PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/113728 Please be advised that this information was generated on 2021-10-11 and may be subject to change. THE HIPPOCAMPAL FORMATION IN NORMAL AGING AND ALZHEIMER'S DISEASE A MORPHOMETRIC STUDY HARKE DE VRIES THE HXX'X'OCÄJVLE'AX. FOFtlVITVrX CMST I IST JsiORjyrzvx. ÍVGXISÍ<3 ÎVISTD г х^ZH:E:xiynE:R » s XiXSEASE г^. ІУІОЬІ^НОІУЕЕТІІХС; STXXDY THE HIPPOCAMPAL FORMATION IN NORMAL· AGING AND ALZHEIMER'S DISEASE A MORPHOMETRIC STUDY een wetenschappelijke proeve op het gebied van de geneeskunde en tandheeIkunde Proefschrift ter verkrijging van de graad van doctor aan de Katholieke Universiteit te Nijmegen volgens besluit van het college van decanen in het openbaar te verdedigen op woensdag 21 februari 1990 des namiddags te 1.30 uur precies door geboren op 27 augustu199s 0195 7 te Badhocvedorp Drukkerij Leijn te Nijmegen Promotores: Prof. dr. R. Nieuwenhuys Prof. dr. G.J. ZwaniJOcen Co-promotor: Dr. J. Meek ...In the beginner's mind there is no thought "I have attained something"... (Shunryu Suzuki, in: Zen Mind, Beginner's Mind) Dedicated to my mother, In memory of my father. ISBN 90-9003283-5 CONTENTS CHAPTER 1 GENERAL INTRODUCTION 2 1.1 Epidemiology of Alzheimer's disease 3 1.2 Diagnosis of Alzheimer's disease 4 1.3 Hypotheses on the etiology of Alzheimer's disease....4 1.4 Infectious agents 5 1. 5 Neurotoxic agents 6 1.6 Dysfunction of the blood-brain barrier 6 1.7 Neurotransmitter and receptor deficiencies, neurotransmitter cytotoxicity 7 1. 8 Genetic factors 8 1. 9 Deposition of abnormal proteins 9 1.10 The neuroanatomical perspective on Alzheimer's disease 11 CHAPTER 2 THE HIPPOCAMPAL FORMATION, AIM OF THE STUDY 2.1 Gross anatomy of the hippocampal formation 15 2.2 Structure and microscopic anatomy of the hippocampal formation, the pre- and parasubiculum and of the entorhinal and perirhinal cortices 19 2.3 Some remarks on the history of the terms "hippocampus", "pes hippocampi" and "cornu ammonis" ( "Ammon's horn" ) 35 2.4 A brief description of the phylogenesis and the morphogenesis of the hippocampal formation and of the entorhinal cortex 36 2.5 The histogenesis of the hippocampal formation and of the entorhinal cortex 39 2.6 Connections of the hippocampal formation, the presubiculum and the parahippocampal cortex 43 2.7 Atlas of the hippocampal formation 59 2.8 Considerations on the functions of the hippocampal formation 64 2.9 Distribution of neuropathological features within the hippocampal formation in Alzheimer's disease and normal aging, with emphasis on neurofibrillary tangles and senile plaques, as reported in the literature 74 2.10 Aim of the study 82 CHAPTER 3 MATERIALS AND METHODS 3. 1 Microscopy 88 3.2 Macroscopy 88 3.3 Histological procedures 89 3.4 "Systematic random sampling" 90 3.5 Surface areas of hippocampal subfields per section 91 3.6 Seni le plaques 93 3.7 Neurofibrillary tangles 93 3.8 Neuronal densities 94 3.9 Towards neuronal numbers per hippocampus 95 3.10 The shape and size of the normal hippocampus 96 3.11 The volumes of the sampled hippocampal subfields....99 3.12 Calculation of neuronal numbers 100 3.13 Statistical analysis 100 CHAPTER 4 RESULTS 4.1 Senile plaques 103 4.2 Neurofibrillary tangles 106 4.3 Neuronal density 109 4.4 The volume of pyramidal cell layers 109 4.5 cell loss Ill 4.6 Comparison and correlations of SP's, NFT's and cell loss in the hippocampal formation and parahippocampal cortices in AD 112 4.7 Summarizing illustrations of the distribution patterns of senile plaques, neurofibrillary tangles and pyramidal cell loss 117 CHAPTER 5 GENERAL DISCUSSION 5 .1 Seni le Plaques 140 5.2 Neurofibrillary tangles 141 5 . 3 Pyramidal cell loss 143 Ь.4 Possible causes of selective CAI vulnerability 146 5.5 General conclusions on hippocampal damage in AD....147 5.6 Some final remarks 153 CHAPTER 6 SUMMARY 156 SAMENVATTING 160 REFERENCES 164 DANKWOORD 180 CURRICULUM ІТЛЕ 181 CONTENTS OF CHAPTER 1 1.1 Epidemiology of Alzheimer's disease 1.2 Diagnosis of Alzheimer's disease 1.3 Hypotheses on the etiology of Alzheimer's disease 1.4 Infectious agents 1.5 Neurotoxic agents 1.6 Dysfunction of the blood-brain barrier 1.7 Neurotransmitter and receptor deficiencies, neurotransmitter cytotoxicity 1.8 Genetic factors 1.9 Deposition of abnormal proteins 1.10 The neuroanatomical perspective on Alzheimer's disease 1 GENERAL INTRODUCTION On the 37tri meeting of the "Verein fur sudwestdeutsche Irrenartzte" in Tubingen on the 3·"Λ and 4tn of November in 1906 the german psychiatrist Alois Alzheimer from Munich presented a lecture entitled "Über eine eigenartige Erkrankung der Hirnrinde": the case of a 51 year old woman who showed a broad spectrum of psychopathologie symptoms, the first of which were paranoic delusions. In the course of the diseabe the deterioration of this woman's cognitive functioning ("allgemeine Verblödung"), resulting in a complete state of amnesia, apraxia and agnosia , became more and more outstanding. After a 4ικ7 years duration of the illness the patient died in a state of complete deterioration ("völlig stumpf"). At autopsy the brain of this patient macroscopically showed a regular atrophy with no macroscopic foci and an artenosclens of the greater vessels. Microscopic examination of the Bielschowski-stamed sections of the neocortex showed "a very peculiar transformation of the neuroiilamenLs" within the nerve cells, eventually resulting in cell-death, and replacement of the nerve cell by a "curled up bundle of filaments". Although the origin of this pathological change of neurofilaments remained unclear, Alzheimer suggested that this mtracellulary change, now known as "neurofibrillary tangle" (NFT), was due to disease- transformed neurofilaments with deposition of a morbid product of neuronal metabolism (Alzheimer, 1907). Alzheimer would probably not have had the slightest idea that this case history, the first publication of which was only the title of the lecture (Alzheimer, 1906), was the beginning of the gigantic investigation effort that has been performed everywhere in the world, up to now, into every possible aspect of the disease that, after the nosology of Kraepelin (1910), is now known as Alzheimer's disease (AD), or, when the onset of the disease is after the age of 65 years, senile dementia of the Alzheimer type (SDAT). The aim of the general introduction of this thesis is to give some data obtained in epidemiologic research, as well as to report some of the hypotheses on the pathogenesis of the disease. Before focussing on the latter issue, the criteria for the 2 clinical diagnosis of "probable Alzheimer's disease" and the neuropathologic diagnosis of Alzheimer's disease will be discussed. 1.1 EPIDEMIOLOGY OF ALZHEIMER'S DISEASE One of the reasons of the ever-growing research effort into Alzheimer's disease is the fact that in the developed as well as in the less developed countries there is an increase of the elderly population compared to the younger. Epidemiological studies have shown that, although other factors have been mentioned, age is the most important risk factor for acquiring Alzheimer's disease. With the doubling of the population of the very old within one generation, this would mean that there is coming an epidemic of dementia and, since more than 50% of the dementias is caused by Alzheimer's disease, of Alzheimer's disease (Henderson, 1986). Apart from the human drama that is behind every single case of this dreadful disease which eventually "evaporates" the human personality, there is also an economic aspect linked to it. A reasonable estimate for the dutch population is that 5% of the people of 65 years of age and older suffers from a severe form of dementia, a total of 80.000-100.000 people (Schulte, 1989), whereas at present in the nursing homes in the Netherlands there are only about 50.000 beds available, 20.000 of which are reserved for psychogeriatric patients. The nursing costs in the nursing homes amount to Hfl. 200,= a day at present. It is estimated that with the same quality of care, in the year 2000, a total 61.200 beds, 25.000 of which for the psychogeriatric patients, are needed in the nursing homes (Schrijvers, 1989). Furthermore, in ten years from now, the population of people of 65 years and older will be increased with 20% and the group of 85 years and older, with a prevalence of severe dementia of about 20%, will be increased with 40% (Henderson, 1986)! There is no need to further illustrate the enormous extra economic burden, which will be more in the order of billions than of millions of guilders, this increase will place on the community to nurse these severely demented people. 3 1.2 DIAGNOSIS OF ALZHEIMER'S DISFASE The original definition of Alzheimer's disease was based on the pathologic lesions that were found in microscopical examination of brain tissue. This neuropathologic confirmation is still needed for the definitive diagnosis of Alzheimer's disease (McKhann et al., 1984; Khachaturian, 198Ь; Tierney et al., 1988). The clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions with an intact consciousness. There are no motor, sensory or coordination deficits early in the disease (McKhann et al., 1984). On clinical grounds the diagnosis of Alzheimer's disease can be established with an accuracy of 81%- 88% (Tierney et al., 1988). It should be emphasized that clinical criteria can only establish the diagnosis of probable Alzheimer's disease, and that it is very important to exclude systemic disorders or other brain diseases that in and of themselves could account for the progressive deficits in memory and cognition and some of which are reversible.