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Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K (PK) digested abnormal prion protein (PrPres) identified on Western blotting (type 1 or type 2). These biochemically distinct PrPres types have been considered to represent potential distinct prion strains. However, since cases of CJD show co-occurrence of type 1 and type 2 PrPres in the brain, the basis of this classification system and its relationship to agent strain are under discussion. Different brain areas from 41 sCJD and 12 iatrogenic CJD (iCJD) cases were investigated, using Western blotting for PrPres and two other biochemical assays reflecting the behaviour of the disease-associated form of the prion protein (PrPSc) under variable PK digestion conditions. In 30% of cases, both type 1 and type 2 PrPres were identified. Despite this, the other two biochemical assays found that PrPSc from an individual patient demonstrated uniform biochemical properties. Moreover, in sCJD, four distinct biochemical PrPSc subgroups were identified that correlated with the current sCJD clinico-pathological classification. In iCJD, four similar biochemical clusters were observed, but these did not correlate to any particular PRNP 129 polymorphism or western blot PrPres pattern. The identification of four different PrPSc biochemical subgroups in sCJD and iCJD, irrespective of the PRNP polymorphism at codon 129 and the PrPres isoform provides an alternative biochemical definition of PrPSc diversity and new insight in the perception of Human TSE agents variability

La définition du vieillissement cérébral «normal» dépend de la définition de la normalité. La grande majorité des recherches a montré qu’il existait différentes catégories d’altérations morphologiques associées à l’âge: l’atrophie cérébrale due en partie à la perte neuronale, la pathologie cérébrovasculaire et les lésions de la maladie d’Alzheimer. Elles peuvent être considérées comme «normales» (dans un sens statistique) mais pourraient aussi bien être la conséquence d’affections particulièrement fréquentes chez la personne âgée. Le chiffre de dix pour cent de perte neuronale entre 20 et 100 ans a été avancé, et s’accompagne d’une plasticité des neurones qui survivent. Les lésions caractéristiques de la maladie d’Alzheimer ont été trouvées dans tous les cerveaux de centenaires, en nombre souvent minime, et localisées dans l’hippocampe (aire cérébrale indispensable à l’acquisition des nouveaux souvenirs). Ces lésions sont-elles le témoin d’une maladie d’Alzheimer qui débute et qui aurait évolué vers la démence si la durée de vie était de 150 ans? Ou sont-elles le témoignage du vieillissement normal qui ne ferait que s’accélérer lors de la maladie d’Alzheimer? Il n’y a actuellement pas de réponse, tant que le traitement médical de la maladie d’Alzheimer ne sera pas curatif., NEUROPATHOLOGY AND NORMAL AGING The definition of “normal aging” depends on the definition of normality. Different types of morphologic alterations are indeed associated with age: cerebral atrophy with neuronal loss, cerebrovascular pathology and Alzheimer type lesions. It is impossible to determine presently if they are to be considered normal or if they are the consequences of diseases that are particularly frequent in old age. It has been suggested that the neuronal loss reached 10% between the ages of 20 and 100. The effects of neuronal loss might be partly compensated by plasticity. Alzheimer type lesions have been described in all the centenarian’s brains that have been examined. They are frequently sparse, and located in the hippocampus (an area of the brain that is involved in memory acquisition). Are these lesions evidence of presymptomatic Alzheimer disease which would have caused dementia, had the patient lived longer? Should it be considered as “normal aging“? The question remains debated and will probably remain so, as long as Alzheimer disease will escape treatment.