: Dr Makoto Tanaka, PhD, Department of Neurology, Gunma University School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan. Email: email@example.com
Vascular dementia is as common as Alzheimer's disease in Japan, although its importance has not been duly appreciated and its pathoetiology has not attracted proper attention. This article reviews the importance and pathophysiology of vascular dementia, presenting data obtained from our positron emission tomography (PET) study. Moreover, PET, ultrasonic quantitative blood flow measurements and magnetic resonance imaging findings on two ischemic conditions that may lead to vascular dementia are shown; chronic cerebral circulatory insufficiency (CCCI) and asymptomatic cerebral infarction. The review begins by describing the brief history, definition and classification of vascular dementia. Then, a detailed description of our PET study on patients with dementia as a result of cerebral infarction follows. Vascular dementia includes a large infarction in the territory of the right middle cerebral artery (LID), Binswanger-type infarction (BiD), multiple infarcts in the white matter and the basal ganglia (MID) and left anteromedial thalamic infarction (ThD). In addition, patients with a large infarction in the territory of the right middle cerebral artery (LIN), who did not have dementia, were used as a control group for LID. Healthy volunteers were also examined. This study demonstrates two types of dementia. Dementia observed in LID, MID and BiD reveals an overall reduction of blood flow and oxygen metabolism, which is accentuated in the frontal lobes. The second type, observed in ThD, shows a significant reduction in blood flow and oxygen metabolism in a relatively localized area in the left frontal lobe and the ipsilateral infarcted area. The etiological difference between the two types of dementia and the possible importance of frontal lobe hypoperfusion and hypometabolism are discussed. The review also examines the most important factor in dementia with multiple lacunae, concluding that widespread cerebral ischemia appears to be the most crucial factor. Finally, data on CCCI and asymptomatic cerebral infarction are described, which reveal that even these pre-stroke conditions have mild but significant hypoperfusion, concluding that preventive measures should be taken before ischemia advances.
Vascular dementia is defined as dementia caused by cerebrovascular diseases and the most common cause of vascular dementia is cerebral infarction.1 Even on the basis of our accumulated knowledge concerning strokes and dementia, it is very difficult to predict whether an ischemic stroke will cause dementia. For example, a large infarction in the right middle cerebral artery area causes dementia in some patients, although it may not induce any mental deterioration in other patients. Patients with multiple subcortical infarcts (lacunae) may or may not develop dementia. It is very important to identify the underlying differences between stroke patients with and without dementia. Identifying the underlying mechanisms may also facilitate our understanding of the etiology of vascular dementia.
In this review, we present results from our study that was designed to examine differences between stroke patients with and without vascular dementia and to identify the most important factor underlying vascular dementia using positron emission tomography (PET). Furthermore, Doppler ultrasonography, PET and magnetic resonance imaging (MRI) data on asymptomatic cerebral infarction and chronic cerebral circulatory insufficiency (CCCI) are also presented to show that even these prestroke conditions have mild, but serious, ischemia that may lead to vascular dementia.
DEFINITION AND CLASSIFICATION OF VASCULAR DEMENTIA
Although dementia has been known to occur along with cerebral arteriosclerotic changes since the end of the 19th century in European countries, it has attracted less attention from researchers than Alzheimer's disease and related degenerative dementia. Because the term multi-infarct dementia was coined by Hachinski2 to designate dementia caused by multiple large and small infarcts, it has been widely used all over the world and has sometimes included other forms of dementia resulting from ischemic strokes. Multi-infarct dementia may account for a large proportion of vascular dementia reported in Western countries, but the term is not synonymous with vascular dementia. In contrast, because dementia caused by ischemic stroke is more prevalent in Japan, it has been recognized as one of the most important pathological conditions to be overcome. As early as 1986, the Research Group supported by the Japanese Ministry of Education, Science and Culture established the first diagnostic criteria for vascular dementia, which is summarized as follows: (i) presence of dementia that usually shows stepwise progression (but its course is not stereotyped); (ii) presence of focal neurological signs and symptoms; and (iii) laboratory evidence (computed tomography (CT), etc.) indicative of cerebrovascular disease that is judged to be related to dementia. The NINDS–AIREN criteria, which is one of the worldwide criteria for vascular dementia, was published in 1993.3 There are no essential differences between these two criteria; both of them demand the presence of dementia and cerebrovascular disease that is judged to be etiologically related to dementia. It is sometimes difficult, however, to decide whether or not patients with stroke have dementia because patients tend to show a variety of neuropsychological signs and symptoms that interfere with the evaluation of cognitive function. Therefore, diagnostic criteria must also demand the absence of consciousness disturbance, delirium, psychiatric disorders, severe aphasia and severe sensorimotor disturbances.
There has been a tendency for researchers to use their own classification of vascular dementia depending on individual purposes, including pathological, clinical, epidemiological and genetic targets.4 In 1983 Hirai5 established a clinical and practical classification of vascular dementia from the viewpoint of the location of ischemia on the basis of cumulative pathoanatomical evidence (Fig. 1). Hirai's classification5 has been commonly adopted with or without minor modification in Japan. Although his classification may not cover every type of dementia related to vascular accidents, it is easy and practical to use. Since Hirai's classification5 there have been further classifications proposed by several authorities and international collaborative groups,4 which include all types of vascular dementia irrespective of how rare they are.
CEREBRAL BLOOD FLOW AND OXYGEN METABOLISM IN VASCULAR DEMENTIA
In order to look for a clue to the etiology of vascular dementia, we studied 31 patients, who were classified according to Hirai,1,5 with dementia resulting from cerebral infarction. This group consisted of seven patients with large thrombotic infarction in the whole territory of the right middle cerebral artery (LID, Fig. 1c), four patients with cerebral infarction (leukoaraiosis) of Binswanger-type (BiD, Fig. 1f), 16 with multiple lacunar infarcts in the white matter and basal ganglia (MID, Fig. 1g) and four with left anteromedial thalamic infarction (ThD, Fig. 1h). In addition, we also examined eight patients without dementia who had large thrombotic infarction in the whole territory of the right middle cerebral artery (LIN) as a control group for LID and 17 healthy volunteers. The mean age (years) and number of males and females in each group are summarized in Table 1. No significant age difference among the groups was shown using a one-way anova. We assessed all patients using DSM-III-R,6 evaluated their ischemic lesion(s) using CT, and investigated their individual temporal profile to confirm that dementia was caused by the infarction(s).
Table 1. Patients with vascular dementia and control subjects
Age (years) ± SD
MCA, Middle cerebral artery.
67.2 ± 9.2
71.3 ± 16.5
Multiple small infarction
67.4 ± 8.0
Left anteromedial thalamic infarction
65.0 ± 4.3
Large infarction in the right MCA area
65.6 ± 10.0
Large infarction without dementia
59.5 ± 16.1
57.8 ± 14.2
Positron emission tomography was performed using a PCT-H1 (Hitachi, Tokyo, Japan) that provided seven views per scan cycle, as described previously.7 Prior to the PET study, X-ray CT (CT-HSF, Hitachi, Tokyo, Japan) images were obtained to identify anatomical structures in the PET views and to confirm the location and area of the infarcted lesion(s). PET and X-ray CT scanners were located side by side and joined by rails on which the bed moved with the patient's position fixed, thus providing identical tomographic planes. The best spatial resolution was 7.4 mm full width at half maximum (FWHM) at the center of the scanning field, and the axial resolution at the center was 16 mm (slice thickness). The oxygen-15 steady state technique was employed to measure regional cerebral blood flow (rCBF), and the regional cerebral metabolic rate of oxygen (rCMRO2). Oxygen-15 gas (750–1100 MBq/min) and subsequently oxygen-15 labeled carbon dioxide (350–550 MBq/min) were inhaled continuously and scanning data were collected for 5–8 min.
Image data were processed with a Hitachi image processing computer using system subroutines to reconstruct functional images of 128 × 128 pixels.7 Regions of interest (ROI) were set on the bilateral cerebral cortices (over the frontal, temporal, parietal and occipital lobes), thalamus and cerebellar hemispheres.
A large infarction in the territory of the right middle cerebral artery showed a significant reduction in frontal rCBF and rCMRO2 compared with LIN (Fig. 2). The right frontal rCBF and rCMRO2 were decreased in both groups as expected; there was a large infarction adjacent to that area in the same cerebral hemisphere. The crucial difference between LID and LIN was that the left frontal rCBF and rCMRO2 were significantly reduced in LID. Multiple lacunar infarcts in the white matter and basal ganglia and BiD showed generalized hypoperfusion and hypometabolism that were accentuated in the bilateral frontal lobes as shown in Figs 3 and 4. Left anteromedial thalamic infarction showed decreased blood flow and oxygen metabolism in the left frontal lobe, especially in the frontal cortex adjacent to the orbit, and ipsilateral infarcted thalamus (Fig. 5). Left frontal hypoperfusion and hypometabolism were common to all groups of vascular dementia. Figure 6 was summarized from the perspective of frontal oxygen hypometabolism.
In patients with dementia who had lacunae (MID) or leukoaraiosis (BiD), the PET pattern suggests profound ischemia not only in the deep structures where lacunae or leukoaraiosis are present, but also in the cerebral cortex, in particular in the frontal cortex. Previous studies8 have already shown that the regional oxygen extraction ratio is increased in the cerebral cortex of those patients compared with patients with multiple lacunes and without dementia, indicating misery perfusion.
Large infarction in the territory of the right middle cerebral artery, also showing frontal hypoperfusion and hypometabolism, must result in widespread arteriosclerotic changes in major cerebral arteries other than the occluded right middle cerebral artery. The PET findings indicate that there is considerable ischemia that has not yet caused organic or morphological change in the frontal cortex beyond the infarcted area. This metabolic disturbance induced by ischemia in the frontal lobe could be assigned to an etiologic importance in mental deterioration.
Reduced rCBF and rCMRO2 shown in ThD were restricted to two regions; the left frontal lobe and ispsilateral thalamus. Focal ischemia in the frontal lobe does not suitably explain the PET findings. Because there is a close neural network between the thalamus and the ipsilateral frontal lobe, which is important for memory, diaschisis could explain hypometabolism in the frontal lobe that was suppressed transneuronally by the infarcted lesion in the thalamus.
In conclusion, frontal hypoperfusion and hypometabolism may play an important role in the development of dementia in stroke patients. Moreover, there are two distinct backgrounds; direct ischemia and diaschisis (i.e. a transneuronal remote effect). Finally, this frontal-dominant involvement appears to be one of the characteristics that can distinguish vascular dementia from Alzheimer's disease, which typically shows parietotemporal hypoperfusion and hypometabolism.9
DEMENTIA RESULTING FROM MULTIPLE INFARCTS
The most common cause of vascular dementia in Japan is multiple small infarcts (lacunae) in the white matter and basal ganglia. Multiple lacunae cause dementia in some patients, but not all patients. What is the difference between them? There appear to be several factors influencing the occurrence of dementia in patients with multiple infarcts.
First, the number of lacunae appears to be very important. With increasing numbers of lacunae, mental disturbances naturally become worse. However, some patients with multiple small infarcts in the white matter and basal ganglia show dementia (MID), whereas other patients with MRI or CT findings similar to them may present no symptoms or signs of dementia. This fact indicates that the number of lacunae seen on MRI or CT is important, but not a determinant by itself.
The location of infarction also appears to be crucial for the occurrence of dementia. It is true that the possibility of a strategically placed infarction depends in part on the number of lacunae. However, MID is not always accompanied by a strategically placed infarction. Again, the presence of a strategically placed infarction is not a determinant in itself.
It is not rare that multiple lacunae and Alzheimer's pathology exist together. Dementia with symptoms and signs indicating both vascular and Alzheimer's pathology has been called mixed dementia. This type of dementia with less clinical manifestations of Alzheimer's disease could be judged as only MID. It is pathologically obvious, however, that MID does not necessarily coexist with Alzheimer's disease.
Finally, multiple infarcts on MRI or CT do not always explain how vascular dementia developed. Our study indicates that the development of dementia as a result of multiple lacunae does not depend exclusively on infarcts themselves. Instead, the widespread brain ischemia, including frontal lobes in the background, appears to be the most crucial factor in the development of vascular dementia, which is evident by evaluating PET or SPECT.
CHRONIC CEREBRAL CIRCULATORY INSUFFICIENCY
Patients who do not present neurological deficits or abnormal brain CT or MRI findings sometimes complain of heavy headedness, dizziness or non-localized vague sensory disturbances that cannot be regarded as merely a general malaise or depressive state. This condition, CCCI, has attracted considerable attention in Japan because it appears to be closely related to cerebral arteriosclerotic changes and to stroke risk factors.
We collected samples and examined subjects with CCCI using an ultrasonic quantitative blood flow measurement system QFM2000XA (Nihon Koden, Tokyo, Japan) for the common carotid artery, PET and MRI.10 They consisted of three groups (Table 2): 60 subjects with CCCI (group A), 44 subjects with arteriosclerotic changes and without any neurological abnormalities (group B), and 40 healthy volunteers (group C). PET was also performed using the methods mentioned above.7
Table 2. Number of subjects for the common carotid blood flow study
Group A, subjects with chronic cerebral circulatory insufficiency; Group B, subjects with arteriosclerotic changes and no neurologic abnormalities; Group C, healthy volunteers.
Mean common carotid blood flow decreased with aging in all groups (Fig. 7). It was significantly reduced in group A. Group B also showed a reduction compared with group C. The PET study revealed that rCBF and rCMRO2 in all regions examined were significantly lower in group A than in group C. The incidence of white matter signal intensity abnormalities in MRI increased with aging and was greatest in group A. Moreover, reduction in mean carotid blood flow and cerebral blood flow was associated with the increasing incidence and severity of the signal abnormalities observed by MRI. These findings indicate that CCCI is a pathological condition closely related to diffuse low cerebral perfusion resulting from cerebral arteriosclerosis. Because the symptoms seen in CCCI may warn us of the presence of cerebral ischemia and an impending ischemic stroke, we should pay more attention to CCCI.
ASYMPTOMATIC CEREBRAL INFARCTION
Asymptomatic cerebral infarction refers to an incidental MRI or CT finding indicating cerebral infarction in patients without any neurological symptoms and signs as a result of the infarction. Most of the cases have lacunae in the white matter or basal ganglia. We studied 13 patients (73.9 ± 4.8) with asymptomatic infarction found using MRI (T2-weighted image) and seven healthy volunteers (70.7 ± 6.3) without any neurological symptoms and with normal MRI findings.11 The size of the infarcts ranged from 5 mm to 10 mm. PET was performed using the methods mentioned above.7
The rCBF and rCMRO2 in the cerebral cortex were reduced in patients with asymptomatic cerebral infarction compared with controls, although the difference was not statistically significant. Several studies have demonstrated disturbed cerebral blood flow in asymptomatic cerebral infarction; 133Xe study showing reduced blood flow,12 and PET studies showing reduced CBF, increased OEF and resultantly preserved CMRO213. All these findings indicate that brains with asymptomatic infarction have cerebral hypoperfusion, which PET studies show to be a misery perfusion phenomenon.
There must be at least two types of vascular dementia; one with underlying diffuse hypoperfusion that is accentuated in the frontal lobe and the other with infarction that damages a strategically important region, which plays an important role in memory. The former type is common and the majority of patients with vascular dementia have infarcts with diffuse hypoperfusion rather than an infarct in a strategically important region.14 Before vascular dementia is complete, cerebral circulation declines gradually.15 In the early course of ischemia, patients may experience symptoms indicating CCCI, or incidentally be found to have a silent infarction. With advancing ischemia, patients may have a stroke and relapses may result in multiple lacunar or Binswanger-type dementia (Fig. 8).
Although there is no effective therapeutic approach for complete vascular dementia, the progression of ischemia may be prevented in the early stage. Therefore, it is important to take preventative measures when CCCI is noticed.