LEARNING OBJECTIVES
After reading this article you will be able to:
• discuss the importance of the need for specific biomarkers differentiating between Alzheimer's disease and vascular dementia
• identify the differentiating factors between Alzheimer's disease and vascular dementia
• identify the biomarkers specifically supporting a diagnosis of vascular dementia.
Dementia is a progressive, irreversible clinical syndrome incorporating cognitive and behavioural problems such as memory loss, problems with reasoning and communication, visuospatial deficits and personality changes resulting in increased dependence on others to fulfil daily activities (World Health Organization 2022). The World Health Organization (WHO) has estimated that around 55 million people globally have dementia and there are 10 million new cases each year (WHO 2022). It is estimated that in 2019, there were almost 885 000 older people (aged 65 years and over) with dementia in the UK (Wittenberg Reference Wittenberg, Hu and Barraza-Araiza2019). By 2040, this number is expected to rise to almost 1.6 million as life expectancy is increasing (Wittenberg Reference Wittenberg, Hu and Barraza-Araiza2019). The most common cause of dementia is neurodegenerative disease and the two most common types are Alzheimer's disease (50–75% cases) and vascular dementia (up to 20% of cases) (Sorbi Reference Sorbi, Hort and Erkinjuntti2012).
Mutations in autosomal dominant genes – specifically, the amyloid precursor protein gene (APP) and the presenilin genes (PSEN1 and PSEN2) – have been identified as causes of early-onset Alzheimer's disease (Loy Reference Loy, Schofield and Turner2014), and risk-raising factors such as apolipoprotein E (ApoE) mutation have been posited in late-onset Alzheimer's disease (Schott Reference Schott, Firth, Conlon and Cox2020). Causes specific to vascular dementia include cerebrovascular disorders, vertebral amyloid angiopathy and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Sorbi Reference Sorbi, Hort and Erkinjuntti2012). However, the common risk factors in both Alzheimer's disease and vascular dementia are older age (BMJ Best Practice 2022), cardiovascular disease (Winblad Reference Winblad, Amouyel and Andrieu2016), hypertension, smoking, obesity, diabetes (Winblad Reference Winblad, Amouyel and Andrieu2016), physical inactivity (Norton Reference Norton, Matthews and Barnes2014), depression and alcohol consumption of more than 14 units per week (BMJ Best Practice 2022).
The reason it is necessary to look for specific biomarkers for the diagnosis of vascular dementia is that there are many similarities between Alzheimer's and vascular dementia, making it difficult to distinguish between the two, especially when there are no specific genetic causes or vascular changes identified in the brain. If specific biomarkers that could potentially differentiate between Alzheimer's disease and vascular dementia can be identified, it would broaden the horizon of research opportunities and potentially generate specific treatment for a particular type of dementia, whether it be Alzheimer's disease or vascular dementia. According to National Institute for Health and Care Excellence (NICE) guidelines, acetylcholinesterase inhibitors (AChEIs) such as donepezil, rivastigmine and galantamine and N-methyl-d-aspartate receptor (NMDAR) antagonists such as memantine are recommended in Alzheimer's disease but not in vascular dementia (National Institute for Health and Care Excellence 2018). These medications are indicated in treatment of cognitive, non-cognitive and behavioural symptoms of dementia. For behavioural and psychological symptoms in vascular dementia, the first-line treatment is the antidepressant trazodone and the next step is the antipsychotic risperidone. Therefore, in view of the limitations in the management of vascular dementia, we have focused our review on identifying the biomarkers for that disorder.
Method
We searched MEDLINE, PsycInfo and Research Gate to identify original articles on biomarkers for vascular dementia. We started the search looking for articles on biomarkers for both vascular dementia and Alzheimer's disease, because of their overlapping presentation, hoping that some studies would specifically differentiate between biomarkers for the two. The following search words were used: ‘biomarkers’ AND ‘vascular dementia’ AND ‘Alzheimer dementia’. Inclusion criteria were English-language original articles such as systematic reviews, Cochrane reviews, review articles, randomised double-blind trials, prospective or retrospective observational studies and case reports. Animal studies, commentaries and letters to the editor were excluded. Articles on genetic predispositions to vascular cognitive impairment such as CADASIL or cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) were excluded as this review was mainly based on the differentiation between Alzheimer's and vascular dementia diagnosed in populations aged above 50, which would include early- and late-onset dementia. We also excluded articles on post-stroke dementia (or those parts of studies related to post-stroke dementia), as there is a clear indication of a vascular element. The search was conducted on 17 November 2021 and yielded 643 records.
We excluded 610 out of 643 articles by reading the abstracts. By reading the full texts of the remaining 33, we found 7 studies meeting the inclusion/exclusion criteria (Fig. 1). Frequently used abbreviations and acronyms are listed in Box 1.
Abbreviations and acronyms
APP – amyloid precursor protein
Apo – apolipoprotein (ApoA, ApoB, ApoE)
CADASIL – cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
DHEA – dehydroepiandrosterone
DTI – diffusion tensor imaging
Lp(a) – lipoprotein(a)
MCI – mild cognitive impairment
MMP-9 – matrix metalloproteinase-9
NMDAR – N-methyl-d-aspartate receptor
NT-proSST – N-terminal prosomatostatin
PEN – presenilin
SIVD – subcortical ischaemic vascular disease
TSH – thyroid-stimulating hormone
VCID – vascular cognitive impairment and (vascular) dementia
Flowchart of the literature review.
Results
Thyroid-stimulating hormone (Forti 2012)
Forti et al (Reference Forti, Olivelli and Rietti2012) conducted a prospective cohort study to investigate the correlation between serum thyroid-stimulating hormone (TSH) and the risk of developing mild cognitive impairment (MCI), Alzheimer's disease, and vascular dementia in an elderly population (65–91 years of age) with a 4-year follow-up. The study included 660 participants with normal cognitive function at baseline; 20 participants were taking thyroid medication at baseline. No association was found between baseline TSH levels and multivariable-adjusted risk of MCI or Alzheimer's disease (for the latter, the odds ratio OR = 1.68, 95% CI 0.90–3.14). However, there was a significant association between high baseline levels of TSH and risk of vascular dementia (OR = 3.25, 95% CI 1.01–10.43; P < 0.05). No significant association was found between serum free thyroxine (FT4) and MCI, Alzheimer's disease or vascular dementia.
Homocysteine, DHEA-S and lipoprotein(a) (Ray 2013)
Ray et al (Reference Ray, Khemka and Behera2013) conducted a case–control study in which serum levels of homocysteine, dehydroepiandrosterone sulphate (DHEA-S) and lipoprotein(a) (Lp(a)) were measured by enzyme-linked immunosorbent assay (ELISA) in individuals diagnosed with Alzheimer's disease and vascular dementia compared with matched healthy controls (n = 40 in each group). The results showed higher levels of homocysteine in both the Alzheimer's disease and vascular dementia groups compared with controls, and a significantly higher level in vascular dementia compared with Alzheimer's disease. Serum DHEA-S levels were lower in Alzheimer's disease but not in vascular dementia compared with controls. On the other hand, serum levels of Lp(a) were significantly higher in the vascular dementia group compared with controls (P < 0.01) but not in the Alzheimer's disease group.
Thyroid dysfunction (Chen 2016)
Chen et al (Reference Chen, Liand and Zhang2016) conducted an observational case–control study which assessed the relationship between thyroid dysfunction and subcortical vascular MCI (svMCI). A total of 161 patients with an established diagnosis of subcortical ischaemic vascular disease (SIVD) aged from 54 to 75 were recruited and compared with a control group of 54 healthy individuals. Compared with the control group, free triiodothyronine (FT3) levels were significantly lower in the svMCI and vascular dementia groups (P < 0.01). Moreover, elevated TSH levels were noticed in the svMCI and vascular dementia groups compared with the control group (P < 0.05).
N-terminal prosomatostatin (Holm 2017)
Holm et al (Reference Holm, Nagga and Nilson2017) conducted a prospective cohort study to investigate the correlation between plasma levels of N-terminal prosomatostatin (NT-proSST), which is a precursor fragment of the hormone somatostatin (also known as growth hormone-inhibiting hormone), and the incidence of all-cause dementia. The study included participants from a previous study in 1970 known as the Malmö Preventive Project, which looked at cardiovascular risk factors in that population. A total of 18 240 participants responded out of the original 33 346. Of these, 5347 were selected after excluding individuals who already had dementia and those whose data had missing values. Plasma levels of NT-proSST were measured and the incidence of dementia was assessed after a follow-up period of 4.6 years (s.d. = 1.3 years). A total of 373 were newly diagnosed with dementia at follow-up (83 of whom had vascular dementia and 120 had Alzheimer's disease). High levels of NT-proSST (>563 pmol/L) were associated with an increased risk of developing vascular dementia (hazard ratio (HR) per 1 s.d. = 1.29; 95% CI 1.05–1.59; P = 0.016) but were not associated with Alzheimer's (HR per 1 s.d. = 0.99; 95% CI 0.81–1.20; P = 0.91) or any other form of dementia (HR per 1 s.d. = 1.04; 95% CI 0.94–1.16; P = 0.44) or mixed dementia (HR per 1 s.d. = 0.98; 95% CI 0.79–1.21; P = 0.84).
White matter changes (Palesi 2018)
Palesi et al (Reference Palesi, Rinaldis and Vitali2018) conducted an observational cross-sectional study which assessed specific changes in white matter patterns to help distinguish Alzheimer's disease from vascular dementia. The study included 93 participants (31 with Alzheimer's disease, 27 with vascular dementia and 35 healthy controls) between 69 and 85 years of age. The study was based on diffusion tensor imaging (DTI) analysis of the whole brain. The parameters of DTI used to characterise dementia were fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity. The findings revealed a distinction in how the white matter was affected in the two disorders. The main differences were observed in the parahippocampal tracts, corpus callosum and thalamic radiations. In Alzheimer's disease it was clear that the parahippocampal tracts, mainly the anterior part, were the most affected region; the splenium of the corpus callosum was more affected in Alzheimer's disease, whereas the genu of the corpus callosum was mainly affected in vascular dementia. Increases in mean diffusivity, radial diffusivity and axial diffusivity in the genu were seen only in vascular dementia; this suggests more involvement of the corpus callosum in vascular dementia. In Alzheimer's disease, thalamic radiations showed only a decrease in fractional anisotropy, whereas in vascular dementia they showed an increase in all three diffusivity parameters (mean, radial and axial) in addition to the decrease in fractional anisotropy. In Alzheimer's disease there was an increase in the three diffusivity parameters in the posterior part of the bilateral coagulum, a decrease in fractional anisotropy and increase in radial diffusivity in the cerebellar posterolateral region, and an increase in fractional anisotropy in the corticospinal tracts. Increases in the three diffusivity parameters and a decrease in fractional anisotropy in the posterior cerebellar lobules and fractional anisotropy reduction and diffusivity increase in superior longitudinal fasciculi were seen in vascular dementia.
β-amyloids and tau proteins (Tang 2018)
Tang et al (Reference Tang, Yang and Chen2018) looked at increases in plasma levels of β-amyloids (Aβ-40 and Aβ-42) and tau proteins in people who had suffered a stroke. Their cross-sectional study included 61 individuals who had had a stroke (27 without dementia and 34 with dementia), 21 people with Alzheimer's disease and 24 controls. The age range was 67–86 years. They found increases in Aβ-42 and tau levels in the Alzheimer's group as expected, together with the lowest levels of Aβ-40 (P < 0.01). Plasma tau and Aβ-42 levels in the stroke groups were lower than those in the Alzheimer's group but higher than in controls; in contrast, Aβ-40 levels were lower in the stroke groups compared with controls (P < 0.01 and P < 0.05 respectively). However, Aβ-42 was at a significantly higher level in the stroke group with dementia compared with the stroke group without dementia (P < 0.01). There was significant linear correlation between plasma levels of Aβ-42 and scores in the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) in both stroke groups (with dementia: r = −0.44, P = 0.001; without dementia: r = −0.46, P = 0.002). On the contrary, there were no significant associations of plasma levels of Aβ-40 and tau with MoCA and MMSE scores. The authors concluded that Aβ-42 is a potential biomarker for dementia in people who have suffered a stroke.
Neuroinflammation, CNS tissue injury, coagulation and thrombosis, and circulatory microRNAs (Cipollini 2019)
In a literature review, Cipollini et al (Reference Cipollini, Troili and Giubilei2019) discuss various biomarkers associated with vascular cognitive impairment in terms of pathophysiological pathways. Although studies related to CADASIL (or those parts of studies related to CADASIL) were excluded, the review highlighted other biomarkers such as inflammatory markers IL-6, CRP, MMP-9 and circulatory microRNAs. The biomarkers were divided into the following four categories.
• Biomarkers of inflammatory response: interleukin 6 (IL-6) results in C-reactive protein (CRP) production by the liver, which at high levels is associated with an increased risk of dementia. Elevated levels of matrix metalloproteinase-9 (MMP-9) are associated with vascular cognitive impairment and (vascular) dementia (VCID) and mixed dementia but not Alzheimer's disease.
• Biomarkers of central nervous system (CNS) tissue injuries: NMDAR, IgG, IgM and/or IgA autoantibody titres were found to be elevated in the serum of people with small vessel disease (SVD), which is associated with VCID. Neurofilament light chain, which is a biomarker for neuronal damage, was found to be correlated with CADASIL, which is a type of stroke that can cause VCID.
• Biomarkers of coagulation and thrombosis: increased levels of fibrinogen, which is involved in the coagulation cascade, were associated with an increased risk of both Alzheimer's disease and vascular dementia. Elevated levels of lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme expressed by leucocytes, were also associated with an increased risk of dementia. Tissue factor and thrombomodulin, which are markers of endothelial activation and damage, were associated with SVD. Von Willebrand factor, a glycoprotein seen after tissue damage, was significantly elevated in people with CADASIL. Endothelial progenitor cells and circulating progenitor cells are involved in the maintenance of the structure and homeostasis of the endothelium; lower levels of endothelial progenitor cells were found in people with CADASIL and SVD, which could be an indicator of vascular dementia, whereas high levels of circulating progenitor cells in CADASIL were associated with cognitive and motor deficits as well neuroimaging changes.
• Circulatory microRNAs (miRNAs): studies have shown that miRNAs (small, single-stranded, non-coding RNA molecules) can be used as biomarkers for various forms of dementia. However, most research has been into their use as biomarkers in Alzheimer's disease. Deregulated miRNAs are associated with target genes related to Alzheimer's disease pathology. Four miRNAs (miR-409-3p, miR-503-3p, miR-486-5p and miR-451a) have been used as biomarkers to differentiate people with SVD from healthy controls and they might therefore be used in VCID.
Discussion
In this literature review, we set out to identify specific biomarkers that can be used in diagnosis to differentiate between vascular dementia and Alzheimer's disease. The seven studies included in the review reported several significant biomarkers that can add to the existing literature and potentially differentiate between the neuropathology of vascular dementia and Alzheimer's disease.
Thyroid dysfunction
Forti et al (Reference Forti, Olivelli and Rietti2012), in their cohort of older adults, found that baseline levels of TSH were not related to the risk of developing MCI or Alzheimer's disease, but high baseline TSH levels were associated with an increased risk of vascular dementia. They suggested the need for further research using larger samples to establish the role of TSH as a predictor of vascular dementia. To buttress the findings by Forti et al, the study by Chen et al (Reference Chen, Liand and Zhang2016) on the correlation between thyroid dysfunction and cognitive impairments induced by SIVD found a close correlation between thyroid status and cognitive dysfunction in SIVD. In their study, serum total triiodothyronine (TT3) and free triiodothyronine (FT3) levels decreased, whereas serum TSH levels increased with the decline in cognitive function. In addition, TT3 levels showed a positive correlation, whereas TSH levels showed a negative correlation, with the MMSE scores. They suggested that thyroid function was associated with cognitive impairments induced by SIVD and that TT3 and TSH levels might also be used as biomarkers for cognitive dysfunction.
Several literature reviews have identified thyroid dysfunction, especially subclinical hypothyroidism, as being associated with cognitive impairment, with high TSH levels increasing the risk of dementia (Davis Reference Davis, Stern and Flashman2003; Kalmijn Reference Kalmijn, Mehta and Pols2000; Elbadawy Reference Elbadawy, Mansour and Abdelrassoul2020). The Forti et al (Reference Forti, Olivelli and Rietti2012) and Chen et al (Reference Chen, Liand and Zhang2016) studies were more specific regarding the type of dementia associated with increased TSH. Forti et al (Reference Forti, Olivelli and Rietti2012) explained that previous population-based studies of baseline TSH and the risk of clinically diagnosed dementia in the elderly are rare and limited to the Alzheimer's disease subtype. They therefore advised that their study should be interpreted with caution, as the negative findings do not exclude the possibility that risk for MCI and Alzheimer's disease might be predicted by TSH variations in the range for overt thyroid disease, and the lack of association between TSH and Alzheimer's disease does not exclude the possible role of TSH in Alzheimer's disease pathogenesis, considering the small number of overt hypothyroidism cases in their sample (n = 149 with MCI; n = 53 with Alzheimer's disease; and n = 28 with vascular dementia). Moreover, the ageing process is associated with alterations in TSH response to physiological stimulation and several non-thyroid illnesses can cause variations in TSH levels (Mariotti Reference Mariotti, Franceschi and Cossarizza1995). Therefore, in older adults, serum TSH may not be a reliable indicator of thyroid dysfunction (Mariotti Reference Mariotti, Franceschi and Cossarizza1995).
Despite the fact that these studies are not conclusive that a high TSH level is directly associated with vascular dementia compared with Alzheimer's disease, a high level of TSH in combination with other associated risk factors for vascular dementia can increase the accuracy of diagnosis of vascular dementia.
Lipoproteins
It has been suggested that an age-related loss of cognitive function might be driven by atherosclerotic effects associated with altered lipid patterns. Studies in the past found a link between higher lipoprotein concentrations and dementia but few have stated the specific relationship between lipoprotein and vascular dementia. The study by Ray et al (Reference Ray, Khemka and Behera2013) demonstrated a significantly higher level of Lp(a) in vascular dementia but not in Alzheimer's disease, which is in accord with the observation that in vascular dementia the pathogenesis is predominantly vascular in nature and lipoprotein potentiates the atherogenic processes in blood vessels through multiple mechanisms (Tsimikas Reference Tsimikas and Hall2012; Berglund Reference Berglund and Ramakrishnan2004). Lipoprotein has not been studied much in the context of Alzheimer's disease or vascular dementia, but the elevated level of Lp(a), which contains both apolipoprotein (Apo) A and ApoB, is considered to be an independent genetic risk factor for cardiovascular diseases (Tsimikas Reference Tsimikas and Hall2012).
Some studies have suggested high lipoprotein levels are associated with an increased risk of vascular dementia, thus interpreting an increased occurrence of cardiovascular diseases, ischaemia and inflammation promoted by Lp(a) as a possible mechanism for cerebrovascular disease and cognitive decline (Urakami Reference Urakami2000). Abnormally high serum levels of Lp(a) in people with cerebrovascular disease and vascular dementia seem to be due to specific increases in low-molecular-weight ApoA isoforms in Lp(a) (Urakami Reference Urakami2000). It may be deduced that high serum levels of Lp(a) could be considered a clinical hallmark to distinguish vascular dementia from Alzheimer's disease.
Homocysteine (Ray 2013)
Ray et al (Reference Ray, Khemka and Behera2013) also found that serum homocysteine is markedly elevated in both Alzheimer's disease and vascular dementia, but to a significantly higher extent in vascular dementia. This is in keeping with previous studies suggesting a strong association of hyperhomocysteinaemia with both diseases (Leblhuber Reference Leblhuber, Walli and Artner-Dworzak2000; Seshadri Reference Seshadri, Beiser and Selhub2002; Ravaglia Reference Ravaglia, Forti and Maioli2005). Hyperhomocysteinaemia is a well-known vascular risk factor and a higher level of serum homocysteine in people with vascular dementia is probably causal, owing to the vascular lesions underlying this disorder (Chacón Reference Chacón, Molero and Pino-Ramírez2009). Ray et al (Reference Ray, Khemka and Behera2013) suggested that the elevated level of serum homocysteine in the Alzheimer's disease group compared with age-matched controls seen in their own and other studies probably contributes to the genesis of vascular pathology in Alzheimer's disease. This view of hyperhomocysteinaemia accounting for the vascular component of Alzheimer's disease pathology has also been proposed by Chacón et al (Reference Chacón, Molero and Pino-Ramírez2009). Although this study suggests significantly higher homocysteine levels in vascular dementia than in Alzheimer's disease, it does not provide clear evidence of homocysteine levels specifically related to vascular dementia. However, considering the high levels of homocysteine found in other vascular aetiologies, such as ischaemic heart disease and cerebrovascular disease (Ganguly Reference Ganguly and Alam2015), it can be related to the vascular risk factors of dementia.
N-terminal prosomatostatin
N-terminal prosomatostatin (NT-proSST) is a risk marker for cardiovascular disease in the general population (Hedbäck Reference Hedbäck, Almgren and Nilsson2016), and Holm et al (Reference Holm, Nagga and Nilson2017) demonstrated that elevated plasma concentrations of NT-proSST predicts the development of vascular dementia in community-dwelling older adults. The increased incidence of dementia has been previously associated with the higher prevalence of major cardiovascular risk factors and a history of cardiovascular disease. However, studies establishing a link between circulating cardiovascular disease biomarkers and the risk of dementia are very sparse. Holm et al (Reference Holm, Nagga and Nilson2017) presented a longitudinal relationship between increased plasma concentrations of NT-proSST, a biomarker associated with incident cardiovascular disease, and the development of vascular dementia in older individuals. They concluded that their results might be of importance for the understanding of pathological mechanisms underlying development of dementia, in particular of the vascular type, in older adults.
Neuroimaging for white matter lesions
Neuropsychological profiles of both Alzheimer's disease and vascular dementia often overlap and white matter lesions are observed in both diseases, making differentiating between vascular dementia and Alzheimer's disease difficult. Functional neuroimaging studies of dementia have largely focused on Alzheimer's disease, making the distinctive characterisation of different forms of dementia challenging. Palesi et al (Reference Palesi, Rinaldis and Vitali2018) carried out statistical analyses of whole-brain DTI data to identify quantitative imaging biomarkers specific to Alzheimer's disease or vascular dementia. The study focused on changes in white matter patterns and found that the parahippocampal tracts were mainly affected in Alzheimer's disease, whereas vascular dementia showed more wide-spread white matter damage associated with involvement of the thalamic radiations. The genu of the corpus callosum was predominantly affected in vascular dementia, whereas the splenium was predominantly affected in Alzheimer's disease, thus revealing the existence of specific patterns of alteration useful in distinguishing between the two conditions. The authors concluded that DTI parameters of these regions could be informative in understanding the pathogenesis of dementia and in supporting its aetiological diagnosis. They suggested that further studies on larger cohorts characterised for brain amyloidosis could confirm and integrate their findings and elucidate the mechanisms of mixed dementia, both of which will be essential in translating these advances into clinical practice. However, DTI scans are not regularly used in clinical practice, limiting their availability.
Causes of vascular cognitive impairment are heterogeneous. In addition to direct cognitive impairment caused by acute stroke, conditions such as chronic vascular insufficiency-related neurodegeneration and neuroinflammation as well as mixed Alzheimer's pathology have been proposed as possible pathophysiological mechanisms for vascular cognitive impairment. Increases in plasma of β-amyloids (Aβ) and tau proteins have been noted in people with Alzheimer's disease. Tang et al (Reference Tang, Yang and Chen2018) investigated the associations of plasma β-amyloids and tau proteins with dementia in people who had had a stroke and found significantly increased plasma levels of Aβ-42 post-stroke, suggesting that plasma Aβ-42 is a potential biomarker for dementia following a stroke. Further studies are needed to clarify the pathophysiological role of Aβ-42 in vascular cognitive impairment before it can be translated into clinical practice.
Emerging biomarkers
In addition to the possible biomarkers listed above, CNS tissue injuries and inflammatory responses have more recently been suggested as biomarkers associated with VCID. However, Cipollini et al (Reference Cipollini, Troili and Giubilei2019) have reported that evidence from the literature is heterogeneous and mostly inconclusive. They evaluated pathophysiological pathways, analysing biomarkers of inflammatory responses, CNS tissue injuries, coagulation and thrombosis, and circulatory microRNAs. They found evidence of inflammatory biomarkers and molecules involved in endothelial dysfunction and the coagulation cascade in VCID, although some of these have also been described as altered in Alzheimer's disease. They concluded that evidence on peripheral biomarkers for VCID is still weak and that large-scale prospective studies are needed to translate their findings into clinical practice in order to establish different combinations of biomarkers to use for differential diagnosis among types of dementia.
Limitations
One of the limitations of our review is that the identified biomarkers, particularly the neuroimaging studies, are reported to be inconclusive owing to apparent overlap with Alzheimer's disease. Moreover, the sample size supporting the evidence on the blood biomarkers mentioned above is small. Therefore, a more robust review with a larger sample is required before any diagnostic and clinical conclusion can be drawn.
Clinical and research implications
Diagnosis of dementia is mainly based on history from the patient and collateral history from the nearest relative. If there is difficulty in establishing the diagnosis, radiological investigations such as computed tomography (CT) or magnetic resonance imaging (MRI) may be required for confirmation. However, sometimes, it can be challenging to differentiate between Alzheimer's disease and vascular dementia owing to the similarity in risk factors, clinical presentation and radiological findings. Therefore, based on this review, in addition to the clinical presentation, we would like to recommend the following specific biomarkers, which can help to establish the diagnosis of vascular dementia:
• high level of TSH
• high level of Lp(a)
• high level of homocysteine
• high level of N-terminal prosomatostatin.
These four biomarkers are measured in blood tests that are easily accessible and cost-effective. These biomarkers have been identified from cohort and case–control studies, which are considered to be the best observational studies to determine temporal association between exposure and disease (Song Reference Song and Chung2010). Moreover, our literature search has found that these biomarkers have shown better statistical significance compared with the neuroimaging studies despite the small sample size. Therefore, we postulate that a study with a larger sample could be the way forward in identifying specific biomarkers for vascular dementia focusing on these four practically feasible biomarkers.
Data availability
No new data were created or analysed in this study.
Author contributions
Q.J.: conception and design of the work, literature search, analysis and interpretation, drafting the article, critical revision of the article and final approval of the version to be published. A.A.: analysis and interpretation, drafting discussion section of the article and critical revision of the article. A.U.: literature search, analysis and interpretation, drafting introduction and results section of the article.
Funding
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Declaration of interest
None.
MCQs
Select the single best option for each question stem
1 Which of the following is not a genetic cause specific to Alzheimer's dementia?
a amyloid precursor protein
b presenilin-1 gene
c presenilin-2 gene
d apolipoprotein E
e CADASIL.
2 The anti-dementia drug recommended in vascular dementia is:
a galantamine
b memantine
c rivastigmine
d donepezil
e none of the above.
3 Somatostatin is also called:
a N-terminal prosomatostatin
b somatotropin
c prosomatostatin
d growth hormone-inhibitory hormone
e growth hormone-releasing hormone.
4 Patterns of white matter changes specific to vascular dementia predominantly occur in the:
a genu of the corpus callosum
b splenium of the corpus callosum
c parahippocampal tracts
d caudate nucleus
e cerebellum.
5 Which of the following is not a biomarker specific for vascular dementia?
a high level of Lp(a)
b high level of homocysteine
c high level of TSH
d low free thyroxine (FT4)
e high level of N-terminal prosomatostatin.
MCQ answers
1 e 2 e 3 d 4 a 5 c
eLetters
No eLetters have been published for this article.