The Sixth Sandbjerg Symposium, May 1992 Dementia Research in Denmark. The Danish Society of Neurosciences New strategies in dementia research Nordberg A Department of Pharmacology, Uppsala University, Uppsala, Sweden
Dementia is one of the major health problem confronting mankind in this century. The most common form is Alzheimer's disease and it constitutes 50-60% of all dementia disorders. Prevalence data suggest that 2% of the population aged over 65 are affected. The prevalence for Alzheimer's disease increases with age. In an ongoing study carried out in Stockholm the prevalence for women above 85 years of age was 32%. Alzheimer's disease can be described in terms of clinical symptoms, neuropsychological tests and laboratory investigations during life time while the final diagnosis is obtained first at postmortem histopathological examinations. The expected increasing number of demented individuals in the future stresses the need for diagnostic markers which enables early accurate diagnosis and possibilities to follow the progress of the disease and the effect of therapeutic interventions. The etiology of Alzheimer's disease is still unknown. For the early form the genetic influence is regarded to be of greater importance than for the late onset form. The recent discovery of mutations of the j%amyloid precursor gene in families with early onset of Alzheimer's disease accelerate the research concerning the hallmarks of the disease, the senile plaques and neurofibrillarytangles as well as the search for transgenic mouse model. Neurochemical studies performed in brain tissue obtained at autopsy from Alzheimer patients have revealed deficits in several neurotransmitter systems in the brain. The most consistent changes have been obtained for the cholinergic system which activity also best correlate with cognitive function. A drawback with postmortem studies is that they represent neurochemical changes at the end-stage of the disease. Imaging techniques such as positron emission tomography (PET) and single photon emission tomography (SPECT) will be important tools in the future in studying changes in brain of individuals with dementia disorders. Studies performed with PET in demented patients, especially patients with Alzheimer's disease, have up to now mainly concerned studies of cerebral blood flow and metabolism. Decrease in cerebral blood flow and energy metabolism (oxygen and glucose metabolism) have been reported to occur in cortical areas particularly in the parieto-temporal but also frontal areas of the brain. Metabolic activity
in deeper areas of the brain seem to be relatively preserved. PET studies of neurotransmitter function in Alzheimer patient have up to now concerned cholinergic neurotransmission. Due to losses of nicotine receptors in postmortem cortical tissue from Alzheimer patients attempts have been made to measure nicotinic receptors in vivo. By using "C-nicotine as a labelled ligand the distribution of nicotinic receptors have been traced by PET in brain of normal individuals as well as Alzheimer patients. The uptake of "C-nicotine is reduced in Alzheimer patients. A positive correlation between degree of dementia and uptake (S)( - )"C-nicotine has been observed. Both enantiomers of nicotine are used since (S)( - ) and (R)(+ )"C-nicotine reflect binding to two types of nicotinic receptors. A significant lower uptake of (R)( + )"C-nicotine has been measured in Alzheimer patients compared to healthy volunteers. Interestingly, the difference in uptake between the two enantiomers can be observed early in the course of the disease. The findings suggest the possibility of an early diagnostic marker. In the light of a cholinergic hypothesis in Alzheimer's disease therapeutic interventions have been made with drugs affecting the cholinergic system in brain. Promising results have been obtained with the cholinesterase inhibitor (THA). Several clinical trials been performed with THA but the clinical outcome of the treatment has been somewhat difficult to evaluate solely neuropsychological testings. The PET technique provides possibilities to study effects induced in brain and follow the effect of treatment by repeated PET investigations. A parallel increase in number of nicotinic receptors and in brain glucose utilization and neuropsychological testings has been observed in Alzheimer patients treated with THA. The findings was most significant when the treatment was initiated early in the course of the disease. Improved cerebral blood flow, number of nicotinic receptors as well as EEG have been measured in brain following 3 months infusion of nerve growth factor (NGF) intraventricularly to an 69-year-old Alzheimer patient. The PET technique will provide valuable information in the future concerning the effect and underlying mechanisms of potential drugs in dementia disorders.
Abstracts
Dementia research in Denmark Fog R Research Institute for Biological Psychiatry, St. Hans Hospital, Denmark
Dementia is a medical, sociological, and economic problem of enormous dimensions. The number of ageing people is rapidly increasing in the Western world. In USA the population of elderly is increasing at 2.5 times the rate of the general population. Among elderly Americans who are 65 years of age and older 11% have mild to moderate dementia and about 4% are severely demented. The number of individuals affected by Alzheimer’s disease can be expected to double by the year 2000 and to be 5 times as great by the year 2040. We have no exact knowledge of the etiology or pathogenesis of Alzheimer’s disease. There are still no diagnostic tests or biological markers. The clinical diagnoses are difficult because of the inhomogenous presen-
tation of symptoms. The diagnoses of Alzheimer’s disease can only be safely made post mortem. Therefore, research in the biology, sociology, psychology and clinical picture of dementia is very much needed. Danish research in dementia produces front-line investigations in the areas of molecular biology, genetics, neuromorphology, animal models, clinical and psychological investigations, neuropsychopharmacology, imaging techniques, etc. The different areas of dementia research should make bigger efforts in order to perform a synthesis, which might lead to a breakthrough in the understanding and the treatment of the dementia syndromes.
Neurotoxic and neurotrophic factors in Alzheimer dementia Jrargensen 0s Institute of Neuropsychiatry, University of Copenhagen, Rigshospitalet-6 102, Copenhagen, Denmark
Alzheimer disease (AD) cerebral degeneration accounts for about one-half of all cases of late life intellectual failures in Denmark. Recent research indicate that the disease might be initiated either by an overall rise in the transcription and translation of the gene for the Pamyloid precursor protein (BAPP) on chromosome 21 or by a selective increase in the fraction of BAPP that is metabolized to the 42 amino acid amyloid Ppeptide (ABP) and aggregated into amyloid plaques. (Review: Selkoe, D.J. 1991. The molecular pathology of Alzheimer’s disease. Neuron 6: 487-498). These plaques are surrounded by dystrophic nerve processes and are infiltrated by activated astrocytes and microglia cells. The amount of neuronal atrophy is a subject still under debate but in associative cerebral cortex and hippocampus clear evidence has been found for brain tissue shrinkage and for decreased efficacy of several neurotransmitter systems, including the cholinergic. Both in vitro, and in vivo in rats, strong neurotoxic activity of soluble ABP-like peptides has been demonstrated by Yankner and co-workers. In culture, they have shown that toxic-
ity was especially pronounced under conditions where ABP was present together with an appropriate neurotrophic factor. However, it has also been shown that protein-containing extracts from AD brains are more trophic than corresponding extracts from normal brains. By means of specific marker proteins (NCAM, D3 and GFAP) our research group has demonstrated increased synaptic remodelling in AD cortex concomitant with activation of astrocytes. Moreover, a high molecular weight soluble fraction of AD frontal cortex added to a primary culture of nerve cells was found to be more neurotrophic than a similar extract from normal frontal cortex. In conclusion, evidences are accumulating for a scenario in which increased accumulation of the BAPP metabolite ABP induces subtle degenerative processes in nerve cells and activation of astrocytes. Neurotrophic factors produced by the astrocytes might eventually accelerate the degenerative process through intensified synaptic remodelling. (Supported by grants from The Danish Medical Research Council, Eli and Egon Larsens Fond and Ivan Nielsens Fond).
Alzheimer’s disease and amyloid precursor protein Linnemann D The Protein Laboratory, University of Copenhagen, Panum Institute, Copenhagen, Denmark
In Alzheimer’s disease, a characteristic neuropathological finding is the amyloid plaques consisting mainly of the 42 amino acid long peptide, PA4. This peptide seems to play a central role in the pathogenesis of the disease. The PA4 peptide is derived from the larger amyloid precursor protein (APP) by proteolytic cleavage. APP is a glycosylated membrane protein which under normal circumstances is cleaved within the PA4 sequence thereby preventing the production of PA4 fragments. However overexpression of APP or structural changes
of the protein seem to facilitate an alternative cleavage mechanism which produce the PA4 fragment. The function of APP is not established. However, studies indicate that the protein is involved in cell adhesive phenomena. We are initiating studies of the adhesive function of APP using cell culture systems. APP is expressed in all cells investigated including primary cultures of rat astroglia and neurons. APP seems to be accumulated in processes suggesting a function in process extension.
533
Abstracts
Neuron network in an experimental set-up. focus on intracellular calcium Und6n M Research Institute of Biological Psychiatry, Sct. Hans Hospital, Roskilde, Denmark
Intracellular calcium is now established as a primary, secondary and tertiary cytosolic or intracellular signal transmitter. Calcium regulation may be a very important link uniting degeneration of cellular mechanisms in normal and pathologic aging. The ability to trace quantitatively and in real time the dynamics of this intracellular messenger systems in single cells and networks has become a tool in neuro biological research. The detection of intracellular calcium in dynamic
mode involving videomicroscopy and the fluorescent intracellular marker FURA-2 to measure calcium dynamics as a function of cellular stimulation is described. The complexity of the brains information processing capacity is addressed and the analog to in vitro neuron networks is described and examples of actual Alzheimer research given.
Molecular approaches towards understanding ageing Rattan SIS Laboratory of Cellular Ageing, Department of Chemistry, Aarhus University, Denmark
It is being progressively realized that the intrinsic process of ageing forms the basis of many diseases commonly associated with old age. These diseases include atherosclerosis, arthritis, amyloidosis, cataract, diabetes, osteoporosis, dementia and cancers of most types. Significant progress has been made regarding our understanding of the ageing process at physiological, cellular, biochemical and molecular levels. Recent approaches towards understanding ageing and elucidatingmolecular links between ageing and disease involve studies on the integrity and stability of the genome and the gene products. Particularly, studies on protein synthesis, post-translational modifications, stability and turnover of proteins during ageing and disease
will be crucial for understanding the mechanisms of age-related decline in the efficiency and the production of hormones, antibodies, neurotransmitters and other products. Similarly, studies on the components of protein synthesizing machinery (such as initiation factors, elongation factors, ribosomes and tRNAs) during ageing and agerelated diseases will be important in allowing the development of the new tools for diagnosis and for possible treatment of the disease. At the same time, methods of protein engineering and genetic manipulation may provide new strategies for prevention and cure of diseases of old age, the molecular basis of which lie in the process of ageing itself.
J~rgensenAL Cytogenetic Laboratory, Risskov, Denmark
In a collection of unselected brain specimens from patients that died in psychiatric hospitals in the period 1945-1981 we found 316 specimens with neuropathological diagnosis of Alzheimer’s disease. The age of death ranged from 43 to 97. Most of the late onset cases were not diagnosed clinically as Mb. Alzheimer, because Danish psychiatrists before 1975 used this diagnosis only in early onset cases. We devided the 316 patients into three groups: 1) 48 patients with age of onset before 55 years; 2) 125 patients with onset between age 55 and 65; 3) 143 patients with onset after age 65. Medical records and brain specimens from all patients in Group 1 have been re-examined and the Alzheimer diagnosis reconfirmed (3 of the originally 5 1 patients
534
were excluded; 1 was schizophrenic and 2 because of disagreement with previous histological diagnosis). We are in the midst of establishing which of the 48 cases familial. DNA from all 48 brain specimens in Group 1 has been extracted. The DNAs appear quite degraded on agarose gel with most of the fragments running in the 200-300 bp range. The DNA quality, however, allows for PCR amplification. Using BclI digestion we screened PCR products of exon 17 of the amyloid precursor protein (APP) gene for the Val-Ile (“Hardy”) mutation. None in Group 1 had the mutation and we are currently sequencing exon 17 of the APP gene from these patients.
Abstracts
New stereology on the neurosciences: neurostereology Pakkenberg B Neurological Research Laboratory, Bartholin Instituttet, Kommunehospitalet, Copenhagen, Denmark
The term stereology is now approximately 30 years old while “new” stereology has been used in the central nervous system - neurostereology - for five to six years. The remarkable efficiency of the new stereology has surprised established neuroscientists. The disector was first applied to brains of chronic schizophrenic patients and revealed a 40 and 50% decreased in total cell number in two regions of importance for that disease. A number of neurostereological studies has followed, mainly concentrating on the brain under normal circumstances, and recently expanding to diseased and experimental condi-
tions. For neuroscientists, the importance of unbiased stereology is just beginning to show. The biggest task to overcome is the lack of knowledge among most neurobiologists regarding the field of applied mathematics. Although the rules for everyday use of the disector, the nucleator, the rotator, etc. are indeed very simple, many still regard stereology as overwhelmingly difficult. This need not be the case and in fact stereology is a field in which both mathematicians and biologists may see the importance of each others work in a new and inspiring way.
Neuron loss in the aging human hippocampus West MJ, Gundersen HJG Stereological Research Laboratory, University of Aarhus, Denmark
There is a growing consensus that memory is a multi-component process that involves different parts of the brain. Specific components of this process are compromised to varying degrees during normal human aging, including the reduction in performance on tasks involving configurations and relationships. The identification of morphological correlates of age related memory deficits can contribute to a better understanding of senescent memory dysfunction and aid in the identification of the mechanisms involved in the apparent selectivity of the deficits. An attempt has been made to identify potential morphological correlates in terms of age-related neuron losses in specific subdivisions of the hippocampus, a region of the brain known to be intimately involved in relational memories that are known to decline with age, using recently developed stereological methods. The key features of the new methods are: systematic sampling of the entire structure, unbiased counting techniques, and optimized sampling strategies.
Through the application of these new methods, it has been possible for the first time to make unbiased estimates of the total number of neurons in each of the five major subdivisions of the hippocampus of a large number of subjects that ranged from 13 to 85 years of age. A significant negative correlation between total neuron number and age was found in two of the subdivisions, hilus and subiculum, representing losses of 31 % and 52% of the neurons in these regions, respectively, over the age range studied. There was no evidence of neuron loss in the three other subdivisions, dentate granule cell layer, CA3-2, or CAI, indicating that the age-related loss of neurons in the human hippocampus is regionally specific. The losses qualify as potential morphological correlates of senescent memory decline in that the resulting disruption in the circuitry of the hippocampus can be expected to compromise relational memory.
No neocortical nerve cell loss in brains from women patients with senile dementia of Alzheimer’s type Regeur L Neurological Research Laboratory, Bartholin Instituttet, Kornmunehospitalet, Copenhagen, Denmark
Over the last years stereological principles have been developed, which allow unbiased estimation of total neocortical neuron number. In this study, using the optical disector, precise estimates of total neuron number in neocortices of 11 women, mean age 82.6 years (range 79 to 88) with severe senile dementia of the Alzheimer’s type (SDAT) were compared with total neuron number in 10 age-matched normal women, mean age 84.1 years (range 74 to 92). The total nerve cell number in the SDAT group was 16.9.10’ with a coefficient of vari-
ation (CV) = 0.14, while total neuron number in the control group was 18.1.109, CV=O.18. The reduction of 6% in the SDATs is neither statistically nor biologically significant. All SDATs were severely demented, mean score 5.6 on 1-to-7-scale of dementia, and had multiple neocortical plaques (Bielschowsky silver stain). All the controls had lived an independent life at home until shortly before death and none had neocortical plaques. Neurological diseases, cerebral infarction and other brain pathologies were exclusion criteria in both groups.
535
Abstracts
Total neocortical neuronnumber in brains from chronic alcoholics Jensen GB Neurological Research Laboratorium, Bartholin Instituttet, Kommunehospitalet, Copenhagen A precise and unbiased stereological study of 11 chronic alcoholic and 11 control subjects showed no nerve cell loss in the neocortices of the alcoholic group. The total neocortical neuron number was 23.4 x lo9 in the alcoholic group and 23.2 x lo9 in the control group. The two groups were matched according to sex (males), age (46.8 yrs vs 46.9 yrs) and bodyheight (178.8 cm vs 176.5 cm). Macroscopic brain
differences were found: a 11% reduction in the volume fraction of white matter and a 30% reduction in the volume of archicortex in the alcoholics. The volume of the ventricles in the alcoholic group was enlarged by 26%, which was not statistically significant. This is the first study in which the total neocortical nerve cell number has been estimated in brains from alcoholic patients.
volumes were also estimated and only two statistically significant
Quantitation of the human cerebellum and volume estimation of Purkinje cells Andersen BB, Korbo L Neurological Research Laboratory, Bartholin Instituttet, Kommunehospitalet, Copenhagen, Denmark
Estimates of total number of neuron and glial cells types in cortex and the dentate nuclei of the human cerebellum were obtained using new stereological methods based on unbiased principles and estimators. The average total number of neurons and glial cells found using the optical disector/Cavalieri methods in the human cerebellum of five elderly men is 105000~106;of these the granule cells constitutes 101000~106and the Purkinje cells 30.5.106.The average number of neurons in the dentate nucleus is 5.01.106. Using a vertical design the average surface area of the human cerebellum was estimated to
1160 cm2. The nucleator was applied to estimate the volume of the large and unevenly distributed Purkinje cells. The mean volume of Purkinje cell perikaryon is 114000 pm3 with a coefficient of variation (CV = SD/mean) between individuals of 23 %. The data are compared with the mean Purkinje cell perikaryon volume in rats. These have been estimated to be 5300pm3 with a CV of 5%. Expectedly, the variation in Purkinje perikaryon volume between individuals are larger in humans than the individual variation between rats.
Learning and memory models for dementia including the Alzheimer type Christensen AV, Scheel-Kruger J Research Institute of Biological Psychiatry, St. Hans Hospital, Roskilde, Denmark
Recent years have seen a major expansion in the number of behavioral paradigms that have been proposed as animal models of dementia. The validity of animal models may be assessed on four sets of criteria: 1) The degree of symptomatic resemblance between the model and the clinical condition, 2) predictive validity concerning the extent to which the model responds appropriately to drugs that are clinically effective and those that are not, 3) similarity of the underlying mechanisms, and 4) similarity of inducing conditions. Based on these assumptions the models can be separated in 3 parts: Pharmacological, ethological/etiological and models based on lesions in specific brain areas. However there is a lot of overlap between the groups. The most important of these four criteria for a model is to show a maximum of sensitivity to different kinds of nootropics (absence of false negatives) while at the same time showing a maximum of selectivity (absence of false positive). Many of the early models involved the interaction of nootropic drugs with drugs of other pharmacological classes. In general, these procedures serve as bioassays for specific neurochemical
536
actions of dementia, and it has not been seriously proposed that they simulate the disease. Other groups of models were introduced on empirical grounds; they do not at present have a theoreficd context, but may at some points acquire one. The ethological/etiologicalmodels is optimal based on formation of pamyloid in mice, rats and monkeys, and studies in ages animals. Neuroscience work would be facilitated by a simplified model that could be used routinely. Lesion studies include neurotoxical, surgical and ischemic lesion in specific brain areas. These approaches have furthered our understanding of cognitive operations that involve the integration of multiple sensory stimuli leading to the production of complex behavioral adaptive responses. The existence of behavioral similarity to the clinical target would represent an important advantage in that such model would then be less likely to discover only “me-too” compounds. Furthermore the similarity to the clinical target is necessary for investigation of the etiology and pathogenesis of the disease.
Abstracts
Reversible dementia, indications for brain biopsy in dementia Gjerris F, Juhler
M, Garde L
University Clinic of Neurosurgery, Rigshospitalet, Copenhagen, Denmark
Dementia may occur at any age but is most common in patients above 65 years of age. Dementia is only a symptom. In the examination of a patient with symptoms and signs of dementia, it is vital to pay attention to the existence of reversible dementia. Important are metabolic and deficiency diseases, chronic subdural haematoma, normal pressure hydrocephalus and brain tumours, either located in the frontal lobe or in the midline ventricular system resulting in increased intracranial pressure (high pressure hydrocephalus). The main indi-
cation for brain biopsy in dementia has been to get a correct pathological diagnosis of predictive value for the prognosis. Moreover biochemical examinations of the tissue may lead to further knowledge in Alzheimer and Picks disease, in Creutzfeldt-Jacob disease and in chronic encephalitis as in children with genetic syndromes or disorders. It is to be emphasized, that a brain biopsy implies a risk of infection of haemorrhage and that the indication should be clearly defined.
Secundary psychiatric phenomena in Alzheimer’s disease. Borderland between psychiatry and neuropsychology Gulmann N Psychiatric Hospital, Risskov, Denmark
The symptoms of dementia are grouped around three areas: Cognetive defects, functional impairments and emotional disturbances. The emotional symptoms can be subdividet in behavioural disturbances and psychotic manifestations. The latter phenomena in dementia in Alzheimertype (AD) has until recently been neglected, though Alzheimerin his original paper described a patient with prominent delusions and hallucinations. In the last years it has been shown in several studies that delusions and hallucinations are common affecting between 30 and 80% of subjects with AD, that these symptoms tend to
be chronic and put a much greater strain on caregivers than the cognetive and functional defects. Neuropsychology seems to offer a more fertile understanding of the “Alzheimer-psychoses” than traditional psychopathology especially when combined with the concept of adaptation. The neuropathology of AD as an i.a. parietal disease together with the findings of Luria in wartime casualties can explain the agnostic misidentification-syndromes which are the most “neurological” or the manifestations of the Alzheimer-psychoses and the basis of several common delusional symptoms.
Autobiographical memory in normals and in demented patients (Alzheimer type) Fromholt F Department of Gerontopsychiatry, Risskov University Hospital, Aarhus, Denmark
Autobiographical memory in dementia has attracted considerable scientific interest in later years. According to traditional theories of regressive forgetting and clinical impressions old memories are preserved better than later one. This hypothesis has not been confirmed in experimental research. In our study comparing autobiographical memory in normal aging and dementia (Alzheimer type) by free narratives we find a chronological distribution across the life span show-
ing few memories from childhood, a peak in young adulthood and increase in recent years. With progression of dementia memories get increasingly inaccessible, they loose details and a temporal structure. Our findings are interpreted as reflecting internal mechanisms of the cognitive system and sociocultural and developmental determinants of memorability.
537
Abstracts
Incidence and prevalence of dementia in the Odense elderly, A project Lolk’ A, Nielsen2 H, Kragh-Ssrensen’ P, Odense University Hospital, Departments of ‘Psychiatry, 2Neurology, Odense, Denmark
The aim of the study is to examine the prevalence and incidence (over a three year period) of dementia among elderly aged 65 to 84 years inclusive. Five thousand persons aged 65 to 84 years, who live in Odense municipality, will be randomly drawn from the National Register. The first 150 individuals who accept to participate in the study will be evaluated by a psychiatrist, who administers The Cambridge Examination for Mental Disorders of the Elderly (CAMDEX). In addition, they receive a neuropsychological examination. Based on the normative data from this initial part of the study an optimal cut score for Cambridge Cognitive Examination (CAMCOG), which is a subsection of CAMDEX, will be determined. The remaining part of the sample will accomplish CAMCOG, and the subjects who score below the selected lower limit will be referred to further evaluation: A psychiatrist will administer the total CAMDEX, and in addition they will
receive a neuropsychological examination. The final diagnosis is determined at a consensus meeting. The diagnosis of Alzheimer’s disease (AD) will be based on the NINCDS-ADRDA Word Group criteria and the diagnosis of vascular dementia (VD) will be made in accordance with the DSM-111-R criteria. Dementia which cannot be classified as AD or VD is termed “other”. The severity of dementia is determined by means of the Global Deterioration Scale. Demented persons will undergo laboratory tests. Three years followingthe screening all surviving persons will be screened again, and new cases of dementia will be identified. If possible, demented persons who die during the three year period will undergo autopsy. The study is part of the European Community Concerted Action on the Epidemiology of Dementia (EURODEM).
Excitatory amino acids and serotonin in dementia Msller SE Research Institute for Biological Psychiatry, Department of Clinical Pharmacology, St. Hans Hospital, Roskilde, Denmark
The excitatory amino acids (EAAs) glutamate and aspartate are neurotransmitters of the hippocampus and cerebral cortex and are likely to play a role in memory and learning processes. There is evidence of a dysfunction of EAA pathways in Alzheimer’s disease (AD), and EAAs might be involved in the pathogenesis of AD by virtue of their excitotoxic properties. Hence, the EAA system associates with the distribution of pathology in AD and contributes in producing neurofibrillary tangles and neuronal disruption. There is furthermore evidence that presynaptic EAA neurons are damaged in AD, and the loss of cortical and hippocampal EAA receptors and ion channels is likely to further impair communication between various regions of cortex. Several amino acids affect neuronal EAA function, e.g., alanine is substrate for released glutamate, and glycine is co-agonist at the glutamate receptor, where it potentiates the activity of E M S . Taurine and GABA are two major inhibitory neurotransmitters, which antag-
538
onize EAA function. Taurine is reduced in the CSF of AD patients, and the post mortem GABA level is inversely correlated with the number of tangles in the hippocampus of patients with Down’s syndrome. However, in the case of amino acids in AD most data from brain samples are contradictory, mainly because of the difference between amino acid levels in biopsies collected ante mortem and post mortem, and because of the lack of informations about the duration and severity of the disease. A significant direct relationship between the levels of GABA and the serotonin precursor tryptophan has been shown in various human brain regions, and one of the most consistent findings in AD is a reduced serotonergic function. This may have relevance to the occurrence of the noncognitive symptoms aggressive behaviour and depressed mood in some patients with AD. However, there is suggestive evidence that serotonergic dysfunction may contribute also to the disturbed cognitive function.
Abstracts
SPECT with [ 99mTc]-d,l-HMPA0in dementia of the Alzheimer type: topographical heterogeneity of neocortical cerebral blood flow deficits Waldemar’ G, Bruhn’ P, Kristensen4 M, Johnsen‘ A, Lassen3 NA, Paulson’ OB Departments of ‘Neurology, *Radiology, University Hospital, Rigshospitalet, 3Clinical Physiology, Bispebjerg Hospital, 4Tranehaven Geriatric Rehabilitation Center, Copenhagen, Denmark
We studied regional cerebral blood flow (rCBF) with high resolution brain dedicated single photon emission computer tomography (SPECT) and [99”Tc]-d,l-hexamethyl-propylene-amine-oxime (HMPAO) in 25 patients with probable or possible Alzheimer’s disease (AD) and in 25 control subjects, selected according to rigorous inclusion and exclusion criteria. Cranial CT was without focal pathology in all patients and subjects. The median age patients as well as of the control subjects was 70 years (range: 53-83). The median Mini Mental Status score was 14 (range: 3-27). In the group of AD patients as a whole, diffuse reductions of rCBF were found in all neocortical regions as well as in the hippocampus, subcortical grey matter structures, and central white matter. Global CBF, relative to the cerebellum, was 74.2 f 9.0% in the AD group and 84.8 & 8.4% in the control group (p
Dementia is one of the major health problem confronting mankind in this century. The most common form is Alzheimer's disease and it constitutes 50-60% of all dementia disorders. Prevalence data suggest that 2% of the population aged over 65 are affected. The prevalence for Alzheimer's disease increases with age. In an ongoing study carried out in Stockholm the prevalence for women above 85 years of age was 32%. Alzheimer's disease can be described in terms of clinical symptoms, neuropsychological tests and laboratory investigations during life time while the final diagnosis is obtained first at postmortem histopathological examinations. The expected increasing number of demented individuals in the future stresses the need for diagnostic markers which enables early accurate diagnosis and possibilities to follow the progress of the disease and the effect of therapeutic interventions. The etiology of Alzheimer's disease is still unknown. For the early form the genetic influence is regarded to be of greater importance than for the late onset form. The recent discovery of mutations of the j%amyloid precursor gene in families with early onset of Alzheimer's disease accelerate the research concerning the hallmarks of the disease, the senile plaques and neurofibrillarytangles as well as the search for transgenic mouse model. Neurochemical studies performed in brain tissue obtained at autopsy from Alzheimer patients have revealed deficits in several neurotransmitter systems in the brain. The most consistent changes have been obtained for the cholinergic system which activity also best correlate with cognitive function. A drawback with postmortem studies is that they represent neurochemical changes at the end-stage of the disease. Imaging techniques such as positron emission tomography (PET) and single photon emission tomography (SPECT) will be important tools in the future in studying changes in brain of individuals with dementia disorders. Studies performed with PET in demented patients, especially patients with Alzheimer's disease, have up to now mainly concerned studies of cerebral blood flow and metabolism. Decrease in cerebral blood flow and energy metabolism (oxygen and glucose metabolism) have been reported to occur in cortical areas particularly in the parieto-temporal but also frontal areas of the brain. Metabolic activity
in deeper areas of the brain seem to be relatively preserved. PET studies of neurotransmitter function in Alzheimer patient have up to now concerned cholinergic neurotransmission. Due to losses of nicotine receptors in postmortem cortical tissue from Alzheimer patients attempts have been made to measure nicotinic receptors in vivo. By using "C-nicotine as a labelled ligand the distribution of nicotinic receptors have been traced by PET in brain of normal individuals as well as Alzheimer patients. The uptake of "C-nicotine is reduced in Alzheimer patients. A positive correlation between degree of dementia and uptake (S)( - )"C-nicotine has been observed. Both enantiomers of nicotine are used since (S)( - ) and (R)(+ )"C-nicotine reflect binding to two types of nicotinic receptors. A significant lower uptake of (R)( + )"C-nicotine has been measured in Alzheimer patients compared to healthy volunteers. Interestingly, the difference in uptake between the two enantiomers can be observed early in the course of the disease. The findings suggest the possibility of an early diagnostic marker. In the light of a cholinergic hypothesis in Alzheimer's disease therapeutic interventions have been made with drugs affecting the cholinergic system in brain. Promising results have been obtained with the cholinesterase inhibitor (THA). Several clinical trials been performed with THA but the clinical outcome of the treatment has been somewhat difficult to evaluate solely neuropsychological testings. The PET technique provides possibilities to study effects induced in brain and follow the effect of treatment by repeated PET investigations. A parallel increase in number of nicotinic receptors and in brain glucose utilization and neuropsychological testings has been observed in Alzheimer patients treated with THA. The findings was most significant when the treatment was initiated early in the course of the disease. Improved cerebral blood flow, number of nicotinic receptors as well as EEG have been measured in brain following 3 months infusion of nerve growth factor (NGF) intraventricularly to an 69-year-old Alzheimer patient. The PET technique will provide valuable information in the future concerning the effect and underlying mechanisms of potential drugs in dementia disorders.
Abstracts
Dementia research in Denmark Fog R Research Institute for Biological Psychiatry, St. Hans Hospital, Denmark
Dementia is a medical, sociological, and economic problem of enormous dimensions. The number of ageing people is rapidly increasing in the Western world. In USA the population of elderly is increasing at 2.5 times the rate of the general population. Among elderly Americans who are 65 years of age and older 11% have mild to moderate dementia and about 4% are severely demented. The number of individuals affected by Alzheimer’s disease can be expected to double by the year 2000 and to be 5 times as great by the year 2040. We have no exact knowledge of the etiology or pathogenesis of Alzheimer’s disease. There are still no diagnostic tests or biological markers. The clinical diagnoses are difficult because of the inhomogenous presen-
tation of symptoms. The diagnoses of Alzheimer’s disease can only be safely made post mortem. Therefore, research in the biology, sociology, psychology and clinical picture of dementia is very much needed. Danish research in dementia produces front-line investigations in the areas of molecular biology, genetics, neuromorphology, animal models, clinical and psychological investigations, neuropsychopharmacology, imaging techniques, etc. The different areas of dementia research should make bigger efforts in order to perform a synthesis, which might lead to a breakthrough in the understanding and the treatment of the dementia syndromes.
Neurotoxic and neurotrophic factors in Alzheimer dementia Jrargensen 0s Institute of Neuropsychiatry, University of Copenhagen, Rigshospitalet-6 102, Copenhagen, Denmark
Alzheimer disease (AD) cerebral degeneration accounts for about one-half of all cases of late life intellectual failures in Denmark. Recent research indicate that the disease might be initiated either by an overall rise in the transcription and translation of the gene for the Pamyloid precursor protein (BAPP) on chromosome 21 or by a selective increase in the fraction of BAPP that is metabolized to the 42 amino acid amyloid Ppeptide (ABP) and aggregated into amyloid plaques. (Review: Selkoe, D.J. 1991. The molecular pathology of Alzheimer’s disease. Neuron 6: 487-498). These plaques are surrounded by dystrophic nerve processes and are infiltrated by activated astrocytes and microglia cells. The amount of neuronal atrophy is a subject still under debate but in associative cerebral cortex and hippocampus clear evidence has been found for brain tissue shrinkage and for decreased efficacy of several neurotransmitter systems, including the cholinergic. Both in vitro, and in vivo in rats, strong neurotoxic activity of soluble ABP-like peptides has been demonstrated by Yankner and co-workers. In culture, they have shown that toxic-
ity was especially pronounced under conditions where ABP was present together with an appropriate neurotrophic factor. However, it has also been shown that protein-containing extracts from AD brains are more trophic than corresponding extracts from normal brains. By means of specific marker proteins (NCAM, D3 and GFAP) our research group has demonstrated increased synaptic remodelling in AD cortex concomitant with activation of astrocytes. Moreover, a high molecular weight soluble fraction of AD frontal cortex added to a primary culture of nerve cells was found to be more neurotrophic than a similar extract from normal frontal cortex. In conclusion, evidences are accumulating for a scenario in which increased accumulation of the BAPP metabolite ABP induces subtle degenerative processes in nerve cells and activation of astrocytes. Neurotrophic factors produced by the astrocytes might eventually accelerate the degenerative process through intensified synaptic remodelling. (Supported by grants from The Danish Medical Research Council, Eli and Egon Larsens Fond and Ivan Nielsens Fond).
Alzheimer’s disease and amyloid precursor protein Linnemann D The Protein Laboratory, University of Copenhagen, Panum Institute, Copenhagen, Denmark
In Alzheimer’s disease, a characteristic neuropathological finding is the amyloid plaques consisting mainly of the 42 amino acid long peptide, PA4. This peptide seems to play a central role in the pathogenesis of the disease. The PA4 peptide is derived from the larger amyloid precursor protein (APP) by proteolytic cleavage. APP is a glycosylated membrane protein which under normal circumstances is cleaved within the PA4 sequence thereby preventing the production of PA4 fragments. However overexpression of APP or structural changes
of the protein seem to facilitate an alternative cleavage mechanism which produce the PA4 fragment. The function of APP is not established. However, studies indicate that the protein is involved in cell adhesive phenomena. We are initiating studies of the adhesive function of APP using cell culture systems. APP is expressed in all cells investigated including primary cultures of rat astroglia and neurons. APP seems to be accumulated in processes suggesting a function in process extension.
533
Abstracts
Neuron network in an experimental set-up. focus on intracellular calcium Und6n M Research Institute of Biological Psychiatry, Sct. Hans Hospital, Roskilde, Denmark
Intracellular calcium is now established as a primary, secondary and tertiary cytosolic or intracellular signal transmitter. Calcium regulation may be a very important link uniting degeneration of cellular mechanisms in normal and pathologic aging. The ability to trace quantitatively and in real time the dynamics of this intracellular messenger systems in single cells and networks has become a tool in neuro biological research. The detection of intracellular calcium in dynamic
mode involving videomicroscopy and the fluorescent intracellular marker FURA-2 to measure calcium dynamics as a function of cellular stimulation is described. The complexity of the brains information processing capacity is addressed and the analog to in vitro neuron networks is described and examples of actual Alzheimer research given.
Molecular approaches towards understanding ageing Rattan SIS Laboratory of Cellular Ageing, Department of Chemistry, Aarhus University, Denmark
It is being progressively realized that the intrinsic process of ageing forms the basis of many diseases commonly associated with old age. These diseases include atherosclerosis, arthritis, amyloidosis, cataract, diabetes, osteoporosis, dementia and cancers of most types. Significant progress has been made regarding our understanding of the ageing process at physiological, cellular, biochemical and molecular levels. Recent approaches towards understanding ageing and elucidatingmolecular links between ageing and disease involve studies on the integrity and stability of the genome and the gene products. Particularly, studies on protein synthesis, post-translational modifications, stability and turnover of proteins during ageing and disease
will be crucial for understanding the mechanisms of age-related decline in the efficiency and the production of hormones, antibodies, neurotransmitters and other products. Similarly, studies on the components of protein synthesizing machinery (such as initiation factors, elongation factors, ribosomes and tRNAs) during ageing and agerelated diseases will be important in allowing the development of the new tools for diagnosis and for possible treatment of the disease. At the same time, methods of protein engineering and genetic manipulation may provide new strategies for prevention and cure of diseases of old age, the molecular basis of which lie in the process of ageing itself.
J~rgensenAL Cytogenetic Laboratory, Risskov, Denmark
In a collection of unselected brain specimens from patients that died in psychiatric hospitals in the period 1945-1981 we found 316 specimens with neuropathological diagnosis of Alzheimer’s disease. The age of death ranged from 43 to 97. Most of the late onset cases were not diagnosed clinically as Mb. Alzheimer, because Danish psychiatrists before 1975 used this diagnosis only in early onset cases. We devided the 316 patients into three groups: 1) 48 patients with age of onset before 55 years; 2) 125 patients with onset between age 55 and 65; 3) 143 patients with onset after age 65. Medical records and brain specimens from all patients in Group 1 have been re-examined and the Alzheimer diagnosis reconfirmed (3 of the originally 5 1 patients
534
were excluded; 1 was schizophrenic and 2 because of disagreement with previous histological diagnosis). We are in the midst of establishing which of the 48 cases familial. DNA from all 48 brain specimens in Group 1 has been extracted. The DNAs appear quite degraded on agarose gel with most of the fragments running in the 200-300 bp range. The DNA quality, however, allows for PCR amplification. Using BclI digestion we screened PCR products of exon 17 of the amyloid precursor protein (APP) gene for the Val-Ile (“Hardy”) mutation. None in Group 1 had the mutation and we are currently sequencing exon 17 of the APP gene from these patients.
Abstracts
New stereology on the neurosciences: neurostereology Pakkenberg B Neurological Research Laboratory, Bartholin Instituttet, Kommunehospitalet, Copenhagen, Denmark
The term stereology is now approximately 30 years old while “new” stereology has been used in the central nervous system - neurostereology - for five to six years. The remarkable efficiency of the new stereology has surprised established neuroscientists. The disector was first applied to brains of chronic schizophrenic patients and revealed a 40 and 50% decreased in total cell number in two regions of importance for that disease. A number of neurostereological studies has followed, mainly concentrating on the brain under normal circumstances, and recently expanding to diseased and experimental condi-
tions. For neuroscientists, the importance of unbiased stereology is just beginning to show. The biggest task to overcome is the lack of knowledge among most neurobiologists regarding the field of applied mathematics. Although the rules for everyday use of the disector, the nucleator, the rotator, etc. are indeed very simple, many still regard stereology as overwhelmingly difficult. This need not be the case and in fact stereology is a field in which both mathematicians and biologists may see the importance of each others work in a new and inspiring way.
Neuron loss in the aging human hippocampus West MJ, Gundersen HJG Stereological Research Laboratory, University of Aarhus, Denmark
There is a growing consensus that memory is a multi-component process that involves different parts of the brain. Specific components of this process are compromised to varying degrees during normal human aging, including the reduction in performance on tasks involving configurations and relationships. The identification of morphological correlates of age related memory deficits can contribute to a better understanding of senescent memory dysfunction and aid in the identification of the mechanisms involved in the apparent selectivity of the deficits. An attempt has been made to identify potential morphological correlates in terms of age-related neuron losses in specific subdivisions of the hippocampus, a region of the brain known to be intimately involved in relational memories that are known to decline with age, using recently developed stereological methods. The key features of the new methods are: systematic sampling of the entire structure, unbiased counting techniques, and optimized sampling strategies.
Through the application of these new methods, it has been possible for the first time to make unbiased estimates of the total number of neurons in each of the five major subdivisions of the hippocampus of a large number of subjects that ranged from 13 to 85 years of age. A significant negative correlation between total neuron number and age was found in two of the subdivisions, hilus and subiculum, representing losses of 31 % and 52% of the neurons in these regions, respectively, over the age range studied. There was no evidence of neuron loss in the three other subdivisions, dentate granule cell layer, CA3-2, or CAI, indicating that the age-related loss of neurons in the human hippocampus is regionally specific. The losses qualify as potential morphological correlates of senescent memory decline in that the resulting disruption in the circuitry of the hippocampus can be expected to compromise relational memory.
No neocortical nerve cell loss in brains from women patients with senile dementia of Alzheimer’s type Regeur L Neurological Research Laboratory, Bartholin Instituttet, Kornmunehospitalet, Copenhagen, Denmark
Over the last years stereological principles have been developed, which allow unbiased estimation of total neocortical neuron number. In this study, using the optical disector, precise estimates of total neuron number in neocortices of 11 women, mean age 82.6 years (range 79 to 88) with severe senile dementia of the Alzheimer’s type (SDAT) were compared with total neuron number in 10 age-matched normal women, mean age 84.1 years (range 74 to 92). The total nerve cell number in the SDAT group was 16.9.10’ with a coefficient of vari-
ation (CV) = 0.14, while total neuron number in the control group was 18.1.109, CV=O.18. The reduction of 6% in the SDATs is neither statistically nor biologically significant. All SDATs were severely demented, mean score 5.6 on 1-to-7-scale of dementia, and had multiple neocortical plaques (Bielschowsky silver stain). All the controls had lived an independent life at home until shortly before death and none had neocortical plaques. Neurological diseases, cerebral infarction and other brain pathologies were exclusion criteria in both groups.
535
Abstracts
Total neocortical neuronnumber in brains from chronic alcoholics Jensen GB Neurological Research Laboratorium, Bartholin Instituttet, Kommunehospitalet, Copenhagen A precise and unbiased stereological study of 11 chronic alcoholic and 11 control subjects showed no nerve cell loss in the neocortices of the alcoholic group. The total neocortical neuron number was 23.4 x lo9 in the alcoholic group and 23.2 x lo9 in the control group. The two groups were matched according to sex (males), age (46.8 yrs vs 46.9 yrs) and bodyheight (178.8 cm vs 176.5 cm). Macroscopic brain
differences were found: a 11% reduction in the volume fraction of white matter and a 30% reduction in the volume of archicortex in the alcoholics. The volume of the ventricles in the alcoholic group was enlarged by 26%, which was not statistically significant. This is the first study in which the total neocortical nerve cell number has been estimated in brains from alcoholic patients.
volumes were also estimated and only two statistically significant
Quantitation of the human cerebellum and volume estimation of Purkinje cells Andersen BB, Korbo L Neurological Research Laboratory, Bartholin Instituttet, Kommunehospitalet, Copenhagen, Denmark
Estimates of total number of neuron and glial cells types in cortex and the dentate nuclei of the human cerebellum were obtained using new stereological methods based on unbiased principles and estimators. The average total number of neurons and glial cells found using the optical disector/Cavalieri methods in the human cerebellum of five elderly men is 105000~106;of these the granule cells constitutes 101000~106and the Purkinje cells 30.5.106.The average number of neurons in the dentate nucleus is 5.01.106. Using a vertical design the average surface area of the human cerebellum was estimated to
1160 cm2. The nucleator was applied to estimate the volume of the large and unevenly distributed Purkinje cells. The mean volume of Purkinje cell perikaryon is 114000 pm3 with a coefficient of variation (CV = SD/mean) between individuals of 23 %. The data are compared with the mean Purkinje cell perikaryon volume in rats. These have been estimated to be 5300pm3 with a CV of 5%. Expectedly, the variation in Purkinje perikaryon volume between individuals are larger in humans than the individual variation between rats.
Learning and memory models for dementia including the Alzheimer type Christensen AV, Scheel-Kruger J Research Institute of Biological Psychiatry, St. Hans Hospital, Roskilde, Denmark
Recent years have seen a major expansion in the number of behavioral paradigms that have been proposed as animal models of dementia. The validity of animal models may be assessed on four sets of criteria: 1) The degree of symptomatic resemblance between the model and the clinical condition, 2) predictive validity concerning the extent to which the model responds appropriately to drugs that are clinically effective and those that are not, 3) similarity of the underlying mechanisms, and 4) similarity of inducing conditions. Based on these assumptions the models can be separated in 3 parts: Pharmacological, ethological/etiological and models based on lesions in specific brain areas. However there is a lot of overlap between the groups. The most important of these four criteria for a model is to show a maximum of sensitivity to different kinds of nootropics (absence of false negatives) while at the same time showing a maximum of selectivity (absence of false positive). Many of the early models involved the interaction of nootropic drugs with drugs of other pharmacological classes. In general, these procedures serve as bioassays for specific neurochemical
536
actions of dementia, and it has not been seriously proposed that they simulate the disease. Other groups of models were introduced on empirical grounds; they do not at present have a theoreficd context, but may at some points acquire one. The ethological/etiologicalmodels is optimal based on formation of pamyloid in mice, rats and monkeys, and studies in ages animals. Neuroscience work would be facilitated by a simplified model that could be used routinely. Lesion studies include neurotoxical, surgical and ischemic lesion in specific brain areas. These approaches have furthered our understanding of cognitive operations that involve the integration of multiple sensory stimuli leading to the production of complex behavioral adaptive responses. The existence of behavioral similarity to the clinical target would represent an important advantage in that such model would then be less likely to discover only “me-too” compounds. Furthermore the similarity to the clinical target is necessary for investigation of the etiology and pathogenesis of the disease.
Abstracts
Reversible dementia, indications for brain biopsy in dementia Gjerris F, Juhler
M, Garde L
University Clinic of Neurosurgery, Rigshospitalet, Copenhagen, Denmark
Dementia may occur at any age but is most common in patients above 65 years of age. Dementia is only a symptom. In the examination of a patient with symptoms and signs of dementia, it is vital to pay attention to the existence of reversible dementia. Important are metabolic and deficiency diseases, chronic subdural haematoma, normal pressure hydrocephalus and brain tumours, either located in the frontal lobe or in the midline ventricular system resulting in increased intracranial pressure (high pressure hydrocephalus). The main indi-
cation for brain biopsy in dementia has been to get a correct pathological diagnosis of predictive value for the prognosis. Moreover biochemical examinations of the tissue may lead to further knowledge in Alzheimer and Picks disease, in Creutzfeldt-Jacob disease and in chronic encephalitis as in children with genetic syndromes or disorders. It is to be emphasized, that a brain biopsy implies a risk of infection of haemorrhage and that the indication should be clearly defined.
Secundary psychiatric phenomena in Alzheimer’s disease. Borderland between psychiatry and neuropsychology Gulmann N Psychiatric Hospital, Risskov, Denmark
The symptoms of dementia are grouped around three areas: Cognetive defects, functional impairments and emotional disturbances. The emotional symptoms can be subdividet in behavioural disturbances and psychotic manifestations. The latter phenomena in dementia in Alzheimertype (AD) has until recently been neglected, though Alzheimerin his original paper described a patient with prominent delusions and hallucinations. In the last years it has been shown in several studies that delusions and hallucinations are common affecting between 30 and 80% of subjects with AD, that these symptoms tend to
be chronic and put a much greater strain on caregivers than the cognetive and functional defects. Neuropsychology seems to offer a more fertile understanding of the “Alzheimer-psychoses” than traditional psychopathology especially when combined with the concept of adaptation. The neuropathology of AD as an i.a. parietal disease together with the findings of Luria in wartime casualties can explain the agnostic misidentification-syndromes which are the most “neurological” or the manifestations of the Alzheimer-psychoses and the basis of several common delusional symptoms.
Autobiographical memory in normals and in demented patients (Alzheimer type) Fromholt F Department of Gerontopsychiatry, Risskov University Hospital, Aarhus, Denmark
Autobiographical memory in dementia has attracted considerable scientific interest in later years. According to traditional theories of regressive forgetting and clinical impressions old memories are preserved better than later one. This hypothesis has not been confirmed in experimental research. In our study comparing autobiographical memory in normal aging and dementia (Alzheimer type) by free narratives we find a chronological distribution across the life span show-
ing few memories from childhood, a peak in young adulthood and increase in recent years. With progression of dementia memories get increasingly inaccessible, they loose details and a temporal structure. Our findings are interpreted as reflecting internal mechanisms of the cognitive system and sociocultural and developmental determinants of memorability.
537
Abstracts
Incidence and prevalence of dementia in the Odense elderly, A project Lolk’ A, Nielsen2 H, Kragh-Ssrensen’ P, Odense University Hospital, Departments of ‘Psychiatry, 2Neurology, Odense, Denmark
The aim of the study is to examine the prevalence and incidence (over a three year period) of dementia among elderly aged 65 to 84 years inclusive. Five thousand persons aged 65 to 84 years, who live in Odense municipality, will be randomly drawn from the National Register. The first 150 individuals who accept to participate in the study will be evaluated by a psychiatrist, who administers The Cambridge Examination for Mental Disorders of the Elderly (CAMDEX). In addition, they receive a neuropsychological examination. Based on the normative data from this initial part of the study an optimal cut score for Cambridge Cognitive Examination (CAMCOG), which is a subsection of CAMDEX, will be determined. The remaining part of the sample will accomplish CAMCOG, and the subjects who score below the selected lower limit will be referred to further evaluation: A psychiatrist will administer the total CAMDEX, and in addition they will
receive a neuropsychological examination. The final diagnosis is determined at a consensus meeting. The diagnosis of Alzheimer’s disease (AD) will be based on the NINCDS-ADRDA Word Group criteria and the diagnosis of vascular dementia (VD) will be made in accordance with the DSM-111-R criteria. Dementia which cannot be classified as AD or VD is termed “other”. The severity of dementia is determined by means of the Global Deterioration Scale. Demented persons will undergo laboratory tests. Three years followingthe screening all surviving persons will be screened again, and new cases of dementia will be identified. If possible, demented persons who die during the three year period will undergo autopsy. The study is part of the European Community Concerted Action on the Epidemiology of Dementia (EURODEM).
Excitatory amino acids and serotonin in dementia Msller SE Research Institute for Biological Psychiatry, Department of Clinical Pharmacology, St. Hans Hospital, Roskilde, Denmark
The excitatory amino acids (EAAs) glutamate and aspartate are neurotransmitters of the hippocampus and cerebral cortex and are likely to play a role in memory and learning processes. There is evidence of a dysfunction of EAA pathways in Alzheimer’s disease (AD), and EAAs might be involved in the pathogenesis of AD by virtue of their excitotoxic properties. Hence, the EAA system associates with the distribution of pathology in AD and contributes in producing neurofibrillary tangles and neuronal disruption. There is furthermore evidence that presynaptic EAA neurons are damaged in AD, and the loss of cortical and hippocampal EAA receptors and ion channels is likely to further impair communication between various regions of cortex. Several amino acids affect neuronal EAA function, e.g., alanine is substrate for released glutamate, and glycine is co-agonist at the glutamate receptor, where it potentiates the activity of E M S . Taurine and GABA are two major inhibitory neurotransmitters, which antag-
538
onize EAA function. Taurine is reduced in the CSF of AD patients, and the post mortem GABA level is inversely correlated with the number of tangles in the hippocampus of patients with Down’s syndrome. However, in the case of amino acids in AD most data from brain samples are contradictory, mainly because of the difference between amino acid levels in biopsies collected ante mortem and post mortem, and because of the lack of informations about the duration and severity of the disease. A significant direct relationship between the levels of GABA and the serotonin precursor tryptophan has been shown in various human brain regions, and one of the most consistent findings in AD is a reduced serotonergic function. This may have relevance to the occurrence of the noncognitive symptoms aggressive behaviour and depressed mood in some patients with AD. However, there is suggestive evidence that serotonergic dysfunction may contribute also to the disturbed cognitive function.
Abstracts
SPECT with [ 99mTc]-d,l-HMPA0in dementia of the Alzheimer type: topographical heterogeneity of neocortical cerebral blood flow deficits Waldemar’ G, Bruhn’ P, Kristensen4 M, Johnsen‘ A, Lassen3 NA, Paulson’ OB Departments of ‘Neurology, *Radiology, University Hospital, Rigshospitalet, 3Clinical Physiology, Bispebjerg Hospital, 4Tranehaven Geriatric Rehabilitation Center, Copenhagen, Denmark
We studied regional cerebral blood flow (rCBF) with high resolution brain dedicated single photon emission computer tomography (SPECT) and [99”Tc]-d,l-hexamethyl-propylene-amine-oxime (HMPAO) in 25 patients with probable or possible Alzheimer’s disease (AD) and in 25 control subjects, selected according to rigorous inclusion and exclusion criteria. Cranial CT was without focal pathology in all patients and subjects. The median age patients as well as of the control subjects was 70 years (range: 53-83). The median Mini Mental Status score was 14 (range: 3-27). In the group of AD patients as a whole, diffuse reductions of rCBF were found in all neocortical regions as well as in the hippocampus, subcortical grey matter structures, and central white matter. Global CBF, relative to the cerebellum, was 74.2 f 9.0% in the AD group and 84.8 & 8.4% in the control group (p
