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Volume 45, 2013 - Issue 3
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Review Article

Geriatric syndromes—vascular disorders?

Timo E. Strandberg Department of Medicine, Geriatric Clinic, University of Helsinki, and Helsinki University Hospital, Finland; Institute of Health Sciences, University of Oulu, and Oulu University Hospital, and Health Center, Oulu, FinlandCorrespondencetimo.strandberg@oulu.fi
,
Kaisu H. Pitkälä Helsinki University Hospital, Unit of General Practice, Helsinki, Finland
,
Reijo S. Tilvis Department of Medicine, Geriatric Clinic, University of Helsinki, and Helsinki University Hospital, Finland
,
Desmond O’Neill Centre for Aging, Neuroscience and the Humanities, Trinity College Dublin, Ireland
&
Timo J. Erkinjuntti Department of Neurological Sciences, University of Helsinki and Department of Neurology, Helsinki University Central Hospital, Finland
Pages 265-273
Received 25 Mar 2012
Accepted 13 Jul 2012
Published online: 16 Oct 2012

Review Article

Geriatric syndromes—vascular disorders?

Abstract

The term geriatric syndrome is used to characterize multifactorial clinical conditions among older people which are not subsumed readily into disease entities, but which nevertheless predispose older people to disability and death. Commonly included are frailty, dementia, delirium, incontinence, falls, and dizziness. Geriatric syndromes are common among older people: in a recent survey, 50% of those aged more than 65 had one or more of these conditions. Better methods for prevention and treatment are needed, but current strategies have lacked a coherent conceptual and diagnostic framework. Prevention and interventions need to be targeted at earlier ages, with geriatrics expertise needed in the definition and operationalization of these complex entities. In this review we consolidate evidence that vascular disorders, including vascular ageing and vascular diseases, are key etiological factors of geriatric syndromes. Identifying this vascular dimension would offer opportunities for more efficient preventive strategies and mandates earlier intervention, especially for women, among whom vascular disease is often expressed more insidiously than among men. This would entail a sensitization of the health care system to the systematic detection of the syndromes, which are currently underdiagnosed. Further disentangling of the mechanisms of vascular ageing may offer therapies for vascular diseases and geriatric syndromes alike.

Key messages

  • The term geriatric syndrome has been used to characterize multifactorial and common conditions among older people predisposing them to disability and death.

  • Vascular ageing and vascular diseases are likely to be key upstream factors in the development of geriatric syndromes.

  • Therefore, geriatric syndromes could be considered an under-recognized but important consequence of cardiovascular risk.

Introduction

How to find unity in diversity, and how to find a permanent principle in the midst of flux. (1)

‘Geriatric syndromes’, ‘geriatric conditions’, and ‘geriatric giants’ are terms used interchangeably to characterize multifactorial clinical conditions which occur commonly among older people, but are not readily subsumed into single disease entities or categories (Table I) (2–4). These conditions are associated with increased levels of disability, nursing home placement, and death, and therefore the human, economic, and societal impact of these conditions is enormous in a world with increasing populations of older people. In a recent epidemiological survey in the US almost 50% of adults aged 65 years or over had one or more geriatric conditions (5).

Table I. Clinical conditions often described as geriatric syndromes (in alphabetical order) due to their heterogeneous background, multiple etiology, and common prevalence among older people.

Despite their prevalence, the conceptualization of these geriatric conditions is under-developed and the nomenclature often ill-defined and overlapping. In this review, we have chosen to use the term ‘geriatric syndromes’, a term elaborated during the first decade of the twenty-first century (cf. 2–4). The concept of ‘syndrome’ in this context differs from the conventional usage of the term ‘syndrome’ mainly due to multiple causative factors and numerous pathological interactions between patient-specific impairments and situation-specific stressors, as illustrated in the interactive concentric model of geriatric syndromes (Figure 1). There is also considerable heterogeneity in the clinical course of the geriatric syndromes, even though the final manifestation—such as gait instability or cognitive impairment—may be defined and measurable. As geriatric syndromes are common and related to adverse outcomes, there is increasing need for their detection, early prevention, and treatment.

Figure 1. Differences in pathological pathways in illness, syndrome, and geriatric syndrome. Modified scheme according to references (2–4).

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In this review we will consider evidence that vascular factors, consisting of vascular ageing intertwining with various clinical and subclinical cardiovascular diseases (6–10) and increasingly fueled by diabetes (11), are an important source for geriatric syndromes—‘simplicity on the other side of complexity’. In the vascular disease pathology, atherosclerosis and stiffening of large vessels, arteriosclerosis, and small vessel dysfunction are the cardinal, underlying causes for disturbances in end organs, such as the brain (12–14). Recognizing the vascular dimension of geriatric syndromes would give new impetus to their prevention and treatment.

Vascular foundations

An important truism is that in order to develop a ‘geriatric syndrome’ one has to be old. All patients with these syndromes are selected: they have avoided, postponed, or survived serious complications of predisposing illnesses earlier in life. Selection may explain why the majority of patients with geriatric syndromes are women, although also gender-specific factors may contribute (vide infra). But selection ensures that all patients with geriatric syndromes have been exposed to vascular ageing, consequences of which form an ideal substrate for vascular disease processes to develop (Figure 2) (6–10). These broad, initial molecular and pathological phenomena include mitochondrial dysfunction, oxidative stress, nitric oxide (NO) instability, endothelial dysfunction, vascular calcification, glycosylation, and alterations in elastin–collagen balance. They further predispose to intimal atherosclerosis and inflammation in large and medium-sized arteries (large-vessel disease) and promote stiffening of central, proximal arteries such as aorta and its large branches (12). Similar factors promote small-vessel disease (15). The ensuing increase in systolic blood pressure and extended pulsatile forces fuel further structural and functional damage in small arteries and arterioles. Contributory factors to small-vessel disease include impaired autoregulation, decrease and fluctuation of arterial flow, endothelial dysfunction, perivascular changes, decreased vascular density, apoptosis, and reduced angiogenesis. Small vessels are then predisposed to occlusions leading to hypoperfusion in end organs such as the brain, heart, kidney, and retina, but also in muscle and bone.

Figure 2. Interplay between vascular ageing, vascular dysfunction, and vascular events. Stiffening of central arteries leads to systolic hypertension and stress for small arteries.

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Because every cell of every organ is dependent on proper oxygenation and nutrient supply maintained by adequate blood circulation, systemic large- and small-vessel disease intertwining with vascular ageing could be essential pathophysiological links also to the geriatric syndromes (16). The molecular research connecting mechanisms of ageing and vascular function is rapidly evolving, but also many questions and discrepancies exist. Details of this expanding field are beyond the scope of the present review, and the reader is referred to well-referenced overviews on these fascinating topics (17–21). In the following review of vascular foundations of geriatric syndromes we still take a more ‘conventional’ perspective and will first shortly discuss large-vessel disease from a life-course and geriatric viewpoint, and in the case of small-vessel disease focus on the vascular burden on the brain.

Large-vessel disease

Large-vessel atherosclerosis is associated with symptomatic cardiovascular illness, such as myocardial infarction, ischemic stroke, or claudication (22). Large- and small-vessel disease- related pathology is also recognized as an important independent risk factor for vascular cognitive impairment (13) and Alzheimer's disease (10,23,24), opening new avenues for prevention. But recognition of vascular diseases as an etiologic factor for geriatric syndromes would have an even wider impact in ageing societies, with the attendant possibility that these malign outcomes could be prevented, postponed, or attenuated through early prevention and treatment of recognized vascular risk factors such as smoking, dyslipidemia, arterial hypertension, obesity, and diabetes (25) along with established non-pharmacologic (diet, physical activity) and pharmacologic means (especially statins and drugs affecting the renin– angiotensin–aldosterone (RAA) system).

The link between vascular risk and geriatric syndromes is, however, often complicated and not straightforward from cause to effect, as for example between hypertension and stroke. In particular, reverse epidemiology distorts the relationship in cross-sectional or short-term studies in older people because evolving pathology such as cognitive decline may modify vascular risk factors long before the diagnosis of Alzheimer's disease is established. This can perplex physicians when studies of older people show that obesity, for example, is paradoxically associated with better prognosis (26). This may especially apply to older women who on average have less reserve than men (27), and consequently are more prone to frailty and its consequences. In women, a further contributing factor is that they are less vulnerable than men to the life-threatening, acute thrombotic and obstructive complications of atherosclerosis, such as epicardial disease in premenopause (28). Surviving women are thus prone to complications from subclinical large-vessel atherosclerosis, small-vessel disease, and hypoperfusion. Long-term follow-up studies in women support this notion by showing a high frequency of subclinical atherosclerosis (29) and the effect of premenopausal risk factors on vascular disease in postmenopause (30).

At present, vascular risk among asymptomatic persons is assessed using classifications based on prospective studies, such as in the Framingham and Systematic COronary Risk Evaluation (SCORE) equations (31,32). These charts emphasize the relatively short-term (5–10-year) risk of symptomatic, traditionally defined, cardiovascular complications which are less frequent among women than men below the age of 65 years. Thus, women are generally considered to be protected from ‘male’ diseases, such as myocardial infarction, and preventive measures are neglected until menopause or even further. Accepting geriatric syndromes as a clinically meaningful vascular end-point would lead to important change in the assessment of lifetime ‘vascular risks’ in women.

Two vascular brains

Cerebrovascular disease may involve both large (including cardiac embolism) and small vessels, and in this context we can conceptualize ‘two brains’: the large-vessel disease, ‘stroke brain’; and the small-vessel disease, ‘network brain’. The traditional focus on the former is recently broadening to recognize the vital role of the latter, more networked, brain functions. Cognition may be affected by both critical strokes and small-vessel disease (lacunar infarcts and ischemic white matter lesions) (10,33).

Small arterial networks include 1) the long perforators, which are end arteries irrigating the deep white matter areas in a watershed fashion; and 2) the deep perforators irrigating the deep gray matter and adjacent white matter structures. Small arterial disease includes arteriolosclerosis (concentric hyaline thickening of the vessel wall) and lipohyalinosis (fibrinoid necrosis), which both affect arterioles and small arteries (34). Atherosclerosis similar to large-vessel disease may also affect small arteries. In long perforators arteriolosclerosis and lipohyalinosis lead to ischemic white matter lesions and small lacunar infarcts, which often are asymptomatic, silent infarcts (15,35). In the deep perforators, small arterial disease leads to large lacunar infarcts and traditional lacunar stroke syndromes.

The advent of new imaging technologies, especially magnetic resonance imaging (MRI), has led to an ‘epidemic’ of white matter lesions, which may be identified in most older people (36,37). Currently, extensive white matter lesions are recognized as a surrogate of small-vessel disease (15,38,39). When confluent and extensive, they affect the prefrontal-subcortical circuits, giving rise to the dysexecutive syndrome, including impairments in psycho-motor speed, attention, goal formulation, initiation, planning, and organizing (40,41). Mood is also commonly affected (42). In a clinical context this is seen not only as a higher risk of stroke recurrence and death (43,44), but also as the cognitive decline and dementia syndrome (45), disability (39), depression (42), gait impairment, and instability (46,47).

Vascular contribution to various geriatric syndromes

Frailty

Because frailty is a broader concept—it can be viewed as ‘a syndrome of geriatric syndromes’—it is presented first of the geriatric syndromes. As a relatively new concept (48), a strict consensus of its definition is still lacking (49–51), and both a phenotype definition (vide infra) and an index method (sum of existing disabilities and diseases whatever their cause) have been used to define it (50). As a phenotype, frailty is associated with high vulnerability for disability, loss of autonomy, falls, and increased mortality risk (52). Phenotypic frailty is derived from multiple declines of molecular, cellular, and physiological systems in the aged body and is characterized clinically by anorexia, sarcopenia, osteoporosis, fatigue, falls, and poor physical health status. The five Fried criteria (48), or their modifications, have been frequently used in epidemiological studies: unintentional weight loss, exhaustion, low energy expenditure, slowness, and weakness; meeting three or more criteria denotes frailty. A large recent survey demonstrated that phenotypic frailty is common among older Europeans (53). Clinical use of the Fried criteria is not always straightforward, and, for example, the definition of weight loss may be difficult (54); the criteria have also been criticized for lack of a cognitive dimension (50).

Much of the research on phenotypic frailty so far has concentrated on definition and characterization of the syndrome, with much less devoted to its etiology (51). The limited existing data suggest that even subclinical cardiovascular disease is associated with development of phenotypic frailty (55)—and a recent study showed that cardiovascular risk factors and overweight in healthy midlife predicted frailty in old age, 26 years later (56). In that longitudinal study the association between former cardiovascular risk and phenotypic frailty was independent of co-morbidity in old age, but frailty and cardiovascular disease can coexist (57) also due to a bidirectional relationship.

An important clinical characteristic in phenotypic frailty is sarcopenia (58), a form of muscle atrophy to which diffuse ischemia in old age may contribute. As a whole, skeletal muscle contains a substantial part of the small-vessel network in the body, its microcirculation is also the major vascular resistance network (59), and an effective capacity to increase blood flow is essential for proper muscle function. Small-vessel disease and low-grade inflammation may disturb endothelial function, impair blood flow, and exacerbate sarcopenia. Furthermore, sarcopenia has been associated with atherosclerosis and its risk factors, including arterial stiffness (60,61). For prevention of frailty and sarcopenia, non-pharmacologic means (diet, protein, and physical activity) are the primary counter-measures, but it is interesting that a cardiovascular drug (an ACE inhibitor) may be of value in the short term (62).

Cognitive decline and dementia syndrome

The traditional spectrum of dementias included ‘pure’ Alzheimer's disease (AD) at one end, and the ‘multi-infarct, multi-stroke dementia’ in the other. This simplistic view missed the important interactions between Alzheimer and vascular pathologies, both common among older people. In addition, the clinical, stroke-driven ‘multi-infarct dementia’ prototype underplayed the role of small-vessel disease, the cardinal cause of vascular cognitive impairment (10,13,63).

According to current views, the three main pathologies associated with cognitive decline and dementia in old age are: 1) Alzheimer's disease (amyloid and tau-protein related), 2) small- and large-vessel vascular disease, and 3) Lewy-body disease (LBD) (alpha-synuclein protein-related). In old age, however, the three main pathologies frequently coexist. The important interactions between degenerative (both AD and LBD) and vascular pathologies (23) are highlighted by the findings that vascular risk factors and small-vessel disease are independent risk and predisposing factors for the clinical presentation of Alzheimer's disease (10,64).

Although the clinical presentations may be very heterogeneous, the two common clinical presentations of cognitive decline are the amnestic and dysexecutive phenotypes. The amnestic phenotype is related to Alzheimer-type medial temporal lobe pathology (65), and the dysexecutive one to small-vessel disease-type (deep white and gray matter) pathology where arterial hypoperfusion and macro- and microbleeds interact (10,15,33,63). Also large-vessel atherosclerosis, and possibly venous changes, may contribute to Alzheimer's disease (66).

Delirium

Delirium is a clinical syndrome characterized by an acute decline in selective attention leading to cognitive and behavioral impairments (67). It is a common syndrome among hospitalized older patients and has a substantial economic impact, comparable to falls and diabetes (68). The immediate somatic precipitants may be multiple, from infections to brain disease such as stroke (69,70). Many chronic conditions predispose to delirium, but it is particularly interrelated with frailty, cognitive decline, including neurotransmitter deficiency, and small-vessel-related executive network insufficiency. Cardiovascular risk factors and diseases have been associated with delirium, although not clearly independent of cognitive decline (71).

More direct proof of vascular etiology was demonstrated in a study where vascular risk factors were independently related to several-fold increased risk for delirium after non-cardiac surgery in patients without gross cognitive impairment (72). Post-stroke delirium is frequent and relates to dementia syndrome in the short term (70). Whether treatment of risk factors would reduce incidence of delirium in old age is difficult to demonstrate in epidemiological studies where reverse causation (cardiovascular medications are a marker of more severe vascular disease) may be at play.

Depression, apathy, self-neglect

In all age groups, depression is a multi-faceted syndrome with multiple etiologies. Causes may be clearly exogenous—negative life events—psycho-social stressors, or endogenous, possibly genetic. In old age, depression may be secondary to stroke or may accompany the early stages of dementia (73). There is also a bidirectional relationship: vascular disease induces depression, and depression worsens vascular disease (74). But what actually is ‘depression’ in old age, over 80 years of age? Is it simply one presentation of the dysexecutive phenotype (vide supra)? Post-stroke depression and dysexecutive syndrome relate to poor survival (73). In a study about the relationships between depression, resilience, apathy, and disability (75), depression was most highly correlated with apathy among those over 80 years of age. Apathy, but not depression, was associated with vascular disease in the Leiden 85-plus Study (76). Furthermore, apathy is a major component of self-neglect, another geriatric syndrome, which is characterized by inattention to health and hygiene issues and has relationships with both depression and cognitive decline (77). Because of this variable and circular background and relationships as well as vague definitions, it may be difficult to confirm simple pathways.

The hypothesis of ‘vascular depression’ has been proposed to connect white matter lesions and other cerebrovascular lesions with mood, and to be a subtype of late-life depression (78,79). This hypothesis is not unequivocal, however, although moderately supported by the results of a systematic review of white matter lesions in late-life depression (80). From the clinical viewpoint, important characteristics of vascular depression are impairment in executive function and resistance to common antidepressant therapy (79).

It is evident that cardiovascular disease may precipitate depression, but vascular disorders can also be etiological in affective disorders, although studies on this are few (81), and long-term follow-up is necessary to differentiate reactive and secondary depression. A birth cohort study implicated low birth weight as a possible underlying factor for both symptomatic cardiovascular disease and depression (82). Greater cardiovascular risk without manifest disease in midlife was associated not only with worse survival but also with more depressive symptoms in old age when followed up 29 years later (83).

Gait disturbance, falls, and fractures

Peripheral arterial disease is associated with several features disturbing lower-extremity functioning. These include pathological changes in calf muscles (atrophy, fat infiltration) and impaired nerve function (84). But as in the case-study outlined above, gait disturbances that cannot be explained by focal neurological signs are common among older people, and are most commonly due to vascular higher-level gait disorders (85), which are often neither diagnosed nor treated, despite evidence of effective treatment (86). The vascular associations with gait disorder are further supported by a relationship between white matter lesions and imbalance (47). In addition, such higher-level gait disorders are often associated with mild cognitive impairment (87) and dementia (88), adding to the risk of falls.

Falls and consequent fractures are important and costly geriatric syndromes which are intimately connected with frailty and impaired leg function due to both lower- and higher-level dysfunction. It is estimated that nearly one-third of individuals over 65 years old fall at least once yearly (89). Fear of falling with consequent limitations of activity may further aggravate frailty. Several short-term risk factors for falls in older people have been identified, such as disorders of balance, muscle weakness, and poor vision (89). Orthostatic hypotension, common in older people (90), also contributes to the tendency to fall, and has strong associations with vascular disease (91).

Falls prevention programs have led to varying benefits, are generally multifactorial, and should take into account the frailty often associated with the syndrome. However, a meta-analysis showed that the mean effect of current fall prevention strategies in old age is modest even if clinically meaningful (92). It would be important to investigate whether a greater preventive yield would arise from tackling the biological etiological factors at an earlier stage in life. Cerebral white matter pathology has important effects on balance control, and consequently white matter lesions have been related to gait impairment, instability, and falls (47). In accordance, white matter lesions (93), peripheral artery disease (94), and heart failure (95) have been associated with increased fracture risk. These studies suggest strongly that vascular disease and its risk factors (midlife hypertension) can also be seen as risk factors for geriatric fractures, which are often osteoporotic.

Osteoporosis

In old age, osteoporosis is closely related to most fractures, not only in vertebrae or hips (96). Although both conditions increase with age, there are several lines of evidence suggesting a direct relationship between atherosclerosis, vascular calcification, and osteoporosis (‘calcification paradox’) (8,97–100). Appropriate blood circulation is essential for bone health and repair, and endothelial function is impaired in individuals with lowered bone mineral density. Patients with femoral fractures had more vascular pathology than control patients with osteoarthritis, and osteoporosis in the hip was associated with advanced atherosclerosis in older women. Conversely, atherosclerotic vascular disease was observed more often among women with osteoporosis or osteopenia than in those women without these conditions. Finally, in a prospective study of older men, peripheral artery disease was associated with bone loss and fracture risk (94).

Dizziness and hearing and vision impairments

The main clinical manifestations of dizziness are vertigo, presyncopal state, dysequilibrium, and ‘giddiness’, and they are frequent symptoms among older people in the community (101). While the etiology of the syndrome is heterogeneous, a contribution from cerebrovascular disease and small-vessel disease to dysequilibrium is likely. This has been demonstrated for positional vertigo (102). Age-related hearing impairment has been connected to diabetes and cardiovascular risk factors such as hypercholesterolemia, smoking, and high body mass index (103–105), and one study has demonstrated an association between hearing loss and gait disorders (106). The same cardiovascular risk factors have also been suggested to be important in the etiology of choroidal neovascularization leading to vision impairment in older people (107), and retinal microvascular abnormalities have been associated with executive dysfunction, slower gait, and possibly depressive mood (108).

Incontinence

Urinary incontinence (usually urge or mixed-type) with other lower urinary tract dysfunctional states has a major effect on the well-being and autonomy of older people (109). Urinary incontinence may occur independently or be associated with a brain disorder such as dementia or stroke. Detrusor underactivity is probably the most frequent reason for incontinence among frail older persons, although the opposite phenomenon, bladder hyperreactivity, is also common. In the more severe manifestations of overt vascular disease, particularly stroke or dementia, the development of incontinence is not unexpected, but more subtle connections between vascular pathology and incontinence are emerging. In an experimental study, mild forebrain ischemia, without infarction, induced bladder hyperreactivity (110), and in humans type 2 diabetes is a strong, independent predictor of urinary incontinence in older women living in the community (111). The suspected etiology is microvascular damage caused by diabetes (11,112), and accordingly white matter lesions have been related to urinary urge and incontinence in older people (113).

Therapeutic implications

New and expanding research on the molecular foundations of vascular ageing may bring new therapeutic options also for vascular diseases and geriatric syndromes. Among new possibilities are Forkhead box ‘O’ (FOXO) and sirtuin-based therapies such as resveratrol and calorie restriction mimetics, inhibitors of the mammalian target of rapamycin (mTOR), and methods intervening with the insulin-like growth factor-1 (IGF) signaling pathways (17,19,21). After clinical trials with current antioxidants have been a disappointment in cardiovascular medicine, new research on mitochondrial-targeted antioxidants and more generally mitochondrial rejuvenating therapies (18) may offer solutions even in older age. Clinical application of these mechanisms to prevent or treat geriatric syndromes is still awaited.

At present, the available clinical evidence that preventing and treating vascular diseases would also prevent geriatric syndromes is largely indirect and consequently hypothesis-generating. As prevention should start early, before irreversible complications occur, designing controlled drug studies with sufficient follow-up—even decades—are challenging or impossible. An important exception may be antihypertensive treatment. Less white matter lesion progression was observed in the group of ischemic post-stroke patients assigned to antihypertensive treatment (perindopril plus indapamide) as compared to placebo in a sub-study of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) (114). There is also some trial evidence that treating blood pressure would prevent dementia or cognitive decline (115–117), a rather surprising finding given the short duration (2–5 years) of antihypertensive trials. Also the type of antihypertensive therapy may have different effects on cognitive function (118). Although these results are promising, it is of note that these randomized clinical trials have been performed in relatively well-functioning older patients (119), and extrapolation of their results to geriatric syndromes should be done cautiously.

Various lifestyle interventions related to cardiovascular diseases, such as nutrition, physical activity, and prevention of obesity are important also in the prevention of frailty, cognitive decline, and other geriatric syndromes (119–121), but it may be difficult to define which proportion of benefit is specifically due to vascular effects.

Conclusions

Given that geriatric syndromes are under-recognized in routine clinical practice (122), training in systematic detection and grading of geriatric syndromes is needed. There should also be greater recognition of geriatric syndromes as important end-points in cardiovascular disease guidelines. These developments may be difficult without more emphasis on geriatric medicine, the training of which continues to be highly variable among physicians in the developed world (123).

Although older patients may be beyond the point where risk factor intervention would have substantial clinical benefits, detection and treatment are still often effective (86,124). Clinicians may be unduly pessimistic about plasticity in later life, which is surprisingly robust (125). While geriatricians usually work with patients for whom intervention on vascular risk factors is often considered to be of lesser impact, it is still not negligible, as evidenced by studies addressing vascular risk factors and dementia in older people (115–117). Even though the key time for intervening in preventing geriatric syndromes is during earlier life (126), geriatricians retain a very important role in ensuring a consciousness within the public health community of geriatric syndromes, particularly in terms of seeing them as end-points for vascular prevention. A review of vascular prevention guidelines indicated that only 20% of them include cognitive impairment as an important end-point for prevention of vascular disease (127).

In order better to tackle geriatric syndromes and their disabling consequences, we argue that prevention of geriatric syndromes should be taken as a further important long-term goal and stimulus for global vascular risk modification, especially among women. In particular, prevention and treatment of small-vessel disease deserves special attention and further clinical research. In the future, on-going research on the foundations of vascular ageing is increasingly likely to lead to better prevention of vascular diseases including geriatric syndromes.

Declaration of interest: This work was supported by the Jahnsson Foundation, the University Central Hospitals of Oulu and Helsinki (EVO funding), and the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse. The funding sources had no role in the design and conduct of the review, nor in the preparation, review, or approval of the manuscript.

While we assume no direct conflict of interest, all authors have had various co-operation with companies and associations that may potentially benefit from the conclusions of this review.

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