Asymptomatic Spontaneous Cerebral Emboli Predict Cognitive and Functional Decline in Dementia

doi:10.1016/j.biopsych.2006.12.010

Biological Psychiatry

Volume 62, Issue 4, 15 August 2007, Pages 339-344

https://doi.org/10.1016/j.biopsych.2006.12.010 Get rights and content

Background

Spontaneous cerebral emboli (SCE) are frequent in Alzheimer’s disease (AD) and vascular dementia (VaD). We investigated the effect of SCE on the rates of cognitive and functional decline in AD and VaD.

Methods

One hundred thirty-two patients with dementia (74 AD, National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association [NINCDS/ADRDA] criteria; 58 VaD, National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l’Enseignement en Neurosciences [NINDS/AIREN] criteria) underwent 1-hour transcranial Doppler for detection of SCE (mean [SD] age 75.5 (7.4) years; 46% female). Neuropsychological tests (Mini-Mental State Examination [MMSE], Alzheimer’s Disease Assessment Scale-Cognitive subscale [ADAS-Cog], and Neuropsychiatric Inventory [NPI]) and assessment of activities of daily living (Interview for Deterioration in Daily Living Activities in Dementia [IDDD]) were performed initially and 6 months later. SCE positive (SCE+ve, n = 47) and SCE negative (SCE-ve, n = 85) patients were compared using repeated measures analyses of variance (ANOVAs) adjusted for age, gender, and cardiovascular risk factors.

Results

SCE+ve patients with dementia, both AD and VaD, suffered a more rapid decline in cognitive functioning over 6 months (ADAS-cog, mean increase 7.1 for SCE+ve compared with 3.3 for SCE-ve, p = .006) and activities of daily living (IDDD, mean increase 24.4 for SCE+ve compared with 10.8 for SCE-ve, p = .014).

Conclusions

Asymptomatic SCE are associated with an accelerated cognitive and functional decline in dementia. SCE may be a potentially treatable cause of disease progression in dementia.

Section snippets

Patients

All 170 patients with dementia (85 AD, 85 VaD) who participated in a case-control study on SCE in AD and VaD (Purandare et al. 2006) were asked to participate in this follow-up study. New patients were also recruited using the same recruitment protocol and inclusion/exclusion criteria. In brief, patients were recruited from old age psychiatry services in Greater Manchester (United Kingdom). The National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and

Patient Recruitment

Of the 170 patients in the original case-control study, 117 agreed to participate in the follow-up study. This sample was extended with 39 newly recruited dementia patients. The newly recruited group was similar to the original patient group with respect to all baseline variables (data not shown). Excluded patients of the overall sample (n = 77; Figure 1) were significantly older (77.9 [SD 6.5] versus 75.5 [SD 7.4] years, p = .015). Both groups were similar with respect to gender (p = .13),

Discussion

In patients with dementia, SCE positive status predicted a more rapid deterioration in cognition and function over 6 months. The most plausible mechanism is that of subtle neuronal damage caused by cerebral ischemia due to SCE without causing “major” and/or clinical neurological events. The type of dementia, AD or VaD, did not affect this association, which is in line with previous research prospectively linking cardiovascular risk factors not only to VaD but also to AD (for review, see de la

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A linear relationship between the process of mechanically unstable areas of carotid plaques and cognitive decline suggests a contributory role of microembolization in silent strokes.613 Several studies showed that embolic signals are associated with faster cognitive deterioration and dementia in elderly despite an absence of neurologic symptoms.625-627 Although patients with evidence of carotid stenosis have impaired cognitive function compared with healthy controls independent of common vascular risk factors,615,628 vascular disease shares common risk factors with cognitive decline.
Micro-structural white matter abnormalities and cognitive impairment in asymptomatic carotid plaque patients: A DTI study using TBSS analysis
2020, Clinical Neurology and Neurosurgery
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The possible mechanisms are as follows: 1. The plaque falling off to form cerebral micro infarct or asymptomatic stroke leads to the damage of white matter [10,11]; 2. Cerebral hypoperfusion leads to brain dysfunction [12]; 3.
It has been shown that symptomatic or severe carotid atherosclerosis is closely related to cognitive impairment and brain white matter damage. However, there is still a lack of effective and non-invasive imaging biomarkers to identify early high-risk cerebrovascular diseases. Therefore, the purpose of this study is to explore the integrity of brain white matter and cognitive impairment in patients with asymptomatic carotid plaques by using imaging technology.
All subjects were from a project of Stroke Risk Screening and Prevention and were defined as stroke high-risk patients (with three or more stroke risk factors). Tract-based spatial statistics (TBSS) based on diffusion tensor imaging (DTI) was used to analyze the whole brain white matter abnormalities in 61 patients with carotid artery plaque and in 40 healthy controls. At the same time, the general clinical data between the two groups were compared, such as age, gender, smoking, hypertension and cognitive function scores etc. Furthermore, the plaque group was divided into the have-hyperintensities group and the no-hyperintensities group to compare their microstructure of white matter injuries.
The cognitive scores of plaque group were significantly lower than that of control group. We found that when plaque group and control group were compared, no white matter fiber tracts with difference was found in FA, MD, AD and RD. However, the decrease of FA and the increase of RD were found in some white matter regions (P < 0.05) when comparing the have-hyperintensities group and the no-hyperintensities group. These white matter regions included anterior thalamic radiation, corticospinal tract, cingulum (cingulate gyrus), forceps minor, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus. What’s more, there were significant differences in blood pressure between the two groups.
The cognitive function of patients with early high-risk cerebrovascular diseases (asymptomatic carotid plaques) has a downward trend. TBSS based on DTI can help to find out the actual damage of brain white matter in patients with early carotid plaque, and reflect the early pathological changes from the micro level.
Extracranial arterial wall volume is increased and shows relationships with vascular MRI measures in idiopathic Parkinson's disease
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Recently, MRI measures of neurovascular status have found prolonged arterial arrival time, thought to be related to age driven structural cerebrovascular changes, in patients with IPD compared to age and cardiovascular risk matched controls [17]. We have previously demonstrated that cerebral emboli have a role in the pathophysiology of AD and vascular dementia (VaD), two other common neurodegenerative disorders [18–23]. Cerebral emboli showed similar frequency, and similar association with cognitive decline, in both AD and VaD, suggesting some commonalities in pathophysiology.
Idiopathic Parkinson’s disease (IPD) is the second most common neurodegenerative disorder, often complicated by dementia. Cardiovascular risk factors and spontaneous cerebral emboli (SCE) are strongly associated with Alzheimer’s (AD) and vascular dementia (VaD). We measured SCE in the middle cerebral artery and arterial wall volume in the extracranial arteries in patients with IPD and controls, and explored the relationships with structural and physiological MRI brain neurovascular measures.
Arterial wall volume over 2cm of the axillary and internal carotid arteries (ICA) bilaterally was measured by 3-D tomographic ultrasound in 15 IPD patients and 16 age/gender matched controls. SCE were counted by Transcranial Doppler (TCD) using international consensus criteria. Venous to arterial circulation shunting (v-aCS), usually through a patent foramen ovale (PFO), was measured using a TCD technique with intravenous microbubble contrast. Structural and physiological MRI brain neurovascular measures, acquired separately, comprised white matter lesion volume (WMLV), cerebral blood flow (CBF) and arterial arrival time (AAT).
Mean (95% CI) axillary and ICA wall volume was higher in IPD patients at 523 mm³ (446, 600) and 455 mm³ (374, 536) respectively compared with 412 mm³ (342, 483) and 408 mm³ (362, 454) in controls being significant for the axillary artery (p = 0.04).
Cerebral WMLV was related to mean arterial wall volume for both axillary (r = 0.555, p = 0.009) and ICA (r = 0.559, p = 0.026) in all participants.
SCE were detected in four IPD patients and three controls (p = 1.00). Two IPD patients and three controls were positive for a v-aCS equivalent to PFO (p = 0.477).
Although frequent in AD and VaD, neither SCE nor v-aCS were associated with IPD. This is the first study to demonstrate arterial wall volume is increased in IPD and relates to WMLV.
Correlation of cognitive function with ultrasound strain indices in carotid plaque
2014, Ultrasound in Medicine and Biology
Instability in carotid vulnerable plaque can generate cerebral micro-emboli, which may be related to both stroke and eventual cognitive abnormality. Strain imaging to detect plaque vulnerability based on regions with large strain fluctuations, with arterial pulsation, may be able to determine the risk of cognitive impairment. Plaque instability may be characterized by increased strain variations over a cardiac cycle. Radiofrequency signals for ultrasound strain imaging were acquired from the carotid arteries of 24 human patients using a Siemens Antares with a VFX 13-5 linear array transducer. These patients underwent standardized cognitive assessment (Repeatable Battery for the Assessment of Neuropsychological Status [RBANS]). Plaque regions were segmented by a radiologist at end-diastole using the Medical Imaging Interaction Toolkit. A hierarchical block-matching motion tracking algorithm was used to estimate the cumulated axial, lateral and shear strains within the imaging plane. The maximum, minimum and peak-to-peak strain indices in the plaque computed from the mean cumulated strain over a small region of interest in the plaque with large deformations were obtained. The maximum and peak-to-peak mean cumulated strain indices over the entire plaque region were also computed. All strain indices were then correlated with RBANS Total performance. Overall cognitive performance (RBANS Total) was negatively associated with values of the maximum strain and the peak-to-peak for axial and lateral strains, respectively. There was no significant correlation between the RBANS Total score and shear strain and strain indices averaged over the entire identified plaque for this group of patients. However, correlation of maximum lateral strain was higher for symptomatic patients (r = −0.650, p = 0.006) than for asymptomatic patients (r = −0.115, p = 0.803). On the other hand, correlation of maximum axial strain averaged over the entire plaque region was significantly higher for asymptomatic patients (r = −0.817, p = 0.016) than for symptomatic patients (r = −0.224, p = 0.402). The results reveal a direct relationship between the maximum axial and lateral strain indices in carotid plaque and cognitive impairment.
Microemboli detection in patients with carotid artery stenting - A potential marker for future cognitive impairment?
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Another study reports improved cognitive function after 6 months following CEA/CAS without significant differences between the two procedures [19]. Given that ES have been shown to be an aggravating factor for cognitive decline [20], the results in the latter study could be explained by the increased cerebral flow. This increase in the cerebral perfusion of patients who have undergone carotid revascularization should translate in a decreased number of cerebral white matter lesions (WML) because even though recent studies raise the possibility that WML are associated with intracranial rather than extracranial atherosclerosis [21], there is consistent evidence that high total cerebral blood flow is associated with a decreased number of WML [22].
To monitor the long-term cognitive function evolution of patients undergoing carotid artery stenting (CAS), using detection of embolic signals (ES) as a potential marker of cognitive decline.
This is an ongoing prospective nonrandomized single-center study of patients undergoing carotid artery angioplasty and stenting using standard techniques. Neurologic status is evaluated by history, physical examination and the National Institutes of Health Stroke Scale. A complete Doppler-ultrasound investigation of the brain-supplying arteries has been performed in every patient. A 45 minute cognitive battery designed to assess motor speed/coordination and executive function, psychomotor speed, language (naming), working memory/concentration, verbal fluency, and learning/memory is performed by a certified neuropsychologist in the first week after CAS and repeated a year after the procedure. Each patient undergoes bilateral ultrasonographic-Doppler monitoring of the middle cerebral artery (MCA) for microemboli detection. The patients are monitored during the first week after CAS and again a year after stenting.
32 patients were included. The mean baseline Mini-Mental State Examination (MMSE) score was 28.7 points. During the first ultrasonographic monitoring 28 patients (87.5%) had at least three times more ES detected on the stented side (a mean of 24ES/30 minutes was detected in the stented side compared to a mean of 4ES/30 min in the non-stented side). At the one-year follow-up 68% of the patients who have undergone CAS maintain a high number of ES detected in the territory of the stented carotid artery, finding that is well correlated with the cognitive decline in those patients, as assessed by the MMSE score.
ES detection is a useful tool for predicting cognitive decline that can be used to monitor CAS patients and adjust preventive measures in order to avoid progression of vascular cognitive impairment. It is important that further studies comparing carotid endarterectomy and CAS monitor long-term cognitive function outcome.
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Silent microembolic events can be observed even in patients with asymptomatic carotid artery stenosis.15 Using transcranial Doppler ultrasound, Purandare et al demonstrated that asymptomatic microembolic signals were associated with accelerated cognitive and functional decline.16 In addition, eradication of the sources of microemboli is considered to result in preservation or improvement of cognitive functions.14
The right and left sides of the brain play different roles in cognition. Therefore, the side of treatment should be taken into consideration when evaluating cognitive outcome following revascularization. Thus, we designed a study to evaluate changes in right hemisphere cognitive function in patients undergoing right carotid artery stentings (CAS) and left hemispheric cognitive function in patients undergoing left CAS. In addition, we studied CAS-related changes in regional cerebral blood flow to determine potential correlations with changes in cognitive function.
We performed a prospective assessment of 39 CAS patients, all of whom were right-handed. Patients with contralateral stenotic lesions were excluded. Twenty-one patients underwent CAS of the right internal carotid artery (Right CAS group) and 18 underwent CAS of the left internal carotid artery (Left CAS group). Neuropsychological testing was performed preoperatively and 6 months after endovascular treatment. Cerebral blood flow was determined by 123I-labeled N-isopropyl-p-iodoamphetamine single-photon emission computed tomography before and 6 months after CAS.
In the Right CAS group, postoperative performance intelligence quotient score (91.1 ± 18.2) was significantly improved compared with the preoperative score (84.9 ± 16.7; P < .001). In the Left CAS group, postoperative verbal intelligence quotient score (104.0 ± 18.8) was significantly higher than that before endovascular treatment (97.9 ± 15.8; P < .005). Postoperative regional cerebral blood flow was not significantly different from that before endovascular treatment in either group. However, regional cerebrovascular reactivity of the treated side showed significant improvement after treatment.
Amelioration of cognitive function may be dependent on the side of revascularization. Performance intelligence quotient improved after CAS in patients with severe carotid artery stenosis on the right side. Verbal intelligence quotient also improved on the left side after endovascular treatment. These effects seemed to involve improvement in regional cerebrovascular reactivity by CAS.

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Original ArticleAsymptomatic Spontaneous Cerebral Emboli Predict Cognitive and Functional Decline in Dementia

Background

Methods

Results

Conclusions

Section snippets

Patients

Patient Recruitment

Discussion

J Thorac Cardiovasc Surg

Pyschiatr Res

Eur J Vasc Endovasc Surg

J Neurol Sci

Clin Radiol

Eur J Ultrasound

The course of neuropsychiatric symptoms in dementiaPart I: Findings from the two-year longitudinal Maasbed study

Int J Geriatr Psychiatry

Natural history of Alzheimer’s disease and other dementias: Review of the literature in the light of the findings from the Kungsholmen project

Int J Geriatr Psychiatry

Alzheimer’s disease and vascular dementiaSome points of confluence

Ann N Y Acad Sci

Progression of dementia associated with lacunar infarctions

Dement Geriatr Cogn Disord

The progression of cognitive impairment in dementia with Lewy bodies, vascular dementia and Alzheimer’s disease

Int J Geriatr Psychiatry

Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events

N Engl J Med

Cholinesterase inhibitors for Alzheimer’s disease

Cochrane Database Syst Rev

Association between intraoperative cerebral microemboli signals and postoperative neuropsychological deficit: Comparison between patients with cardiac valve replacement and patients with coronary artery bypass grafting

J Neurol Neurosurg Psychiatry

Progression of cognitive impairment in Alzheimer’s disease

J Am Geriatr Soc

Doppler microembolic signals predict ischemic recurrences in symptomatic carotid stenosis

Acta Neurol Scand

Natural history of vascular dementia

Alzheimer Dis Assoc Disord

Basic identification criteria of Doppler microembolic signals

Stroke

The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia

Neurology

Alzheimer disease as a vascular disorderNosological evidence

Stroke

Original Article
Asymptomatic Spontaneous Cerebral Emboli Predict Cognitive and Functional Decline in Dementia