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Stroke. 1995;26:735-742

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(Stroke. 1995;26:735-742.)
© 1995 American Heart Association, Inc.

Articles

Prospective CT Confirms Differences Between Vascular and Alzheimer's Dementia

John Stirling Meyer, MD; Kazuhiro Muramatsu, MD; Karl F. Mortel, PhD; Katsuyuki Obara, MD Toshitaka Shirai, MD

From the Cerebrovascular Research Laboratories, Department of Veterans Affairs Medical Center, and the Department of Neurology, Baylor College of Medicine (J.S.M.), Houston, Tex.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose Cognitive test performances were correlated prospectively with changes in cerebral CT measurements of atrophy, infarct volume, ventricular enlargement, local tissue density, and local perfusion to contrast annual rates of changes among patients with ischemic vascular dementia (IVD) or dementia of the Alzheimer type (DAT).

Methods The cerebral atrophic index (ATI; ratio of cerebrospinal fluid or infarcted brain to intracranial volume), infarct volume ratio, ventricular volume ratio (VVR; ventricular volume/intracranial volume), cortical and subcortical gray and white matter local perfusion (local cerebral blood flow [LCBF]), and local Hounsfield unit (HU) density were measured concurrently and compared longitudinally with Cognitive Capacity Screening Examinations (CCSE) scores among 24 treated IVD (age, 68.2±9.7 years; follow-up, 42±27 months) and 24 DAT patients (age, 74.2±6.2 years; follow-up, 30±19 months).

Results IVD annual changes were as follows: CCSE, +1.2±5.9; ATI, +2.1%/y; VVR, +3.2%/y; and LCBF in the subcortical basal ganglia, -0.74 mL · 100 g-1 · min-1 · y-1 (-1.8%/y). DAT annual changes were as follows: CCSE, -1.8 /y; ATI, +8.1%/y; VVR, +9.6%/y; cortical LCBF, -2.0 mL · 100 g-1 · min-1 · y-1 (-5.2%/y); LCBF in the basal ganglia, -3.0 mL · 100 g-1 · min-1 · y-1 (-6.7%/y); white matter LCBF, -0.75 mL · 100 g-1 · min-1 · y-1 (-4.1%/y); and all cortical tissue densities, -0.83 HU/y (-2.1%/y). In IVD, multiple regression analyses correlated cognitive changes directly with (1) recurrent silent infarctions and (2) bidirectional changes of perfusions within frontal white matter, thalamus, and internal capsules. In DAT, cognitive declines correlated with cerebral atrophy and cortical hypoperfusion related to frontotemporal and parietal cortical polioaraiosis (decreased gray matter tissue densities).

Conclusions In IVD, recurrent strokes were not observed clinically during risk factor control, and antiplatelet therapy and cognitive impairments improved or stabilized. In DAT, cognitive performance relentlessly declined. Ischemic pathogenesis for vascular dementia is supported by the following: (1) cognitive declines correlate directly with recurrent "silent" strokes, and (2) bidirectional cognitive changes correlate directly with frontal white matter, thalamic, and internal capsular perfusional changes.


Key Words: Alzheimer's disease • cerebral blood flow • dementia • tomography


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
In the United States, ischemic vascular dementia (IVD) is second to dementia of the Alzheimer type (DAT) as the most common cause of cognitive impairments among the elderly.1 2 3 4 However, the definition, prevalence, and very existence of IVD remain controversial.5

To document pathogenetic differences between IVD and DAT, concurrent, longitudinal measurements among demented patients with either IVD or DAT were determined to compare annual rates of change in neurological, psychometric, and CT manifestations.

Cognitive impairments in IVD have been correlated with (1) risk factors for stroke, (2) cerebral atrophy, (3) numbers and sites of cerebral infarctions, and (4) limited educational and occupational levels.6 7 8 9 10 11 Among DAT patients, cognitive impairments have been correlated with (1) ventricular enlargement12 13 14 15 16 17 and (2) bihemispheric declines in cortical blood flow and metabolism.18 19 20 21 22 Progressive declines in cortical perfusion in DAT were ascribed to decreased cortical metabolic demands resulting from Alzheimer's degenerative changes, which principally affect the cerebral cortex.18 19 20 21 22

Among IVD patients, prospective studies designed to correlate cognitive test performances with changes in local cerebral perfusion, recurrent strokes, and cerebral atrophy have been extremely rare,23 and longitudinal comparisons of cognitive test scores with cerebral atrophy, infarct volumes, changes in cortical density, and local perfusion compared between DAT and IVD patients are not available.

For these reasons the present prospective and concurrent study was designed to compare annual rates of change in neurological, psychometric, and cerebral CT measurements between groups of patients with probable IVD or DAT to correlate annual changes in cognitive test performance with annual changes in (1) ventricular volume, (2) atrophic index, (3) cerebral infarct volume, (4) volume of normal and abnormal cortical and subcortical gray and white matter, (5) local tissue density, and (6) local tissue perfusion.


*    Subjects and Methods
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 up arrowIntroduction
 *Subjects and Methods
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As displayed in Table 1Down, 24 patients with probable IVD due to multiple small strokes (mean age, 68.2±9.7 years) were compared during follow-up with 24 probable DAT patients (mean age, 74.2±6.2 years) by the use of identical concurrent longitudinal designs. Patients were admitted sequentially after referral by local physicians, the Alzheimer's Disease and Related Disorders Association, and Stroke Groups of Houston.


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  		Table 1. Demographics Compared Between Patients With Ischemic Vascular Dementia or Dementia of the Alzheimer Type

Informed consents were signed according to protocols approved by the Institutional Review Board of Baylor College of Medicine. Participants returned for serial testing as outpatients at 6- to 12-month intervals. Mean follow-up intervals were 42.3±27.2 months (range, 6 to 89 months) for IVD patients and 30.1±18.7 months (range, 10 to 75 months) for DAT patients. At each visit, patients underwent medical, neurological, and neuropsychological examinations by the authors. Neuropsychological test batteries performed included the Cognitive Capacity Screening Examinations (CCSE),24 25 26 Hamilton Depression Rating Scale,27 Wechsler Adult Intelligence Scale (Revised), Mini-Mental State Examination,28 Diagnostic and Statistical Manual of Mental Disorders, edition 3, revised (DSM-III-R) dementia rating scales,29 and standard tests of memory, motor performance, and language.

At entry, dementia met DSM-III-R criteria.29 Both groups had CCSE scores that fell below the cutoff score of 25, which is known to indicate cognitive impairments. Among high school graduates, CCSE test scores <25 also correlate with impairments demonstrated by standard neuropsychological and neurobehavioral testing.24 25 26 CCSE scoring is reliable and reproducible (±1) for quantitating cognitive changes among elderly patients with IVD and DAT. In the present series of patients, more extensive test battery scores were determined and correlated well with CCSE testing. CCSE scores were selected as the indicator for assessing changes in cognitive status for purposes of the present study.

At each visit, 26% xenon gas was inhaled for 8 minutes during serial CT brain scanning to provide an x-ray dense contrast indicator for measuring cerebral perfusion. Clinical and laboratory evaluations were determined among both groups to detect associated risk factors for stroke and adequacy of their control. Controlled risk factors included hypertension, atherosclerotic heart disease, hyperlipidemia, diabetes mellitus, and cigarette smoking.

IVD patients were not admitted until >=3 months after their last stroke. Patients with large thromboembolic strokes >50 mm in diameter by CT scanning and with severe neurological deficits were excluded30 31 because aphasia, neglect, and severe motor involvement interfere with the reliability and reproducibility of neuropsychological testing and because large cerebral infarctions are less remediable.

Inclusion criteria for IVD patients were (1) DSM-III-R listings for dementia; (2) Hachinski ischemic scales >6; (3) multiple strokes by history or neurological examination; and (4) CT confirmation of multiple small infarctions. Exclusion criteria were (1) large thromboembolic cerebral infarctions with major neurological deficits; (2) CT evidence of normal pressure hydrocephalus, subdural hematoma, or mass lesion; (3) central nervous system infections; (4) hypothyroidism; (5) vitamin B12 deficiency; (6) Hamilton Depression Scale score >=17; or (7) drug and alcohol abuse. These criteria conform to the criteria for probable IVD recommended by Chui et al32 and the criteria for IVD due to lacunar strokes recommended by the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN).33

Patients with probable DAT met criteria of the National Institute of Neurological Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association.34 DAT patients were required to have Hachinski ischemic scores <4. Exclusion criteria were (1) clinical or CT evidence of stroke; (2) CT evidence of normal pressure hydrocephalus, subdural hematoma, or mass lesion; (3) dementia after cardiac arrest or coronary bypass; (4) progressive supranuclear palsy, Parkinson's, Wilson's, Huntington's, Creutzfeldt-Jakob, Pick's lobar atrophy, or probable Lewy body disease35 ; (5) central nervous system infections; (6) hypothyroidism, folic acid, and vitamin B12 deficiency; (7) Hamilton Depression Scale score >=17; or (8) drug and alcohol abuse.

Hypertensive patients were treated with standard antihypertensive medications (calcium channel blockers, ß-blockers, angiotensin converting-enzyme inhibitors, diuretics) to maintain blood pressures at or near 150 mm Hg systolic and 90 mm Hg diastolic.36 Diabetic patients were treated with diet, oral hypoglycemic agents, and insulin. Patients with hyperlipidemia were treated with diet, lovastatin, or gemfibrozil. Smokers were persuaded to desist. The 24 IVD patients were treated daily with 325 mg aspirin (n=18) and 500 mg ticlopidine (n=6).

During CT imaging, electroencephalograms, electrocardiograms, and PECO2 were monitored and blood pressures recorded before and after each xenon gas inhalation. CT images were obtained with two high-resolution scanners (Siemens Somatom DR-H or Picker Synerview model 1200SX) standardized regularly with a phantom. Images had a 512x512 matrix and pixel size of 0.47x0.47 mm with settings at 96 kilovolts (peak), 540 mA, 8 mm thickness with 5-second scanning times for the Siemens and 130 kV(p), 140 mA, 10 mm thickness with 2-second scanning times for the Picker unit. SDs were ±0.2 Hounsfield units (HU). Lower slices were selected parallel to orbitomeatal lines from lateral views, and upper slices were selected 10 mm higher. Films were retained for repositioning in later studies at the same settings. These slices provided standard regions of interest (ROIs) throughout both cerebral hemispheres to include the frontal, temporal, parietal, and occipital cortices; caudate nucleus; putamen; thalamus; frontal, capsular and occipital white matter; and centrum semiovale.37 38 39 40

Among IVD patients, CT definitions to identify small cerebral infarction subtypes were as follows: (1) lacunar infarctions: <=15 mm in diameter in territories of deep penetrating arteries; (2) cortical infarctions: superficial hypodensities involving cortex and subcortical white matter in major cerebral arterial territories; (3) subcortical nonlacunar infarctions: in subcortical white matter and basal ganglia measuring >15 mm but <50 mm in diameter; and (4) border-zone infarctions: cortical and subcortical hypodensities in border zones of major cerebral arteries.

CT estimates of infarctions were made at study entry and follow-up, without reference to earlier records to determine numbers of "silent" as well as symptomatic cerebral infarctions.

Interval perfusions were measured at entry and follow-up during xenon gas inhalation delivered by a rapid enhancer.37 Information from CT tapes was transferred to desktop computers, and local cerebral blood flow (LCBF) and CT densities were measured directly on CT slices. Noncontrasted scans functioned as baseline, and progressively enhanced scans computed color-coded CT cerebral blood flow (CBF) maps from local tissue saturation curves.37

At each measurement, both cerebral hemispheres were cursored for 10 ROIs, including frontal, temporal, parietal, and occipital cortices; caudate nucleus; putamen; thalamus; frontal, occipital, and capsular white matter; and total cortical and subcortical gray and white matter. Infarcted volumes showing zero flow were measured as a separate variable for analysis but were excluded from regional perfusion and tissue volume measurements. Regions adjacent to the calvaria were avoided to minimize beam-hardening artifacts. We excluded cerebrospinal fluid (CSF) volumes defined as HU values <17 and calcific or bony overlaps defined as HU values >90. Mean LCBF and HU values for ROIs were summated from bihemispheric means. Annual percent LCBF changes, adjusted for differences in initial values, were calculated from annual changes in LCBF, divided by mean LCBF at entry and adjusting follow-up intervals to 12 months, as follows:


Among IVD patients, ventricles, subarachnoid spaces, and infarcted volumes were cursored on noncontrasted CT images by summating all voxels with HU values <25 for estimating the atrophic index (ATI), since 25 HU is the established threshold for infarcted brain and CSF.38 39

Among DAT patients, ventricles and subarachnoid spaces were cursored to summate CSF voxels between 0 and 17 HU for estimating ATI.38 39 ATI was calculated as ratio of atrophic or infarcted brain volume/intracranial volumex100. ATI estimates residual cerebral parenchyma as a percentage ratio, which adjusts for differences in head size. After we adjusted for differences in initial values, annual percent changes in ATI were calculated as follows:


Factors considered that might influence cognitive changes among IVD and DAT patients were analyzed by multiple linear regressions, with CCSE changes as dependent variables. These included total and regional cerebral atrophy, local tissue density, perfusion in gray and white matter, and size and recurrence of cerebral infarctions. Volume of infarction and leukoaraiosis were sequestered as separate variables.

We compared IVD and DAT patients using standard statistical methods including MANOVA. Mean±SD group values at entry and follow-up were compared by paired t tests.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 
No group differences were found for electroencephalograms, electrocardiograms, PECO2, or blood pressure levels during or between CT CBF measurements.

More men had IVD, and more women had DAT (Table 1Up). CCSE and Mini-Mental State Examination scores were lower and mean ages older among DAT patients; this persisted during follow-up because there were no dropouts. Patients with IVD had less education than DAT patients. Hypertension, atherosclerotic heart disease, hyperlipidemia, and diabetes mellitus were more frequent among IVD patients. Cigarette smoking was similar between groups.

At entry, IVD patients had the following neurological deficits: (1) left hemiparesis (n=4; 16.7%); (2) left hemisensory (n=1; 4.2%); (3) combined left hemiparesis and hemisensory (n=2; 8.3%); (4) left ataxic hemiparesis (n=3; 12.5%); (5) right hemiparesis (n=5; 20.8%); (6) right hemisensory (n=1; 4.2%); (7) right hemiparesis and hemisensory (n=6; 25.0%); and (8) right ataxic hemiparesis (n=2; 8.3%).

Carotid Doppler, contrast, or MR angiography was routinely carried out among IVD but not DAT patients; occlusion or >75% intracranial stenosis of the left internal carotid artery was detected among 6 (25.0%). Follow-up neurological examinations among IVD patients improved or did not change, but DAT patients showed progressive deterioration.

At entry 94 cerebral infarctions were detected among IVD patients, including 90 lacunar, 2 border zone, 1 cortical, and 1 subcortical of the nonlacunar type. The mean number of infarctions per patient was 3.9±1.4. Locations for lacunar infarctions were as follows: (1) left caudate (n=3; 3.3%); (2) left globus pallidus (n=4; 4.4%); (3) left putamen (n=6; 6.6%); (4) left thalamus (n=1; 1.1%); (5) left frontal white matter (n=10; 11.1%); (6) left internal capsule (n=13; 14.4%); (7) left centrum semiovale (n=8; 8.8%); (8) left occipitoparietal white matter (n=1; 1.1%); (9) right caudate (n=6; 6.6%); (10) right putamen (n=3; 3.3%); (11) right thalamus (n=7; 7.8%); (12) right frontal white matter (n=13; 14.4%); (13) right internal capsule (n=6; 6.6%); and (14) right centrum semiovale (n=9; 10.0%). The mean volume ratio for cerebral infarctions was 0.65±0.3%, which did not correlate with CCSE scores.

Four IVD patients (three men and one woman; 16.7%) suffered recurrent silent lacunar infarctions detected by serial CT imaging located as follows: (1) left frontal white matter (n=2); (2) right frontal white matter (n=1); and (3) right thalamus (n=1). They were judged to be silent because clinical histories and serial neurological examinations failed to disclose new symptoms or signs, although all showed CCSE declines as follows: (1) 23 to 18; (2) 12 to 8; (3) 9 to 4; and (4) 18 to 13.

Fig 1Down compares changes in cerebral ATIs during follow-up among IVD patients (top panel) and DAT patients (bottom panel). At entry (Table 2Down), ATI values were 12.1±5.4 for IVD and 8.9±2.6 for DAT patients, but during IVD follow-up (Table 3Down), the annual increase of ATI was +2.1%, which was less than the +8.1% among DAT patients (P<.01). Annual changes in volume ratios for infarctions and for leukoaraiosis did not correlate with CCSE changes. Rapidly progressive cerebral and cortical atrophy in DAT patients correlated directly with cognitive declines (P<.0002, single linear regression),40 which was not noted in IVD patients. According to MANOVA, progressive increases in ATI were less among IVD (P=.001) than among DAT patients (dependent variables=ATI; covariates=retest intervals, age, CCSE scores).



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  		Figure 1. Scatterplots show atrophic indexes plotted longitudinally against advancing age, comparing patients with ischemic vascular dementia (IVD) (top) with patients with dementia of the Alzheimer type (DAT) (bottom).


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  		Table 2. CT Measures Compared Between Patients With Ischemic Vascular Dementia or Dementia of the Alzheimer Type


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  		Table 3. Annual Changes in Atrophic Indexes and Ventricular Volume Ratios Among Patients With Ischemic Vascular Dementia or Dementia of the Alzheimer Type

Fig 2Down displays pooled regional perfusion (LCBF) values at entry and at completion for 10 ROIs among IVD patients (top panel) compared with DAT patients (bottom panel). Among IVD patients, LCBF values were the same at follow-up compared with entry except for decreases within caudate and putamen by paired t testing. Among DAT patients, all LCBF values declined at follow-up. Among IVD patients at entry, perfusion values within the occipital cortex and capsular and fronto-occipital white matter were lower than in DAT patients, but at follow-up cortical perfusion had declined only in DAT patients.



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  		Figure 2. Bar graphs show pooled local cerebral blood flow (LCBF) values measured in patients with ischemic vascular dementia (IVD) (top) and patients with dementia of the Alzheimer type (DAT) (bottom) within 10 regions of interest compared at entry and at completion. Among IVD patients, LCBF values became significantly reduced over time in both caudate and putaminal basal nuclei (paired t test). Among DAT patients, all LCBF values had declined further at exit compared with entry (paired t test). FC indicates frontal cortex; TC, temporal cortex; PC, parietal cortex; OC, occipital cortex; CAU, caudate; PUT, putamen; THA, thalamus; FW, frontal white matter; INT, internal capsule; and OW, occipital white matter. Error bars represent SDs. *P<.05; **P<.01.

Table 4Down summarizes LCBF regression lines, by linear regression analyses, among IVD patients at follow-up within major gray and white matter cerebral compartments and 10 ROIs. Only LCBF values within subcortical gray matter declined. Annual mean percent declines for LCBF within subcortical gray matter were -1.8% (the largest declines were in both putamens: -2.6%). Among DAT patients, frontal, temporal, parietal, and occipital cortical perfusion values all declined. Annual percent decreases in cortical perfusion were as follows: frontal, -6.5%; temporal, -6.0%; parietal, -6.2%; and occipital, -6.8%. Annual percent values of subcortical gray matter perfusion likewise declined in DAT patients: caudate, -4.9%; putamen, -6.2%; and thalamus, -5.8%. In DAT patients, white matter perfusion values also declined diffusely (4.1%) (frontal, -4.0%; internal capsule, -3.4%; and occipital, -5.6%).


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  		Table 4. Annual Changes in Local Cerebral Perfusion Among Patients with Ischemic Vascular Dementia or Dementia of the Alzheimer Type

Among IVD patients, only frontal cortical tissue density (expressed in local HU) declined at follow-up, but DAT patients showed significant declines in cortical tissue density in frontal, temporal, parietal, and occipital cortices.

Tables 5Down and 6Down summarize different stepwise multiple linear regression analyses among IVD patients for predicting bidirectional changes in CCSE scores. In analysis 1 (Table 5Down), which used nine demographic explanatory variables, CCSE declines correlated directly with recurrent, silent cerebral infarctions (P=.0031). Factors not correlating with CCSE changes were sex, age, risk factors for stroke, and educational levels. In analysis 2 (Table 6Down), increases and decreases of cerebral perfusion within frontal white matter (P=.0001), thalamus (P=.003), and internal capsule (P=.007) correlated bidirectionally with cognitive improvements or declines. In DAT patients, factors contributing to CCSE changes were similarly analyzed, but no localized regions were found where declines in cerebral perfusion correlated directly with cognitive deterioration, although diffuse decreases of cerebral perfusion in DAT patients did correlate with cognitive declines when single linear regression was used. The statistical powers of regional results in DAT patients were as follows: frontal cortex, P=.002; temporal cortex, P=.007; parietal cortex, P=.009; occipital cortex, P=.009; frontal white matter, P=.003; occipital white matter, P=.001; putamen, P=.005; internal capsule, P=.02; thalamus, P=.02; and caudate, P=.03.


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  		Table 5. Stepwise Multiple Linear Regression Analysis of Demographic Variables That Might Predict Change in Cognitive Capacity Screening Examination Scores Among Patients With Ischemic Vascular Dementia


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  		Table 6. Stepwise Multiple Linear Regression Analysis of Local Cerebral Perfusion Variables That Might Predict Change in Cognitive Capacity Screening Examinations Scores Among Patients With Ischemic Vascular Dementia


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
We detected the following differences between IVD versus DAT patients. (1) Educational levels were lower in IVD patients. (2) Risk factors for stroke (hypertension, atherosclerotic heart disease, hyperlipidemia, and diabetes mellitus) were more prevalent in IVD patients. (3) Progressive cerebral atrophy and ventricular enlargement were much greater in DAT patients. (4) Cerebral perfusion decreased progressively but diffusely in DAT patients, whereas in IVD patients only putaminal perfusion declined. (5) Age-related tissue density decreases were limited to the frontal cortex in IVD patients but also included the parietotemporal cortex in DAT patients. (6) In IVD patients, bidirectional changes in cognitive test performance correlated directly with perfusional changes within the frontal white matter, thalamus, and internal capsule. (7) Progressive cognitive declines in DAT correlated with diffuse cerebral cortical atrophy and perfusional decreases.

Although DAT patients were older and more cognitively impaired at entry and were followed up for slightly shorter time intervals, they provided annual rates of change for the variables studied for purposes of comparison with IVD patients that adjusted for these differences. One explanation for these demographic differences between the two groups may be selection of IVD patients with small strokes rather than larger cerebral infarctions.

Recurrent strokes were not recognizable clinically among the IVD group throughout 42 months of follow-up, but 16.7% developed silent cerebral infarctions by serial neuroimaging, all associated with cognitive declines. Recurrent strokes among treated IVD patients are reported to be reduced with risk factor control and antiplatelet therapy.41 Among the present treated IVD patients, 67% cognitively improved or stabilized and 33% declined, which contrasts sharply with DAT patients who cognitively deteriorated.

Among IVD patients, annual declines in cerebral perfusion were limited to subcortical gray matter, while among DAT patients there were more diffuse and severe perfusional declines. The annual rate of decline in mean cortical perfusion among DAT patients of -2.0 mL · 100 g-1 · min-1 is 13 times larger than that of -0.15 mL · 100 g-1 · min-1 reported among age-matched normal volunteers.40 42 43 44 Diffuse reduction of cortical perfusion among DAT patients has been shown by positron emission tomography scanning to result from reduction in cerebral cortical metabolic demands as a result of Alzheimer's changes.18 19 22 The present results are in agreement with previously reported annual declines of cortical perfusion in DAT patients.43 44

Among IVD patients, improvements or declines in CCSE scores correlated directly with bidirectional changes in perfusion within the frontal white matter, thalamus, and internal capsule. Furthermore, declines in cognitive performance correlated directly with recurrent silent strokes involving the same regions. The annual rate of -2.1% for overall cerebral atrophy among IVD patients is impressively less than the -8.1% measured among DAT patients. Overall cerebral atrophy in DAT is associated with marked cortical atrophy, diffuse cortical hypoperfusion, and diffuse decreases in cortical tissue density or polioaraiosis (defined as decreased tissue density measured in gray matter40 ). Polioaraiosis in IVD patients was limited to the frontal cortex, which occurs in normal aging42 and should be expected among aging IVD patients. However, temporoparietal cortical polioaraiosis appears to be a biological marker for DAT, since this is not seen in normal aging42 and was not seen in IVD patients. When the present observations are considered together, they provide evidence that cognitive impairments in IVD are due to the combined effects of cerebral ischemia and infarction and have identifiable differences in time courses compared with DAT. These differences are best detected by serial neuroimaging, particularly if accompanied by neurological and psychometric reassessments. These courses of changes over time in IVD contrast with those in DAT, in which progressive and diffuse cortical atrophy, cortical hypoperfusion, and frontotemporal and parietal polioaraiosis correlate with cognitive declines.40 45

Others have reported that regional decreases in cerebral perfusion correlate directly with cognitive declines in IVD patients, including IVD due to large strokes, in which changes in cognitive test performance correlated directly with fluctuations in cortical perfusion.46 Kitagawa et al47 also correlated deficits in cognitive test performance with declines in perfusion within the thalamus and frontotemporal cortex, and Kawamura et al23 contrasted IVD patients showing cognitive improvements with those who deteriorated and concluded that reduced perfusion values within the frontal cortex, white matter, and thalamus were responsible for cognitive declines.

Albert et al48 suggested that enlarged ventricles provide useful information for diagnosing DAT, but Wippold et al49 emphasized that DAT cannot be predicted from a single CT measurement. Present documentation of +8.1% annual rates of cerebral cortical atrophy with ventricular enlargements of +9.6% in DAT exceed those seen in IVD caused by small cerebral infarcts. Thus, repeated cerebral imaging after 6 months should estimate annual rates of cerebral atrophy among demented patients, which helps in differentiating between IVD and DAT.

Reported sites of infarctions responsible for IVD include dominant or both thalami,50 both caudates,51 52 and thalamocortical projection systems.7 47 Among 30 patients with autopsy-confirmed IVD, Ishii et al6 reported lacunar infarctions to consistently involve both caudate nuclei and adjacent periventricular frontal white matter. Rodier et al52 reported longitudinal studies in a single patient suffering progressive dementia from cumulative infarctions involving both caudates and adjacent white matter confirmed by serial neurological, psychometric, neuroimaging, and postmortem studies, and others have correlated frontal lobe infarctions with cognitive impairments.9 11

In the present investigation four IVD patients were shown by neuroimaging to have recurrent silent cerebral infarctions, all associated with cognitive declines and located in frontal white matter and thalamus. Silent strokes hasten cognitive decline by acting synergistically with earlier infarctions53 and mimic DAT since they obscure the expected stepwise progression of IVD.5

Time courses of change in IVD versus DAT confirm that annual rates of cerebral atrophy in IVD of the lacunar type are less than in DAT40 45 and do not correlate with cognitive impairments. Differences in time courses between IVD and DAT support its vascular pathogenesis and separate it from the abiotrophy of DAT. Progressive polioaraiosis of the temporal and parietal cortices is a hallmark of DAT that is not seen in IVD or normal aging.42

Bracco et al54 followed up 19 patients with cerebrovascular disease for 4 years comparing cognitive testing with leukoaraiosis and atrophy measured by serial MRI and were unable to correlate cerebral atrophy with cognitive declines. De Reuck et al26 used positron emission tomographic measurements among patients with cerebral infarctions and different degrees of leukoaraiosis and measured cerebral oxygen extraction fractions within leukoaraiotic white matter. Oxygen extraction fractions were preserved or increased in leukoaraiosis despite white matter hypoperfusion, confirming the existence of a state of reversible ischemia and "incomplete infarction" of white matter.

In our IVD patients, risk factor control plus antiplatelet treatment were routinely administered, which probably accounts for the lack of correlation between cognitive test performance and associated risk factors54 55 56 and for the clinical absence of recurrent strokes. Long-term control of risk factors, particularly hypertension, is known to improve cerebral perfusion among stroke patients,36 55 56 and aspirin or ticlopidine reduces the risk of recurrent cerebral infarctions.41 In the present study both DAT and IVD patients had risk factors controlled, but only IVD patients received antiplatelet treatment.

We conclude that recurrent, frequently silent strokes decrease cerebral perfusion within the frontal white matter, thalamus, and internal capsule, resulting in cognitive impairments. Silent strokes in IVD often mimic DAT, although serial neuroimaging will unveil this subtle cause of dementia. Clinical identification of cognitive impairments after small strokes is important because institution of secondary prevention may stabilize or improve cognitive performance.


*    Acknowledgments
 
This study was supported by the Department of Veterans Affairs Central Office (Washington, DC), the Gordon and Mary Cain Foundation, and a grant from Harry K. Smith (Houston, Tex). Dianne B. Bailey processed the manuscript. Patricia M. Wills, LVN, BS, Ada Hinds, CRT, James Simon, CRT, and Diana Brigham, CRT, provided technical assistance during CT scanning. Gerald Timpe and Zihong Zhang, PhD, of Diversified Diagnostic Products (Houston, Tex) collaborated in developing the xenon enhancer and computer programming for CBF and other CT measurements.


*    Footnotes
 
Reprint requests to John Stirling Meyer, MD, CBF Laboratory, Bldg 110, Room 225, Veterans Affairs Medical Center, 2002 Holcombe Blvd, 151A, Houston, TX 77030.

Received November 21, 1994; revision received February 23, 1995; accepted February 23, 1995.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Tomlinson BE, Blessed G, Roth M. Observations of the brains of demented old people. J Neurol Sci. 1970;11:205-242. [Medline] [Order article via Infotrieve]
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