Incidence of Dementia in Very Elderly Individuals: A Clinical, Neuropathological and Molecular Genetic Study

Department of Pathology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Neuroepidemiology (Impact Factor: 2.56). 02/2006; 26(2):76-82. DOI: 10.1159/000090252
Source: PubMed


To evaluate the effect of medical record use on figures for the incidence of dementia and the effect of apolipoprotein E (APOE) polymorphism on this incidence and neuropathologically defined Alzheimer's disease (AD) in very elderly individuals.
Cognitive functions were examined in a cohort of 328 (92% of the very elderly people of a town participated in this study) nondemented Finnish elderly individuals 85 years of age or more in 1991. The examination was repeated in survivors in 1994, 1996, 1999 and 2001. Medical notes and social work records were evaluated. All these individuals were genotyped for APOE. Neuropathological analysis of AD-type pathology was performed on 159 of 303 subjects who died during the follow-up.
Age group, gender or APOE did not significantly affect the incidence of dementia, which was over 20% higher (85 vs. 69 per 1,000 person-years) if the cognitive status at death was ascertained by medical and social work records than without this evaluation. The APOE upsilon4 allele was highly significantly (p=0.002) and age almost significantly (p=0.06) associated with neuropathological AD in nondemented individuals.
Medical records should be analyzed in studies on the incidence of dementia in very elderly individuals. APOE polymorphism does not affect the incidence of dementia in this age group. However, clinical dementia diagnosis in very elderly individuals does not necessarily correlate well with the presence of neuropathological AD which, even in this age group, is significantly associated with the APOE upsilon4 allele.

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    ABSTRACT: Populations in developed countries are ageing fast. The elderly have the greatest incidence of de-mentia, and thus the increase in the number of demented individuals, increases the immediate costs for the governments concerning healthcare and hospital treatment. Attention is being paid to disorders behind cognitive impairment with behavioural and psychological symptoms, which are enormous contributors to the hospital care required for the elderly. The highest dreams are in prevention; however, before discovering the tools for preventing dementia, the pathogenesis behind dementia disorders needs to be understood. Dementia with Lewy bodies (DLB), a relatively recently discovered dementia disorder compared to Alzheimer’s disease (AD), is estimated to account for up to one third of primary degenerative dementia, thus being the second most common cause of dementia in the elderly. Nevertheless, the impact of neuropathological and genetic findings on the clinical syndrome of DLB is not fully established. In this present series of studies, the frequency of neuropathological findings of DLB and its relation to the clinical findings was evaluated in a cohort of subjects with primary degenerative dementia and in a population-based prospective cohort study of individuals aged 85 years or older. α-synuclein (αS) immunoreactive pathology classifiable according to the DLB consensus criteria was found in one fourth of the primary degenerative dementia subjects. In the population-based study, the corresponding figure was one third of the population, 38% of the demented and one fifth of the non-demented very elderly Finns. However, in spite of the frequent discovery of αS pathology, its association with the clinical symptoms was quite poor. Indeed, the common clinical features of DLB, hypokinesia and visual hallucinations, associated better with the severe neurofibrillary AD-type pathology than with the extensive (diffuse neocortical) αS pathology when both types of pathology were taken into account. The severity of the neurofibrillary AD-type pathology (Braak stage) associated with the extent of αS pathology in the brain. In addition, the genetic study showed an interaction between tau and αS; common variation in the αS gene (SNCA) associated significantly with the severity of the neurofibrillary AD-type pathology and nominally significantly with the extensive αS pathology. Further, the relevance and temporal course of the substantia nigra (SN) degeneration and of the spinal cord αS pathology were studied in relation to αS pathology in the brain. The linear association between the extent of αS pathology in the brain and the neuron loss in SN suggests that in DLB the degeneration of SN proceeds as the αS pathology extends from SN to the neocortex instead of early destruction of SN seen in Parkinson’s disease (PD). Furthermore, the extent of αS pathology in the brain associated with the severity of αS pathology in the thoracic and sacral autonomic nuclei of the spinal cord. The thoracic αS pathology was more common and more severe compared to sacral cord, suggesting that the progress of αS pathology proceeds downwards from the brainstem towards the sacral spinal cord. Väestön jatkuvasti ikääntyessä Lewyn kappale -dementian ja muiden dementoivien sairauksien merkitys lääketieteellisenä, sosiaalisena sekä taloudellisena ongelmana lisääntyy. Tutkimuksen aiheena oli selvittää immunohistokemiallisin menetelmin Lewyn kappale -dementia -nimiseen rappeuttavaan eli degeneratiiviseen aivosairauteen liittyvien neuropatologisten löydöksien esiintyminen yli 85-vuotiailla henkilöillä ja yksilöissä joilla esiintyy myös jokin muu rappeuttava aivosairaus. Erityisenä kiinnostuksen kohteena oli α-synukleiini -niminen proteiini, jota kertyy keskushermoston soluihin Parkinsonin taudissa, Lewyn kappale -dementiassa ja muissa rappeuttavissa aivosairauksissa kuten Alzheimerin taudissa (AT), mutta lisäksi α-synukleiini -kertymiä tavataan myös normaaliin ikääntymiseen liittyen. Tehdyssä työssä selvitettiin myös missä määrin α-synukleiini -kertymät/ patologia ovat oireita aiheuttavia, ja vaikuttaako niiden esiintyvyyteen geenivariaatiot. Tutkimuksessa α-synukleiini patologian esiintyvyys määritettiin kuoleman jälkeen irrotetuista kudosnäytteistä, joiden lisäksi oli käytettävissä potilasmateriaaleihin liittyvät kliiniset tiedot ja geneettiset arvot. Tutkittavana oli väestöotokseen perustuvan 304 ikäihmisen aivo- ja selkäydinnäytteet sekä 55 rappeuttavaa aivosairautta sairastaneen henkilön aivokudosnäytteet. Geneettinen variaatio arvioitiin 272 ikäihmisestä. Suurin osa tätä ennen saadusta tutkimustiedosta perustuu nuorempaan potilasmateriaaliin. Lisäksi tähän asti on ollut epäselvää mikä on α-synukleiini patologian merkitys, sillä monissa aiemmissa tutkimuksissa α-synukleiini -kertymien on automaattisesti ajateltu olleen yhteydessä henkilöiden elämänaikaisiin oireisiin. Ensimmäisessä osajulkaisussa osoitettiin, että 29%:lla muuta rappeuttavaa aivosairautta sairastavalla esiintyy samanaikaisesti α-synukleiini patologiaa keskushermostossa, ja heistä 25%:lla patologia oli jakautunut Lewyn kappale –dementialle tyypillisesti. Toisessa osatyössä osoitettiin, että ikäihmisillä Lewyn kappale –dementiaksi luokiteltava α-synukleiini patologia on vieläkin yleisempää ja esiintyy 32%:lla koko tutkitusta väestöstä, 38%:lla dementoituneista, ja 20%:lla niistä joilla dementoitumista ei oltu todettu. α-synukleiini patologia ennusti kliinistä Lewyn kappale -dementian oireistoa heikosti (ennustearvo oli keskinkertainen 13%:lla ja korkea 13%:lla). Lisäksi korkean ennustearvon omaavista vain 77% oli dementoituneita. Kliininen Lewyn kappale -dementian oireisto oli voimakkaammin yhteydessä AT:lle ominaiseen neurofibrillipatologiaan kuin α-synukleiini patologiaan. Kolmannessa osatyössä todettiin, että α-synukleiinin geenivariaatiot vaikuttavat sekä vahvasti neurofibrillipatologiaan (hyperfosforyloitunut tau-proteiini) että heikommin α-synukleiini patologiaan. Neljännessä osatyössä todettiin ikäihmisillä α-synukleiini patologian esiintyvän yleisesti myös tahdosta riippumattoman eli autonomisen hermoston selkäytimen tumakkeissa. Tämä havaittiin eritoten niillä joilla α-synukleiini patologiaa oli laajalti levinneenä myös aivoissa.
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