Mechanisms of Ageing and Development, 9 (19 79) 173 - 183
173
©Elsevier Sequoia S.A., Lausanne - Printed in the Netherlands
RELEVANCE FUNCTION*
OF
CEREBROVASCULAR
CHANGES
TO
MENTAL
VLADIMIR HACHINSK! MacLachlan Stroke Unit, Sunnybrook Medical Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5 (Canada) (Received January 15, 1978)
Less is known about the function than about the malfunction of the hippocampus. Although the role of the hippocampus in mental function remains incomplete and controversial [1 ], it has been known since the last century that destruction of the hippocampi leads to memory inpairment and other mental changes. Brown and Sch~ifer in 1888 [2], first described what was to be rediscovered and eponymized as the Kl~iver-Bucy syndrome [3]. The latter two workers removed large parts of the temporal lobes in monkeys. The animals did not seem to understand the significance of visual stimuli despite an intact visual sensory system;they tended to place objects into their mouths, were easily distracted, showed decreased emotional responsiveness and increased sexual behaviour. Scoville and Milner [4] first reported a patient who underwent bilateral temporal lobe surgery for the treatment of epilepsy. The medial surface of both temporal lobes was removed, including the anterior two-thirds of the hippocampus, the uncus and the amygdala. Post-operatively, the patient's IQ increased from 104 to 117 points (probably because of the cessation of seizures). However, he showed a marked retrograde and anterograde amnesia. The retrograde amnesia gradually shrunk with time but the anterograde amnesia remained. He was unable to learn new material and would forget a task that he had performed just minutes before. He read the same magazines and solved the same jigsaw puzzles over and over again, apparently unaware that he was repeating his activities. By contrast, patients with unilateral temporal lobectomy did not show serious alterations in memory [5] .When unilateral temporal lobectomy has produced memory loss [6-10], most cases had evidence of previously unsuspected disease in the nonoperated temporal lobe [ 11 ]. Not only surgery but vascular changes (to be discussed below), involvement of the hippocampus and its connections in herpes encephalitis, in the Wernicke Korsakoff syndrome, in brain tumour and brain trauma can cause mental changes. Thus, there is little doubt that gross involvement of the hippocampus by infective, neoplastic or vascular disease leads to behavioural changes. The precise role of subtler cerebrovascular changes in the aging hippocampus, however, is much less certain. *Basedon a paper presented at a specialgroup of Symposiaentitled, "Frontiers in AgingResearch", arranged by the program committee of the Biological Sciences Section of the Gerontological Society, San Francisco Meeting, November 18-22, 1977.
174 THE BLOOD SUPPLY TO THE HIPPOCAMPUS The vascular anatomy of the hippocampus is unlike that of the rest of the brain. The arteries supplying the hippocampus are arranged in a rake-like fashion, branches arising at right angles to the main trunks and penetrating the hippocampus as end arteries. This feature led Scharrer [12] to suggest that whereas a drop in blood pressure is distributed equally in blood vessels branching dichotomously, in the rake-like pattern of the hippocampus the blood pressure would drop critically before this condition occurs elsewhere in the brain. Hence the hippocampus would be damaged earlier and more severely than the rest of the brain. Furthermore, Coceani and Gloor [13] pointed out that the hippocampus lies in the watershed between the carotid and vertebro-basilar arteries territories; any drop in blood pressure renders the hippocampus susceptible to ischemic damage, since the blood flow would cease earliest at the branches furthest away from the blood supply. It is well established that the hippocampus is one of the areas selectively vulnerable to severe falls in blood pressure [14]. However, the cerebral blood flow (CBF) is independent of systemic blood pressure over a wide range [15], so that blood pressure would have to fall below the critical level of CBF autoregulation to have an adverse effect on the function of the hippocampus. Recently, Myers and coworkers [16] have shown that even patients prone to severe drops in blood pressure on standing, do not show deterioration in mental function after being upright. It is possible, however, that multiple small areas of brain softenings (infarcts) may occur in patients prone to 'repeated bouts of profound falls in blood pressure due to disturbances of the heart rhythm. Corsellis [17] has noted that atherosclerosis and multiple small infarcts are more common in the hippocampus than elsewhere in the brain. Microscopically, the hippocampi show a remarkable correlation between the arrangement of cell and fiber layers and the vascular architecture [18]. Ball [19] made quantitative studies of neurofibrillary tangles and granulovacuolar degeneration in the hippoeampi of elderly patients and those with Alzheimer disease. He found that the severity of the changes was similar in distribution to that seen in neural damage caused by oxygen and blood insufficiency and speculated that changes in the microcirculation may be a factor in causing acute and chronic lesions in the hippocampus. De Boni et al. [20] have suggested that if a focal disturbance in CBF changed the permeability of the bloodbrain barrier, that neurotoxic agents such as aluminum may penetrate the brain and cause neurofibrfllary tangles seen in the aging brain and in Alzheimer's disease. The ' Scheibels [I, 21], on the basis of Golgi impregnation studies of neurons and their dendrites in aged subjects, suggest that the regularly occurring "spindle bodies" on adjacent apical shafts of entorhinal pyramidal neurons may also be related to the vascular microanatomy of the hippocampus. In fact, involvement of the smaller vessels by amyloidosis is not uncommon in Alzheimer's disease and in some senile brains [22-24]. Miyakawa [25] reported a four-fold thickening of the basement membrane of these vessels. Wisniewski (personal communication, 1977) has also observed extensive involvement of small vessels in aged humans and animals, and has speculated that this may lead to impaired exchange of chemicals between the blood and the brain. Rarely, amyloid
175 infiltrated vessels rupture and produce brain hemorrhages and mental impairment; however, there is no evidence that amyloid in the vessels narrows them critically or interferes with the nutrition of brain tissue. It is clear that the hippocampal circulation plays a role in the changes of mental function with aging. The extent and directness of this role remains uncertain.
CLINICALAND PATHOLOGICALSTUDIES OF CEREBROVASCULARDISEASEOF THE HIPPOCAMPUS Transient global amnesia [26-31] offers a model of a cerebrovascular event resulting in a change in mental function.
Illustrative case 1
One morning, a healthy, intelligent 65-year-old woman suddently appeared "confused". She asked her sister about cards on the mantel and a wrapped gift, forgetting that they had set up the Christmas cards and wrapped the gift the previous night. The sister's answers satisfied the patient only for a matter of minutes, similar questions being asked repeatedly because the answer was forgotten almost as soon as given. The inability to learn or remember only applied to the recent past, since she was able to carry out tasks that she had learned years before, such as driving herself to work and finding her desk at the office. Once at work, however, she did not know what she was supposed to do that day, and continued to ask questions to which answers had been given. By the time she was brought to hospital by her coworkers (some four hours after the onset of her "confusion"), her impairment of recent memory was beginning to clear, the patient only being aware that something unusual had happened that morning. Transient global amnesia usually occurs in the middle aged and elderly. It is characterized by a sudden onset of amnesia for recent events and a retrograde amnesia extending for days, months or years, that usually shrinks until the amnesia is only for the episode. Although in specific instances it may be caused by temporal lobe epilepsy, in the majority of cases, it is probably due to transient insufficiency of blood carried by the posterior cerebral arteries to the hippocampal structures. This is suggested by its association with other symptoms and signs of vascular insufficiency in the vertebro-basilar circulation in over half the cases [29, 30]. Since the hippocampus is also supplied by the anterior choroidal artery, some authors believe that transient global amnesia can also be caused by internal carotid circulation insufficiency [31 ], particularly when the' posterior cerebral arteries arise from the internal carotid arteries instead of the basilar artery. Thus, in some patients, the entire supply of the hippocampus comes from the internal carotid artery and disturbances in its blood supply will affect the hippocampi. Transient global amnesia can also be caused by a blood clot going from the heart to the brain [32]. Furthermore, sudden global amnesia is not always transient.
176 Illustrative case 2
Six months prior to admission to hospital, a 7 I-year-old woman suddenly collapsed to the ground, having lost consciousness briefly. She had some difficulties speaking, but recovered within a matter of minutes. An electrocardiogram showed a normal heart rhythm. The patient remained well for six months until she was admitted with a sudden onset of confusion. She was disorientated to time and place, and even when she was told where she was, she would forget from one minute to the next. Two months later, she still had fairly severe defect of recent memory. Medical investigation suggested that her memory deficit was due to a blood clot from the heart lodging in the arteries supplying the hippocampi. Bechterew in 1900 [33] described a similar case with severe memory loss for a number of years. An autopsy showed infarction of both hippocampi, and the lingual, fusiform and hippocampal gyri. Other cases with a severe memory defect and bilateral infarction in the posterior cerebral territory at autopsy have been described subsequently [34--39]. Hachinski [40] reported a case of a 42-year-old man with epilepsy and memory loss who had an arteriovenous malformation in the left temporal lobe, and who showed evidence of right temporal lobe damage on electroeneephalography. Cerebral angiography and CBF studies suggested that damage to the right temporal lobe was caused by shunting of blood from the initially healthy fight hemisphere to the left arteriovenous malformation ("symptomatic intracranial steal"). The vascular malformation probably had already caused damage to the left temporal lobe by compression and scarring, resulting in bilateral hippocampal lesions. The question as to whether unilateral hippocampal lesions also can cause amnesia is more controversial. Geschwind and Fusillo [41] described in detail a patient with amnesia, a fight homonymous hemianopia, alexia without agraphia and color agnosia. The amnesia cleared in three months. Examination of the brain at autopsy demonstrated lesions in the left medial temporal, diencephalic and calcarine areas. Mohr et al. [42] reported a man with severe loss of recent memory and a right superior quadrantopia. At autopsy, a patchy infarct of the left hippocampus, left lateral geniculate body and left posterior thalamus was demonstrated. Benson and colleagues [43] reported ten patients with amnesia following posterior cerebral artery blockage. Six cases had bilateral blockages but four had only left posterior cerebral artery obstructions. The authors concluded that left-sided lesions can produce temporary amnesia, but that the evidence for permanent amnesia is inconclusive. Cerebral blood flow studies
Cerebral blood flow (CBF) reflects brain function, and offers one way of studying the brain in rive. Methods of measuring total cerebral blood flow have been available since the 1940s [44]. The method is based on the Fick principle, whereby the rate at which the cerebral venous content of an inert gas approaches the arterial blood content depends upon the volume of blood flowing through the brain. The subject inhaled nitrous oxide and blood
177 samples were obtained from a peripheral artery and the internal jugular vein. The CBF is expressed as miUilitres of blood per 100 g of brain per minute and represented the total blood flow throughout the entire brain. It was only in the 1960s that reliable methods of measuring the CBF in different areas of the brain (rCBF) were developed using chemically inert rapidly diffusible radioactive gases. A small amount of aSKr or LlaXe dissolved in saline is injected into the internal carotid artery and the speed of washout in the brain is measured by external probes [45, 46], varying in number from 8 to 254 [47, 48]. Estimates of fast and slow flow components can also be made. Recently, a method has been described for estimating rCBF by inhaling the gas, hence avoiding any hazards association with arterial puncture [49]. Although less accurate than the carotid xenon method, it is repeatable, it measures CBF in both hemispheres simultaneously, and monitors vertebralbasilar blood flow, which cannot be sampled with the intracarotid technique.
CEREBRALBLOODFLOWIN NORMALAGING Datsur et al. [50] studied a group of healthy elderly subjects without any detectable medical, psychiatric or neurological disease. In this group, the CBF and CMRO2 (cerebral metabolic rate of oxygen) were the same as that of young healthy control subjects studied in the same way. A second group of elderly patients with minimal physical abnormalities, but mentally normal, had significantly lower CBF and CMRO2 values. Wang et al. [51] also studied two groups of healthy aged community volunteers. The mean CBF of the elderly subjects (52 ml/100 g/min) was significantly lower than that of healthy young adults (75 ml/100 g/min) studied by the same method. However, there was considerable overlap between the CBF values of the two groups: 33 to 72 ml/ 100 g/rain in the elderly subjects and 57 to 92 ml/lO0 g/min for the young adults. Although there may be a gradual slow decrease of CBF with age, the extent of this fall probably depends more on pathological changes than on age p e r s e [52].
CEREBRALBLOODFLOWIN ABNORMALAGING(DEMENTIA) In the initial stages, CBF and oxygen consumption of the brain are normal. Later, CBF, oxygen and glucose metabolism are all disturbed in a pattern characteristic of the underlying pathology [53]. In more advanced cases of Alzheimer's disease, the decrease in CBF is roughly proportional to the degree of mental impairment. Furthermore, in some cases, the decreased CBF is most marked in the frontotemporal area, where electroencephalographic and pathological changes are also maximal [52]. Cerebral blood flow studies in dementia have been complicated by disagreement about the, clef'tuition of dementia, by different beliefs about the presumed cause, by
178 the heterogeneity of the patients studied and by the deteriorated state of some of the subjects. In an attempt to obviate some of these difficulties, we studied 24 patients with early dementia [54]. By applying an ischemic scoring system, the patients fell into two clear groups: 14 scored low on the scale, and were considered to have primary degenerative dementia (Alzheimer disease), and ten patients scored high on the scale, and were termed multi-infarct dementia [55]. The two groups were of comparable age and degree of mental deterioration. The proportion of fast clearing tissues as determined by CBF studies (mainly gray matter) was decreased in both groups. The mean cerebral hemispheric CBF was within normal limits for the Alzheimer group, but decreased in the multi-infarct group in proportion to the mental impairment. The hippocampal blood flow could not be measured directly because the intracarotid method records mainly the cerebral cortical blood flow and the CBF of the structures nearest to the detectors. Furthermore, only if xenon reaches the hippocampus via the anterior choroidal artery or a posterior cerebral artery arising from the internal carotid artery, will the hippocampal blood flow contribute to the CBF measured extracranially. Nevertheless, it was interesting that areas of low CBF tended to duster in the temporal lobe of both groups of patients. This suggests that temporal lobe damage, however caused, is an important common denominator of the two main types of dementia.
FRONTIERS IN RESEARCH At a recent international conference on cerebral function, metabolism and blood flow [56, 57], evidence was produced to indicate that the blood supply to the brain is not even, and that the normal resting pattern changes with various mental functions. Using a 254 channel intracarotid rCBF method, at rest, the brain shows a hyperfrontal rCBF pattern, with relatively high blood flow in the frontal area and relatively low blood flow in the partial and temporal regions (Fig. 1). Listening to music increases the rC'BF in the posterior part of both superior temporal gyri, listening to words shows additional increases in Broca's and Wernicke's speech areas (Fig. 2). With automatic speech, rCBF increases in the temporal auditory and the rolandic face area of both hemispheres, and in the left motor supplementary areas (Fig. 3). rCBF changes also occur with looking, touching, actual or imagined limb movements, and problem solving. This refined intracarotid rCBF method can also be used to detect changes that occur in abnormal states, such as a severe attack of complicated migraine [58] (Fig. 4). Non-invasive methods of measuring glucose and oxygen metabolism in man are also being developed. ClSO2 and lsO2 [59] are inhaled and nC-glucose and nC-bicarbonate are injected intravenously [60]. Maps of metabolic brain activity could then be compared to the anatomic detail obtainable in rive through computerized tomography of the brain (Fig. 5). After "physiograms" are developed for the normal brain, it may be
Fig. 1. Normal resting patterns of regional cerebral blood flow (rCBF). Lateral views of the left (upper) and right (lower) hemispheres. Each shaded grey square represents the local CBF as a percentage above or below the mean hemispheric rCBF (labelled "00" on the scale on the right). CBF is relatively high in the frontal area and relatively low in the temporal and parietal areas. (Reproduced with permission from N. A. Lassen, P. E. Roland, B. Larsen, E. Melamed and K. Sob, Mapping of human cerebral functions: a study of the regional cerebral blood flow pattern during rest, its reproductivity, and the activations seen during basic sensory and motor functions, Acta Neurol. Scand., 56 (Suppl. 64) 262.)
Fig. 2. Average changes from rest in the rCBF during a simple listening test. The shaded code is as in Fig. 1, except that the mean hemispheric CBF is labelled "I00", There are CBF increases in both temporal auditory areas, as well as in Broca's and Wernicke's speech areas in the left hemisphere, (Reproduced with permission from B. Larsen, E. Skinh~j, K. Soh, H. Endo and N. A. Lassen, The pattern of cortical activity provoked by listening and speech revealed by rCBF measurements, Acta Neurol. Scand., 56 (Suppl. 64) 268.)
Fig. 3. Average changes from rest in the rCBF pattern during automatic speech. The shaded code is as in Fig. 2. rCBF increases are seen in both temporal auditory and rolandic face areas and in the left supplementary motor areas. (Reproduced with permission from B. Larsen, E. Skinh6j, S, Koh, H. Endo and N. A. Lassen, The pattern of cortical activity provoked by listening and speech revealed by rCBF measurements, Acta Neurol. $cand., 56 (Suppl. 64) 268.)
Fig. 4. ICBF changes during an attack of complicated migraine. The shaded code is as in Fig. 1, exept that the scale on the fight represents rCBF in ml/100 g/rain. The upper figure represents rCBF in the right hemisphere,'flve minutes after the onset of a migraine attack; there is an area of high flow, but the rCBF is otherwise decreased. At 25 minutes 0ower figure), the rCBF is decreased further, some values being at levels thought to cause brain malfunction due to poor blood supply. (Reproduced with permission from V. C. Hachinski, 5. Olesen, J. W. Norris, B. Larsen, E. Enovoldsen and N. A. Lassen, Y. Can. Sci. Neurol., 4 (1977) 245.)
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Fig. 5. Computerized tomography of the brain. Serial horizontal representations of the brain of an elderly subject showing considerable anatomic detail.
possible to learn the "pathograms" of different brain diseases. Physiological and pharmacological experiments may also become possible. The change in the physiological patterns after selective impairment of memory with scopolamine [61 ], for example, may teach us more about the function of the hippocampus in health and disease. It also may become possible to label enzymes that are altered with vascular changes and use them as an index of cerebrovascular disease. Only then will we know the true relevance of cerebrovascular changes to mental function.
SUMMARY Sudden, severe impairment of the blood flow to the hippocampus is known to produce mental changes, particulary impairment of recent memory. Whether more subtle changes in the vascular supply to the hippocampus play a role in the mental changes associated with aging, is less certain. Newer methods of determining the structure and function of the brain in vivo may help provide some answers.
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©Elsevier Sequoia S.A., Lausanne - Printed in the Netherlands
RELEVANCE FUNCTION*
OF
CEREBROVASCULAR
CHANGES
TO
MENTAL
VLADIMIR HACHINSK! MacLachlan Stroke Unit, Sunnybrook Medical Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5 (Canada) (Received January 15, 1978)
Less is known about the function than about the malfunction of the hippocampus. Although the role of the hippocampus in mental function remains incomplete and controversial [1 ], it has been known since the last century that destruction of the hippocampi leads to memory inpairment and other mental changes. Brown and Sch~ifer in 1888 [2], first described what was to be rediscovered and eponymized as the Kl~iver-Bucy syndrome [3]. The latter two workers removed large parts of the temporal lobes in monkeys. The animals did not seem to understand the significance of visual stimuli despite an intact visual sensory system;they tended to place objects into their mouths, were easily distracted, showed decreased emotional responsiveness and increased sexual behaviour. Scoville and Milner [4] first reported a patient who underwent bilateral temporal lobe surgery for the treatment of epilepsy. The medial surface of both temporal lobes was removed, including the anterior two-thirds of the hippocampus, the uncus and the amygdala. Post-operatively, the patient's IQ increased from 104 to 117 points (probably because of the cessation of seizures). However, he showed a marked retrograde and anterograde amnesia. The retrograde amnesia gradually shrunk with time but the anterograde amnesia remained. He was unable to learn new material and would forget a task that he had performed just minutes before. He read the same magazines and solved the same jigsaw puzzles over and over again, apparently unaware that he was repeating his activities. By contrast, patients with unilateral temporal lobectomy did not show serious alterations in memory [5] .When unilateral temporal lobectomy has produced memory loss [6-10], most cases had evidence of previously unsuspected disease in the nonoperated temporal lobe [ 11 ]. Not only surgery but vascular changes (to be discussed below), involvement of the hippocampus and its connections in herpes encephalitis, in the Wernicke Korsakoff syndrome, in brain tumour and brain trauma can cause mental changes. Thus, there is little doubt that gross involvement of the hippocampus by infective, neoplastic or vascular disease leads to behavioural changes. The precise role of subtler cerebrovascular changes in the aging hippocampus, however, is much less certain. *Basedon a paper presented at a specialgroup of Symposiaentitled, "Frontiers in AgingResearch", arranged by the program committee of the Biological Sciences Section of the Gerontological Society, San Francisco Meeting, November 18-22, 1977.
174 THE BLOOD SUPPLY TO THE HIPPOCAMPUS The vascular anatomy of the hippocampus is unlike that of the rest of the brain. The arteries supplying the hippocampus are arranged in a rake-like fashion, branches arising at right angles to the main trunks and penetrating the hippocampus as end arteries. This feature led Scharrer [12] to suggest that whereas a drop in blood pressure is distributed equally in blood vessels branching dichotomously, in the rake-like pattern of the hippocampus the blood pressure would drop critically before this condition occurs elsewhere in the brain. Hence the hippocampus would be damaged earlier and more severely than the rest of the brain. Furthermore, Coceani and Gloor [13] pointed out that the hippocampus lies in the watershed between the carotid and vertebro-basilar arteries territories; any drop in blood pressure renders the hippocampus susceptible to ischemic damage, since the blood flow would cease earliest at the branches furthest away from the blood supply. It is well established that the hippocampus is one of the areas selectively vulnerable to severe falls in blood pressure [14]. However, the cerebral blood flow (CBF) is independent of systemic blood pressure over a wide range [15], so that blood pressure would have to fall below the critical level of CBF autoregulation to have an adverse effect on the function of the hippocampus. Recently, Myers and coworkers [16] have shown that even patients prone to severe drops in blood pressure on standing, do not show deterioration in mental function after being upright. It is possible, however, that multiple small areas of brain softenings (infarcts) may occur in patients prone to 'repeated bouts of profound falls in blood pressure due to disturbances of the heart rhythm. Corsellis [17] has noted that atherosclerosis and multiple small infarcts are more common in the hippocampus than elsewhere in the brain. Microscopically, the hippocampi show a remarkable correlation between the arrangement of cell and fiber layers and the vascular architecture [18]. Ball [19] made quantitative studies of neurofibrillary tangles and granulovacuolar degeneration in the hippoeampi of elderly patients and those with Alzheimer disease. He found that the severity of the changes was similar in distribution to that seen in neural damage caused by oxygen and blood insufficiency and speculated that changes in the microcirculation may be a factor in causing acute and chronic lesions in the hippocampus. De Boni et al. [20] have suggested that if a focal disturbance in CBF changed the permeability of the bloodbrain barrier, that neurotoxic agents such as aluminum may penetrate the brain and cause neurofibrfllary tangles seen in the aging brain and in Alzheimer's disease. The ' Scheibels [I, 21], on the basis of Golgi impregnation studies of neurons and their dendrites in aged subjects, suggest that the regularly occurring "spindle bodies" on adjacent apical shafts of entorhinal pyramidal neurons may also be related to the vascular microanatomy of the hippocampus. In fact, involvement of the smaller vessels by amyloidosis is not uncommon in Alzheimer's disease and in some senile brains [22-24]. Miyakawa [25] reported a four-fold thickening of the basement membrane of these vessels. Wisniewski (personal communication, 1977) has also observed extensive involvement of small vessels in aged humans and animals, and has speculated that this may lead to impaired exchange of chemicals between the blood and the brain. Rarely, amyloid
175 infiltrated vessels rupture and produce brain hemorrhages and mental impairment; however, there is no evidence that amyloid in the vessels narrows them critically or interferes with the nutrition of brain tissue. It is clear that the hippocampal circulation plays a role in the changes of mental function with aging. The extent and directness of this role remains uncertain.
CLINICALAND PATHOLOGICALSTUDIES OF CEREBROVASCULARDISEASEOF THE HIPPOCAMPUS Transient global amnesia [26-31] offers a model of a cerebrovascular event resulting in a change in mental function.
Illustrative case 1
One morning, a healthy, intelligent 65-year-old woman suddently appeared "confused". She asked her sister about cards on the mantel and a wrapped gift, forgetting that they had set up the Christmas cards and wrapped the gift the previous night. The sister's answers satisfied the patient only for a matter of minutes, similar questions being asked repeatedly because the answer was forgotten almost as soon as given. The inability to learn or remember only applied to the recent past, since she was able to carry out tasks that she had learned years before, such as driving herself to work and finding her desk at the office. Once at work, however, she did not know what she was supposed to do that day, and continued to ask questions to which answers had been given. By the time she was brought to hospital by her coworkers (some four hours after the onset of her "confusion"), her impairment of recent memory was beginning to clear, the patient only being aware that something unusual had happened that morning. Transient global amnesia usually occurs in the middle aged and elderly. It is characterized by a sudden onset of amnesia for recent events and a retrograde amnesia extending for days, months or years, that usually shrinks until the amnesia is only for the episode. Although in specific instances it may be caused by temporal lobe epilepsy, in the majority of cases, it is probably due to transient insufficiency of blood carried by the posterior cerebral arteries to the hippocampal structures. This is suggested by its association with other symptoms and signs of vascular insufficiency in the vertebro-basilar circulation in over half the cases [29, 30]. Since the hippocampus is also supplied by the anterior choroidal artery, some authors believe that transient global amnesia can also be caused by internal carotid circulation insufficiency [31 ], particularly when the' posterior cerebral arteries arise from the internal carotid arteries instead of the basilar artery. Thus, in some patients, the entire supply of the hippocampus comes from the internal carotid artery and disturbances in its blood supply will affect the hippocampi. Transient global amnesia can also be caused by a blood clot going from the heart to the brain [32]. Furthermore, sudden global amnesia is not always transient.
176 Illustrative case 2
Six months prior to admission to hospital, a 7 I-year-old woman suddenly collapsed to the ground, having lost consciousness briefly. She had some difficulties speaking, but recovered within a matter of minutes. An electrocardiogram showed a normal heart rhythm. The patient remained well for six months until she was admitted with a sudden onset of confusion. She was disorientated to time and place, and even when she was told where she was, she would forget from one minute to the next. Two months later, she still had fairly severe defect of recent memory. Medical investigation suggested that her memory deficit was due to a blood clot from the heart lodging in the arteries supplying the hippocampi. Bechterew in 1900 [33] described a similar case with severe memory loss for a number of years. An autopsy showed infarction of both hippocampi, and the lingual, fusiform and hippocampal gyri. Other cases with a severe memory defect and bilateral infarction in the posterior cerebral territory at autopsy have been described subsequently [34--39]. Hachinski [40] reported a case of a 42-year-old man with epilepsy and memory loss who had an arteriovenous malformation in the left temporal lobe, and who showed evidence of right temporal lobe damage on electroeneephalography. Cerebral angiography and CBF studies suggested that damage to the right temporal lobe was caused by shunting of blood from the initially healthy fight hemisphere to the left arteriovenous malformation ("symptomatic intracranial steal"). The vascular malformation probably had already caused damage to the left temporal lobe by compression and scarring, resulting in bilateral hippocampal lesions. The question as to whether unilateral hippocampal lesions also can cause amnesia is more controversial. Geschwind and Fusillo [41] described in detail a patient with amnesia, a fight homonymous hemianopia, alexia without agraphia and color agnosia. The amnesia cleared in three months. Examination of the brain at autopsy demonstrated lesions in the left medial temporal, diencephalic and calcarine areas. Mohr et al. [42] reported a man with severe loss of recent memory and a right superior quadrantopia. At autopsy, a patchy infarct of the left hippocampus, left lateral geniculate body and left posterior thalamus was demonstrated. Benson and colleagues [43] reported ten patients with amnesia following posterior cerebral artery blockage. Six cases had bilateral blockages but four had only left posterior cerebral artery obstructions. The authors concluded that left-sided lesions can produce temporary amnesia, but that the evidence for permanent amnesia is inconclusive. Cerebral blood flow studies
Cerebral blood flow (CBF) reflects brain function, and offers one way of studying the brain in rive. Methods of measuring total cerebral blood flow have been available since the 1940s [44]. The method is based on the Fick principle, whereby the rate at which the cerebral venous content of an inert gas approaches the arterial blood content depends upon the volume of blood flowing through the brain. The subject inhaled nitrous oxide and blood
177 samples were obtained from a peripheral artery and the internal jugular vein. The CBF is expressed as miUilitres of blood per 100 g of brain per minute and represented the total blood flow throughout the entire brain. It was only in the 1960s that reliable methods of measuring the CBF in different areas of the brain (rCBF) were developed using chemically inert rapidly diffusible radioactive gases. A small amount of aSKr or LlaXe dissolved in saline is injected into the internal carotid artery and the speed of washout in the brain is measured by external probes [45, 46], varying in number from 8 to 254 [47, 48]. Estimates of fast and slow flow components can also be made. Recently, a method has been described for estimating rCBF by inhaling the gas, hence avoiding any hazards association with arterial puncture [49]. Although less accurate than the carotid xenon method, it is repeatable, it measures CBF in both hemispheres simultaneously, and monitors vertebralbasilar blood flow, which cannot be sampled with the intracarotid technique.
CEREBRALBLOODFLOWIN NORMALAGING Datsur et al. [50] studied a group of healthy elderly subjects without any detectable medical, psychiatric or neurological disease. In this group, the CBF and CMRO2 (cerebral metabolic rate of oxygen) were the same as that of young healthy control subjects studied in the same way. A second group of elderly patients with minimal physical abnormalities, but mentally normal, had significantly lower CBF and CMRO2 values. Wang et al. [51] also studied two groups of healthy aged community volunteers. The mean CBF of the elderly subjects (52 ml/100 g/min) was significantly lower than that of healthy young adults (75 ml/100 g/min) studied by the same method. However, there was considerable overlap between the CBF values of the two groups: 33 to 72 ml/ 100 g/rain in the elderly subjects and 57 to 92 ml/lO0 g/min for the young adults. Although there may be a gradual slow decrease of CBF with age, the extent of this fall probably depends more on pathological changes than on age p e r s e [52].
CEREBRALBLOODFLOWIN ABNORMALAGING(DEMENTIA) In the initial stages, CBF and oxygen consumption of the brain are normal. Later, CBF, oxygen and glucose metabolism are all disturbed in a pattern characteristic of the underlying pathology [53]. In more advanced cases of Alzheimer's disease, the decrease in CBF is roughly proportional to the degree of mental impairment. Furthermore, in some cases, the decreased CBF is most marked in the frontotemporal area, where electroencephalographic and pathological changes are also maximal [52]. Cerebral blood flow studies in dementia have been complicated by disagreement about the, clef'tuition of dementia, by different beliefs about the presumed cause, by
178 the heterogeneity of the patients studied and by the deteriorated state of some of the subjects. In an attempt to obviate some of these difficulties, we studied 24 patients with early dementia [54]. By applying an ischemic scoring system, the patients fell into two clear groups: 14 scored low on the scale, and were considered to have primary degenerative dementia (Alzheimer disease), and ten patients scored high on the scale, and were termed multi-infarct dementia [55]. The two groups were of comparable age and degree of mental deterioration. The proportion of fast clearing tissues as determined by CBF studies (mainly gray matter) was decreased in both groups. The mean cerebral hemispheric CBF was within normal limits for the Alzheimer group, but decreased in the multi-infarct group in proportion to the mental impairment. The hippocampal blood flow could not be measured directly because the intracarotid method records mainly the cerebral cortical blood flow and the CBF of the structures nearest to the detectors. Furthermore, only if xenon reaches the hippocampus via the anterior choroidal artery or a posterior cerebral artery arising from the internal carotid artery, will the hippocampal blood flow contribute to the CBF measured extracranially. Nevertheless, it was interesting that areas of low CBF tended to duster in the temporal lobe of both groups of patients. This suggests that temporal lobe damage, however caused, is an important common denominator of the two main types of dementia.
FRONTIERS IN RESEARCH At a recent international conference on cerebral function, metabolism and blood flow [56, 57], evidence was produced to indicate that the blood supply to the brain is not even, and that the normal resting pattern changes with various mental functions. Using a 254 channel intracarotid rCBF method, at rest, the brain shows a hyperfrontal rCBF pattern, with relatively high blood flow in the frontal area and relatively low blood flow in the partial and temporal regions (Fig. 1). Listening to music increases the rC'BF in the posterior part of both superior temporal gyri, listening to words shows additional increases in Broca's and Wernicke's speech areas (Fig. 2). With automatic speech, rCBF increases in the temporal auditory and the rolandic face area of both hemispheres, and in the left motor supplementary areas (Fig. 3). rCBF changes also occur with looking, touching, actual or imagined limb movements, and problem solving. This refined intracarotid rCBF method can also be used to detect changes that occur in abnormal states, such as a severe attack of complicated migraine [58] (Fig. 4). Non-invasive methods of measuring glucose and oxygen metabolism in man are also being developed. ClSO2 and lsO2 [59] are inhaled and nC-glucose and nC-bicarbonate are injected intravenously [60]. Maps of metabolic brain activity could then be compared to the anatomic detail obtainable in rive through computerized tomography of the brain (Fig. 5). After "physiograms" are developed for the normal brain, it may be
Fig. 1. Normal resting patterns of regional cerebral blood flow (rCBF). Lateral views of the left (upper) and right (lower) hemispheres. Each shaded grey square represents the local CBF as a percentage above or below the mean hemispheric rCBF (labelled "00" on the scale on the right). CBF is relatively high in the frontal area and relatively low in the temporal and parietal areas. (Reproduced with permission from N. A. Lassen, P. E. Roland, B. Larsen, E. Melamed and K. Sob, Mapping of human cerebral functions: a study of the regional cerebral blood flow pattern during rest, its reproductivity, and the activations seen during basic sensory and motor functions, Acta Neurol. Scand., 56 (Suppl. 64) 262.)
Fig. 2. Average changes from rest in the rCBF during a simple listening test. The shaded code is as in Fig. 1, except that the mean hemispheric CBF is labelled "I00", There are CBF increases in both temporal auditory areas, as well as in Broca's and Wernicke's speech areas in the left hemisphere, (Reproduced with permission from B. Larsen, E. Skinh~j, K. Soh, H. Endo and N. A. Lassen, The pattern of cortical activity provoked by listening and speech revealed by rCBF measurements, Acta Neurol. Scand., 56 (Suppl. 64) 268.)
Fig. 3. Average changes from rest in the rCBF pattern during automatic speech. The shaded code is as in Fig. 2. rCBF increases are seen in both temporal auditory and rolandic face areas and in the left supplementary motor areas. (Reproduced with permission from B. Larsen, E. Skinh6j, S, Koh, H. Endo and N. A. Lassen, The pattern of cortical activity provoked by listening and speech revealed by rCBF measurements, Acta Neurol. $cand., 56 (Suppl. 64) 268.)
Fig. 4. ICBF changes during an attack of complicated migraine. The shaded code is as in Fig. 1, exept that the scale on the fight represents rCBF in ml/100 g/rain. The upper figure represents rCBF in the right hemisphere,'flve minutes after the onset of a migraine attack; there is an area of high flow, but the rCBF is otherwise decreased. At 25 minutes 0ower figure), the rCBF is decreased further, some values being at levels thought to cause brain malfunction due to poor blood supply. (Reproduced with permission from V. C. Hachinski, 5. Olesen, J. W. Norris, B. Larsen, E. Enovoldsen and N. A. Lassen, Y. Can. Sci. Neurol., 4 (1977) 245.)
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Fig. 5. Computerized tomography of the brain. Serial horizontal representations of the brain of an elderly subject showing considerable anatomic detail.
possible to learn the "pathograms" of different brain diseases. Physiological and pharmacological experiments may also become possible. The change in the physiological patterns after selective impairment of memory with scopolamine [61 ], for example, may teach us more about the function of the hippocampus in health and disease. It also may become possible to label enzymes that are altered with vascular changes and use them as an index of cerebrovascular disease. Only then will we know the true relevance of cerebrovascular changes to mental function.
SUMMARY Sudden, severe impairment of the blood flow to the hippocampus is known to produce mental changes, particulary impairment of recent memory. Whether more subtle changes in the vascular supply to the hippocampus play a role in the mental changes associated with aging, is less certain. Newer methods of determining the structure and function of the brain in vivo may help provide some answers.
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