Cerebral Artery Pulsatility is Associated with Cognitive Impairment and Predicts Dementia in Individuals with Subjective Memory Decline or Mild Cognitive Impairment

Abstract

The concept that excess pulsation in cerebral arteries might be involved at the early stage of dementia is based on the results of studies on aorta stiffness. In these studies, aorta stiffness is cross-sectionally associated with cognitive impairment and longitudinally related to cognitive decline in non-demented subjects. However, a direct measure of cerebral artery pulsatility is absent in the literature. We aimed to investigate the associations between cerebral artery pulsatility and (1) different cognitive-domains and (2) conversion to dementia in non-demented individuals at the prodromal-stage of Alzheimer’s disease (AD). Non-demented individuals with subjective memory decline or mild cognitive impairment were included. Neuropsychological tests at baseline and cognitive status at 6 years were evaluated. Cerebral pulsatility was assessed in the middle cerebral artery (MCA) and posterior cerebral artery by transcranial color-coded sonography. Multivariate-analyses of 79 subjects with robust acoustic windows showed that increased pulsatility in cerebral arteries was significantly associated with impairment in corresponding cognitive domains. Analyses in 54 subjects who completed 6-year follow up revealed that high left MCA pulsation (pulsatility index≥1.1) independently predicted conversion to AD with an odds-ratio of 11.2. Our results demonstrate the spatio-temporal relationship between increased cerebral artery pulsation and cognitive impairment and suggest that increased cerebrovascular pulsation might be involved in the early pathogenesis of AD. Cerebrovascular pulsation may be a therapeutic target to prevent/delay AD onset. Future studies with other AD biomarkers and animal/cell models of increased vascular-pulsation are needed to elucidate the mechanisms by which cerebrovascular pulsatile injury initiates or precipitates neurodegeneration in AD.

Keywords

Alzheimer’s disease cerebral artery cognitive function pulsatility index

INTRODUCTION

Alzheimer’s disease (AD) is a continuum that involves progressive neurodegeneration and cognitive decline; patients are usually asymptomatic at the preclinical stage and may experience subjective memory decline or mild cognitive impairment (MCI) several years before dementia can be detected with neuropsychological tests [1, 2]. Researchers have made efforts to identify AD biomarkers at preclinical stages that would help select subjects at risk of conversion to dementia as well as elucidate the early pathophysiology of AD. The ultimate aim is to identify a therapeutic target for AD before clinical dementia becomes evident, potentially reversing the disease process.

Several lines of evidence link vascular factors to AD. Epidemiological studies have shown that, besides age, vascular risk factors (VRFs) are associated with AD, particularly hypertension and hyperlipidemia [3, 4]. Furthermore, MCI patients with treatment for VRFs have lower risks of developing AD than MCI patients without treatment [4]. This implies that vascular factors might be a potential target for reversing the AD disease process at an early stage. Aorta stiffness, a condition of vascular aging hastened by hypertension [5], might be a potential mechanism linking VRFs and cognitive impairment in AD. In non-demented individuals, increased stiffness and pulsatility in central vasculature are associated with cognitive impairment, as suggested by the findings of a few cross-sectional studies and a recent longitudinal study [6 –9]. It is postulated that elevated central vascular pulsation might transmit into the brain, causing cerebral microvascular and brain tissue damage. However, there is no direct evidence showing that increased cerebral artery pulsatility is associated with cognitive impairment or predicts conversion to AD.

Several studies found a higher pulsatility index (PI) in cerebral arteries, mainly the middle cerebral artery (MCA), in patients with AD compared with non-demented subjects [10, 11]. Since most of these were cross-sectional studies, the mechanism by which increased cerebral artery pulsatility effects cognitive functions and cognitive decline is unknown. The present study used transcranial color-coded sonography (TCCS) to measure PI in both MCA and posterior cerebral arteries (PCA) in non-demented individuals with subjective memory decline or MCI. These subjects received neuropsychological tests in a variety of domains at baseline and were followed for 6 y to assess their cognitive status. We hypothesized that increased cerebral artery pulsatility is associated with impairment in corresponding cognitive domains and could predict future dementia in non-demented individuals at the possible prodromal-stage of AD. These results would elucidate the role of increased vascular pulsation in the pathophysiology of AD.

MATERIALS AND METHODS

Study population

Between December 2008 and December 2010 and between June 2013 and September 2016, Taiwan residents consecutively admitted to a memory clinic (Dr. Wang) at Taipei Veterans General Hospital, Taiwan, due to subjective memory complaints by themselves or/and their family were assessed for inclusion in this study. Neurologists performed clinical and neurologic evaluations on each patient. Tests, including Mini-Mental State Examination (MMSE) [12], Geriatric Depression Scale (GDS) [13], brain computed topography (CT), and color-coded duplex ultrasonography evaluating neck and intracranial arteries, were performed. Subjects eligible for participation in the current study were 50 y or older and non-demented. Dementia, and the type of dementia, were diagnosed using the DSM (Diagnostic and Statistical Manual of Mental Disorders)-IV criteria [14]. Exclusion criteria were the presence of major depression revealed by GDS, a history of stroke or malignancy, the presence of lacunae or silent infarcts on brain CT, or the presence of severe (>50% stenosis) large artery atherosclerotic stenosis (neck and intracranial arteries) on ultrasonography. All subjects received an extensive neuropsychological test of different cognitive domains at baseline. Participants included between December 2008 and December 2010 received a clinical follow-up at year 6. The follow-up assessments included clinical and neurologic evaluations by a neurologist (Dr. Wang), MMSE, GDS, and brain CT. Conversion to dementia was determined with DSM-IV criteria [14]. The hospital’s Institutional Review Board (IRB, Taipei Veterans General Hospital) approved the study and each participant provided informed consent (IRB no. 97-04-10A).

VRFs were defined according to international guidelines and prospectively identified using all available information including medical charts, laboratory results, patient interviews, and neurological examinations. Hypertension was defined as a self-report of a current antihypertensive medication prescription or as a measurement of systolic blood-pressure≥140 mmHg or diastolic blood-pressure≥90 mmHg [15]. Diabetes mellitus (DM) was defined as a self-report of current DM treatment or a measurement of HgbA1c≥6.5% [16]. Hyperlipidemia was recorded if there was a self-report of the use of a statin agent or a total blood cholesterol level≥240 mg/dL [17]. Cigarette smoking was determined by patients’ history.

Neuropsychological assessment

All participants received a face-to-face neuropsychological examination carried out by trained interviewers. In addition to global cognitive performance, which was examined using the MMSE, five different cognitive domains were assessed using tests as follows:

Verbal memory: immediate (30 s) free recall in the Chinese Version of the Verbal Learning Test (CVVLT) [18]

Praxis: Motor Praxis Test. Subjects were asked to perform four motor tasks with hand and objects by orders. In each task, a score of 0–2 was given. A score of 2 was given if the task was correctly performed by oral order. A score of 1 was given if task was performed only through imitation, delayed more than 5 s, or obscured between hands and objects. A score of 0 was given if the patient failed to perform the task.

Visuospatial function was measured using the number position test of Visual Object and Space Perception Battery (VOSP) [19]

Language was measured using the Boston Naming Test (BNT) [20]

Executive function was assessed using the Digit Backward Test [21] and Trail B Test [22]

Cerebral artery pulsatility assessment by TCCS

TCCS was conducted in all participants by one examiner (Hsiang-Ying Lee) using the Phillips ultrasound system (iU22; Philips, New York, NY, USA). We used a center transmitted frequency of 2 MHz in color mode and Doppler gate at 5 to 10 mm. Angle-corrected velocity was determined whenever the angle correction was less than 60 degrees in a straight arterial segment of at least 2 mm in length in all other cases. PIs of both sides’ MCAs and PCAs were examined. The M1 segment of the MCA and P1 segment of the PCA were determined through temporal skull window from depths of 50 to 75 mm as unidirectional signals toward the probe at the mesencephalic plane and their anatomical association with the other intracranial arterial segments. Parameters measured were peak systolic, end-diastolic, and mean flow velocity (Vsys, Vdiasto, and Vmean). PI was defined by (Vsys –Vdiasto)/Vmean.

Statistical analyses

All values were expressed as mean (SD) for continuous variables and number (percentages) for discrete variables. Univariate and multivariate analyses were used to assess the relationship between PIs in MCA and PCA and each cognitive function test. Comparisons between subjects with and without conversion to AD were analyzed with non-parametric Mann-Whitney U test. A chi-square (χ ²) test or Fisher’s exact test was performed for categorical variables. Multivariate analyses adjusting for confounding factors were then performed to test if these associated factors were independent predictors for conversion to AD. All analyses were performed with SAS software, version 9.1 (SAS Institute, Cary, NC, USA).

RESULTS

Subjects’ demographics and cognitive functions

A total of 101 subjects were included in the study. We excluded 22 subjects with poor temporal acoustic windows. Among these 79 subjects included [mean (SD): 73.6 (8.7) y; 47 (59.5) men], hypertension, DM, hyperlipidemia, and a cigarette smoking habit were present in 43.0%, 11.4%, 17.7%, and 3.8% of subjects, respectively. All subjects were right-handed. The results of neuropsychological tests are shown in Table 1. In addition, 45 were mild cognitive impairment (MCI) patients, which was defined by Clinical Dementia Rating (CDR) scale = 0.5. Among 59 [74.7 (8.4) y; 37 (62.7% men)] subjects recruited, 54 had completed the 6-year follow up. The follow-up assessment showed that 20 (37.0%) had converted to AD.

Table 1

Neuropsychological tests’ scores of study population (n = 79)

	Study population,
	mean (SD), range
Education, y	12.7 (3.2), 6–18
MMSE, scores	27.4 (2.0), 22–30
Verbal memory: 30-s CVVLT, scores	7.0 (1.9), 2–9
Motor Praxis Test, scores	7.7 (1.0), 4–8
Visuospatial function: VOSP, scores	8.4 (1.5), 5–10
Language function: BNT, scores	27.7 (2.3), 19–30
Executive function
Digit backward test, scores	4.7 (1.2), 2–7
Trail B test, seconds	68.5 (38.8), 16–120

SD, standard deviation; MMSE, Mini-Mental State Examination; CVVLT, Chinese Version of the Verbal Learning Test; VOSP, Number position test of Visual Object and Space Perception Battery; BNT, Boston Naming Test.

Cerebral artery pulsatility measured by TCCS

The PIs of cerebral arteries were as follows: left MCA mean (SD, range) 1.00 (0.21, 0.68–1.63), right MCA 0.99 (0.18, 0.58–1.49), left PCA 0.97 (0.20, 0.59–1.62), and right PCA 0.97 (0.17, 0.56–1.54).

The association between cerebral artery pulsatility and cognitive function

We first performed cross-sectional analyses between the relationship between baseline TCCS and neuropsychological findings. The multivariate linear analyses in 79 subjects showed that increased cerebral artery pulsatility was associated with cognitive impairment (Table 2); increased PI in left PCA was significantly associated with poor verbal memory function, while increased PIs in left and right MCAs were significantly associated with poor motor praxis and visuospatial function, respectively (Fig. 1). These associations were independent of age, gender, education year, and VRFs (hypertension, DM, hyperlipidemia, and cigarette smoking).

Table 2

Multivariate linear analyses of the association between intracranial artery pulsatility (pulsatility index) and cognitive functions

	Beta	P value^a	Beta	P value^b
	coefficient^a		coefficient^b
MMSE
Left MCA	–0.18	0.249
Right MCA	–0.20	0.216
Left PCA	–0.10	0.523
Right PCA	–0.62	0.541
Verbal memory: 30-sec CVVLT
Left MCA	–0.20	0.162
Right MCA	–0.06	0.706
Left PCA	–0.33	0.024	–0.32	0.028
Right PCA	–0.28	0.058
Motor Praxis Test
Left MCA	–0.50	0.016	–0.45	0.030
Right MCA	–0.11	0.654
Left PCA	–0.22	0.283
Right PCA	–0.39	0.091
Visuospatial function: VOSP
Left MCA	–0.41	0.055
Right MCA	–0.58	0.012	–0.55	0.033
Left PCA	–0.23	0.307
Right PCA	–0.40	0.188
Language function: BNT
Left MCA	–0.20	0.139
Right MCA	–0.12	0.400
Left PCA	0.01	0.946
Right PCA	–0.08	0.600
Executive function: Digit Backward Test
Left MCA	–0.04	0.778
Right MCA	–0.02	0.998
Left PCA	–0.17	0.242
Right PCA	–0.25	0.097
Executive function: Trail-B Test
Left MCA	0.09	0.548
Right MCA	–0.01	0.962
Left PCA	–0.08	0.561
Right PCA	0.21	0.156

^aAdjusted for age, gender, and education years. ^bAdjusted for age, gender, education years, and vascular risk factors (hypertension, diabetes, hyperlipidemia, and cigarette smoking). Only variables statistically significant in univariate analyses were included. PCA, posterior cerebral artery; MCA, middle cerebral artery; MMSE, Mini-Mental State Examination; CVVLT, Chinese Version of the Verbal Learning Test; VOSP, Number position test of Visual Object and Space Perception Battery; BNT, Boston Naming Test.

Increased cerebral artery pulsatility and conversion to AD

The comparisons of baseline characteristics between 54 subjects, who completed 6-year follow-up, with and without conversion to AD are shown in Table 3. The results showed that individuals with conversion had higher prevalence of DM, lower baseline MMSE score, and a higher PI in left MCA. We then performed multivariate analyses adjusting for age, sex, baseline MMSE, and VRFs and used the 75th percentile of left MCA PI (75th percentile of all study subjects = 1.1) as the cutoff value. The results showed that left MCA PI≥1.1 at baseline was a significant and independent predictor of conversion to AD for non-demented individuals with subjective memory decline or MCI (Table 4).

Table 3

The comparisons between subjects with and without conversion to Alzheimer’s disease at 6 years

	Conversion to AD
	+	–	p
	(n = 20)	(n = 34)
Age, y	76.9 (6.5)	73.4 (9.2)	0.181
Sex, men	8 (40.0%)	12 (35.3%)	0.776
Education, y	11.9 (3.2)	12.8 (3.4)	0.304
MMSE	27.0 (1.9)	28.0 (1.9)	0.048
Hypertension	9 (45.0%)	18 (52.9%)	0.779
Diabetes mellitus	7 (35.0%)	4 (11.8%)	0.077
Hyperlipidemia	3 (15.0%)	8 (23.5%)	0.510
Cigarette smoking	0	3 (8.8%)	0.287
Poor acoustic temporal window	4 (20.0%)	9 (26.5%)	0.746
Pulsatility index
Left MCA	1.2 (0.2)	1.0 (0.2)	0.028
Right MCA	1.1 (0.2)	1.0 (0.2)	0.387
Left PCA	1.0 (0.3)	1.0 (0.2)	0.681
Right PCA	1.1 (0.2)	0.9 (0.2)	0.114

Data are shown as mean (SD) or number (percentage). AD, Alzheimer’s disease; MMSE, Mini-Mental State Examination; PCA, posterior cerebral artery; MCA, middle cerebral artery.

Table 4

Predictors of conversion to Alzheimer’s disease in individuals with subjective memory decline or mild cognitive impairment

	OR	95% CI	p
Age, per 1 y increase	1.0	0.9–1.2	0.804
Men, versus women	1.9	0.2–14.6	0.557
Hypertension, yes versus no	0.7	0.1–4.5	0.694
Diabetes mellitus, yes versus no	7.3	0.9–61.5	0.066
Hyperlipidemia, yes versus no	1.8	0.2–18.5	0.618
Baseline MMSE, per 1 score increase	1.0	0.5–2.0	0.953
left MCA PI≥1.1, yes versus no	11.2	1.4–93.1	0.025

MMSE, Mini-Mental State Examination; MCA, middle cerebral artery; PI, pulsatility index.

DISCUSSION

The present study showed that in non-demented individuals with subjective memory decline or MCI, (1) increased pulsatility in cerebral arteries was correlated with impairment in corresponding cognitive domains, and (2) a higher left MCA pulsatility at baseline was associated with the future conversion to AD. These results suggest that increased cerebrovascular pulsatility might be involved in the early phase of AD.

The concept that excess pulsation in cerebral arteries might be involved in the pathophysiology of dementia is based on the findings of several studies on aorta stiffness [6 –9]. In these large community-based studies with non-stroke and non-demented populations, higher carotid-femoral pulse-wave velocity, a marker of aorta stiffness, or/and central pulse pressure is cross-sectionally associated with cognitive impairment and longitudinally related to cognitive decline. It is hypothesized that increased and accelerated central artery pulsation in the aorta or/and central artery stiffness might transmit through cerebral arteries into the brain, leading to brain tissue damage or initiating the pathophysiology cascade of dementia. However, a direct measure of cerebral artery pulsatility is lacking in these studies. Our results, which showed that increased cerebral pulsatility was associated with cognitive impairment and conversion to dementia, have provided evidences supporting this “cerebrovascular pulsatile injury” postulate.

We are also able to demonstrate a possible spatial relationship between increased cerebral artery pulsation and cognitive impairment by measuring PIs in both MCAs and PCAs. In our study, increased pulsation in the left PCA, left MCA, and right MCA was associated with brain dysfunction in their respective blood supply regions: impaired verbal memory is mediated by the left medial temporal region (left PCA) [23], impaired motor praxis is mediated by the left fronto-parietal region (left MCA) [24], and visuospatial function versus right parietal region (right MCA) [25]. These results again support a potential causal relationship between increased cerebral artery pulsation and brain damage.

Higher cerebral artery pulsation has been found to be associated with AD in several clinical studies [10 , 26]. Several studies have shown that, patients with AD have higher PIs in cerebral arteries compared with normal controls. A recent longitudinal study in patients with mild to moderate AD also found that PI increment in cerebral arteries was associated with aggravation of cognitive decline [26]. However, most of these studies used AD patients and lacked a longitudinal component that could reveal any temporal relationship between increased cerebral pulsation and the AD disease process. We are the first to reveal that in non-demented individuals with subjective memory decline or MCI, possibly at the prodromal stage of AD, increased cerebral artery pulsation is significantly associated with conversion to AD during a 6-year follow up. This is strong evidence to support the hypothesis that increased cerebral artery pulsation might be involved in the early pathogenesis of AD. We also showed that increased pulsation in the left MCA, but not the memory impairment-related left PCA, was a predictor of conversion to AD. This is consistent with a previous study measuring hemodynamics of several intracranial arteries in patients with AD [11]. They also found that higher PI in MCA could differentiate between AD patients and normal controls more significantly than the PCA. This could be because the left MCA was supplying larger brain regions, i.e., the dominant hemisphere rather than the other cerebral arteries. Therefore, increased pulsation in left MCA might cause a more widespread and severe cognitive impairment and a higher risk of conversion to dementia.

Several evidences have also shown that cerebral microvascular disease or cerebral small vessel disease (CSVD) is involved in the pathophysiology of AD. Cerebral microvascular pathologies, including cerebral amyloid angiopathy, arteriosclerosis, or lipohyalinosis, have been revealed in a large proportion of patients with AD [27, 28]. Besides abnormal structures, impaired cerebral microvascular functions such as blood-brain barrier breakdown, impaired cerebral vasoreactivity, and decreased cerebral blood flow have also been found in AD [10 , 29–31]. These findings correspond with several imaging studies that have detected white matter hyperintensity (WMH), cerebral microbleeds and brain atrophy, markers of CSVDs, in patients with AD [31 –34]. Since in several clinical studies, increased pulsation in both central and cerebral arteries, mainly MCA, is also associated with CSVDs such as WMH or/and brain atrophy [6–9 , 36], it is suggested that increased cerebral artery pulsation might cause brain damage and consequent cognitive impairment via cerebral microvascular injury.

There are limitations in the present study. We did not measure central artery hemodynamics. The presumption that increased cerebral artery pulsation in our population originated from the aorta or central artery stiffness is reasonable according to previous studies [35, 37]. These have shown that cerebral artery PI is positively associated with the severity of aorta stiffness. However, other factors, such as increased downstream cerebral microvascular resistance, may also contribute to increased PI in MCA and PCA, though the extent of its contribution is believed to be less [35]. Markers of CSVDs, such as WMH, cerebral microvascular function, and AD biomarkers related to β-amyloid accumulation and clearance were not evaluated in the present study. Analysis of these markers would help elucidate the mechanisms linking between increased cerebrovascular pulsation and cognitive impairment. Lastly, we would need a larger population in the future to test the sensitivity and specificity of left MCA PI as a biomarker for AD prediction. In the present study, the percentage of poor acoustic windows, which increases with age [38], was more than 20%. Thus, despite the benefits of non-invasive imaging and cheap and fast acquisition, this characteristic might limit the use of transcranial ultrasound to measure cerebrovascular pulsatility for future clinical applications, particularly in the elderly. Other tools, such as magnetic resonance imaging with the relevant measuring software [36], could be used in future studies.

The strengths of our study include the study population of non-demented individuals with subjective memory decline or MCI, a possible prodromal stage of AD, and the longitudinal observation for the presence of conversion to AD. Our results provide information regarding the early pathogenesis of AD, which suggest that increased cerebral artery pulsation may be a potential therapeutic target to prevent or reverse the AD disease process. In the future, we will require animal or cell models of increased vascular pulsation to further understand the mechanisms by which cerebrovascular pulsatile injury initiates or precipitates neurodegeneration in AD.

Footnotes

ACKNOWLEDGMENTS

Drs. Chung and Wang received grants from Taiwan Ministry of Science and Technology (MOST 104-2314-B-075-MY3; 102-2314-B-010-051-MY2) and Taipei Veterans General Hospital (V102E9-004).

Authors’ disclosures available online ().

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