy evidence of central cholinergic deficits in senile dementia. Lancet 1 189, 1977 Perry EK, Tomhnson BE, Blessed G, et al Correlation of cholinergic abnormahties with senile plaques and mental test scores in senile dementia. BMJ 2 1457-1459, 1978... 

Patients with ALS/PDC also show a moderate loss of choline acetyl transferase activity in the midfrontal and inferior parietal cortex and a severe loss in the superior temporal cortex (Masliah et al., 2001). This deficit is similar to that seen in Alzheimer disease and less severe than in Lewy body disease. Thus, cholinergic deficits in the neocortex may contribute to some of the cognitive alterations in ALS/PDC. 

Masliah E., Alford M., Galasko D., Salmon D., Hansen L. A., Good R F., Perl D. P., and Thai L. (2001). Cholinergic deficits in the brains of patients with parkinsonism-dementia complex of Guam. NeuroReport 12 3901-3903. 

In addition to the cholinergic deficit, Alzheimer s disease has also been shown to be characterized by marked deficits in the monoamine neurotransmitters norepinephrine and serotonin, as well as in glutamate and some neuropeptide neurotransmitters (Figure 27.6). 

Donepezil HC1, a piperidine, is a highly selective inhibitor of the enzyme AChE [3,4] that is chemically unique from other AChE inhibitors [5, 6]. In vitro and preclinical studies have demonstrated that donepezil is approximately 1200 times more selective for AChE in the brain than for butyrylcholinesterase (BuChE) in the periphery [3, 4, 7]. Phase II and III studies conducted in the United States have shown that donepezil (5 or 10 mg once daily) produces statistically significant improvements in cognition and global function in patients with AD [8-10]. Its clinical efficacy and minimal side-effect profile are thought to be related to its specific inhibition of AChE in the areas of the brain affected by the cholinergic deficit that typifies this disease [3, 4, 7],... 

Regarding the cholinergic system, there is evidence that the pathway from the substantia innominata to the cortex degenerates in Parkinsonism, and that the septohippocampal pathway is also functioning suboptimally. As more than 30% of Parkinsonian patients exhibit intellectual deterioration with deficits in cognitive function and memory, it is possible that these cholinergic deficits may account for at least some of the symptoms of parkinsonian dementia. 

Metrifonate has been used for the treatment of schistosomiasis for almost 40 years. Its identification as a cholinesterase inhibitor, together with recognition of the cholinergic deficit in Alzheimer s disease, has led to its use in Alzheimer s disease. 

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