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July 05, 2011; 77 (1) Articles

Identification of pure subcortical vascular dementia using 11C-Pittsburgh compound B

J.H. Lee, S.H. Kim, G.H. Kim, S.W. Seo, H.K. Park, S.J. Oh, J.S. Kim, H.K. Cheong, D.L. Na
First published May 18, 2011, DOI: https://doi.org/10.1212/WNL.0b013e318221acee
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Abstract

Background: Subcortical vascular dementia (SVaD) is considered the most common type of vascular dementia and often follows a slowly progressive course, simulating Alzheimer disease (AD). Whether the progressive cognitive decline is associated with pure SVaD or concomitant AD remains unknown. The purpose of this study was to determine what proportion of patients with SVaD lack abnormal amyloid imaging, and to examine differences in the clinical or MRI features between subjects with SVaD with cortical amyloid deposition and those without.

Methods: We measured brain amyloid deposition using 11C-Pittsburgh compound B (PiB) PET in 45 patients (men: women = 19:26; mean age 74.2 ± 7.6 years) with SVaD. They all met DSM-IV criteria for vascular dementia and had severe white matter high signal intensities without territorial infarction or macrohemorrhage on MRI.

Results: Thirty-one (68.9%) of 45 patients with SVaD were negative for cortical PiB binding. There was significant difference between 11C-PiB-positive and 11C-PiB-negative groups in terms of age (79.5 vs 71.9 years), Mini-Mental State Examination score (18.6 vs 22.6), the number of lacunes (3.9 vs 9.0), and the visual rating scale of hippocampal atrophy (3.1 vs 2.3). The neuropsychological assessments revealed that patients with 11C-PiB-negative SVaD performed better on the delayed recall of both the verbal and visual memory test than did those with 11C-PiB-positive scan.

Conclusion: SVaD without abnormal amyloid imaging was more common than expected. Patients with SVaD with and without abnormal amyloid imaging differed in clinical and MRI features, although there was considerable overlap.

Subcortical vascular dementia (SVaD) is considered the most common type of vascular dementia and often follows a slowly progressive course simulating Alzheimer disease (AD).1,–,3 Whether the cognitive decline of patients with SVaD is due to a pure vascular lesion or underlying AD pathologies remains unknown.

The ability to distinguish pure vascular dementia from mixed AD with cerebrovascular disorder (CVD) at the premortem stage is clinically important because these conditions differ in prognosis and therapeutic interventions. Pittsburgh compound B (PiB) is an amyloid PET tracer designed to bind to the fibrillar form of β-amyloid.4,–,6 This tracer can sensitively detect amyloid plaques in the brain and provides an opportunity to visualize amyloid deposition in vivo. It is increasingly used to make an early and specific diagnosis of AD.7,–,10 Of particular interest is the potential of PiB to differentiate mixed AD with CVD from pure Alzheimer or vascular dementia.

The current study was based on a 5-year longitudinal study called Amyloid PET Imaging for Subcortical Vascular Dementia (AMPETIS). The primary goals of the current study were to look at the frequency of pure SVaD in relation to mixed AD with CVD and to specifically examine differences in the clinical and MRI features in patients with PiB-positive vs PiB-negative SVaD.

METHODS

Patients.

Since September 2008, we have been prospectively recruiting new or follow-up patients with SVaD to participate in the AMPETIS study conducted by the Memory Disorder Clinic at Samsung Medical Center or at Asan Medical Center in Seoul, Korea. The AMPETIS study is part of a project of the Clinical Research Center for Dementia of South Korea (CREDOS), funded by the Korean government. Over this period of time a total of 364 patients were evaluated: 196 patients were diagnosed with probable AD according to published criteria (National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association [NINCDS-ADRDA])11 with minimal evidence of cerebrovascular disease, 86 patients were diagnosed with possible AD but had significant ischemia, and 82 patients had clinically probable SVaD.

All patients with SVaD fulfilled the following criteria: 1) 50 ≤ age ≤ 85 years; 2) Mini-Mental State Examination (MMSE) score ≥10; 3) DSM-IV criteria for vascular dementia12; and severe white matter high signal intensities (WMHS) on MRI. The DSM-IV criteria include the presence of focal signs suggestive of CVD; therefore, we defined the presence of focal signs as at least 2 focal neurologic signs out of corticobulbar, pyramidal, extrapyramidal signs, and gait abnormalities. Severe WMHS on MRI was defined as a cap or band ≥10 mm as well as a deep white matter lesion ≥25 mm, as modified from Fazekas ischemia criteria. We excluded patients with other structural lesions on brain MRI such as territorial infarction, intracranial hemorrhage, hydrocephalus, or WMHS associated with radiation, multiple sclerosis, or vasculitis.

As of October 2009, of the 82 patients who met the criteria for SVaD, 51 underwent a 11C-PiB PET scan. However, 6 of the 51 patients failed to complete the scan because of poor cooperation (2/6) or unsuccessful PiB synthesis (4/6). Of the remaining 31 patients who had not yet undergone the 11C-PiB PET scan, 14 patients were still on the waiting list for the scan and 17 patients were removed from the list for the following reasons: withdrawal from follow-up care (7/17), caregiver's refusal (4/17), recent development of cancer (3/17), hemorrhagic stroke (1/17), hypoxic brain damage (1/17), and aggressive behavior (1/17).

Therefore, the final sample for the current study consisted of 45 patients. Our study population did not differ from the 37 patients who were excluded from the study regarding age, sex, and education, whereas they had higher MMSE scores than those without PiB scans (21.3 ± 5.1 vs 18.1 ± 3.8).

Patients completed laboratory tests including APOE genotyping and underwent detailed neuropsychological tests. All diagnostic tests were performed 3 months before or after the PiB scan.

Control groups for statistical parametric mapping analysis.

The PiB scans of patients with SVaD were compared with those of 2 control groups.

Normal controls.

The normal control group consisted of 10 healthy volunteers with no history of neurologic or psychiatric illnesses, and no abnormalities on neurologic examinations. They were family members of outpatients at Memory Disorder Clinic of Asan Medical Center. Their demographic profiles are shown in table 1.

View this table:
Table 1

Demographic, clinical, and MRI characteristics of PiB+ and PiB− patients

Patients with AD.

A total of 14 control patients with AD were recruited. The diagnosis of AD was made on the basis of criteria for probable AD proposed by NINCDS-ADRDA.11 Their demographic profiles are shown in table 1.

Standard protocol approvals, registrations, and patient consents.

We obtained written consents from each participant and the Institutional Review Board of Asan Medical Center and Samsung Medical Center approved the study protocol.

Neuropsychological tests.

All patients underwent neuropsychological tests using a standardized battery called the Seoul Neuropsychological Screening Battery.13 This battery assesses attention, language, praxis, elements of Gerstmann syndrome, visuospatial/constructive function, verbal and visual memory, and frontal/executive function.

Assessment for motor impairment.

We quantified motor deficits using the Pyramidal and Extrapyramidal Scale (PEPS) that has been standardized by our group.14 The PEPS is a 60-point scale consisting of 5 subtests: corticospinal (6), corticobulbar (9), extrapyramidal (30), gait abnormality (9), and gait severity (6). Higher scores indicate more severe motor impairment. Detailed description of the PEPS is provided as appendix e-1 on the Neurology® Web site at www.neurology.org.

MRI acquisition.

All patients were referred to Samsung Medical Center for MRI, which were acquired via 5 different techniques (i.e., 3-dimensional T1 turbo field echo, fluid-attenuated inversion recovery [FLAIR], T1, T2, and fast field echo [FFE]) using identical imaging protocols on a 3.0-T MRI scanner (Achieva, Philips 3.0 T, Eindhoven, Netherlands).

Rating of lacunes and microbleeds on MRI.

Two neurologists blinded to clinical information counted the total numbers of lacunes and microbleeds. Lacunar infarction was defined as a small lesion less than 15 mm in diameter with a low signal on T1-weighted images, a high signal on T2-weighted images, and a perilesional halo on FLAIR images.15 Because our FLAIR images were obtained with a thickness of 2 mm and no gap, we counted the number of lacunes on every other FLAIR slice. A microbleed was defined as a homogeneous round signal loss lesion with a diameter ≤10 mm on the FFE image.15 Intrarater correlations were obtained by the same rater with a 3-month interval between ratings.

Visual rating of medial temporal lobe atrophy on MRI.

Medial temporal lobe atrophy (MTA) was assessed visually16 by 2 neurologists who were blinded to the diagnosis and age of the subjects after a series of training sessions. The T1 coronal images were used for the visual assessment and left and right MTA were rated separately. The degree of MTA was rated from 0 (no atrophy) to 4 (severe atrophy). Intrarater correlations were measured at the same interval as described above.

11C-PiB PET.

All patients were referred to Asan Medical Center for 11C-PiB scans, which were obtained using identical image parameters and PET scanner.

Radiochemistry.

The specific radioactivity of 11C-PiB at the time of administration was more than 1,500 Ci/mmol for patients and the radiochemical yield was more than 35%. The radiochemical purity of the tracer was more than 95% in all PET studies.

Scanning protocol.

All subjects underwent a PET scan using a Discovery STe PET/CT scanner (GE Medical Systems, Milwaukee, WI) in a 3-dimensional scanning mode that examined 35 slices of 4.25-mm thickness that spanned the entire brain. The 11C-PiB was injected into an antecubital vein as a bolus with a mean dose of 420 MBq (i.e., range 259–550 MBq). A CT scan was performed for attenuation correction at 60 minutes after the injection. A 30-minute emission static PET scan was then initiated.

Data analysis.

The cerebellum was used as a reference region for analysis. Ratio parametric images representing 11C-PiB uptake in each voxel were created to determine the region-to-cerebellum ratio of radioactivity.

Statistical parametric mapping analysis.

A voxel-based statistical analysis was performed using the Statistical Parametric Mapping program, version 2 (SPM2), and Matlab 6.5 for Windows (Mathworks, Natick, MA). Spatial normalization of the ratio parametric images of 11C-PiB PET was performed using a coregistered MRI.

Automated region of interest analysis.

We compared PiB retention in global cortices and regions of interest (ROIs) among groups by calculating the cortical PiB uptake ratio in an anatomically defined ROI. The global cortical PiB uptake ratio was determined by combining the bilateral frontal, parietal, and temporal cortices, and posterior cingulate gyrus.

PiB-positive vs PiB-negative.

Patients with SVaD were classified as PiB-positive (PiB+) or PiB-negative (PiB−) according to measured global PiB uptake ratio values. Patients were considered PiB+ if their global PiB uptake value was more than 2 standard deviations of the mean of the normal controls. PiB+ SVaD was construed as mixed AD with CVD and PiB− SVaD as pure SVaD.

Statistical analyses.

Statistical analyses were performed using the Statistical Package for the Social Sciences 17.0. Descriptive statistics of the initial workup were performed using demographic and clinical scores from neuropsychological tests and the motor scale (PEPS). Student t tests were used to assess continuous variables and χ2 tests to assess dichotomous variables. Interrater and intrarater reliability were examined using the κ statistic with regards to visual ratings of MTA, and intraclass correlation coefficient analysis with regards to counting lacunes and microbleeds. Statistical significance was defined as p < 0.05.

RESULTS

Interrater/intrarater reliability of lacune/microbleed counts and visual ratings of MTA.

We excluded one patient from our analyses because of an extremely large number of microbleeds (91, across the entire brain) on the FFE MRI. The intrarater correlation coefficient was 0.968 (p < 0.001) for lacune counts and 0.927 (p < 0.001) for microbleeds (p < 0.001), reflecting a high level of correlation. The interrater reliabilities for lacune and microbleed counts were also high, 0.798 (p < 0.001) and 0.877 (p < 0.001), respectively. In addition, the intrarater reliability for visual ratings of MTA was 0.914, which also revealed very high comparability. The interrater reliability of MTA was 0.534 (κ, p < 0.001), which was similar to that in previous reports.17

Frequency of SVaD with PiB+ vs PiB−.

A total of 31 (68.9%) of the 45 patients tested negative for PiB retention, while 14 (31.1%) tested positive for PiB retention.

Demographic, clinical, and MRI characteristics of patients with PiB+ vs PiB− SVaD.

Table 1 shows the demographic characteristics and MRI variables of patients with PiB+ and PiB− SVaD. There were significant differences between the 2 groups in terms of age, MMSE score, number of lacunes, and visual ratings of MTA. Patients with PiB− SVaD were younger, performed better on the MMSE, and had a greater number of lacunes but less severe hippocampal atrophy observed on MRI scans than did patients with PiB+ SVaD (figure 1). However, when age was adjusted as a covariate, MMSE score and the severity of hippocampal atrophy were the only statistically significant variables. There were no significant differences between the 2 groups with regards to vascular risk factors, APOE4 allele frequency, and focal neurologic findings, although urinary incontinence or gait abnormalities were frequently found in both groups (table 1).

Figure 1
Figure 1 Representative cases of Pittsburgh compound B (PiB) PET

(A) PiB− subcortical vascular dementia (SVaD) vs (B) PiB+ SVaD. PiB− SVaD had more lacunes and less severe hippocampal atrophy on MRI than did PiB+ SVaD.

Neuropsychological performance of patients with PiB+ vs PiB− SVaD.

As shown in table 2 , patients with PiB− SVaD performed better on tests of immediate and delayed recall of the verbal learning test and Rey Complex Figure test than did patients with PiB+ SVaD. In addition, patients with PiB− SVaD scored better on one of the semantic verbal fluency tests.

View this table:
Table 2

Neuropsychological function of PiB+ and PiB− patients

Quantitative and SPM analysis for PiB retention in patients with PiB+ SVaD.

A quantitative analysis of 11C-PiB PET revealed that patients with PiB+ SVaD exhibited a higher PiB uptake ratio of the frontal, parietal, temporal, and posterior cingulate cortices to cerebellum than that of the PiB− SVaD group. The mean uptake ratio of patients with PiB+ SVaD was as high as that of patients with AD, whereas the average uptake ratio of patients with PiB− SVaD was similar to that of normal controls (figure 2).

Figure 2
Figure 2 Scatterplots of the global Pittsburgh compound B (PiB) uptake ratio for normal controls, PiB− subcortical vascular dementia (SVaD), PiB+ SVaD, and Alzheimer disease

The mean uptake ratio of patients with PiB+ SVaD was as high as that of patients with Alzheimer disease, whereas the average uptake ratio of patients with PiB− SVaD was similar to that of normal controls. VaD = vascular dementia.

SPM analysis using MMSE score as a covariate revealed that patients with PiB+ SVaD retained greater levels of PiB retention in the frontal, parietal, temporal, and posterior cingulate cortices than did normal controls, which was very similar to those with AD (figure 3). Compared with patients with AD, however, patients with PiB+ SVaD exhibited more PiB retention in bilateral perirolandic areas and the midcerebellar peduncle (i.e., regions of the brain that are rarely involved in AD) (figure 3).

Figure 3
Figure 3 Statistical parametric mapping analysis of Pittsburgh compound B (PiB) retention in PiB+ subcortical vascular dementia (SVaD)

(A) Patients with PiB+ SVaD exhibited increased PiB retention in the frontal, parietal, temporal, and cingulate cortices vs normal controls. (B) PiB retention was nearly similar to that of Alzheimer disease (AD). (C) Compared with patients with AD, the PiB+ SVaD group exhibited more PiB retention in bilateral perirolandic areas and the midcerebellar peduncle.

DISCUSSION

The main finding of the present study is that a significant proportion of elderly patients with clinically diagnosed SVaD lacked abnormal amyloid imaging. We infer that the cognitive disorder in those patients with SVaD without abnormal amyloid imaging is largely ischemic in origin. In the field of dementia, the prevailing view has been that pure vascular dementia is rare and underlying AD is mostly responsible for cognitive decline.18,–,21 Thus, AD has been considered the predominant pathologic process in the dementia etiology, regardless of the severity of white matter ischemic changes or presence of lacunar infarcts. However, our study found that 68.9% of the patients who satisfied our SVaD criteria had no amyloid plaque pathologies in the brain, indicating that pure SVaD is much more common than might be expected.

One of the primary goals of this study was to investigate differences between patients with PiB-positive and PiB-negative SVaD, in terms of clinical, neuropsychological, and MRI profiles. As expected, advanced age, more prominent episodic memory loss, and greater MTA were predictive of a PiB-positive scan. These findings are consistent with previous studies, given that old age is associated with AD4 and that MTA with consequent episodic memory loss is a hallmark of AD.5,6,8 Another predictive factor for PiB positivity might be the presence of the APOE4 allele, which, however, was not statistically significant, although the APOE4 frequency was higher in the PiB+ group (46.2%) than the PiB− group (18.5%). Conversely, our analysis revealed that younger age and a greater number of lacunes could predict a PiB-negative scan in patients with SVaD, thereby increasing the likelihood of detecting pure vascular dementia. The number of lacunes was among the most significant MRI variables used to predict PiB negativity; a greater number of lacunes increased the likelihood of a negative PiB scan. Our results are consistent with previous reports that subcortical lacunar infarcts are predominantly mediated by small-vessel disease and that their presence in SVaD strongly indicates that an individual has pure SVaD.22

Contrary to our expectations, the PiB+ and PiB− groups did not differ regarding the frequency of vascular risk factors, Hachinski Ischemic Scale, and the severity of motor symptoms. It has been known that patients with dementia with white matter changes in the absence of focal signs such as urinary incontinence or gait abnormalities are more likely to have Alzheimer pathology than pure vascular lesion.2 However, our finding that PiB+ and PiB− groups did not differ in terms of the frequency of focal neurologic signs including incontinence and gait disturbance argues against this previous notion.

Because our patients with SVaD had severe ischemia as well as focal signs indicative of stroke, one might assume that vascular pathology may be the major etiology of dementia, while AD pathology may be minor even if they have a PiB+ scan. Thus, we expected that the SPM analysis would show less deposition of brain amyloid in patients with PiB+ SVaD than in those with probable AD. Contrary to our expectations, the 2 groups largely overlapped in terms of the amount and distribution of cortical PiB retention. Rather, patients with PiB+ SVaD exhibited more PiB retention in bilateral perirolandic areas and the cerebellum.

These findings may have implications with respect to the pathogenesis of PiB+ SVaD or mixed dementia. First, patients with PiB+ SVaD might develop Alzheimer and vascular pathologies concurrently; patients who eventually develop AD also have vascular risk factors for SVaD, and vice versa. Second, the fact that patients with PiB+ SVaD had additional amyloid deposits in the perirolandic area and cerebellum indicates that the pathogenesis of amyloid deposition differs from that of AD, because these areas are rarely involved in AD. Some interaction between Alzheimer pathology and vascular burden may explain this finding.23 For instance, arteriosclerotic arteries/arterioles associated with SVaD may inhibit elimination of β-amyloid (Aβ) along capillary walls and consequently alter the distribution of amyloid deposition in the cerebral cortex. Third, our findings make it unlikely that PiB+ SVaD represents cerebral amyloid angiopathy (CAA). The amyloid deposits detected by PiB PET are not only parenchymal but also vascular amyloid. However, the lobar anatomic distribution of amyloid deposition in CAA seems different from the pattern observed in our patients with PiB+ SVaD (i.e., occipital PiB retention was significantly greater in patients with CAA than in patients with AD).24

There is a strong inverse relationship between PiB PET amyloid imaging and CSF Aβ 42 levels.25 Our findings with PiB PET in SVaD might not necessarily reflect what goes on in the CSF, and further studies will be needed to address that issue.

There are some limitations to our study. First, PiB− SVaD may not necessarily indicate pure SVaD, because PiB imaging reveals only amyloid pathology and not neurofibrillary tangle pathology. Therefore, tangle-predominant AD would have been considered pure SVaD due to lower levels of Aβ undetectable by PiB. Furthermore, some individuals with a clinical diagnosis of AD do not have a positive PiB scan.9 Some PiB-negative cases may, in fact, have amyloid pathology at autopsy because the threshold of Aβ concentration required for PiB detection has not yet been determined in vivo for the human brain. One might expect that in a situation with dual pathology (i.e., vascular lesion and Aβ) the lower levels of Aβ might have an effect on cognition but would be undetectable by PiB. Second, all of our subjects had to have severe white matter ischemic changes for the diagnosis of SVaD. We have no idea as to how the severity of white matter ischemic burden may affect PiB retention. It would be interesting to investigate whether similar PiB PET findings are seen in patients with dementia with mild to moderate white matter ischemia as in those with severe white matter ischemia.

AUTHOR CONTRIBUTIONS

Dr. Lee participated in drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, study supervision, and obtaining funding. Dr. S.H. Kim participated in drafting/revising the manuscript, analysis or interpretation of data, acquisition of data, statistical analysis, and study supervision. Dr. G.H. Kim participated in drafting/revising the manuscript, analysis or interpretation of data, acquisition of data, and statistical analysis. Dr. Seo participated in drafting/revising the manuscript and acquisition of data. Dr. Park participated in drafting/revising the manuscript and acquisition of data. Dr. Oh participated in study concept or design and acquisition of data. Dr. J.S. Kim participated in drafting/revising the manuscript, analysis or interpretation of data, and acquisition of data. Dr. Cheong participated in drafting/revising the manuscript, study concept or design, analysis or interpretation of data, and study supervision. Dr. Na participated in drafting/revising the manuscript, study concept or design, analysis or interpretation of data, contribution of vital reagents/tools/patients, acquisition of data, study supervision, and obtaining funding.

DISCLOSURE

Dr. Lee, Dr. S.H. Kim, and Dr. G.H. Kim report no disclosures. Dr. Seo receives research support from the Ministry of Health and Welfare, Korea. Dr. Park, Dr. Oh, Dr. J.S. Kim, and Dr. Cheong report no disclosures. Dr. Na receives research support from the Ministry of Health and Welfare, Korea.

Footnotes

  • Study funding: Supported by the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A050079), the Asan Institute for Life Sciences (2006-159), and the Converging Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010K001054).

  • Editorial, page 12

  • Supplemental data at www.neurology.org

  • Aβ=
    β-amyloid;
    AD=
    Alzheimer disease;
    AMPETIS=
    Amyloid PET Imaging for Subcortical Vascular Dementia study;
    CAA=
    cerebral amyloid angiopathy;
    CREDOS=
    Clinical Research Center for Dementia of South Korea;
    CVD=
    cerebrovascular disorder;
    DSM-IV=
    Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
    FFE=
    fast field echo;
    FLAIR=
    fluid-attenuated inversion recovery;
    MMSE=
    Mini-Mental State Examination;
    MTA=
    medial temporal lobe atrophy;
    NINCDS-ADRDA=
    National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association;
    PEPS=
    Pyramidal and Extrapyramidal Scale;
    PiB=
    Pittsburgh compound B;
    ROI=
    region of interest;
    SPM=
    statistical parametric mapping;
    SVaD=
    subcortical vascular dementia;
    WMHS=
    white matter high signal intensities.

  • Received September 24, 2010.
  • Accepted December 22, 2010.

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