Mohammed T. Abou-Saleh

260 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRYthe cause of dementia in diffuse LBD is cortical 22,23 . However, thedistribution of neuritic plaques and neurofibrillary tangles doesnot necessarily parallel the distribution of Lewy bodies 24 and, insome cases with Lewy bodies in the cerebral cortex and brainstemnuclei, AD-type changes are not present 25 .The precise nosological relationship between DLB and AD, andbetween DLB and patients with Parkinson’s disease whosubsequently become demented, requires elucidation 3 .CREUTZFELDT–JAKOB DISEASECreutzfeldt–Jakob disease (CJD) belongs to the family oftransmissible spongiform encephalopathies affecting humansand animals 26 . In humans the main forms are sporadic CJD,iatrogenic CJD (associated mostly with pituitary hormonesprepared from cadaver pituitaries), familial forms, includingGerstmann–Straussler–Scheinker (GSS) syndrome and variantCJD (vCJD).Sporadic CJD is typically a rapidly progressive dementia withassociated myoclonus, but a number of different clinical andpathological variants have been described 27,28 . The worldwideincidence is approximately 1–2/million/year 29 , although theaverage annual incidence in England and Wales was 0.3 in1970–1979 30 , and 0.49 in 1980–1984 31 . The highest reportedincidence of 75 is amongst Libyan Jews 32 . Although often apresenile dementia, the peak age-specific mortality rate in Englandand Wales is in the seventh decade, with a mean of 63.2 years anda range of 33–82 31 .Approximately 10–15% of cases of CJD are familial and seemto follow an autosomal dominant pattern of inheritance 33 . GSS isalso familial, but clinically and pathologically more closelyresembles kuru than CJD, although caused by the sametransmissible agent 34,35 .To date, there has been only one reported case of vCJD in theelderly 36a . All of the other cases have been younger (mean age atdeath 29 years). The presenting features in both age groups arebehavioural change and sensory symptoms with later developmentof cerebellar ataxia, dementia and mycoclonus 36 .Although pathological variants of CJD have been described,the principal features are fluctuating spongiform change of thegrey matter, with neuronal loss, and astrocytic hypertrophy andhyperplasia 37 . Amyloid plaques, particularly in the cerebellum, arepresent in 5–10% of cases of CJD and the majority of cases ofkuru and GSS 34 . Florid amyloid plaques of prion protein are alsocharacteristic of vCJD.The transmissible nature of CJD has been known for manyyears 37,38 . Prions 39,40 as proteinaceous infectious particlesconsisting of one protein (PrP 27-30), which is encoded by acellular gene and derived from a larger protein. PrP 27-30 isinseparable from the infectivity of the scrapie agent andconstitutes the amyloid of cerebral plaques in ‘‘prion’’ diseases.The PrP or a closely-related gene clearly controls the clinicalexpression of the disease.The causal relationship of PrP with the disease isstrengthened by the presence of disease-specific mutationslinked to, or tracking with, inherited ‘‘prion’’ diseases, suchas the substitution of leucine for proline at PrP codon 102 inataxic forms of GSS 41 and the substitution of lysine forglutamate at codon 200 in Libyan Jews 42 . Similarly, the valine129 homozygous genotype is associated with susceptibility toiatrogenic CJD 43 and methionine 129 homozygosity withvCJD 36 .The continued unravelling of the molecular biology of theprion diseases is likely to reveal as many surprises in the futureas have already been provided by this fascinating group ofdisorders. However, it seems improbable that ‘‘priondementias’’ constitute a large group of as yet unrecognizedneurodegenerative disorders and, for all practical purposes,transmissible spongiform encephalopathies in humans and‘‘prion dementias’’, are the same 44 .HUNTINGTON’S DISEASEHuntington’s disease (HD) is a disorder of midlife onset (meanage 41 years) characterized by progressive chorea, psychologicalchanges and dementia, although not necessarily in that order.The disease is encountered in the senium, sometimes because ofprolonged survival of presenile cases, but also because chorea onlyappears in 28% of HD patients after the age of 50 and,occasionally, not until the seventh or eighth decade 45 . HD isinherited as an autosomal dominant trait with 100% penetranceand the HD gene has been localized near the telomere on the shortarm of chromosome 4 46 .The principal neuropathological features are neuronal loss andgliosis in the corpus striatum, and a five-grade system has beendevised for pathologically classifying HD 47 , which closelycorrelates with the degree of clinical disability 48 . Most of theneuropathologically studied cases fall into Grades 2 and 3(79%) 49 ; 50% of neurones have been lost from the caudatenucleus by the time grade 1 pathological changes are recognizableand 95% by grade 4. There is an accompanying increase inastrocytes and oligodendrocytes, reaching a maximum that issignificantly different from control material in grade 4 for theformer and grades 0–2 for the latter 47 .The distribution of neuronal loss within the corpus striatumis non-uniform. In Grades 1 and 2 the medial caudate nucleusis more severely affected than the lateral, although thisdistinction is lost when the pathological changes become moresevere 47 . The anteroventral part of the putamen is also spared 50 .Not only is the disease process in the corpus striatumanatomically variable, but also not all neuronal populationsare equally affected. The small to medium-sized spiny neurones(which have a large synaptic surface and distant connections)are most affected in HD, and these neurones contain g-aminobutyric acid (GABA) enkephalins and substance P 51,52 .On the other hand, medium aspiny neurones, containingNADPH-diaphorase, somatostatin and neuropeptide Y, andlarge cholinergic neurones, are relatively spared 53,54 . Thedecreased concentration of GABA and enzymes involved inits metabolism, which has been known for many years 55 ,together with the decreased concentrations of substance P andthe enkephalins, can be explained on the basis of selective lossof striatal neuronal populations.The disease is caused by expansion of a trinucleotide CAGrepeat beyond 35 repeats in the first exon of the huntingtingene on chromosome 4 56 . The CAG repeats are translated topolyglutamine repeats in huntingtin and, although the normalfunction of huntingtin is incompletely understood, it appearsto be associated with the cytoskeleton and necessary forneurogenesis, and expression of mutant huntingtin is necessaryfor disease development. The ability of huntingtin to interactwith other proteins is influenced by CAG length and it ispossible that neuronal apoptosis may be triggered byabnormal interaction with caspase 3 57,58 . Furthermore, thereis also evidence of abnormal metabolism in HD brain tissue,resulting in the generation of free radicals, so that more thanone mechanism may be operating to produce cell death inHD 59 .Although corpus striatum changes dominate the pathologicalpicture in HD, other areas of the brain are involved. The