Neuroimaging and psychopharmacology in the diagnosis and treatment of dementia

Prog. Neuro-Psychopharmacol. 6 Biol. Psychiot. Printed in Great Britain. All rights reserved.

NEUROIMAGING

1986, Vol. 10. pp. 493-500 Copyright

0

0278-5846186 1986 Pergamon

$0.00 + .50 Journals Ltd.

AND PSYCHOPHARMACOLOGY IN THE DIAGNOSIS AND TREATMENT OF DEMENTIA RICHARD A. MARGOLIN'

and THOMAS A. BAN*

1

Departments of Psychiatry and Radiology and Radiological Sciences *Department of Psychiatry, Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A.

(Final form, July 1986)

Contents Abstract Introduction Neuroimaging Computed Tomography (CT) Magnetic Resonance Imaging (MRI) Positron Emission Tomography (PET) z. 3: - Psychopharmacology Interference with Protein Synthesis 3.1. Acetylcholine Deficiency z.3'. Aluminum Deposition of Dementia 4: * Pharmacotherapy Sumnary 5. References

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1. 2. 2.1.

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494 494 495 495 496 496 496 497 ‘197

498 498 Abstract

Margolin, Richard A., and Ban, Thomas A.: Neuroimaging and Psychopharmacology Prog. Neuro-Psychopharmacol. & in the Diagnosis and Treatment of Dementia. Biol. Psychiat. 1986, 3 (3-5): 493~500. 1.

2.

3.

Contributions of noninvasive brain imaging technologies to the diagnosis of organic dementias with special reference to Alzheimer's disease are Included among the different techniques are: reviewed. a. computed tomography b. magnetic resonance imaging c. positron emission tomography. Biochemical hypotheses with possible relevance to the pathogenesis of Alzheimer's disease are presented and their therapeutic implications are Included among the different hypotheses are: discussed. a. interference with protein synthesis b. acetylcholine deficiency aluminum deposition. 'Piesent status of the pharmacotherapy of Alzheimer's disease is outlined.

Keywords: Alzheimer's disease, computed emission tomography, psychopharmacology

tomography,

dementia,

neuroimaging,

positron

Abbreviations: acetylcholine (ACh), Alzheimer's disease (AD), cerebral blood flow (CBF), choline acetyltransferase (ChATI, computed tomography (CT), fluorodeoxyglucose (FDG),

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and T. A. Ban

magnetic resonance imaging (MRI), multi-infarct dementia (MID), patchy white matter lesions (PWML), positron emission tomography (PET), single photon emission computed tomography (SPECT), white matter (WM).

1.

Introduction

The current rapid increase in the proportion of the aged in the general population is In 1978 there were about 2.5 million expected to continue over the next several decades. people 85 years of age or older in the United States and, by the year 2000, more than 6 million are expected to be that old (Merrill, 1986).

It is a well recognized fact that the prevalence of dementia increases with age. For example, while 2% of the population between 60 to 70 years of age suffers from dementia, 20% of the population above age 80 are afflicted. Since approximately 50% of all cases of dementia represent Alzheimer's disease (AD), a global tidal wave of patients suffering from AD is threatening to engulf us by the year 2000 (Lehmann, 1985). AD is a neurological disorder which is characterized by deterioration of cognitive functions such as memory, attention and judgment. The course of the disease is progressive and irreversible, although its rate of progression is variable. It begins with simple forgetfulness and is followed gradually by noticeable and then severe changes in memory and personality. Although AD originally referred to a form of presenile dementia, today the term embraces also the disease previously called senile dementia (Merrill, 1986). There is substantial evidence that both structural and functional (especially neurochemical) changes in the brain accompany the progressive clinical changes in AD. Two disciplines which stand at the crossroads of basic and clinical studies are neuroimaging and psychopharmacology. 2. 2.1.

Computed

Tomography

Neuroimaging

(CT)

In the past two decades a number of noninvasive imaging technologies have been developed with the capability to provide information on the structure and/or functioning of the brain. Among these new techniques computerized axial tomography (CT), magnetic resonance imaging (MRI), and positron and single photon emission computed tomography (PET and SPECT, respectively) are either of clinical use or possess research potential in the diagnosis and treatment of dementia. CT is a structural imaging method which reveals details =oY cerebral morphology as well as physical abnormalities in the brain. After its introduction in England in the early 1970's, CT rapidly became a standard tool in diagnostic neuroradiology. In one of the earliest clinical studies with CT, Huckman et al. (19751 found ventricular enlargement and cerebral atrophy in a diagnostically mixed group of demented patients. These findings have been substantiated by a number of other groups. Ihterpretation of such CT results as dementia-specific, however, is confounded by the increase in CSF space size which occurs as a part of the normal aging process (Schwartz et al., 1985). Although Brinkman et al. (19841 determined from serial CT scans that the increase in CSF space in dementia is considerably greater than that which could be attributed to an aging effect, the fact remains that dementia cannot be diagnosed reliably in an individual patient on the basis of CSF space size alone. In addition to CSF space changes, white matter density was studied in AD and found to be abnormally low (Zatz et al., 1982). As with CSF space size, the decrease in white matter density was also found to be age-dependent (Schwartz et al., 19851. Because of this, white matter density changes are equally inadequate for the diagnosis of dementia.

Neuroimaging and psychopharmacology

Although no single CT parameter can be used independently for diagnosing dementia, there are reasons to believe that the presence of both increased CSF space size and reduced white matter density can identify individual patients with dementia more reliably. 2.2.

Magnetic

Resonance

Idging

(MRI)

MRI has the potrntial to be both a structural and a functional imaging technique, although only its structural capabilities have been so far developed for human use. As a structural imaging technique, it can provide neuroanatomical information (e.g., CSF space size) as well as data about physicochemical abnormalities of the brain. MRI's grey matter/white matter contrast resolution is considerably better than that of CT, a fact which permits the quantification of atrophy of individual brain regions in dementia. While anatomically optimized MRI studies have confirmed the CT finding of increased CSF space size in AD (McGeer et al., 1986), it is in the detection of abnormalities of tissue composition that MRI really represents a major advance in the diagnosis of dementia. Physicochemically optimized MRI is very sensitive to white matter (WM) abnormalities. Two types of WM pathology can be identified by MRI: diffusely reduced proton density (Besson et al., 1983) and patchy white matter lesions (PWML) (Brant-Zawadzki et al., 1985). PWML are the presumptive MRI correlates of WM infarcts, including lacunes. Because PWML are relatively infrequently encountered in AD (Erkinjuntti et al., 1984; Friedland et al., 1984), it has been suggested that their presence is diagnostic of multi-infarct dementia (MID). In spite of this, there is not universal agreement about the diagnostic significance of PWML. We have examined data from our own population of 42 cases of various types of dementia, 15 of whom had both CT and MRI scans. Of these 15, five had PWML on MRI scans without corresponding CT abnormalities. Contrary to expectation, two of the five cases (40%) had been clinically diagnosed as AD. Until clarification of the significance of PWML is achieved by neuropathological studies, they should not be overused in the diagnosis of MID. Two practical advantages of MRI over CT are that it does not involve the use of ionizing radiation and that images in different planes besides the transverse can be acquired (e.g., coronal, sagittal). 2.3.

Positron

Emission

Tomography

(PET)

PET is the most advanced functional brain imaging technique developed to date. It can be used to quantify cerebral blood flow (CBF), glucose and oxygen metabolism (CMKglu and CMR02, respectively), protein synthesis, neuroreceptor binding, and potentially many other manifestations of altered physiology. PET studies in dementia have revealed substantial reduction of CBF and CMR02. Frackowiak et al. (1981), for example, found a global reduction in CBF and CMR02 (25 and 24% respectively) in AD. Importantly, they found no simultaneous increase in the oxygen extraction fraction. This suggests that occult hypoperfusion is not a causal factor in AD. In addition to CBF and CMKD2, CMKglu has been studied in dementia. This has been accomplished with the glucose analog 18F-fluorodeoxyglucose (FDG). Early FDG studies reported either generalized reduction in CMRglu (Ferris et al., 1980) or prominent reduction in frontal lobe metabolism (Farkas et al., 1982). More recent studies have confirmed the generalized reduction in CMRglu in advanced AD. Instead of the frontal lobes, however, they have consistently identified reduction in the posterior temporal and parietal lobes (Friedland et al., 7&i: lY!&:! et al ., 1984; McGeer et al., 1986). The availability of the technology to identify regional metabolic changes prompted Chase and his associates (Foster et al., 1983) to test the hypothesis that AD patients with distinctly different clinical features have distinctly different PET images. They found that, in patients with a prevailing language defect, the CMKglu reduction was most

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marked in the left temporal lobe, whereas in patients with visuospatial abnormalities was most marked in the right parietal region. In patients with prevailing memory impair~nt, no focal abnormalities were detectable.

it

In this An important future clinical use of PET could be the early detection of AD. reoard Cutler et al. (1985) found that oatients with earlv AD had varietal lobe reductions which could be identified with a normalization"procedure, even though absolute In contrast, patients with more advanced disease values were not necessarily reduced. demonstrated obvious reductions in absolute values of CMR glu. While the tomographic imaging in man by PET of biophysical processes (such as CBF) and metabolic processes isuch as-C%@ and CM lu) represent important advances, it can be arsued that an even more valuable contribu? ion PET can make in the future is the direct imaging of neurotransmitter physiology. Important early contributions to this field include the publications of Frey et al. (19851, Holman et al. (19851, and McGeer et al. (1986). Transmitter systems studied so far are those of dopamine (pre- and postsynaptic aspects) and acetylcholine (muscarinic and nicotinic receptor binding). 3. There are numerous 3.1.

Interference

hypotheses

with Protein

Psychopharmacology

regarding

the pathogenesis

of AD.

Synthesis

protein synthesis may lead to One of the -.. leading hypotheses is that intereference with This hypothesis is based on observations that drugs which inhibit protein dementia. synthesis, such as acetoxycycloheximide, anisomycin, cycloheximide, puromycin, and also some other antibiotics impair memory storage (at least in mice and goldfish). Similar findings were obtained with nucleic acid inhibitors, such as actinomycin D, a substance which is incorporated into nucleic acid. In favor of this hypothesis are the findings that drugs which decrease folic acid and consequently tetrahydrofolic acid levels, may induce dementia in the course of chronic administration. Corresponding also are the findings that substances used in the treatment of epilepsy such as barbiturates and diphenylhydantoin, which decrease serum folic acid levels, and substances used in the treatment of tumors, such as methotrexate, are frequently associated with dementia (Libiger and Ban, 19811. Recently there have been some indications that decreased protein synthesis may play a role in AD (Merrill, 1986). 3.2. Acetylcholine

Deficiency

Another possible factor in the development of AD is a deficiency of acetylcholine (AChf. The hypothesis that ACh deficiency may lead to AD is based on observations that anticholinergic drugs which produce consciousness disturbance, delirium and confusional states impair acquisition and retention in animals. In contrast to drugs which have this effect, such as atropine, hyoscine, and Ditran, cholinergic agonists such as diisopropylfluorophosphate and physostigmine exert an opposite effect. In human pharmacological studies it was revealed that physostigmine reversed scopolamine and Ditran-induced memory disturbance. This finding indicates that the memory impairment induced by scopolamine and Ditran is probably related to the cholinergic blockade produced by these compounds. In favor of the hypothesis that cholinergic agonists may have a salutary effect on mer~ory are the findings that parenteral administration of arecoline, another cholinergic agonist, significantly enhanced serial learning in normal subjects and reversed scopolamine-induced memory impairment (Drachman, 1978). The importance of the cholinergic system in AD received great support from the dramatic deficiencies found in the activity of the ACh synthetic enzyme choline acetyltransferase (ChAT),in the brains of Alzheimer patients (Bowen et al., 1976; Davies and Maloney, 1976; Perry et al., 1977; Reisine et al., 1978; Rossor et al., 1980; Sims et al., 1983; White et al., 1977; Yates et al., 1981). Furthermore, in addition to ChAT,

Neuroimaging and psychopharmacology

most enzymes and/or functions of cholinergic neurons were found to be deficient in AD Although choline uptake and ACh release have been shown to be (Sims et al., 1983). deficient in biopsied samples of AD brain already at an early stage of the disease, evidence exists that muscarinic ACh receptors are present in normal concentrations. This indicates that the postsynaptic neurons involved in ACh transmission are still present in apparently normal numbers and that a potential target for therapeutic agents is not destroyed by the disease (Davies, 1985). Corresponding with such neurochemical changes are the clinical psychopharmacological findings that precursor therapy with choline or lecithin is not an effective treatment in These negative findings can be explained by the "dramatic" AD (Rosenberg et al., 19831. This deficiency implies that exogenous choline or lecithin cannot be deficiency of ChAT. In contradistinction to precursor treatment, effectively utilized for ACh formation. clinincal trials with acetylcholinesterase inhibitors, such as physostigmine and tetrahydroaminoacridine, and with muscarinic agonists, such as arecoline are more Since the potential target for these agents is not destroyed encouraging (Crook, 1985). by the disease, it is reasonable to assume that the favorable findings with acetylcholinesterase inhibitors and choline agonists are valid. The same also explains the favorable results to the combined administration of physostigmine and lecithin (Thai et al., 1984). There are two other psychopharmacological approaches employed to increase ACh levels in the brain and to improve cognition in AD. One of these approaches utilizes 3,4diaminopyridine, a substance which enhances the flow of calcium into nerve terminals and as a result increases the release of ACh. Another approach employs the administration of In preliminary clinical investigations naloxone which affects ACh levels indirectly. naloxone was found to be effective in iiaproving cognitive functions in several AD patients (Merrill, 1986). 3.3.

Aluntinum Deposition

A third possible mechanism in the development of AD is the deposition of aluminum in Since the description of an aluminum-induced encephalopathy and the brain. neurofibrillary degeneration in experimental animals, there has been considerable interest in the possible role of this element in the etiology of AD. Aluminum-induced neurofibrillary degeneration appears to be a particularly attractive model for the study of AD because a single intracerebral injection of aluminum is followed (after an asymptomatic period of 10 to 20 days) by a progressive reduction in learning and decrease in memory which is proportional to the degree of neurofibrillary degeneration (Crapper et However, the aluminum-induced neurofibrillary changes differ al., 1973). ultrastructurally from the neurofibrillary degeneration seen in AD. Nevertheless, despite these ultrastructural differences it is also known that aluminum produces an alteration of functions in hippocampal neurons (DeBoni and McLachlan, 1981). Furthermore, since aluminum has been shown to accumulate in the nuclear chromatin of neurons in patients with AD, it has been suggested that aluminum should be considered as a possible neurotoxic factor. If the role of aluminum accumulation were more certain in AD, it would be reasonable to consider the administration of chelating agents in For the past several years, clinical trials have been prophylaxis and treatment. Results underway with desferoxamine, a chelating agent that has affinity for aluminum. of these clinical trials are inconclusive (DeBoni and McLachlan, 1981). Another chelating agent which has been considered is disodium edetate calcium, a substance which has a similar binding constant for aluminum. 4.

Pharmacotherapy

of Dementia

During the past decade there has been a steady increase in the number of different pharmacological substances which have been employed in clinical trials with demented elderly patients. Since reduced cerebral glucose utilization has been reported in the aged, several drugs have been tried to prevent and/or counteract this change in brain metabolism. Included among them is naftidrofuryl, one of a series of new drugs which

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and T. A. Ban

produces a dose related rise in endooenous respiration in brain tissue. In-vitro studies have shown that the brain utilizes m&e glucose (possibly as a result of increased cerebral ATP formation) in naftidrofuryl-treated animals (Fontaine et al., 1969). Correspondinq with this are the findinqs of Branconnier and Cole (19771, who reported statistically significant improvement in short-term memory functions inasymptohatic volunteers with the daily administration of 300 mg of naftidrofuryl over a period of 90 days. Probably even more important is the fact that Judge and Urquhart (1972) and Bouvier et al. (1976) found statistically significant improvement in intellectual performance with the same dosage of naftidrofuryl in demented elderly patients. Findings with pyritinol, a substance which can normalize markedly reduced glucose consumption, are less consistent. Another substance which has been employed in the treatment of dementia in the aged is piracetam, which is usually considered to be the prototype nootropic agent. By definition, a nootropic is a substance with a direct effect on the higher integrative activity of the brain. Although the action mechanism of piracetam is not fully understood, there are indications that it increases ATP turnover rate and glucose utilization and also inhibits the cortical release of pyroline, a putative neurotransmitter (Giurgea, 1973). In spite of several favorable reports based on uncontrolled and placebo-controlled clinical studies, the place of piracetam in the treatment of AD has not been firmly established. The same applies to dihydroergotoxine (Hydergine), an ergot alkaloid, the most extensively employed substance in psychogeriatric patients. In spite of its extensive use there is no real understanding about its action mechanism. There are indications that dihydroergotoxine prevents the decrease of intracellular cyclic adenosine monophosphate levels which have been shown to occur in the aged. Because of this it is assumed that it can improve the recovery potential of neurons and may delay senescence and/or prevent senility (Meier-Rouge et al., 1978). Other substances which have been explored in the treatment of dementia in the aged include neuropeptides related to the adrenocorticotrophic hormone and vasopressin. In general, findings in clinical studies with these substances are disappointing. The same applies to the use of cerebral vasodilators (Yesavage et al., 1979). The employment of vasodilators is based on the assumption that dementia may result from cerebral arteriosclerosis in which cerebral ischemia is postulated. Since not even in MID is this truly the case (Frackowiak et al., 19811, there is no real justification for the use of vasodilator therapy. These agents actually reduce blood flow in areas of borderline perfusion (Cook and James, 1981). On the other hand, drugs such as nylidrin, pentoxyfylline, suloctodil, vincamine, apovincamine and calcium channel agonists such as nimodipine, through their diverse effects may have therapeutic potential in dementia (Crook, 1985).

5.

Summary

Advances in diagnostic brain imaging relevant to the dementias and especially to AD were reviewed. Different biochemical hypotheses of AD were presented and their therapeutic implications discussed. The present status of pharmacotherapy in AD was also outlined.

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