204 S-16 Alzheirner~ disease." neurochemistry of Alzheimer's disease and its clinical implications

The study of patients assessed retrospectively indicates that pat,ents judged to be aggresswe during life had more severe loss of both 6-HT concentration and pos tsynapt ic6HT 2 receptors These findings prompted the establishment of a prospective study of neurochemlcal correlates of behaviourai change in AD. In the present study, the loss of a structural marker of cortical serotonerglc mnervatlon. [3H] paroxetine binding, from the neocortex was most prominent In those subjects with behawoural symptoms in life, of which those related to depression appear to be the most important determinant Indeed, 13H] paroxetine binding in those cases without significant depression was comparable to control cases,

The major inhibitory neurones of the neocortex appear to be preserved Jn AD as the concentrations of GABA and somatostatin (present in a subset of such neurones) are unchanged, even sometimes increased The biochem istry of the major excitatory transmitter system of the cortex has provec much more difficult to lnvestlgate Studies in human and ammal brain nave indicated that all the maior input and output pyramidal neurone pathways of the hippocampus together with neocortical association areas use glutamate as transmitter. There was cell loss (principally of pyramidal neurones) and tangle formation in the entorhinal cortex, CA1 and association areas n AD patients at postmortem Three independent studies indicated that sever ity of dementia correlates with degeneraton of corticocortlcal pyramidal neurones in association areas Glutamate corcentration of biopsy samDleS from the temporal lobe of AD patients was also reduced and the value fo" individual subjects related to the density of pyramidal neurones ,n layer ill The most straightforward explanation is that !oss of corticocortical assoma tlon fibres influenced the glutamate concentration of these samples These data imply, that in the light of the role of excitatory glutamate~gLc pathways in memory loss of g utamaterglc function almost certainly contributes to the memory dysfunction inAD

The diff culty of replacing lost transrmtter function in a way that m r,'lcs normal neuronal release suggests the use of agents to modify the actlens of rema ning transmitters may be a more effective approach to therapy than one using direct agonists Most clinical studies have been based oq the cholinergic deficit but a acetylcholinesterase mhlb~tor that is ideal (i e long lasting and non toxic) has not yet emerged. Chnlcal trials w~th muscanmc M 1 agonists are also underway However, thepreservat lonof5 HTturnover n AD and electrophysiological studies which indicate that 5HT inhibits pyramidal neurones via the 5-HTrA receptor, suggest that an alternative (or additional) approach may be a 6-HT1A antagonist

Drugs that affect transmission would now seem an importart goal as they will be required for most patients to improve if not reverse functional cognitive disabilities already present, as well as for sufferers during the development of what are currently considered alternative non-transmltte" related strategies. On the basis of the present developments a work ng f'ypothesIs may be advanced whereby drugs such as acetyicholinesterase inhibitors, may also affect beneficially the metabolism of the amylo~o pro cursor in the brain of patients with AD and influence the deposition of other proteins (tau anti apolipoprote,n E} imphcated in sporadic AD

~ - ~ AIzheimer's disease: neurochemistry of Alzheimer's disease and its clinical implications

Luigi Amaducci Department of Neurological and Ps'ychiatnc Sciences, University of Florence, Via/e Morgagni 85, 50134 Florence, Italy

Alzheimer's disease is a chronic neurodegeneratlve disease that causes pro (3ress:ve dementia Several studies have been carried out to date m or~er to elucidate the eOologyand pathogenesis of this complex illness Genetic: and environmental factors has been considered Recent molecular studies have identified genehc loci on chromosome 21, 19 and 14 and fve different rmssense mutat, ons of the gene encoding for the amyloid precursor protein {APP) in at least 12 k,ndreds of early onset familial AD (EOFAD) isee for re wew, Kennedyeta l 1994) More recently an association of the E4alle!eo+ apolipoprotein E (ApoE) both with late onset familial AD (Corder et al 1993) and sporadic cases had been reported (Poirier et al., 1993: Saunders et al 1993). Recently Sorbi and coi l (~n press) described a new FAD kindred ir' 'which the diseasecosegregates with theAPP717Val~ lie mutat,on n whlc~ al of the three most common ApoE alleles are represented and they appear to influence the age at onset of the disease

As concern environmental factors, several hypothesis has beer" put for ward from aluminum (Goodeta l 1976)to, more recently, electromagnehc fields, during occupational exposure (dressmakers and sewers)tSobel et a! 1994)

Severa biochemical and neurotransmltter alteration have been deserl~ed m the brain of AD patients With respect to neurochemicalfeatures, Iowe" concenVatlons O; dopamlne, no*eplnephnne somatostatin cortlcotrnplrl re

leasing factor, glutamate and serotonm have been reported in the brains of patients affected by AD (Adolffson et al. 1979). A significant reduction in choline acetyltransferase activity, a marker of the coiinergic system, and ~n acetylcholine (Ach) synthesis have therefore been found in postmortem and biopsy brain specimen from AD patients (Pope et al. 1964}. It is well known that Ach ~s synthesized from acetyl CoA and choline in the cytoplasm. Glu~ cose and oyruvate are the main precursors of the acetyl carbons of Ach in the adult mammalian brain (Browning and Schulman, 1968). In vivo studies by positron emission tomography (PET) have shown a decrease in brain glucose metabolism in temporal and parietal regions of the cortex (Duara et al. 1986; Friedland et al. 1989). Several glycolytic enzymes (phosphofrut- tokmase, pyruvate dehydrogenate complex, hexokinase) have been found decreased both in the brain (Bowen et al. 1979; Iwangoff et al. 1980; Sorbi etal 1983) and in skinfibroblasts from AD patients (Sorbi and Blass 1983; Sorbiet at 1990} In addition other mitochondrialenzymes reported to be deficient m AD brain include carnitine acetyltranferase (Kalaria and Harik, !992) and cytocrome oxidase (Kish et al. 1992; Parker et al. 1994). Recently the alfachetoglutarate dehydrogenase complex (KGDHC) have been found decreased in fibroblasts from patients belonging to chromosome 14-1inked families, suggesting that E2k (the alterated component of KGDHC) is a can- d~date gene for the chromosome 14-1inked form of FAD (Sheu et al. 1994). Since the synthesis of Ach is strictly linked to energy metabolism, it is likely that an alteration in glucose or/and mitochondrial metabolism could be re- sponsible of the decrease of this neurotransmitter. Most strategies have focused on replacement therapy of known neurotransmitter deficits in pa- tients with AD, in particular the cholinergic deficit. Cholinomimetic therapies ,nclude the use of choline precursors (e.g., lecithin}, cholinergic agonists (e g , bethanecol), and cholinesterase inhibitors (e.g., physostigmine and tetrahydroaminoacridine). Preliminary results of a recent study (Wilcock et ai 1995) have shown that a possession of an Apo E4 allele appears to decrease the chance of responding to tacrine. Other therapies have been proposed for AD. A recent report suggests that nimodipine may have a beneficial effect in AD, acting through the block of {ntracellular calcium increase glutamate-induced (Tollefson, 1990). Neurotrophic factors, since trqey are believed to promote neuron survival, have been also considered for AD therapy(Tuszynsky et al. 1991)

Taken altogether, neuchemical, biochemical and genetics studies suggest that AE) must be considered the clinical expression of several different g~seases, in this view, biological markers could allow the identification of homogenous groups of patients with different clinical course, prognosis and possible therapLes

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ease. Colloques medecine et recherche, Foundation IPSEN, Paris May 26. 1995

Treatment strategies in Alzheimer's disease

q Levy Section ofO/dAge Psychlat~ Institute of Psych/at04, De Crespigny ,Dark. t_ondon, SE5 8AF

Fne author will review the strategies currently available for the biological treatment of Alzheimer's disease