Jooske Boomsma

The general objective of this thesis was to investigate the clinical features and prognosis of patients with vascular cognitive impairment (VCI) in a memory clinic setting. To this end, the TRACE-VCI study was initiated, resulting in a large, unique cohort of 860 patients from three Dutch outpatient clinics at two university hospitals. In this final chapter, the main findings of the studies on the TRACE-VCI cohort and their implications and future directions for further research will be discussed. The first part of this thesis (chapter 2 to 4) described the clinical features and cognitive profile of patients with VCI in a memory clinic setting. The second part of the thesis (chapter 4 to 6) focused on the risk of cognitive decline and prediction of poor clinical outcome. The main findings of part one and two are summarized in respectively figure 1 and 2.

Figure 1: main findings regarding the clinical features and cognitive profile in the TRACE-VCI cohort (chapter 2 to 4).

Abbreviations: WMH, white matter hyperintensities; MCI, mild cognitive impairment; NOCI, no objective cognitive impairment.

Figure 2: primary results regarding the risk of cognitive decline and poor clinical outcome in the TRACE-VCI cohort (chapter 4 to 6).

Abbreviations: NOCI, no objective cognitive impairment; MCI, mild cognitive impairment; MTA, medial temporal atrophy; DAD, disability assessment for dementia; NPI, neuropsychiatric inventory.

Vascular cognitive impairment; clinical features and cognitive profile

The first part of this thesis focused on the clinical features and cognitive profile of the patients included in the TRACE-VCI cohort. Figure 1 shortly summarizes the main results of chapter 2 to 4. Chapter 2 described the design and clinical features of the TRACE-VCI cohort regarding type of vascular brain injury, severity of cognitive impairment and combination with other neurodegenerative etiologies. In this memory clinic population with VCI, the main types of vascular brain injury were moderate/severe WMH (46%), microbleed(s) (43%) and lacunar infarct(s) (22%). In total, 52% of patients showed dementia, in which 86% had a neurodegenerative etiology, mostly Alzheimer’s disease (79%). Chapter 3 showed that type and severity of vascular brain injury explained little of the variation in cognitive profile. The cognitive profile was remarkably similar across all types of vascular brain injury. Chapter 4 showed no different cognitive profile among sexes. Type of vascular brain injury did show differences between sexes; female patients showed larger WMH volumes, while males showed more non-lacunar and lacunar infarct(s).

The TRACE-VCI study is different from most of the existing literature in that we evaluated patients for suspected cognitive problems with all types of vascular brain injury in a memory clinic setting. In studies evaluating VCI in general, the main types of vascular brain injury in VCI are infarcts and white matter hyperintensities (WMH) 1-3. This higher rate of infarct(s) is mostly due to the inclusion of stroke cohorts, which was not the main inclusion criteria of our study that focused on memory clinic patients. Different types of vascular brain injury have partially shared and somewhat different etiologies and affect different parts of the brain. This heterogeneity of vascular brain injury might be reflected in distinct cognitive profiles. In general, patients with VCI have mental slowness and problems with attention and executive function. Also, memory problems, behavioral symptoms and psychological symptoms such as apathy, anxiety and depression are frequently present. In fact, population based studies showed that the total burden of vascular brain injury was associated with poorer general cognitive ability and independently associated with worse performance on processing speed 4,5. Indeed, chapter 3 demonstrated that patients from the TRACE-VCI study population showed worse performances on all cognitive domains, but mainly on information processing speed, attention and executive functioning and memory. Yet, the cognitive profile was remarkably similar across groups, regardless type of vascular brain injury, but also regardless of cerebrospinal (CSF) biomarker Alzheimer status, severity of cognitive impairment and even sex. Although females showed a larger volume of WMH and males showed more non lacunar and lacunar infarct(s), which is also shown in population based studies where microvascular disease is more common in females and large vessel disease is more common in males 6,7, the cognitive profile did not differ significantly between sexes (chapter 4). The most important difference was made by the presence of a positive CSF biomarker Alzheimer profile. A positive CSF biomarker Alzheimer profile by itself markedly affected cognitive performance on all domains showing worse performance on all cognitive domains, especially memory (figure 3). This finding provides support for the theory that vascular brain injury lowers the threshold for symptoms of cognitive impairment in co-occurring Alzheimer pathology.

Figure 3: influence of CSF biomarker Alzheimer profile on the cognitive profile.

Mean unadjusted domain Z-scores for the different forms of vascular brain injury in patients with a positive or negative CSF biomarker Alzheimer profile (n=541). Univariate analyses of variance were performed with CSF biomarker Alzheimer profile as fixed factor and age, sex and education as covariates. * p value < 0.0005 ** p value = 0.04. Abbreviations: CSF, cerebrospinal fluid. Vascular cognitive impairment: risk of cognitive decline and poor clinical outcome. Figure 2 summarizes the main results focusing on the longitudinal outcomes of the TRACE-VCI cohort. Chapter 5 demonstrated that memory clinic patients with VCI and different types of vascular brain injury on MRI showed little differences in cognitive trajectories depending on type of vascular brain injury. Across the TRACE-VCI study population performance declined over time on all tests. The data provided some suggestion that lacunar and non-lacunar infarct(s) were associated with minor differences in tests evaluating attention and executive functioning. These subtle associations were mainly attributable to patients with dementia. Chapter 6 described the creation and external validation of a risk score to predict poor clinical outcome. In 688 patients, follow-up collection was performed after a mean of 2.1 years, in which 170 patients showed poor clinical outcome. We defined a composite primary outcome measure that was robust and clinically relevant including (1) substantial cognitive decline, (2) occurrence of a major cardiovascular event (MACE), (3) death and/or (4) institutionalization due to other reasons than cognitive decline. Age, clinical syndrome diagnosis, Disability Assessment for Dementia, Neuropsychiatric Inventory, medial temporal lobe atrophy most strongly predicted poor outcome and constituted the risk score. None of the vascular risk factors or types of vascular brain injury were predictive for poor clinical outcome. Validation of the prediction score in an independent cohort showed comparable predictive ability. Chapter 4 described no statistically significant differences in poor clinical outcome between sexes. The outcome of the prediction score in chapter 6 is in line with previous studies. Several other studies showed that older age, worse cognitive impairment on baseline level, greater functional impairment in daily living and worse behavioral disturbance (NPI) and MTA score were associated with poor clinical outcome 8-14. However, more relevant is that none of the vascular predictors were retained in this model. Several explanations may explain this result. First, it might be due to the inclusion criteria, all patients were included due to vascular brain injury. Perhaps burden of vascular risk factors and different types of vascular brain injury do not differentiate as much for poor clinical outcome compared to people without these abnormalities. Secondly, vascular brain injury might be less predictive in people with a higher burden of other pathologies, particularly amyloid, such as those visiting a memory clinic in which more neurodegenerative pathology may be present. The fact that medial temporal lobe atrophy was included in the risk score underlines this theory. This might overshadow the effect of vascular brain injury. A non-lacunar infarct in a healthy brain might not lead to cognitive dysfunction, but co-existing subclinical Alzheimer pathology might lead to cognitive impairment. This also supports the theory that Alzheimer pathology and vascular brain injury work in an additive or synergistic way. Thirdly, it might be that other factors such as cognitive reserve may play a part. The cognitive reserve theory suggests that lifetime events (e.g. education, trauma) may either protect or increase the possibility of cognitive decline. Chapter 4 suggested that males were at somewhat higher risk of poor clinical outcome (27%) compared to females (22%), but this was not statistically significant. Female and male patients did not differ in substantial cognitive decline or risk of major cardiovascular events. Males had a higher mortality rate (HR 2.1) compared to females, this effect seemed only partly mediated by medical history of vascular events. Chapter 5 of this thesis demonstrated that memory clinic patients with VCI and different types of vascular brain injury on MRI showed little differences in cognitive trajectories depending on type of vascular brain injury. Subtle associations were mainly attributable to patients with dementia, supporting the concept that vascular brain injury lowers the threshold for symptoms of cognitive impairment in co-occurring Alzheimer pathology. Implications for clinical practice and future perspectives The overall aim of the TRACE-VCI study was the investigation of the clinical features and prognosis of patients with possible VCI in a memory clinic setting. The TRACE-VCI study was introduced at a moment that validated and generally accepted criteria at which visible vascular brain injury may be considered “clinically relevant” in memory clinic patients were still in progress. Around the time of the initiation of the TRACE-VCI study in 2009, diagnostic criteria for VCI had been proposed by several international working groups, including criteria for Vascular Cognitive Impairment from the American Heart Association/American Stroke Association (AHA/ASA) 15 and criteria for vascular cognitive disorders from the International Society of Vascular Behavioral and Cognitive Disorders (VasCog) Society 16. Both the AHA/ASA and the VasCog criteria defined a threshold for severity of cognitive impairment, including only patients with mild cognitive impairment (MCI) or dementia. Also, the new standardized VCI criteria of the Vascular Impairment of Cognition Classification Consensus Study (VICCCS) in 2018 only included patients with impairment in at least one cognitive domain 17. By contrast, in the TRACE-VCI study, we included patients with the entire spectrum of cognitive complaints, also including ‘subjective cognitive impairment’, referring to these patients as no objective cognitive impairment (NOCI), which included 23% of our study population. This is in line with the research framework of the National Institute on Aging and Alzheimer’s Association (NIA-AA) for Alzheimer’s disease (AD) in 2018, where neuropathological changes and clinical symptoms were seen as two different entities, recognizing that cognition does exist as a continuum, including cognitively unimpaired patients 18. Also, in the TRACE-VCI study, patients with co-occurring neurodegenerative pathology were included. The AHA/ASA criteria apply to patients with evidence for co-occurring neurodegenerative or other causes of cognitive impairment, categorizing these patients as possible VCI, similar to our operational definition of VCI. This is different from the VasCog criteria 16, which includes only subjects with evidence for predominantly vascular etiology of cognitive impairment excluding neurodegenerative disorders. The VICCCS showed a revised conceptualization of VCI in 2018 in which VCI was divided in subtypes, also including comorbid neuropathology and differentiating between a temporal and no temporal basis 17. Yet, in most memory clinic patients vascular brain injury probably will not be the only contributor of cognitive complaints and a temporal relationship is rarely present. Therefore, the operationalization of VCI in everyday practice should also include patients with subjective complaints and accept co-occurring neurodegenerative pathology. Patients with subjective cognitive complaints are very relevant for research proposes, in terms of preventive strategy and patient perspective. The fact that neuropsychological assessments are not able to objectify these cognitive complaints underestimate its impact in daily life. Future research is needed to reveal the etiology of subjective cognitive complaints and its interactions with other factors such as cognitive reserve. Evaluation at test level might be a better way to objectify these complaints, which might also select patients at risk for further cognitive decline. This is the main question in a current project in which we try to objectify these subjective complaints in patients after a stroke or TIA. This thesis showed that the presence of co-existing Alzheimer pathology by itself markedly affected baseline cognition and decline, while type of vascular brain injury was hardly related to these outcomes. Our prediction model also showed that other factors might overshadow the presence of vascular brain injury, because of their stronger effects on poor clinical outcome. Is it therefore important to determine all types of brain pathology contributing to cognitive impairment? From a patient's perspective it is important to identify these different pathologies, since it will guide prognostic information. Also, if disease-modifying treatments for Alzheimer’s disease are available, this mechanism-based diagnosis is relevant in terms of treatment and prevention. And what is the place of vascular risk factor modulation in this setting? The current sets of diagnostic criteria for VCI or Alzheimer disease do not have guidelines for mixed pathology, which is often present in a memory clinic setting. Treatment of vascular risk factors might reduce the risk of dementia, especially vascular dementia, based on the initial data from the Framingham study 19. On the other hand, randomized cardiovascular preventive trials showed not enough evidence for the prevention of VCI 20. Future research creating a risk score combining dementia risk scores (e.g. the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) Dementia Risk Score) 21,22 and dementia-related and neuroimaging biomarkers are needed. Also, since the CAIDE Dementia Risk score is based on simple cutoff for risk factors, it is important to develop tools that are even more sensitive to capture lifestyle changes and their potential impact on brain structure in middle-aged healthy people without cognitive impairment or, even more in line with this thesis, in memory clinic patients with vascular brain injury and no objective cognitive impairment. In conclusion, the overall aim of the TRACE-VCI study was to investigate the clinical features and prognosis of patients with possible VCI in a memory clinic setting. This thesis showed that type of vascular brain injury in a memory clinic population explained little of the variance in cognitive profile and trajectory. The presence of co-existing Alzheimer pathology by itself markedly affected cognitive performance on all domains. Prediction of poor clinical outcome in the TRACE-VCI study was mainly influenced by age, type of cognitive impairment, MTA score, neuropsychiatric symptoms and disability in daily living on baseline visit. Also here, no vascular predictors were retained in this model.