Vascular Disease and Cognitive Impairment

Vascular disease seems to be important in cognitive impairment and dementia in the elderly. The entities implicated comprise various vascular risk factors and cerebrovascular disease including large cortical infarcts, single strategically-placed or multiple small infarcts, cerebral hemorrhage, cortical changes due to hypoperfusion (eg, hippocampal sclerosis, ischemic-anoxic damage, cortical laminar sclerosis), white matter changes, and a variety of vasculopathies (eg, lipohyalinosis, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral amyloid angiopathy). The traditional view is that the two most common causes of dementia are vascular dementia and Alzheimer's disease. While there is general agreement that vascular dementia is caused by cerebrovascular disease and its risk factors, their contribution to what we define clinically as Alzheimer's disease, theoretically characterized by the deposition of amyloid beta, is less clear. More recently, the concept of vascular cognitive impairment has been coined as an umbrella term that encompasses all instances of cognitive impairment due to vascular risk factors and cerebrovascular disease, including vascular dementia, and Alzheimer’s disease with a vascular contribution.¹ As our understanding grows, new questions arise: does cerebrovascular disease, including white matter lesions and silent infarcts, lead to a specific pattern of cognitive impairment, and if so, how? Does cerebrovascular disease lead to a dementia syndrome indistinguishable from Alzheimer's disease? What are the molecular mechanisms underlying the associations between the various vascular risk factors and cognitive impairment? Do changes in the microvasculature lead to the development of Alzheimer pathology?

Leys et al.² summarized previous studies that explored the impact of clinical stroke on the risk of post-stroke dementia (PSD). Accordingly, stroke increases the risk of dementia, with a prevalence ranging from 13.6 to 32% within 3 months to 1 year after stroke, and after stroke incidence rates of new onset dementia range from 24% within 3 years to 33.3% within 5 years.² The impact of stroke on dementia risk seems to be independent of pre-stroke cognitive function.³ Mechanisms through which stroke could lead to cognitive impairment include destruction of brain parenchyma with atrophy,^{4, 5} damage in strategic locations that lead to amnestic syndromes, such as thalamic strokes,⁶ or an increase in the deposition of amyloid β protein. Stroke could also decrease the threshold of Alzheimer's disease pathology for the manifestation of dementia⁷ implying that stroke and Alzheimer's disease have an additive effect on dementia. Recent evidence suggests that overexpression of p25 and cyclin dependent kinase 5(cdk5) lead to increased levels of BACE1 mRNA and protein, which in turn is correlated with amyloidogenic processing.⁸ Increased production of p25 and enhancement of cdk5 activity has been shown to occur in rodent models of ischemia and hypoxia due to hypoperfusion.⁹

The effect of silent infarcts and CT- and MRI-detected white matter changes on cognition is more controversial. These vascular lesions are seen in healthy individuals with intact cognitive function, and it is questioned whether they play a role in cognitive decline in the elderly.¹⁰ On the other hand, the results of many clinical, epidemiological, and pathological studies suggest that people with these types of white matter changes and silent infarcts are more likely to develop cognitive impairment and dementia,^{11, 12} and that the extent and location of the white matter changes determine the neuropsychological profile.^13-15 The mechanisms through which these small-vessel pathologies lead to cognitive decline are unclear, but one putative mechanism is the disconnection of cortical-subcortical -possibly cholinergic- pathways.^{16, 17} The thalamus is a key component in these pathways, not only of frontal-subcortical circuits but also of temporo-limbic circuits important for memory storage and retrieval. Thalamic changes due to local lesions or subcortical diaschisis lead to lower performance on multiple cognitive behaviors associated with frontal and temporal lobe function.^{13, 18}

Vascular risk factors including diabetes,^19-22 insulin resistance,²³ hypertension,²⁴ heart disease,²⁵ smoking,^{26, 27} and obesity,²⁸ are each independently associated with an increased risk of cognitive impairment and dementia and are frequent in the elderly. The associations between vascular risk factors and dementia may depend on the stage of the lifespan in which they are examined. For example, high blood pressure and obesity in middle-age have been found as risk factors for dementia in old age.^{29, 30} In old age, however, these associations seem to be attenuated or inverse for reasons that are uncertain.^31-33

Although these vascular factors may increase dementia risk through cerebral small or large-vessel disease, they may also act through non-cerebrovascular mechanisms. Diabetes can directly affect amyloid accumulation in the brain.³⁴ Hyperinsulinemia, which either precedes or accompanies diabetes,³⁵ disrupts brain amyloid β clearance by competing for the insulin degrading enzyme.³⁶ In addition receptors for advanced glycosilation products, which have been identified immunohistochemically in senile plaques and neurofibrillary tangles have been shown to be specific cell surface receptors for amyloid β, and glycation of amyloid β enhances its aggregation in vitro.³⁷ Hypertension is also associated with increased vascular permeability with protein extravasation,³⁸ leading in turn to chronic edema and tissue necrosis.³⁸ Dysfunction of the blood-brain barrier can induce penetration of substances from the blood into the brain tissue, where they may interact with neuronal or synaptic function or influence accumulation of amyloid β leading to cognitive impairment.³⁹ Recent evidence also indicates that in obese persons adipose tissue is active producing adipokines critical in metabolism, and cytokines important in inflammation Adiponectin,⁴⁰ leptin,⁴¹ resistin,⁴¹ tumor necrosis factor-α and interleukin-6, are also produced and correlate with insulin resistance and hyperinsulinemia. Whether peripherally secreted adipokines and cytokines are directly related to Alzheimer's disease or whether they are only markers of insulin resistance and hyperinsulinemia is unclear.

It is possible that vascular risk factors and cerebrovascular disease are not causal but rather concomitant diseases frequent in the elderly with dementia. It is important to clarify whether they in fact affect cognition in old age, and -if yes- how. While the incidence of cardiovascular disease and stroke is decreasing due to better preventive and treatment measures (e.g. treatment of hypertension and dyslipidemia, aspirin), their absolute burden is increasing because of increasing life span. In contrast, obesity, insulin resistance, and type II diabetes are increasing in frequency in the developed and developing world. If the products of adipose tissue, high insulin and glucose levels, and their products have a direct effect on cognitive impairment in addition to those mediated by cerebrovascular disease, the public health impact could be devastating. We estimated that in New York City the presence of diabetes or hyperinsulinemia in elderly people could account for 39% of cases of Alzheimer's disease.⁴² The implication of vascular disease as a causal factor in dementia is that a large proportion of dementia cases could be preventable or treatable. There have been no investigations examining how strategies used to treat cardio- and cerebrovascular disorder might also affect cognition.

Lifestyle intervention and drugs like metformin can decrease hyperinsulinemia and the risk of diabetes, and it is possible that these interventions might also decrease the risk of cognitive impairment. Rosiglitazone treatment of diabetes shows promise in the treatment of Alzheimer's disease,⁴³ although concerns about its safety may limit this drug's usefulness.⁴⁴ The four randomized, placebo-controlled studies that investigated the effects of antihypertensive agents on the incidence of dementia (Systolic Hypertension in Europe (Syst-Eur) study, Study on Cognition and Prognosis in the Elderly (SCOPE), Systolic Hypertension in the Elderly Program (SHEP), and Perindopril Protection Against Recurrent Stroke Study (PROGRESS)) produced inconsistent results. In the Syst-Eur study^{45, 46} active treatment with nitrendipine, enalapril, and/or hydrochlorothiazide reduced the rate of dementia by 50% compared with placebo (p=0.05). In the PROGRESS study⁴⁷ treatment with perindopril and indapamide was associated with reduced cognitive decline (risk ratio 19%, p=0.01), but the SCOPE⁴⁸ (candesartan or hydrochlorothiazide vs placebo) and SHEP trial (chlorthalidone, atenolol, or reserpine vs placebo) found no significant difference between the active treatment and placebo on the incidence of dementia. In the SHEP trial, however, this may have been caused by differential drop out of study participants.⁴⁹ Knowing that the association between blood pressure and cognitive impairment seems to depend on the age of the patient and the stage of the disease process as described above, it seems reasonable that the findings of hypertension treatment trials differ between study populations with different age distributions and pathology burdens. Also, it has been suggested that the effect of antihypertensive medication on cognition differs between drug classes with possibly the strongest effect for calcium channel blockers and ACE inhibitors. The effects of drugs currently used to treat Alzheimer's disease are modest. A meta-analysis concluded that the benefits were of uncertain clinical meaningfulness with any of the approved cholinesterase inhibitors or memantine.⁵⁰ Despite reasons to believe that cholinesterase inhibitors might benefit patients with vascular dementia,⁵¹ previous studies showed limited improvement on cholinesterase inhibitors.

A crucial next step in research of vascular cognitive impairment is the elucidation of the molecular pathways linking the individual vascular risk factors and cerebrovascular changes to cognitive impairment. Understanding of the specific pathways linking each of these factors to cognitive decline will help identify specific targets for treatment, and may point to appropriate treatment strategies. The exponential progress in genomics, proteomics and functional and structural brain imaging made in the past few years provides the potential to achieve this goal.