Association of Cerebral Emboli With Accelerated Cognitive Deterioration in Alzheimer's Disease and Vascular Dementia

Patients satisfying DSM-IV criteria for dementia were recruited through a network of community and outpatient geriatric psychiatry clinics in Greater Manchester (United Kingdom). Consultant geriatric psychiatrists explained the study details, including the inclusion/exclusion criteria and study assessments, to the patients and referred those patients who they thought would be able to adhere to the study method. Over a 2-year period, we recruited 156 patients with dementia, of whom 117 (75%) had participated in our previous case-control study (9). Alzheimer's disease, “probable” or “possible,” was diagnosed using the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria (10). Vascular dementia was diagnosed using the National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria (11). Three geriatric psychiatrists reviewed the clinical data, which included results from computerized tomography scans as well as magnetic resonance imaging (MRI), to reach a consensus diagnosis of Alzheimer's disease (N=90) or vascular dementia (N=66), with an independent psychiatrist making the final diagnosis. Patients were excluded from participation in the study if they had aphasia, severe dementia (Mini-Mental State Examination [MMSE] score <10 [12]), or an inadequate transtemporal window for transcranial Doppler insonation of the middle cerebral artery or if they were receiving anticoagulant medication. Patients were examined at baseline and then every 6 months for 24 months. The ethics committees of the National Health Service and the University of Manchester Senate approved the study. All patients with dementia and their caregivers provided written informed consent.

Cardiovascular risk factors were recorded at the interview with the patients and their caregivers and confirmed by reviewing case notes. Smoking status (current/former/nonsmoker), heavy alcohol use (>14 units/week for women and >21 units/week for men), drug history, and a detailed history of cardiovascular events and risk factors were recorded on purpose-designed data entry forms. Each patient's blood pressure was measured manually by sphygmomanometer after a 5-minute resting period, and a venous blood sample was taken to analyze total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels as well as apolipoprotein E (APOE) genotype. Carotid artery disease was imaged by a color duplex ultrasound scanner (ATL Ultramark 9, Advanced Technology Laboratories, Inc., Bothell, Wash.), with the peak systolic velocity in the internal carotid artery used to calculate the severity of stenosis using established criteria (13).

The potential for paradoxical embolization from venous blood into the arterial circulation, usually through a patent foramen ovale, was investigated using a standardized transcranial Doppler method (14). The middle cerebral artery was insonated using transcranial Doppler, and an ultrasound contrast consisting of an air and saline emulsion was injected intravenously. The number of air microemboli entering the middle cerebral artery was counted and the severity of venous-to-arterial circulation was recorded using established criteria, with a significant venous-to-arterial circulation shunt equating to a patent foramen ovale and a major venous-to-arterial circulation shunt equating to a substantial right-to-left shunt across a patent foramen ovale (15, 16). The use of microbubbles as an ultrasound contrast medium to detect patent foramen ovale is routine in cardiology and entirely safe. The minimally invasive technique we used is comparatively sensitive and specific to patent foramen ovale detected by transesophageal echocardiography (14–16).

Patients attended the Vascular Studies Unit at the University Hospital of South Manchester every 6 months (for 2 years) and were independently assessed by vascular scientists who were blinded to dementia diagnoses and outcome measures for the progression of dementia. The method used to detect spontaneous cerebral emboli has been described in detail elsewhere (9) and is based on international consensus criteria (17). Briefly, cerebral emboli were detected by insonating the middle cerebral artery through the temporal window with the best signal by transcranial Doppler (EME Pioneer 4040, Überlingen, Germany) using a 2-MHz pulsed-wave Doppler probe. The insonation depth was set individually and ranged from 40 mm to 55 mm, and the sample volume length was set at 13 mm for all patients. Cerebral emboli were investigated over two separate 1-hour transcranial Doppler sessions at baseline and at 6-month intervals over the next 18 months. Patients were observed throughout each session in a manner that would allow movement artifacts to be recorded on digital tapes of the transcranial Doppler output for subsequent blind analyses by two vascular technologists. Each recording was played back through the same transcranial Doppler system, with a 128-point fast Fourier transform and an overlap of >50%. Embolic signals were identified using standard consensus criteria (17). If a patient was cerebral emboli positive in our original case-control study (9), he or she was considered cerebral emboli positive in the present study.

The following measures of cognition, function, and psychological symptoms were used to assess patients at baseline and at 6-month intervals to measure the progression of dementia: the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog [18]), the Interview for Deterioration in Daily Living Activities in Dementia (19), and the Neuropsychiatric Inventory (20).

We assumed that the overall decline in cognitive functioning as indicated by ADAS-Cog scores over 2 years would be similar in Alzheimer's disease and vascular dementia patients (21) and that ADAS-Cog scores would increase by approximately 7 points (10%) per year among patients with Alzheimer's disease (22). Our study was powered to detect whether spontaneous cerebral emboli would double the rate of progression of dementia from 10% to 20% each year (20% to 40% over 2 years). To achieve a 90% power to detect a doubling in the rate of cognitive deterioration stimulated by cerebral emboli separately in patients with Alzheimer's disease and vascular dementia, assuming a standard deviation of 20% and spontaneous cerebral emboli detection in 25% of patients, a total of 180 patients (accommodating a 30% attrition rate) would need to be examined. We were able to recruit 156 patients, and 144 with outcome data were included in all analyses. The attrition rate was higher than we anticipated, with 99 patients completing follow-up assessments up to 24 months.

Differences in baseline characteristics between patients with Alzheimer's disease and vascular dementia and between those with and without cerebral emboli were assessed using simple t test and chi-squared analysis as appropriate. Changes over the 24-month follow-up period (incorporating information from each of the assessments) in scores on the ADAS-Cog, MMSE, Interview for Deterioration in Daily Living Activities in Dementia, and Neuropsychiatric Inventory were analyzed by longitudinal regression modeling using generalized estimating equations with exchangeable correlation structure. This method enabled data up to the last recorded assessment for those patients who were lost to follow-up assessment before 24 months to be included in the statistical analysis.

The progression in dementia severity over 2 years was compared statistically between patients who had cerebral emboli detected at any time over the first 18 months (emboli positive) with those in whom cerebral emboli were never detected (emboli negative), using generalized estimating equations with exchangeable correlation structure to assess the significance of the interaction between time and presence of cerebral emboli. Covariates in the regression model included age, sex, type of dementia, age at onset, and vascular risk factors found to be related to the rate of progression of dementia at the 10% level of significance.

For each patient, the mean number of emboli detected over the study was calculated as the total number of emboli detected divided by the number of follow-up sessions attended. A ranking score was then derived based on the mean number of emboli detected, and the association between this score and the change in scores on outcome measures over 24 months was assessed using nonparametric Spearman correlations. Analyses were performed using SPSS, version 15 (SPSS, Inc., Chicago), and Stata, version 10 (StataCorp, College Station, Tex.).

A total of 144 of the 156 recruited patients with dementia were included in the analyses (Alzheimer's disease, N=84 [63 “probable” and 21 “possible”]; vascular dementia, N=60) (Figure 1). The mean age of the included patients was 75.2 years (SD=7.3), and 48% were women. Not all patients completed each assessment at all time points, with data on outcome up to 24 months available for 58/84 (69%) of the Alzheimer's disease patients and 41/60 (65%) of the vascular dementia patients.

Patients contributing data to the generalized estimating equation analysis for a time period shorter than 24 months, compared with those with 24-month data, were older (77.3 years [SD=5.8] versus 73.8 years [SD=7.8]) and had lower mean scores on the MMSE (18.6 [SD=6.8] versus 22.2 [SD=5.6]) and higher mean scores on the ADAS-Cog (28.2 [SD=15.6] versus 21.8 [SD=11.7]) and Interview for Deterioration in Daily Living Activities in Dementia (94.8 [SD=44.6] versus 76.8 [SD=40.4]) as well as slightly higher scores on the Neuropsychiatric Inventory (20.1 [SD=12.4] versus 16.9 [SD=11.8]). There was no difference between the two groups with respect to cardiovascular risk factors. The percentage of patients with spontaneous cerebral emboli at baseline was 34% in those with incomplete follow-up data and 39% in those who were followed for the entire 24-month study period.

Vascular dementia patients were more likely (>50% [p=0.03]) to have a history of stroke (p<0.001), transient ischemic attacks (p<0.001), hypertension (p<0.05), and internal carotid artery stenosis than Alzheimer's disease patients (Table 1, Table 2). Patients with Alzheimer's disease were more likely to be receiving acetylcholinesterase inhibitors (p<0.001), while those with vascular dementia were more likely to be receiving antiplatelet medication (p<0.001).

Spontaneous cerebral emboli were detected in 63 (44%) of the 144 dementia patients, 48 (33%) at the initial assessment and an additional 15 (11%) during follow-up assessments. Cerebral emboli were associated with blood pressure, antiplatelet medication (p=0.03), and a significant venous-to-arterial circulation shunt indicating a patent foramen ovale (p=0.04).

The expected progressive deterioration in cognition and function over 2 years was observed (Figure 2). Overall, there was an increase in scores on the ADAS-Cog, by a mean of 10.2 (95% confidence interval [CI]=7.2–13.3), a decrease in scores on the MMSE, by a mean of 5.5 (95% CI=4.2–6.8), and an increase in scores on the Interview for Deterioration in Daily Living Activities in Dementia, by a mean of 38.3 (95% CI=28.5–48.1) (p<0.001). The rate of progression was similar in Alzheimer's disease and vascular dementia patients; APOE4 genotype positivity had little influence.

The changes in outcome measures at 6-month intervals over 2 years between cerebral emboli-positive and emboli-negative patients are shown in Figure 3.

For those patients with emboli detected at any time during the study, the mean number of emboli (the total number of emboli divided by the number of transcranial Doppler sessions) was 0.27 (range=0.09–11.3). The ranking based on the number of emboli detected per Doppler session was significantly correlated with cognitive deterioration over 2 years as indicated by scores on the ADAS-Cog (r_s=0.28, p=0.008), Interview for Deterioration in Daily Living Activities in Dementia (r_s=0.36, p<0.001), and Neuropsychiatric Inventory (r_s=0.42, p<0.001). However, when this was repeated including only the smaller number of emboli-positive patients, the correlations with scores on these measures failed to approach statistical significance.

Patent foramen ovale was detected in 37 (26%) dementia patients. The effect of patent foramen ovale on the progression of dementia was investigated using generalized estimating equation analysis, and no significant association with scores on the ADAS-Cog, MMSE, or Neuropsychiatric Inventory was found. However, functional decline was greater in patients with patent foramen ovale, with a mean increase in score of 46.7 on the Interview for Deterioration in Daily Living Activities in Dementia for these patients, compared with 35.7 for those with no patent foramen ovale (p=0.002).

Although our recruitment target was not achieved, the detection rate for spontaneous cerebral emboli was higher and the deterioration in cognitive functioning in dementia was more rapid than we predicted. We adjusted for the use of cholinesterase inhibitors, antiplatelet medication, and statin therapy but not other medications, such as benzodiazepines, hypnotics, anticholinergics, or antipsychotics. We minimized potential bias in detecting cerebral emboli by recording transcranial Doppler sessions for subsequent analysis conducted by two trained vascular technologists who had no knowledge of the underlying diagnosis or clinical outcomes. The number of transcranial Doppler sessions may have been insufficient to measure a dose effect, and some dementia patients with cerebral emboli may have been wrongly allocated emboli-negative status in this study.