Background
The world’s population is rapidly aging and the total number of people living with dementia is projected to increase globally from 24.3 million in 2001 to 81.1 million in 2040 [
1]. Alzheimer’s disease (AD) and vascular cognitive impairment (VCI) are the two most common causes of cognitive dysfunction [
2]. AD is a neurodegenerative disease characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFT) [
3]. Individuals with AD often present with impaired episodic memory, defined as the conscious retrieval of autobiographical events [
3,
4]. Vascular cognitive impairment can be associated with both large vessel disease and small vessel disease [
5]; this study will focus on those with subcortical VCI (SVCI) as this group is suggested to be a more homogenous group of patients that are expected to show greater predictability in their clinical picture, natural history, outcome, and treatment response [
6]. SVCI is caused by small vessel damage that is typically associated with chronic and diffuse hypoperfusion causing cerebral white matter lesions (WML) and lacunes [
7]. People with SVCI display relatively intact episodic memory, but show impairments on measures of executive functions, defined as higher-order cognitive processes underpinning goal directed behaviors [
8].
AD and SVCI are often reported as two distinct diseases in epidemiological studies; however, evidence from neuropathological studies indicate a high rate of mixed AD-vascular pathology, generally referred to as “mixed dementia”. Mixed pathology is present in approximately half of all clinically diagnosed AD cases [
9‐
13], including participants of AD clinical trials who were extensively screened for pure AD [
14]. An autopsy study reported AD with cerebrovascular lesions to be the second most common pathology after AD [
15]; thus, mixed pathology may often be the rule rather than the exception in clinical diagnosis. Recently, efforts were made in understanding the manifestation of AD with cerebrovascular disease [
16]. For example, at the early AD pathology stage of entorhinal cortical involvement–which is generally clinically asymptomatic–the presence of cerebrovascular lesions is associated with cognitive impairment. This suggests that cerebrovascular lesions may lower the threshold for dementia [
17]. In addition, among those with AD, the presence of ischemic lesions is associated with a greater degree of cognitive deficits compared with pure AD pathology. Overall, it is hypothesized that vascular lesions may magnify the effect of mild AD pathology, result in more severe cognitive impairment, and accelerate disease progression [
18]. Currently, much of our knowledge on mixed dementia stems from the perspective of a primary AD diagnosis and hence, little is known on the effects of secondary AD pathology in a primary SVCI diagnosis. Specifically, it is unclear how co-existing amyloid pathology may affect cognitive function in people with a primary clinical SVCI diagnosis.
To investigate cognitive function in mixed pathology it is important to include cognitive domains associated with both SVCI and AD to understand the full spectrum of cognitive impairment. There is consensus that cognitive measures such as the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) [
19], the Executive Interview Test (EXIT-25) [
20], and the Montreal Cognitive Assessment (MOCA) [
21] should be included for an optimal assessment battery in AD and VCI trials [
22]. The ADAS-Cog is sensitive to a wide range of disease severity specific to the central dysfunctions experienced in AD including memory, praxis, and language; it is regarded as the standard instrument for use in clinical trials as a primary index of cognitive change in AD [
23]. The EXIT-25 and the MOCA provide a standardized clinical assessment of executive control functions relevant to SVCI [
20,
21]. Though it is important to use clinically relevant measures, these generalized tests may not capture specific processes that may be impaired in mixed dementia. As such, additional tests of specific executive functions–i.e. working memory (Digits Forward and Backward Test), attention and response inhibition (Stroop Test), and set shifting (Trail Making Test)–may be more sensitive to subtle change [
24].
The neurocognitive profile of SVCI with co-existing amyloid pathology remains to be elucidated. A better understanding of the cognitive dysfunctions associated with amyloid pathology in SVCI may be a useful adjunct in the clinical assessment of mixed SVCI-AD dementia. Thus, the purpose of this study was to understand whether individual differences in amyloid pathology might explain variations in cognitive impairment among individuals with clinical SVCI, using a clinically relevant neuropsychological test battery that is sensitive to both pathologies.
Discussion
To date, few studies have focused on the role of co-existing amyloid pathology in a primary SVCI diagnosis. Our study found that six out of twenty-two participants with clinical SVCI were PIB-positive. In assessing the effect of amyloid on cognitive function, we found that increased global amyloid deposition–suggestive of co-existing Alzheimer pathology–was significantly associated with worse cognitive function as indicated by the ADAS-Cog and MOCA. Our findings concur with and extend the results of previous literature assessing the role of amyloid on cognitive function in people with mild cognitive impairments (MCI) and healthy older adults.
The ADAS-Cog primarily assesses episodic memory and has been linked to amyloid deposition [
54]. This association is present in both healthy older adults and people with MCI. Longitudinal studies in healthy older adults found that increased PIB binding was associated with greater memory decline over time [
55,
56] and may be indicative of preclinical AD [
56]. A similar association is found in people with MCI. Several studies have found increased PIB binding to be strongly correlated with episodic memory impairments in amnestic MCI subtypes [
57,
58]; furthermore, PIB-positive amnestic MCI patients are more likely to progress to AD [
59,
60]. Together, these previous studies have established the association between amyloid and memory impairments within an AD context. The current study extends previous knowledge of amyloid deposition by showing that greater amyloid deposition on PIB-PET screening is associated with greater memory impairment in a SVCI cohort.
Our study also found increased amyloid to be associated with lower MOCA scores, which assesses a mix of cognitive functions with an emphasis on executive functions. Though AD is typically associated with memory impairments, people in the early stages of AD display executive dysfunctions [
61,
62]; thus, it is plausible that amyloid deposition would also be associated with executive dysfunctions. However, we note that we did not find a significant association with specific executive measures (i.e., Digit Span Test, Stroop test, and Trail Making Test) and the EXIT-25 test. No other studies have reported data on the EXIT-25 and few studies have examined the effect of amyloid deposition on specific executive processes. One reason for these non-significant results may lie in the minimal power of these tests to detect an effect. A complex statistical study conducted by ADNI found a composite score (ADNI-EF included: Category Fluency, Clock Drawing, WAIS-R Digit Symbol, Digit Span Backwards, and the Trail Making Test including Trails A, Trails B, and Trails B minus Trails A) to be superior to any independent measure of executive functioning. Specifically, ADNI-EF was sensitive to capturing changes in cognitive function over time and was the strongest baseline predictor of conversion to AD [
63]. Although the MOCA does include a memory subtest, it places greater emphasis on tasks of executive function and has similar components to ADNI-EF (includes Clock Drawing, Digit Span Backwards, and Trail Making and additionally includes a phonemic fluency task, a two-item verbal abstraction task, a sustained attention task, and a concentration task). Thus, the MOCA–as a global composite measure–may be more sensitive compared with specific executive processes.
Overall, we found that amyloid was associated with impairments in multiple domains of cognitive function including memory and executive dysfunctions in people with clinical SVCI. A similar study conducted by Lee and colleagues [
64] found that PIB retention in people with small vessel MCI was associated with impairments in multiple domains of cognitive function including language, visuospatial, memory, and executive functions. Furthermore, these results concur with a study published by Nordlund and colleagues [
65] who found that people with cognitive impairments in multiple domains (i.e. memory and executive dysfunctions) were more likely to convert to mixed dementia and vascular dementia compared with people who exhibited either memory or executive dysfunction alone.
However, our conclusions are not without limitations. First, this is an exploratory study, and thus, is limited by its small sample size; therefore, we are limited in our ability to detect smaller effects and future studies are required to confirm and extend our current results. We also did not account for the effect of NFT on cognitive function. This is of particular importance as neocortical NFT is more consistently correlated with dementia severity, and it is suggested that NFT may mediate the association of amyloid on cognitive function [
66]. In addition, we were not able to acquire MRI scans in all participants and did not have the sample size to include WML as a covariate. As a result, it is not clear how WML may have uniquely contributed to performance on the ADAS-Cog and MOCA. This is particularly important as declines in memory and executive functions have been linked to increased subcortical white matter disease [
67‐
69]. However, a study published by Park and colleagues [
49] investigating the relationship between cerebrovascular disease, amyloid, and cognitive function in SVCI suggested that amyloid burden and SVCI pathology were largely unrelated and that the effects of amyloid on cognition is independent of markers of SVCI pathology. The unique impact of amyloid on cognitive function is further supported by evidence in cerebrospinal fluid (CSF). A study assessing the role of amyloid beta (the 42-amino-acid form–Aβ
1–42) and neurofilament light (NF-L)–elevated concentration of NF-L in CSF are associated with WML and small vessel disease—in CSF found that only Aβ
1–42 was associated with worse cognitive outcomes in people with cerebral vascular disease [
70]. Overall, the results of our study and previous studies [
64,
70,
71] suggest that increased amyloid is independently associated with worse cognitive outcomes in people with vascular disease.
Acknowledgements
This study was jointly funded by the Canadian Stroke Network and the Heart and Stroke Foundation of Canada. Teresa Liu-Ambrose is a Canada Research Chair in Physical Activity, Mobility, and Cognitive Neuroscience, a Michael Smith Foundation for Health Research (MSFHR) Scholar, a Canadian Institutes of Health Research (CIHR) New Investigator, and a Heart and Stroke Foundation of Canada’s Henry J.M. Barnett Scholarship recipient. John Best is CIHR and Michael Smith Foundation for Health Research Post-Doctoral Fellow. Elizabeth Dao is a CIHR Doctoral Trainee. TRIUMF is gratefully acknowledged for PET tracer production.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
ED, G-YR H, VS, CJ, RT, KD, JRB, TLA contributed to study design, statistical analyses, data interpretation, and manuscript preparation. All authors read and approved the final manuscript.