Is Frailty a Prodromal Stage of Vascular Dementia?
Is Frailty a Prodromal Stage of Vascular Dementia?
To the knowledge of the authors, this study is the first to examine frailty as a risk factor for VaD. Even though impaired cognitive function has been associated with frailty in elderly persons, little research has been aimed at specific forms of dementia. Regarding AD, the results of the present study are consistent with previous studies, even though another study reported contrasting results. Despite being biologically plausible, an association between frailty and VaD has never been reported. A previous study showed that frailty was a risk factor for the development of incident cardiovascular disease (e.g., coronary artery disease), but VaD was not one of the outcomes. The current study shows that individuals classified as frail have a higher risk of incident VaD after 7 years of follow-up. The relationship was independent of all conventional dementia and cardiovascular risk factors. This relationship is remarkable, because the risk of VaD may have been underestimated because, as recommended in Fried's frailty definition, potentially frail participants with prior stroke were excluded from analyses.
Frailty and VaD are complex entities, and multiple factors may explain their relationship. Alterations in hematological, inflammatory, and endocrine–metabolic systems have been identified in frail persons and appear to be at the root of this biological syndrome and its association with multiple cardiovascular complications, including higher mortality and incident VaD. Particular attention has been paid to the inflammatory and hemostatic abnormalities that have been consistently described in the pathogenesis of frailty and VaD, so a common path between these two phenomena is possible. Atherosclerosis could be an intermediate factor because inflammatory and hemostatic markers have been associated with its development and with arterial disease, including brain infarcts. Brain infarct-like lesions on magnetic resonance imaging have also been reported in frail elderly individuals. Atherosclerosis may result in cerebral macro- or microangiopathy that disrupts the integrity of frontal-subcortical circuits. Both types of lesions interfere with the delivery of blood to the brain and contribute to the development of cognitive impairment and dementia. Nevertheless, atherosclerosis plays a major role in the loss of muscle mass that occurs with aging (sarcopenia), a hallmark of the frailty phenotype. Therefore, atherosclerosis could be a common biological pathway that may explain why frailty and cardiovascular diseases are clinically interrelated. This suggests that there may be a pathophysiological link between aging, activation of the blood coagulation and fibrinolytic systems, chronic inflammation, and occurrence of frailty and VaD. Thus, the relationship between frailty and VaD may be the result of a catabolic state with systemic manifestation, although whether these pathways are merely the result of an age-associated dysregulation pathway or activated by an underlying disease process remains to be determined. Nonetheless, previous reports of an association between subclinical cerebrovascular disease and abnormal physical performance, along with the results of the present study, suggest that frailty may be located on the continuum between normal aging and VaD and could be considered to be a prodromal stage of vascular dementia. This proposal should be a working hypothesis for future research.
The lack of cerebral magnetic resonance imaging for all participants could limit the accuracy of the diagnosis of VaD and constitutes the principal limitation of the current study, but in spite of this limitation, in addition to the sample size and the opportunity to adjust analyses for an extensive number of potential confounders, an important strength of this analysis is the use of a prospective study design along with the identification of incident cases of VaD that occurred subsequently.
With the aging of the population and its burden of vascular diseases, an increase in the number of older adults with VaD is expected. The current study shows that frailty is an independent risk factor for incident VaD. More research is needed to determine whether frailty is a herald of VaD. To better understand the relationship between frailty and VaD is of major clinical importance to develop multidimensional preventive measures against cardiovascular risk factors (e.g., hypoglycemic or antihypertensive therapy) and to prevent vascular dementia.
Discussion
To the knowledge of the authors, this study is the first to examine frailty as a risk factor for VaD. Even though impaired cognitive function has been associated with frailty in elderly persons, little research has been aimed at specific forms of dementia. Regarding AD, the results of the present study are consistent with previous studies, even though another study reported contrasting results. Despite being biologically plausible, an association between frailty and VaD has never been reported. A previous study showed that frailty was a risk factor for the development of incident cardiovascular disease (e.g., coronary artery disease), but VaD was not one of the outcomes. The current study shows that individuals classified as frail have a higher risk of incident VaD after 7 years of follow-up. The relationship was independent of all conventional dementia and cardiovascular risk factors. This relationship is remarkable, because the risk of VaD may have been underestimated because, as recommended in Fried's frailty definition, potentially frail participants with prior stroke were excluded from analyses.
Frailty and VaD are complex entities, and multiple factors may explain their relationship. Alterations in hematological, inflammatory, and endocrine–metabolic systems have been identified in frail persons and appear to be at the root of this biological syndrome and its association with multiple cardiovascular complications, including higher mortality and incident VaD. Particular attention has been paid to the inflammatory and hemostatic abnormalities that have been consistently described in the pathogenesis of frailty and VaD, so a common path between these two phenomena is possible. Atherosclerosis could be an intermediate factor because inflammatory and hemostatic markers have been associated with its development and with arterial disease, including brain infarcts. Brain infarct-like lesions on magnetic resonance imaging have also been reported in frail elderly individuals. Atherosclerosis may result in cerebral macro- or microangiopathy that disrupts the integrity of frontal-subcortical circuits. Both types of lesions interfere with the delivery of blood to the brain and contribute to the development of cognitive impairment and dementia. Nevertheless, atherosclerosis plays a major role in the loss of muscle mass that occurs with aging (sarcopenia), a hallmark of the frailty phenotype. Therefore, atherosclerosis could be a common biological pathway that may explain why frailty and cardiovascular diseases are clinically interrelated. This suggests that there may be a pathophysiological link between aging, activation of the blood coagulation and fibrinolytic systems, chronic inflammation, and occurrence of frailty and VaD. Thus, the relationship between frailty and VaD may be the result of a catabolic state with systemic manifestation, although whether these pathways are merely the result of an age-associated dysregulation pathway or activated by an underlying disease process remains to be determined. Nonetheless, previous reports of an association between subclinical cerebrovascular disease and abnormal physical performance, along with the results of the present study, suggest that frailty may be located on the continuum between normal aging and VaD and could be considered to be a prodromal stage of vascular dementia. This proposal should be a working hypothesis for future research.
The lack of cerebral magnetic resonance imaging for all participants could limit the accuracy of the diagnosis of VaD and constitutes the principal limitation of the current study, but in spite of this limitation, in addition to the sample size and the opportunity to adjust analyses for an extensive number of potential confounders, an important strength of this analysis is the use of a prospective study design along with the identification of incident cases of VaD that occurred subsequently.
With the aging of the population and its burden of vascular diseases, an increase in the number of older adults with VaD is expected. The current study shows that frailty is an independent risk factor for incident VaD. More research is needed to determine whether frailty is a herald of VaD. To better understand the relationship between frailty and VaD is of major clinical importance to develop multidimensional preventive measures against cardiovascular risk factors (e.g., hypoglycemic or antihypertensive therapy) and to prevent vascular dementia.
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