Changes in total cerebral blood flow and morphology in aging
Spilt, A.
Citation
Spilt, A. (2006, March 9). Changes in total cerebral blood flow and morphology in aging.
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C
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Late-onset dem enti
a:
Total
cerebral
Late-onset dementia: Total cerebral blood fl ow
Aart Spilt
Annelies W .E. W everling-Rijnsburger
Huub A.M . M iddelkoop
W iesje M . van der Flier
Jacobijn G ussekloo
Anton J.M . de Craen Eduard L.E.M . Bollen G erard J. Blauw M ark A. van Buchem Rudi G .J. W estendorp
Purpose
To prospectively compare indicators of structural brain damage and total cerebral blood fl ow in patients with late onset dementia, subjects of the same age with optimal cognitive function, and young subjects. M aterials and m ethods
The institutional ethics committee approved the studies, and all participants (or their guardians) gave informed consent. The test group included 17 patients older than 75 years (four men; mean age, 83 years) and with a diagnosis of dementia according to the criteria of the Diagnostic and Statistical M anual of M ental Disorders, Fourth Edition. The control group included 16 subjects (four men; mean age, 87 years) with optimal cognitive function, who were selected from among 599 elderly subjects enrolled in a population-based follow-up study, and 15 young healthy subjects (7 men; mean age, 29 years). M easurements of intracranial and total brain volumes, structural brain damage, and cerebral blood fl ow were obtained with magnetic resonance imaging. M eans were compared with the t test, and medians, with the M ann-W hitney U test.
Results
Values for total brain volume were signifi cantly smaller in elderly subjects (P < 0.001) but did not differ signifi cantly between patients with dementia and subjects of the same age with optimal cognitive function (P= 0.69). Among the elderly, signifi cantly higher scores for number and extent of white matter areas of signal hyperintensity (P = 0.028) and lower magnetization transfer ratios (P = 0.016) indicated greater structural brain damage in those with dementia. Cerebral blood fl ow was 246 ml/min lower (P < 0.001) in elderly subjects than in young subjects. In patients with dementia, cerebral blood fl ow 108 ml/min lower than that in subjects of the same age with optimal cognitive function (551 vs. 443 ml/min, P < 0.001).
Conclusion
The combined observations of more structural brain damage and lower cerebral blood fl ow in demented elderly individuals than in subjects of the same age with optimal cognitive function support the hypothesis that vascular factors contribute to dementia in old age.
Introduction
The incidence of dementia and cerebrovascular disease rapidly increases after the age of 70 years. The association between the two disorders has been debated for more than 100 years. The notion that cerebrovascular disease might cause dementia goes back to Binswanger in the beginning of the 20th
century148. At that time, this notion competed with Alzheimer’s interpretation
of the cause of dementia 149. Amyloid plaques are now considered the cause
of dementia in patients with a familial type of dementia. In most of these
patients, a mutation in the presenilin gene is responsible for the occurrence
of dementia before the age of 70150. It is assumed that these abnormal
presenilines lead to amyloid depositions through an impaired DŽ-secretase
function151. This familiar type of early-onset dementia, however, accounts for
the disease in less than 5% of the total number of patients with dementia.
Therefore, this mechanism is unlikely to be the cause of disease in the majority
of patients with late-onset dementia.
Autopsy in a consecutive series of patients with late-onset dementia from the general population showed that amyloid plaque was present in only one out of three patients, according to current histopathologic defi nitions
152. M oreover, amyloid deposition was also present in the brains of elderly
people with no clinical signs of dementia and was even suffi cient to classify
one of six individuals as demented152. The great majority of brains of patients
with dementia also showed evience of multiple pathologic cerebrovascular conditions. Atherosclerotic disease and congophilic angiopathy of the perforating arteries were far more prevalent in brains from demented patients
than in those from control subjects. These data indicate that deposition of
amyloid plaque is neither a necessary nor a suffi cient cause of late-onset dementia. Dementia in old age is better explained as a multifactorial disorder for which several risk factors have been identifi ed, including amyloid deposition
and atherosclerotic disease 153.
W e hypothesized that patients with late-onset dementia had more brain damage and lower cerebral blood fl ow than did subjects of the same age
without dementia, or young subjects. Thus, the purpose of our study was
to prospectively compare indicators of structural brain damage and total cerebral blood fl ow in patients with late-onset dementia, subjects of the same
Changes in Total Cerebral Blood Flow and Morphology in Aging
112
Materials and methods
Participants
From the outpatient memory clinic of the Leiden University Medical Center, Leiden, the Netherlands, 25 consecutive patients with a diagnosis of dementia were selected (10 men; 15 women; median age, 83 years). More information
about the memory clinic is available in a publication by Van der Flier et al154.
Note that the patients reported in that publication are not the same as the 25 in our current study. For all patients, a standardized dementia screening examination was completed. As part of the usual diagnostic work-up, each patient was examined by a geriatrician and a neurologist. Routine blood examination included measurement of erythrocyte sedimentation rate, complete blood cell count, electrolyte levels, liver, renal and thyroid function; presence of antibodies indicating syphilis; and levels of vitamins B1, B6, B12, and folic acid. Full neuropsychological examination and magnetic resonance (MR) imaging of the brain were performed. Diagnosis was made by consensus according to criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. For the present analysis, subjects who received a diagnoses of dementia with a vascular cause were excluded. This means that our study included only subjects with Alzheimer or Parkinson disease. The criterium for late-onset dementia was the occurrence of dementia after the age of 75 years.
As a primary control group, we selected a series of subjects with optimal cognitive function from a large population sample of 85-year-olds in whom MR imaging was not routinely performed. (A detailed description of this study
population is available in a publication by van Exel et al155). In short, all members
of the 1912-1914 birth cohort living in Leiden, the Netherlands, were enrolled
in the month of their 85th birthday. There were no selection criteria basaed
on health or demographic characteristics. Those who were eligible for the study were visited yearly at their place of residence. To investigate the various domains of cognitive function, we used a battery of neuropsychological tests that is widely used in observational studies and proved to have clinical
relevance156,157. To be selected for inclusion in the control group with optimal
14 women; median age: 87 years). A secondary control group of 15 young healthy individuals (eight women and seven men) were recruited through advertisements among students of Leiden University.
The ethics committee of the Leiden University Medical Center approved the studies, and all participants gave informed consent. For subjects wit severe cognitively impairment, informed consent was obtained from a guardian. Imaging and evaluation
All imaging was performed on a 1.5-T MR system (ACS-NT15; Philips Medical Systems, Best, the Netherlands) equipped with a gradient system (Powertrak 6000; Philips Medical Systems). In 11 subjects, the quality of the MR images was because of movement artifacts or the subjects’s unwillingness to complete the imaging examination, and these images were therefore excluded from all analyses. The characteristics of the three fi nal groups are summarized in Table 1. There was a signifi cnant difference between the three groups in age (P < 0.001) but not in percentage of men (P = 0.21).
To assess the extent of the white matter regions of signal hyperintensity, we used a dual turbo spin-echo sequence (3000/27, 120 [repetition time msec/ echo time msec], echo train length, 10; section thickness 3 mm; no intersection gap, matrix, 256 x 256; fi eld of view, 220 mm; acquisition of 80%). A gradient-echo phase-contrast technique (16/9; fl ip angle, 7.5°; number of sections, one; section thickness, 5 mm; matrix, 256 x 256; fi eld of view, 250 mm [76% rectangular]; acquisition of 60%) with velocity encoding of 100 cm/sec was
used for fl ow measurements20. The imaging plane was perpendicular to the
basilar artery and both internal carotid arteries. Flow measurement sequences were applied with and without electrocardiographic triggering. The number of signals acquired was one for electrocardiographically triggered acquisitions and eight for nontriggered acquisitions. For electrocardiographically triggered acquisitions, gating was performed retrospectively with a peripheral pulse unit. Magnetization transfer imaging was performed by using a three-dimensional gradient-echo pulse sequence (106/6; fl ip angle, 12°; section thickness, 5 mm; matrix, 256 x 256; fi eld of view, 220 mm; acquisition of 50%). Two consecutive sets of transverse images were acquired: The fi rst was acquired without a radiofrequency saturation pulse, and the second was acquired with a radiofrequency saturation pulse (sinc shaped for selective excitation at a frequency approximately 1100 Hz downfi eld of the water resonance
frequency)127.
For assessing white matter lesion load, we used a modifi ed version of the
rating scale used by Scheltens et al126. This rating scale is based on the size
Changes in Total Cerebral Blood Flow and Morphology in Aging
114
matter, infratentorial regions, and basal ganglia. Each region was rated separately. The rating scale for the periventricular region was extended, and periventricular lesions larger than 10 mm were given a score of 3. For periventricular lesions, the maximum total score was 9; for deep white matter and infratentorial regions, 24; and for basal ganglia lesions, 30. The images were assessed by an experienced neuroradiologist with more than 10 years of experience with the Scheltens rating scale (M.A.v.B.). This rater also assessed the the image for the presence of cerebal infarct. Infarct was defi ned, on all images regardless of the pulse sequence used, as an area in the brain with a signal intensity that was identical to that of cerebrospinal fl uid and that could not be attributed to perivascular space. The size of infarcts was measured by one of the authors (A.S.) with calipers and was defi ned as the largest diameter
of the infarct on transvere T1 weighted images.
Total cerebral fl ow was analyzed by using a workstation (UltraSparc 10; Sun Microsystems, [Santa Clara, Californië]) with an internally developed
proprietary software package29. Total cerebral blood fl ow was defi ned as the
sum of the fl ow in the basilar artery and both internal carotid arteries and was expressed in milliliter per minute. To correct for systematic difference, between electrocardiographically triggered and nontriggered fl ow measurements, we added 40.4 ml/min to total cerebral blood fl ow measurement obtained without electrocardiographic triggering. The plane of imaging selected was the plane perpendicular to the basilar artery and both internal carotid arteries. More information about blood fl ow measurement, including a reproducibility
study, can be found in a previous publication49.
For semiautomated postprocessing of magnetization transfer images, softwafre (3DVIEWNIX; Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pa) was used. A detailed description of this
procedure has been published previously120. Briefl y, the following steps were
performed: semiautomated segmentation of the intracranial volume from the three-dimensional magnetization transfer imaging study, automated calculation of magnetization transfer ratio (MTR) for every intracranial voxel, and automated display of all voxels to represent the brain as an MTR histogram. The MTR was defi ned as the percentage of change in signal intensity between acquisition with the saturation pulse and those without the saturation pulse, and it was obtained with the following equation:
Voxels with an MTR of less than 20% were defi ned as cerebrospinal fl uid128. The
following parameters were derived from the histogram: intracranial volume,
derived as IV = (Vic x VS), where Vic is the number of intracranial voxels and VS
is the size of each voxel (3.698 ml); parenchymal volume, derived as PV = Vpa x
as MTRnp = (MTRpeak / Vpa) x 1000, where MTRpeak is, in the MTR histogram, the number of voxels in the largest bin. Atrophy was defi ned as the percentage of intracranial voxels with an MTR of less than 20%.
Statistical analysis
Results of a power analysis indicated that 17 subjects in each group were needed to demonstrate a difference of 80 ml/min in total cerebral blood fl ow (D = 0.05; power = 80%; standard deviation = 70 ml/min).
All data were calculated as the mean ± standard deviation or median and range, dependening on the underlying distribution of the data. Means were compared with the t test, and medians were compared with the Mann-Whitney U test. Multivariate logisitic regression analysis was performed to simultaneously assess the data for independent association of total cerebral blood fl ow and of MTR with dementia.
P values of less than 0.05 were considered to indicate statistically signifi cant differences. Data were analyzed by using satistical software (SPSS, version 11.0; SPSS, Chicago, Ill).
Table 1 Clinical and brain volume characteristics of study participants.
Young subjects Elderly subjects
Optimal cognition Demented
n 15 16 17
Clinical characteristics
Female/male (n) 8/7 12/4 13/4
Age (years; median [range]) 29 (21-48) 87 (86-87) 83 (80-91)
MMSE (points; median [range]) - 29 (28-30) 22 (14-26)
Brain volum e characteristics#
Intracranial volume (ml; mean [SD]) 1339 (102) 1331 (121) 1393 (156)
Parenchymal volume (ml; mean [SD]) 1225 (99)* 1045 (82) 1060 (124)
Atrophy (%; mean [SD]) 8.4 (2.7)* 21.4 (3.4) 23.7 (6.2)
# Not available for 5 young subjects
MMSE=Mini Mental State Examination. * = P<0.05 for difference between young and elderly.
Results
Cerebral volume measurements
Changes in Total Cerebral Blood Flow and Morphology in Aging
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Brain fi ndings
As expected, MR images of the brain showed that young subjects, compared with elderly subjects, had fewer cerebral infarctions (P = 0.005) and had a lower load of white matter hyperintensities as assessed by the Scheltens score (P < 0.001) (Table 2). The mean number of infarcts did not differ signifi cantly between elderly subjects with dementia and those with optimal cognition, while the Scheltens score was signifi cantly higher in elderly subjects with dementia than in those with optimal cognitive function (P = 0.028).
Compared with the elderly (whether those with dementia or with optimal cognition), young subjects had less structural damage of the brain (P < 0.001),
as indicated by a higher normalized peak height of the MTR136. Moreover,
Table 2 Cerebral infarctions, white matter hyperintensities, magnetization transfer ratio, and cerebral blood fl ow in study subjects
Young subjects Elderly subjects
Optimal cognition Demented
n 15 16 17
Cerebral infarctions
Number of subjects with infarcts 0* 7 8
Number of infarcts (n; median [range]) - 2 (1-7) 1 (1-4)
Diameter of infarct (mm; median [range]) - 7.4 (3-40) 4.7 (3-10)
W hite M atter Hyperintensities
Scheltens’ Score (points; median [range]) 0 (0-0)* 10 (3-38) 16 (9-38)†
M agnetization Transfer Ratio#
Normalized Peak height (mean [SD]) 120 (10)* 97 (8) 88 (10)†
Cerebral blood fl ow
Total fl ow (ml/min; mean [SD]) 742 (96)* 551 (83) 443 (76)†
# Not available for 5 young subjects
* P<0.05 for difference between young and elderly subjects.
† P<0.05 for difference between optimal cognitive function and demented subjects.
0 50 100 150 Young O ld w ith optim al cognition O ld w ith dem entia M TR n o rm a li se d p e a k h e ig h t (n u m b e r o f p ix e ls )
elderly patients with dementia had signifi cantly more structural brain damage than did elderly subjects with optimal cognitive function. The normalized peak height was 88 au in elderly subjects with dementia and 97 au in those with optimal cognition (P = 0.016). Figure 1 provides an illustration of the individual MTR estimates in the three study groups.
Cerebral blood fl ow
In healthy young subjects, we measured a total cerebral blood fl ow of 742 ml/min (Table 2). Total cerebral blood fl ow was 246 ml/min lower (P < 0.001) in elderly subjects (whether with dementia or with optimal cognition) than in young subjects. When eldery patients with dementia were compared with subjects of the same age with optimal cognitive function, cerebral blood fl ow was 108 ml/min lower (P < 0.001) in those with dementia. Figure 2 provides an illustration of the individual estimates of total cerebral blood fl ow in the three study groups. 0 100 200 300 400 500 600 700 800 900 1000
Young Old with
optimal cognition Old with dementia To ta l C e re b ra l B lo o d F lo w ( m l/ m in )
Changes in Total Cerebral Blood Flow and Morphology in Aging
118
Logistic regression analysis
In a multivariate logistic regression model with total cerebral blood fl ow and MTR simultaneously entered as covariates, there was a signifi cant association between dementia and total cerebral blood fl ow values (P = 0.018), while the MTR was not signifi cantly associated with dementia (P = 0.17).
Discussion
As expected, we found that increasing age was clearly associated with cererbal volume loss, extent of white matter regions of signal hyperintensity, increase of structural brain damage as detected with magnetization transfer imaging (ie, MTR), and a decrease of total cerebral blood fl ow. However, the main fi ndings of our study were greater brain damage and a lower total cerebral blood fl ow in patients with late-onset dementia than in subjects of the same age with optimal cognitive function. We found that both the MTR and the cerebral blood fl ow were lower in the group with dementia, even though patients with a clinical diagnosis of vascular dementia were excluded from the study.
Total blood fl ow through the brain is the net result of cardiac output, arterial caliber, and vasomotor tone, and it largely determines the extent to which
glucose and oxygen are delivered to the brian and consumed31. Old age
is associated with a decrease in cerebral blood fl ow. Based on the data presented in this study, the estimated decrease is 4.4 ml/min per year, which
is similar to values obtained in earlier studies on the topic26.
An argument for a possible causal relation between lower cerebral blood fl ow and dementia is that patients who have Alzheimer disease and white matter
regions of signal hyperintensity158 and patients with silent brain infarctions159 not
only have reduced cerebral blood fl ow but also have an increased oxygen extraction fraction. In our opinion, these observations strongly suggest that decreased cerebral blood fl ow indeed causes brain damage. After all, if the reduced blood fl ow observed in patients with white matter regions of signal hyperintensity had been secondary to a reduced need for oxygen, we would expect the oxygen extraction fraction to be unaltered and not increased. Moreover, in the multivariate analysis, the association found between dementia and decreased cerebral blood fl ow was statistically signifi cant, while that between dementia and MTR was not. These results also indicate that cerebral blood fl ow is more important than MTR.
between cerebral blood fl ow in patients with dementia and that in elderly subjects who are cognitively intact was underestimated in our study. In our sample of subjects with dementia, subjects with vascular dementia were excluded. This means that subjects with Alzheimer-type dementia and a heavy burden of ischemia were also excluded. In these subjects, a lower total cerebral blood fl ow could be expected, not only because of their ischemic burden, but also because of the Alzheimer dementia.
Patients with typical clinical manifestations of vascular dementia were not included in this series. Therefore, we think it is not surprising that the prevalence of infarctions was not increased in our subjects with a clinical diagnosis of dementia according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, compared with the prevalence among elderly subjects with good cognitive functioning.
Investigators in several other studies have shown associations between vascular
risk factors and white matter regions of signal hyperintensity160, vascular
factors and cognitive impairment161, and white matter regions hyperintensity
and cognitive impairment162. In a previous study, we presented additional
arguments for a generalized process when using magnetization transfer imaging, a quantitative MR imaging technique that depicts macroscopic and microscopic brain damage in patients with minimal cognitive impairment
and dementia163. Magnetization transfer imaging was used in patients with
dementia to demonstrate structural changes in all parts of the brain, not only in the entorhinal area of the cortex and the hippocampus. Moreover, the observation of these structural changes in patients with mild cognitive impairment and patients with dementia alike suggests that generalized brain damage is present before dementia is manifested.
There were limitations of our study. First, the elderly with dementia were somewhat younger than the elderly with good cognitive functioning. Since total cerebral blood fl ow and MTR diminish with increasing age, this age difference between the two groups dilutes the association. This means that the association we observed between total cerebral blood fl ow and MTR was actually underetimated. Second, both groups of elderly subjects were small. Despite these small numbers, however, the differences we found were signifi cant.
