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Antemortem markers of Alzheimer's disease: A commentary
402
ROTH
Current theories regarding the etiology of Alzheimer's Disease tend to derive from one of four possible causes: (l) a genetically acquired autosomal dominant trait, (2) a slow viral infection, (3) an environmental toxin, or (4) a systemic metabolic illness. The evidence favoring an autosomal dominant trait is impressive, but vehemently contested on the basis of methodological criticisms. At best, it appears that the type of AD inherited accounts for a subgroup of the total of patients with the diagnosis. The trait is a more prominent feature of AD in late life rather then in the middle aged group and its expression seems to correlate with advanced age. The other possible causes have less firm evidence in their support. The possibility of a slow virus responsible for AD is among the earliest of our theories, succeeded only by prejudice that dementia was a consequence of aging or an acceleration of a basically normal process. Other than face validfly, there is no convincing data that AD is viral. Information concerning environmental toxins or systemic illnesses is even less convincing. Aluminum, while potentially toxic, has been largely discounted as a cause of AD and no other toxin has been found to correlate with the disease. The general decline in many of the body and organ systems reviewed by the authors, is an area easily eclipsed by the profound loss of memory and personality that is so devastating to the patient and the patient's family. However, it is an important area for more investigation, and this work should promote more interest and attention to systems other than the CNS. in spite of our best efforts, the situation is perhaps best summarized by Dr. Peter Whitehouse, from Johns Hopkins University, who comments that " o u r understanding of the
disease is a m ess" [1]. Most of the signs and symptoms observed in patients currently diagnosed as having AD result from impairment of poorly defined cognitive spheres, affectire changes, or personality changes. All of these features comprise a nonspecific "final common pathway" for a host of known and reversible dementias and CNS injuries. The absence of any of these known dementias is the best and. more or less, only diagnostic criteria we have for AD. It is certain that the current criteria are vastly over inclusive and account for the 30% of these patients, described by the authors, "found to be not demented or to have another neurological disorder." The ability to accurately diagnose AD is crucial to progress in research and treatment of the illness. Efforts directed toward rigorous research criteria will perhaps enable us to begin to define and identify a population of patients with a high degree of reliability on the basis of their antemortem symptoms and postmortem findings. On the basis of information obtained from this smaller, but clearly defined group of patients, it may be possible to then develop a body of knowledge about this illness or collection of illnesses we described as Alzheimer's Disease. Drs. Hollander, Mohs and Davis provide us with a thoughtful , carefully selected review of the medical side of AD. Their work is extremely valuable and useful to workers in the field. While it is evident from their review that current theories and research have hardly made a dent in increasing our understanding of the illness, it provides a perspective of where we have been and an encouragement to redouble el'forts to establish reliable diagnostic criteria and to conduct intensive research into the causes of AD,
REFERENCE 1. Whitehouse, P. Alzheimers Disease, A Multi-System Disorder: Implications for the Development of a Therapy. Presented at the New Clinical Drug Evaluation Unit Program, May 27, 1986.
Antemortem Markers of Alzheimer's Disease" A Commentary SIR MARTIN ROTH
l)'initv College, Cambridge, England
The authors have performed a valuable service in their comprehensive review of the literature of antemortem markers in Alzheimer's disease. The discovery of objective and reliable indices in vivo of an illness of obscure causation, constitutes an important forward step in scientific progress towards its accurate diagnosis and discovery of its aetiology. When markers that have a satisfactory correlation with clinical diagnosis on the one hand and post mortem findings on the other have been developed, an acceleration of progress almost invariably follows.
T H E review by Hollander, Davis and Mohs is largely devoted to evaluation of knowledge in respect of neuropharmacological, neurochemical and neuroendocrine markers: the results achieved and the progress foreshadowed in the field of brain imaging are also reviewed. A few basic issues could, with advantage, have been discussed in more detail.
One question that demands a clear answer is the criterion against which the specificity and validity of any markers discovered should be tested. The ultimate criterion in the case of the disease described by Alzheimer has to be the neuropathological change to be found in the brain. For the large part this has to be determined by post mortem investi-
COMMENTARY gation. Brain biopsy can rarely be ethically justified since it will hardly ever yield information of value for the treatment of the individual patient that cannot be obtained by detailed clinical examination and a few laboratory tests. And evidence from post mortem findings entails a long and difficult uphill path since it is rarely possible to follow patients for an adequate period in the community or in hospital and then to secure permission for autopsy in more than a small proportion of patients and control subjects who have been investigated in sufficient depth and detail during life. As this yield will be inevitably small, a very large cohort of patients-and controls would have to be investigated with a given marker for neuropathological evaluation of its discriminating value. This is certainly one type of enquiry that has to be undertaken in the neurobiological study of Alzheimer's disease. But there are many reasons why reliance in the area under discussion should not be placed exclusively on this protracted and costly exercise. Clinical diagnosis provides the usual standard by which the value of antemortem markers has to be estimated. They must in the first instance show an acceptably high correlation with a diagnosis of Alzheimer's disease which has been firmly established. This is the bedrock upon which all biological correlates of psychiatric disorder have to be founded. Of course it is a pre-condition that clinical diagnosis should have been shown to have reached an acceptable level of reliability and validity. But the authors cite some observations which call this in question in the case of Alzheimer's disease. They quote two long term follow-up studies in which the diagnosis of Alzheimer's disease proved erroneous in as many as thirty percent of cases. Each was concerned with the relatively rare 'presenile' forms, from which generalisations should not be made. But this misrepresents the real situation. Moreover, when the diagnosis has been made by a number of different observers using a variety of criteria, drawing upon observations sustained for different periods, discrepancies and errors are unavoidable. It is the irreducible error inherent in making a clinical diagnosis which requires to be determined for scientific purposes; the errors that occur in the course of ordinary clinical practice are of little relevance from this point of view. To determine the accuracy of diagnosis and the extent to which it is upheld over long periods of observation, optimal conditions have to be created to ensure that all relevant sources of information have been drawn upon for the purpose. This demands a standardised interview (a number of satisfactory schedules are now available), systematic evaluation of the mental state which has to be set in the context of the patient's previous history, developmental record and personality. It must include information obtained from an independent observer and a period of observation of the patient while he is engaged in coping with the demands of everyday life. Neuropsychological tests are valuable adjuncts, but a diagnosis that will stand the test of time cannot be extracted from the results of measures of cognitive function alone. Operational criteria for the diagnosis of Alzheimer's disease should be employed and strictly adhered to by all those who participate in a given inquiry into the reliability of clinical diagnosis or its correlation with any hypothetical antemortem marker. It may appear supererogatory to spell out such obvious points. But in none of the enquiries often quoted to establish the inherent unreliability of a clinical diagnosis of Alzheimer's disease have all these conditions been met. It is also incorrect to state that Alzheimer's disease is " . . . a diagnosis of exclusion" and that " . . . a definitive diagnosis
403 of Alzheimer's disease (AD) can only be made at autopsy, or in rare cases with brain b i o p s y . " The symptomatic organic syndromes due to such causes as vitamin B~2 deficiency, hypothyroidism, parathyroid disorders, niacin deficiency disorder or 'silent' hyperthyroidism of late onset can almost invariably be differentiated from Alzheimer's disease by painstaking clinical examination. In many cases the condition is a subacute clouded or delirious state of fluctuating severity and of some months' duration, rather than dementia proper. In those symptomatic cases in which the criteria for the diagnosis of dementia are met the clinical picture presents a less global encroachment upon the individual's cognitive emotional and conative functions and his characteristic behavioural traits. Emotional responses and personality are also far better preserved except in the viral encephalopathies. But the latter pursue a rapid fulminating course over a period of weeks or months. This never occurs in Alzheimer's disease. In each of the symptomatic forms, detailed examination and appropriate laboratory tests of a relatively simple and accessible kind will serve to establish whether one deals with a symptomatic dementia such as that due to a metabolic disorder or a " p r i m a r y " dementia with the pathology of Alzheimer's disease. Symptomatic cases are found at relatively higher prevalence among the middle aged (and they tend to be referred to neurologists) than among those aged 75 and over when the great majority of patients with Alzheimer's disease are manifest; these cases tend to be referred to psychiatrists. In any event conditions such as depressive pseudodementia, normal pressure hydrocephalus (in which cognitive impairment is circumscribed or absent until a well advanced stage), space occupying lesions and drug toxicity (which gives rise to delirious confusional states rather than dementia) which proved to form a substantial proportion of the cases in some of the series quoted by the authors, should rarely present difficulties in diagnosis. The picture of AIzheimer's disease is distinctively different. In short, in their commendable attempt to present a comprehensive review Dr. Hollander and his colleagues [5] are in danger of obscuring the value and importance of the most powerfully discriminating antemortem marker of all: the clinical diagnosis when it is derived from an adequate range of observations, that is, historical as well as cross-sectional data (the latter based upon an in-depth phenomenological analysis) and augmented by findings from neuropsychological tests and the results of at least a limited period of prospective observation. As the authors have pointed out, following the application of strict 'Research Diagnostic Criteria' in a number of studies [4, 6, I1] the diagnosis of Alzheimer's disease made during life has been confirmed post mortem in up to 90% of patients. And contrary to the view of Dr. Hollander e t a/. it is doubtful whether this will inevitably exclude more than a very small minority of patients with Aizheimer's disease. The problem of identifying the earliest stages of dementia remains unsolved. But evidence exists that progression from the early stages occurs in a sufficiently steep manner to give rise to more than limited cognitive deficit even in early but definite cases; a distinctively global symptomatology that includes subtle changes in emotional life and personality and modifications of typical behavioural traits is manifest. In calling into question the ability of histopathological examination to discriminate between changes found in the normal aged and those in Alzheimer's disease, the authors have unwittingly befogged much of the progress in relation to
404 the neuropathology of Alzheimer's disease recorded during the past quarter of a century. Plaques may indeed be found in the majority of aged individuals but only with great rarity will they be present at beyond threshold values [2, 8, 12]. In well preserved subjects tangles are mainly confined to the hippocampus with a few stray cortical tangles in a small minority. When the cerebral cortex shows abundant tangle formation in many areas the finding has nearly always indubitable significance: the patient has had Alzheimer's disease during life. They list the usual conditions mentioned in reviews to testify to the non-specificity of the tangle. Wischik and Crowther [14] have recently reviewed the subject. In the Guam syndrome which comes closest to Alzheimer+s disease in one respect, tangles form without plaques. Moreover, in addition to typical paired helical filaments identical with those in Alzheimer, there are 15 nm 'straight filaments' which are rare in Alzheimer. In sporadic amyotrophic lateral sclerosis there is a marked predominance of 10 nm straight filaments. The same holds for progressive supranuclear palsy. In post-encephalitic Parkinsonism the periodic filaments vary in terms of twist and maximal diameter and the character of the predominant type of filament is unclear. In dementia pugilistica the published data are too scanty to form a judgment as to whether paired helical filaments of Alzheimer type are to be found in more than a minority of 'tangles + or in any. It is seriously open to question whether the devaluation of the 'gold standard' of neuropathoiogy pronounced by the authors is justified. With the aid of quantitative criteria, study of the distribution of Alzheimer changes and the presence otherwise of plaques, tangles and granulo-vacuolar degeneration, a definite judgment as to whether criteria for a pathological diagnosis of Alzheimer's disease are satisfied should be possible in the overwhelming majority of cases. Exceptions occur to every generalisation but in the view of this author most of those published in relation to Alzheimer's disease have been based upon inadequate or flimsy historical, clinical and/or neuropsychological data. In summary, there are sound reasons for establishing modern neurobiological antemortem markers for Alzheimer's disease upon a well tested bedrock of clinical diagnosis built upon strict criteria applied to observations recorded with the aid of neuropsychological evaluation, and where post mortem studies are possible pathological investigation that has utilised quantitative techniques and included observations on the ultrastructure of possible Alzheimer phenomena. The parameter chosen for investigation in depth as a potential antemortem transmitter is bound to have been influenced by the views of workers regarding the nature of a causal agent likely to be operating in Alzheimer's disease, As the cholinergic deficit in the brain of patients with Alzheimer's disease has proved to be the most widespread, consistent and severe neurochemical change detected to date, they have devoted a considerable amount of attention to Acetylcholine and Acetylcholine esterase in CSF and to studies of RBC choline kinetics. As both ACh and measures of RBC choline kinetics appear to correlate with dementia severity the authors are led to suggest that both of these show promise for the development of an antemortem marker of AD and that AD may therefore be a systemic illness of the cholinergic system manifest throughout the body. Changes in respect of the noradrenergic system have proved more difficult to interpret but the relationship between basal plasma cortisol level and severity of dementia is compatible
ROTH with either a somatostatic or a noradrenergic deficiency. These possibilities and other potential causes of the cortisol hypersecretion therefore merit further investigation. There is, however, a considerable body of observations which calls the cholinergic theory of Alzheimer's disease in question. The attempts that have been made with various agents to rectify the cholinergic deficit have met with little success. Lesions in the basal nucleus of Meynert and other structures in the basal forebrain which provide the source for the cholinergic projection to the cerebral cortex have in the past been suggested as a site of the primary lesion in Alzheimer's disease. But severe cellular fall-out in this nucleus is commonly found in Parkinson's disease, as is cellular fall-out in the nucleus locus coeruleus. An attempt has been made to link these lesions with the mental deterioration that may be found in Parkinson's disease. But this occurs at a lower prevalence, according to recent studies, than has been claimed in the past and the available evidence suggests that any dementia that is found can be explained in terms of the fortuitous coincidence of two relatively distinct degenerative diseases in late life (Quinn et al. [17]). A lesion in the nucleus of Meynert is not an essential feature of Alzheimer's disease since it is not found in patients with a "late' onset form of the condition [9]. Experimental interruption of the cholinergic and other projections in the cortex from the basal nuclei do not give rise to any structures such as plaques and tangles in experimental higher animals and theories in terms of neurotransmitters alone are thrown into doubt by the fact that less than 5% of synapses in the cerebral cortex are mediated by one of the amine neurotransmitters. Yet, in a case of well established Alzheimer's disease whether of late or early onset, plaques and tangles are found in great density over extensive areas of cortex. The issue as to whether the basic aetiological factor in Alzheimer's disease is a structural lesion or a neurochemical deficit has not been conclusively resolved. But there is a considerable body of evidence to suggest that the massive fall-out of pyramidal cells in the cerebral cortex and subcortical nuclei are likely to be secondary to the formation of dense aggregates of the paired helical filaments that make up the neurofibrillary tangle. As is well known, this is resistant in the extreme to all known solvents of protein. The P H F are also common ingredients of the neuritic portion of the plaque. This subject may be linked with the authors' appraisal of the promise of the various forms of brain-imaging for the purpose of developing antemortem markers. They have given a clear account of the scope and limitations of the most commonly used imaging techniques and those in process of development. They emphasize the promise of PET which has consistently revealed focal impairment of temporal parietal and posterior parietal glucose utilization in AIzheimer's disease, particularly in frontal cortex. But PET is expensive. There are severe limitations upon its repetitive use to follow the course of Alzheimer's disease. It is also particularly sensitive to minor functional changes in the form of limited voluntary movements or changing thought processes. Both single photon emission tomography (SPET) and electrical activity mapping show at present more promise in this disease than magnetic resonance imaging (MRI). With the increasing refinement of modern imaging techniques it is worth giving consideration to other interesting prospects. The intensity of tangle and plaque formation has been shown to be highly correlated with the severity of dementia in Alzheimer's disease. Might it prove possible to image these structures in the future'?
COMMENTARY
405
A recent analysis has shown that the tangle occupies a position of central importance in the transition from normal
ageing to the late and benign form of Alzheimer's disease [9,10]. R e c e n t studies of its ultra structure using techniques of visual diffraction and c o m p u t e r imaging c o m b i n e d with e l e c t r o n - m i c r o s c o p y have s h o w n it to be made up of a double helical stack of transversely orientated sub-units giving the overall shape o f a ribbon twisted into a left-handed helix [3,13]. It has been suggested that this structure might have arisen by the 'de novo a s s e m b l y of an aberrant p r o t e i n ' [14]. The dimensions of the structural sub-unit suggest a molecular weight o f m o r e than 100 kD. Progress has been made towards its characterization. If success is a c h i e v e d in defining the c h a r a c t e r o f this probably aberrant protein it may p r o v e possible to arrive at m e t h o d s o f imaging it with a ligand. The way would then be open for estimation o f the stage reached in the progress of the specific structural lesions of A l z h e i m e r ' s disease.
Finally, it has to be accepted that clinical evaluation and diagnosis and biological markers which draw upon laboratory techniques will for an indefinite time ahead have to be treated as complementary to each other. If a marker were to be discovered that achieved a 100% accuracy, clinical examination and diagnosis could be dispensed with. Alternatively, if clinical characterization could be brought to perfection so that it showed 100% correlation with post mortem findings the search for biological markers of a quantifiable kind could be abandoned. Neither of these possibilities is likely to materialise. Neither clinical evaluation nor biological antemortem markers is, on a realistic assessment, going to be rendered obsolete in a foreseeable future. Even if rapid advances were to be made, the only issue that would remain would be to determine on an empirical basis what weight should be attached to each in the course of everyday clinical practice on the one hand and specific scientific enquiries on the other.
REFERENCES 1. Barclay, L. L., A. Zemcov and J. P. Blass. Survival in Alzheimer's disease and vascular dementias. Neurology 35: 834-840, 1985. 2. Blessed, G., B. E. Tomlinson and M. Roth. The relationship between quantitative measures of dementia and senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry 114: 797-811, 1968. 3. Crowther, R. A., C. M. Wischik and M. Stewart. Analysis of the structure of paired helical filaments. Proc EMSA 43: 734737, 1985. 4. Eisdorfer, C. and D. Cohen. Diagnostic criteria for primary neuronal degeneration of the Alzheimer type. J Fam Pratt 2: 553-557, 1980. 5. Hollander, E., R. C. Mohs and K. L. Davis. Antemortem markers of Alzheimer's disease. Neurobiol Aging 7: 367-387, 1986. 6. MOlsa, P. K,, L. P~iljerir, J. O. Rinne, V. K. Ruine and E. Silk0. Validity of clinical diagnosis in dementia: A prospective clinico-pathological study. J Neurol Nettrosurg Psychiatry 78: 1085-1090, 1985. 7. Quinn, N. P,, M. N. Rossor and C. D. Marsden. Dementia and Parkinson's disease--Pathological and neurochemical considerations. Br Med Bull 42: 86-90, 1986.
8. Roth, M. Classification and aetiology. In: Mental Disorders o f Old Age. Some Recent Developments. Recent Developments in Psychogeriatrics, edited by D. Kay and A. Walk. Br J Psychiato,, special publications No. 6. London: Headley, 1971, pp.
1-18. 9. Roth, M. The association of clinical and neurobioiogical findings and its bearing on the classification and aetiology of Alzheimer's Disease. Br Med Bull 42: 42-50, 1986. 10. Roth, M. and C. M. Wischik. The heterogeneity of Alzheimer's disease and its implications for scientific investigations of the disorder. In: Recent Advances in Psychogeriatrics vol 1 edited by T. Ane. Edinburgh: Churchdl Livingstone, 1985. 11. Todorov, A. B., R. C. P. Go, J. Constantinidis and R. C. Elston. Specificity of the clinical diagnosis of dementia. J Neurol Sei 26: 81-98, 1975. 12. Tomlinson, B. E., G. Blessed and M. Roth. Observations on the brains of non-demented old people. J Neurol Sci 7: 331-356, 1968. 13. Wischik, C. M,, R. A. Crowther, M. Stewart and M. Roth. Subunit structure of paired helical filaments in Alzheimer's Disease. J Cell Biol 100: 1905-1912, 1985. 14. Wischik, C. M. and R. A. Crowther. Subunit structure of the Alzheimer tangle. Br Med Bull 42: 51-56, 1986. .
.
.
.
EDITORIAL NOTE The preceding commentary arrived too late to be reviewed by Drs. Davis and Mohs and was therefore not addressed in the authors' following "'final commentary."
.
6'
'
'
ROTH
Current theories regarding the etiology of Alzheimer's Disease tend to derive from one of four possible causes: (l) a genetically acquired autosomal dominant trait, (2) a slow viral infection, (3) an environmental toxin, or (4) a systemic metabolic illness. The evidence favoring an autosomal dominant trait is impressive, but vehemently contested on the basis of methodological criticisms. At best, it appears that the type of AD inherited accounts for a subgroup of the total of patients with the diagnosis. The trait is a more prominent feature of AD in late life rather then in the middle aged group and its expression seems to correlate with advanced age. The other possible causes have less firm evidence in their support. The possibility of a slow virus responsible for AD is among the earliest of our theories, succeeded only by prejudice that dementia was a consequence of aging or an acceleration of a basically normal process. Other than face validfly, there is no convincing data that AD is viral. Information concerning environmental toxins or systemic illnesses is even less convincing. Aluminum, while potentially toxic, has been largely discounted as a cause of AD and no other toxin has been found to correlate with the disease. The general decline in many of the body and organ systems reviewed by the authors, is an area easily eclipsed by the profound loss of memory and personality that is so devastating to the patient and the patient's family. However, it is an important area for more investigation, and this work should promote more interest and attention to systems other than the CNS. in spite of our best efforts, the situation is perhaps best summarized by Dr. Peter Whitehouse, from Johns Hopkins University, who comments that " o u r understanding of the
disease is a m ess" [1]. Most of the signs and symptoms observed in patients currently diagnosed as having AD result from impairment of poorly defined cognitive spheres, affectire changes, or personality changes. All of these features comprise a nonspecific "final common pathway" for a host of known and reversible dementias and CNS injuries. The absence of any of these known dementias is the best and. more or less, only diagnostic criteria we have for AD. It is certain that the current criteria are vastly over inclusive and account for the 30% of these patients, described by the authors, "found to be not demented or to have another neurological disorder." The ability to accurately diagnose AD is crucial to progress in research and treatment of the illness. Efforts directed toward rigorous research criteria will perhaps enable us to begin to define and identify a population of patients with a high degree of reliability on the basis of their antemortem symptoms and postmortem findings. On the basis of information obtained from this smaller, but clearly defined group of patients, it may be possible to then develop a body of knowledge about this illness or collection of illnesses we described as Alzheimer's Disease. Drs. Hollander, Mohs and Davis provide us with a thoughtful , carefully selected review of the medical side of AD. Their work is extremely valuable and useful to workers in the field. While it is evident from their review that current theories and research have hardly made a dent in increasing our understanding of the illness, it provides a perspective of where we have been and an encouragement to redouble el'forts to establish reliable diagnostic criteria and to conduct intensive research into the causes of AD,
REFERENCE 1. Whitehouse, P. Alzheimers Disease, A Multi-System Disorder: Implications for the Development of a Therapy. Presented at the New Clinical Drug Evaluation Unit Program, May 27, 1986.
Antemortem Markers of Alzheimer's Disease" A Commentary SIR MARTIN ROTH
l)'initv College, Cambridge, England
The authors have performed a valuable service in their comprehensive review of the literature of antemortem markers in Alzheimer's disease. The discovery of objective and reliable indices in vivo of an illness of obscure causation, constitutes an important forward step in scientific progress towards its accurate diagnosis and discovery of its aetiology. When markers that have a satisfactory correlation with clinical diagnosis on the one hand and post mortem findings on the other have been developed, an acceleration of progress almost invariably follows.
T H E review by Hollander, Davis and Mohs is largely devoted to evaluation of knowledge in respect of neuropharmacological, neurochemical and neuroendocrine markers: the results achieved and the progress foreshadowed in the field of brain imaging are also reviewed. A few basic issues could, with advantage, have been discussed in more detail.
One question that demands a clear answer is the criterion against which the specificity and validity of any markers discovered should be tested. The ultimate criterion in the case of the disease described by Alzheimer has to be the neuropathological change to be found in the brain. For the large part this has to be determined by post mortem investi-
COMMENTARY gation. Brain biopsy can rarely be ethically justified since it will hardly ever yield information of value for the treatment of the individual patient that cannot be obtained by detailed clinical examination and a few laboratory tests. And evidence from post mortem findings entails a long and difficult uphill path since it is rarely possible to follow patients for an adequate period in the community or in hospital and then to secure permission for autopsy in more than a small proportion of patients and control subjects who have been investigated in sufficient depth and detail during life. As this yield will be inevitably small, a very large cohort of patients-and controls would have to be investigated with a given marker for neuropathological evaluation of its discriminating value. This is certainly one type of enquiry that has to be undertaken in the neurobiological study of Alzheimer's disease. But there are many reasons why reliance in the area under discussion should not be placed exclusively on this protracted and costly exercise. Clinical diagnosis provides the usual standard by which the value of antemortem markers has to be estimated. They must in the first instance show an acceptably high correlation with a diagnosis of Alzheimer's disease which has been firmly established. This is the bedrock upon which all biological correlates of psychiatric disorder have to be founded. Of course it is a pre-condition that clinical diagnosis should have been shown to have reached an acceptable level of reliability and validity. But the authors cite some observations which call this in question in the case of Alzheimer's disease. They quote two long term follow-up studies in which the diagnosis of Alzheimer's disease proved erroneous in as many as thirty percent of cases. Each was concerned with the relatively rare 'presenile' forms, from which generalisations should not be made. But this misrepresents the real situation. Moreover, when the diagnosis has been made by a number of different observers using a variety of criteria, drawing upon observations sustained for different periods, discrepancies and errors are unavoidable. It is the irreducible error inherent in making a clinical diagnosis which requires to be determined for scientific purposes; the errors that occur in the course of ordinary clinical practice are of little relevance from this point of view. To determine the accuracy of diagnosis and the extent to which it is upheld over long periods of observation, optimal conditions have to be created to ensure that all relevant sources of information have been drawn upon for the purpose. This demands a standardised interview (a number of satisfactory schedules are now available), systematic evaluation of the mental state which has to be set in the context of the patient's previous history, developmental record and personality. It must include information obtained from an independent observer and a period of observation of the patient while he is engaged in coping with the demands of everyday life. Neuropsychological tests are valuable adjuncts, but a diagnosis that will stand the test of time cannot be extracted from the results of measures of cognitive function alone. Operational criteria for the diagnosis of Alzheimer's disease should be employed and strictly adhered to by all those who participate in a given inquiry into the reliability of clinical diagnosis or its correlation with any hypothetical antemortem marker. It may appear supererogatory to spell out such obvious points. But in none of the enquiries often quoted to establish the inherent unreliability of a clinical diagnosis of Alzheimer's disease have all these conditions been met. It is also incorrect to state that Alzheimer's disease is " . . . a diagnosis of exclusion" and that " . . . a definitive diagnosis
403 of Alzheimer's disease (AD) can only be made at autopsy, or in rare cases with brain b i o p s y . " The symptomatic organic syndromes due to such causes as vitamin B~2 deficiency, hypothyroidism, parathyroid disorders, niacin deficiency disorder or 'silent' hyperthyroidism of late onset can almost invariably be differentiated from Alzheimer's disease by painstaking clinical examination. In many cases the condition is a subacute clouded or delirious state of fluctuating severity and of some months' duration, rather than dementia proper. In those symptomatic cases in which the criteria for the diagnosis of dementia are met the clinical picture presents a less global encroachment upon the individual's cognitive emotional and conative functions and his characteristic behavioural traits. Emotional responses and personality are also far better preserved except in the viral encephalopathies. But the latter pursue a rapid fulminating course over a period of weeks or months. This never occurs in Alzheimer's disease. In each of the symptomatic forms, detailed examination and appropriate laboratory tests of a relatively simple and accessible kind will serve to establish whether one deals with a symptomatic dementia such as that due to a metabolic disorder or a " p r i m a r y " dementia with the pathology of Alzheimer's disease. Symptomatic cases are found at relatively higher prevalence among the middle aged (and they tend to be referred to neurologists) than among those aged 75 and over when the great majority of patients with Alzheimer's disease are manifest; these cases tend to be referred to psychiatrists. In any event conditions such as depressive pseudodementia, normal pressure hydrocephalus (in which cognitive impairment is circumscribed or absent until a well advanced stage), space occupying lesions and drug toxicity (which gives rise to delirious confusional states rather than dementia) which proved to form a substantial proportion of the cases in some of the series quoted by the authors, should rarely present difficulties in diagnosis. The picture of AIzheimer's disease is distinctively different. In short, in their commendable attempt to present a comprehensive review Dr. Hollander and his colleagues [5] are in danger of obscuring the value and importance of the most powerfully discriminating antemortem marker of all: the clinical diagnosis when it is derived from an adequate range of observations, that is, historical as well as cross-sectional data (the latter based upon an in-depth phenomenological analysis) and augmented by findings from neuropsychological tests and the results of at least a limited period of prospective observation. As the authors have pointed out, following the application of strict 'Research Diagnostic Criteria' in a number of studies [4, 6, I1] the diagnosis of Alzheimer's disease made during life has been confirmed post mortem in up to 90% of patients. And contrary to the view of Dr. Hollander e t a/. it is doubtful whether this will inevitably exclude more than a very small minority of patients with Aizheimer's disease. The problem of identifying the earliest stages of dementia remains unsolved. But evidence exists that progression from the early stages occurs in a sufficiently steep manner to give rise to more than limited cognitive deficit even in early but definite cases; a distinctively global symptomatology that includes subtle changes in emotional life and personality and modifications of typical behavioural traits is manifest. In calling into question the ability of histopathological examination to discriminate between changes found in the normal aged and those in Alzheimer's disease, the authors have unwittingly befogged much of the progress in relation to
404 the neuropathology of Alzheimer's disease recorded during the past quarter of a century. Plaques may indeed be found in the majority of aged individuals but only with great rarity will they be present at beyond threshold values [2, 8, 12]. In well preserved subjects tangles are mainly confined to the hippocampus with a few stray cortical tangles in a small minority. When the cerebral cortex shows abundant tangle formation in many areas the finding has nearly always indubitable significance: the patient has had Alzheimer's disease during life. They list the usual conditions mentioned in reviews to testify to the non-specificity of the tangle. Wischik and Crowther [14] have recently reviewed the subject. In the Guam syndrome which comes closest to Alzheimer+s disease in one respect, tangles form without plaques. Moreover, in addition to typical paired helical filaments identical with those in Alzheimer, there are 15 nm 'straight filaments' which are rare in Alzheimer. In sporadic amyotrophic lateral sclerosis there is a marked predominance of 10 nm straight filaments. The same holds for progressive supranuclear palsy. In post-encephalitic Parkinsonism the periodic filaments vary in terms of twist and maximal diameter and the character of the predominant type of filament is unclear. In dementia pugilistica the published data are too scanty to form a judgment as to whether paired helical filaments of Alzheimer type are to be found in more than a minority of 'tangles + or in any. It is seriously open to question whether the devaluation of the 'gold standard' of neuropathoiogy pronounced by the authors is justified. With the aid of quantitative criteria, study of the distribution of Alzheimer changes and the presence otherwise of plaques, tangles and granulo-vacuolar degeneration, a definite judgment as to whether criteria for a pathological diagnosis of Alzheimer's disease are satisfied should be possible in the overwhelming majority of cases. Exceptions occur to every generalisation but in the view of this author most of those published in relation to Alzheimer's disease have been based upon inadequate or flimsy historical, clinical and/or neuropsychological data. In summary, there are sound reasons for establishing modern neurobiological antemortem markers for Alzheimer's disease upon a well tested bedrock of clinical diagnosis built upon strict criteria applied to observations recorded with the aid of neuropsychological evaluation, and where post mortem studies are possible pathological investigation that has utilised quantitative techniques and included observations on the ultrastructure of possible Alzheimer phenomena. The parameter chosen for investigation in depth as a potential antemortem transmitter is bound to have been influenced by the views of workers regarding the nature of a causal agent likely to be operating in Alzheimer's disease, As the cholinergic deficit in the brain of patients with Alzheimer's disease has proved to be the most widespread, consistent and severe neurochemical change detected to date, they have devoted a considerable amount of attention to Acetylcholine and Acetylcholine esterase in CSF and to studies of RBC choline kinetics. As both ACh and measures of RBC choline kinetics appear to correlate with dementia severity the authors are led to suggest that both of these show promise for the development of an antemortem marker of AD and that AD may therefore be a systemic illness of the cholinergic system manifest throughout the body. Changes in respect of the noradrenergic system have proved more difficult to interpret but the relationship between basal plasma cortisol level and severity of dementia is compatible
ROTH with either a somatostatic or a noradrenergic deficiency. These possibilities and other potential causes of the cortisol hypersecretion therefore merit further investigation. There is, however, a considerable body of observations which calls the cholinergic theory of Alzheimer's disease in question. The attempts that have been made with various agents to rectify the cholinergic deficit have met with little success. Lesions in the basal nucleus of Meynert and other structures in the basal forebrain which provide the source for the cholinergic projection to the cerebral cortex have in the past been suggested as a site of the primary lesion in Alzheimer's disease. But severe cellular fall-out in this nucleus is commonly found in Parkinson's disease, as is cellular fall-out in the nucleus locus coeruleus. An attempt has been made to link these lesions with the mental deterioration that may be found in Parkinson's disease. But this occurs at a lower prevalence, according to recent studies, than has been claimed in the past and the available evidence suggests that any dementia that is found can be explained in terms of the fortuitous coincidence of two relatively distinct degenerative diseases in late life (Quinn et al. [17]). A lesion in the nucleus of Meynert is not an essential feature of Alzheimer's disease since it is not found in patients with a "late' onset form of the condition [9]. Experimental interruption of the cholinergic and other projections in the cortex from the basal nuclei do not give rise to any structures such as plaques and tangles in experimental higher animals and theories in terms of neurotransmitters alone are thrown into doubt by the fact that less than 5% of synapses in the cerebral cortex are mediated by one of the amine neurotransmitters. Yet, in a case of well established Alzheimer's disease whether of late or early onset, plaques and tangles are found in great density over extensive areas of cortex. The issue as to whether the basic aetiological factor in Alzheimer's disease is a structural lesion or a neurochemical deficit has not been conclusively resolved. But there is a considerable body of evidence to suggest that the massive fall-out of pyramidal cells in the cerebral cortex and subcortical nuclei are likely to be secondary to the formation of dense aggregates of the paired helical filaments that make up the neurofibrillary tangle. As is well known, this is resistant in the extreme to all known solvents of protein. The P H F are also common ingredients of the neuritic portion of the plaque. This subject may be linked with the authors' appraisal of the promise of the various forms of brain-imaging for the purpose of developing antemortem markers. They have given a clear account of the scope and limitations of the most commonly used imaging techniques and those in process of development. They emphasize the promise of PET which has consistently revealed focal impairment of temporal parietal and posterior parietal glucose utilization in AIzheimer's disease, particularly in frontal cortex. But PET is expensive. There are severe limitations upon its repetitive use to follow the course of Alzheimer's disease. It is also particularly sensitive to minor functional changes in the form of limited voluntary movements or changing thought processes. Both single photon emission tomography (SPET) and electrical activity mapping show at present more promise in this disease than magnetic resonance imaging (MRI). With the increasing refinement of modern imaging techniques it is worth giving consideration to other interesting prospects. The intensity of tangle and plaque formation has been shown to be highly correlated with the severity of dementia in Alzheimer's disease. Might it prove possible to image these structures in the future'?
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A recent analysis has shown that the tangle occupies a position of central importance in the transition from normal
ageing to the late and benign form of Alzheimer's disease [9,10]. R e c e n t studies of its ultra structure using techniques of visual diffraction and c o m p u t e r imaging c o m b i n e d with e l e c t r o n - m i c r o s c o p y have s h o w n it to be made up of a double helical stack of transversely orientated sub-units giving the overall shape o f a ribbon twisted into a left-handed helix [3,13]. It has been suggested that this structure might have arisen by the 'de novo a s s e m b l y of an aberrant p r o t e i n ' [14]. The dimensions of the structural sub-unit suggest a molecular weight o f m o r e than 100 kD. Progress has been made towards its characterization. If success is a c h i e v e d in defining the c h a r a c t e r o f this probably aberrant protein it may p r o v e possible to arrive at m e t h o d s o f imaging it with a ligand. The way would then be open for estimation o f the stage reached in the progress of the specific structural lesions of A l z h e i m e r ' s disease.
Finally, it has to be accepted that clinical evaluation and diagnosis and biological markers which draw upon laboratory techniques will for an indefinite time ahead have to be treated as complementary to each other. If a marker were to be discovered that achieved a 100% accuracy, clinical examination and diagnosis could be dispensed with. Alternatively, if clinical characterization could be brought to perfection so that it showed 100% correlation with post mortem findings the search for biological markers of a quantifiable kind could be abandoned. Neither of these possibilities is likely to materialise. Neither clinical evaluation nor biological antemortem markers is, on a realistic assessment, going to be rendered obsolete in a foreseeable future. Even if rapid advances were to be made, the only issue that would remain would be to determine on an empirical basis what weight should be attached to each in the course of everyday clinical practice on the one hand and specific scientific enquiries on the other.
REFERENCES 1. Barclay, L. L., A. Zemcov and J. P. Blass. Survival in Alzheimer's disease and vascular dementias. Neurology 35: 834-840, 1985. 2. Blessed, G., B. E. Tomlinson and M. Roth. The relationship between quantitative measures of dementia and senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry 114: 797-811, 1968. 3. Crowther, R. A., C. M. Wischik and M. Stewart. Analysis of the structure of paired helical filaments. Proc EMSA 43: 734737, 1985. 4. Eisdorfer, C. and D. Cohen. Diagnostic criteria for primary neuronal degeneration of the Alzheimer type. J Fam Pratt 2: 553-557, 1980. 5. Hollander, E., R. C. Mohs and K. L. Davis. Antemortem markers of Alzheimer's disease. Neurobiol Aging 7: 367-387, 1986. 6. MOlsa, P. K,, L. P~iljerir, J. O. Rinne, V. K. Ruine and E. Silk0. Validity of clinical diagnosis in dementia: A prospective clinico-pathological study. J Neurol Nettrosurg Psychiatry 78: 1085-1090, 1985. 7. Quinn, N. P,, M. N. Rossor and C. D. Marsden. Dementia and Parkinson's disease--Pathological and neurochemical considerations. Br Med Bull 42: 86-90, 1986.
8. Roth, M. Classification and aetiology. In: Mental Disorders o f Old Age. Some Recent Developments. Recent Developments in Psychogeriatrics, edited by D. Kay and A. Walk. Br J Psychiato,, special publications No. 6. London: Headley, 1971, pp.
1-18. 9. Roth, M. The association of clinical and neurobioiogical findings and its bearing on the classification and aetiology of Alzheimer's Disease. Br Med Bull 42: 42-50, 1986. 10. Roth, M. and C. M. Wischik. The heterogeneity of Alzheimer's disease and its implications for scientific investigations of the disorder. In: Recent Advances in Psychogeriatrics vol 1 edited by T. Ane. Edinburgh: Churchdl Livingstone, 1985. 11. Todorov, A. B., R. C. P. Go, J. Constantinidis and R. C. Elston. Specificity of the clinical diagnosis of dementia. J Neurol Sei 26: 81-98, 1975. 12. Tomlinson, B. E., G. Blessed and M. Roth. Observations on the brains of non-demented old people. J Neurol Sci 7: 331-356, 1968. 13. Wischik, C. M,, R. A. Crowther, M. Stewart and M. Roth. Subunit structure of paired helical filaments in Alzheimer's Disease. J Cell Biol 100: 1905-1912, 1985. 14. Wischik, C. M. and R. A. Crowther. Subunit structure of the Alzheimer tangle. Br Med Bull 42: 51-56, 1986. .
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EDITORIAL NOTE The preceding commentary arrived too late to be reviewed by Drs. Davis and Mohs and was therefore not addressed in the authors' following "'final commentary."
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