Can dementias and mild cognitive impairment be influenced in their course by diseases and risk factors? This is the subject of a study reported by Thorleif Etgen and co-authors in the current issue of Deutsches Ärzteblatt International (Dtsch Arztebl Int 2011; 108: 743-50).
Increasingly larger numbers of people are affected by mild cognitive impairments and even dementia, which means that early detection of possible precursors as well as diagnosis and therapy of risk factors that can actually be influenced are gaining in importance. The term “mild cognitive impairment” describes impairments in memory, attention, and intellectual capacity that are common at an advanced age. It is notably below the usual standard for the age group and educational level under investigation, without presenting substantial limitations to people’s everyday lives. Mild cognitive impairment may occur as a precursor stage to actual dementia.
The current data situation is based on less conclusive cross sectional studies and longitudinal studies. In spite of the fact that interventional studies have been negative so far, the authors are of the opinion that a biologically plausible association exists between cognitive degeneration and hypertension, diabetes, and hyperlipidemia. Chronic renal failure has been identified as a new somatic risk factor in recent years. Epidemiological data indicate a protective effect for a Mediterranean diet, physical activity, and moderate alcohol consumption. Smoking, on the other hand, raises the risk for developing cognitive impairments.
Mild Cognitive Impairment and Dementia
Background: Mild cognitive impairment (MCI), a common condition among the elderly, is defined as a deterioration of memor y, attention, and cognitive function that exceeds what would be expected for the individual’s age and level of education, yet does not interfere significantly with the activities of daily living. MCI may be a precursor of dementia; the rate of transition from MCI to dementia is 10% to 20% per year. The role of somatic diseases and modifiable risk factors in MCI and dementia needs further study.
Methods: We analyzed pertinent original articles and reviews publi shed 1990 up to December 2010 that were retrieved by a selective search in PubMed and the Cochrane Library.
Results: MCI and dementia are associated with many somatic disorders and modifiable risk factors. MCI has biologically plausible associations with hypertension, diabetes mellitus, and hyperlipidemia, although the interventional trials performed to date have yielded negative results. Recently, chronic renal failure has also been recognized as a risk factor. Insufficient evidence supports a putative benefit on MCI from the substitution of vitamin B12, vitamin D, or testosterone (when these substances are deficient), the treatment of hyperhomocysteinemia or subclinical thyroid dysfunction, or hormone replacement therapy after menopause. Epidemiological data suggest that a Mediterranean diet, physical activity, and moderate alcohol consumption protect against MCI, while cigarette smoking promotes it and should be stopped.
Conclusion: Modifiable risk factors for MCI should be sought (at the very latest) in persons who already have MCI, as their optimal treatment may improve these patients’ cognitive performance or keep the existing deficits from progressing.
The number of persons affected by dementia is increasing. Therefore, the early detection of possible precursors of dementia and the diagnosis and treatment of modifiable risk factors are assuming increasing importance. A central part is played by the concept of mild cognitive impairment (MCI), because in many cases MCI, particularly the amnestic form (affecting memory), represents an early stage of Alzheimer-type dementia. In ca. 10% to 20% of patients with MCI, the mild impairments progress to manifest dementia in the space of 12 months. Despite its current pronounced heterogeneity, the concept of MCI permits timely identification of patients at high risk of developing dementia, thus opening a potentially larger therapeutic window and increasing the significance of modifiable risk factors. The importance of this becomes clear when one considers that, to date, all trials of antidementive drugs have had negative results. The data on MCI are sparse compared with dementia, and some studies have drawn no clear line between MCI and dementia or have used other terms (e.g., cognitive decline). The present study is therefore intended to provide an up-to-date overview of the common risk factors for MCI and dementia and of the (ideally prospective) interventional trials carried out to date.
To this end, we conducted a selective literature search of PubMed and the Cochrane Library using the terms “dementia”, “mild cognitive impairment”, and “cognitive decline” and analyzed pertinent original articles and reviews published between 1990 and December 2010.
Cardiovascular risk factors
Chronic renal failure
Vitamin B12 deficiency
Vitamin D deficiency
Subclinical thyroid dysfunction
“Classic” cardiovascular risk factors
Hypertension can lead to vascular-related cognitive impairment through any one of a number of mechanisms (arteriosclerosis, hypoperfusion, leukoaraiosis, cerebral infarction). Numerous cross-sectional analyses of the association between high blood pressure and cognitive impairment have yielded divergent results, while the majority of longitudinal studies have demonstrated an association . Seven large randomized, placebo controlled interventional trials have been performed to date, with conflicting results. Five studies revealed no protective action, while two showed a protective effect. The interpretation of these studies was severely restricted by methodological problems, and it is possible -as proposed in a recent Cochrane Review – that more precise results can be yielded only by a meta-analysis on the basis of individual patient data. The specific pharmacological mechanisms of action of the different antihypertensive agents could also play an important role.
Definition of mild cognitive impairment
– Absence of dementia
– Signs of cognitive decline (medical history provided by doctor or patient)
– Demonstration of cognitive disturbance
– Ability to perform regular daily functions preserved; no more than minimal impairment of complex activities
The existence of a causal link between diabetes mellitus and cognitive impairments is supported by numerous biochemical, imaging-related, and histopathological findings. A systematic review of 14 longitudinal studies reported an increased incidence of dementias, although it should be noted that there was often no adjustment for relevant confounding variables (e.g., hypertension or stroke). Recent prospective studies that have taken account of these potential sources of error underline the possible importance of diabetes mellitus as an independent risk factor for cognitive decline. Longer duration of diabetes, lack of antidiabetic medication, and a higher number of hypoglycemic episodes were also associated with an increased risk of cognitive decline. A Cochrane Review in 2002 found no randomized studies investigating the link between the type of treatment for diabetes and the development of MCI or dementia. The only randomized study of antidiabetic medications published in the intervening period showed no influence on cognitive performance in mild dementia.
As early as 2003, autopsy studies described an association between cerebral amyloid deposits and hypercholesterolemia. Large population-based studies then revealed that hyperlipidemia and particularly hypercholesterolemia in middle age are associated with the risk of subsequent occurrence of MCI. In contrast, studies of older subjects (>65 years) showed no association between hypercholesterolemia and cognitive decline. The findings of the majority of prospective observational studies suggested a protective connection between statin intake and cognitive impairment. The Rotterdam Study, for example, with 6992 participants and a mean observation period of 9 years, found that the risk of developing Alzheimer-type dementia was reduced by almost half in those taking statins (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.37 – 0.90). This effect was independent of the type of statin but specific to statins, in that other cholesterol-lowering drugs (fibrate, nicotinic acid) showed no such influence. However, two large placebo-controlled trials of persons at high risk of vascular disease did not demonstrate a similar association. Neither the Heart Protection Study (HPS; simvastatin, >20 000 participants, age 40 – 80 years, observation period 5 years) nor the Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER) trial (pravastatin, almost 6000 participants, age 70 – 82 years, observation period 3 years) showed a protective effect of statins with regard to cognitive decline. This finding was confirmed by the Cochrane Review based on HPS and PROSPER. These negative results may possibly be explained by the fact that neither trial was designed primarily to record cognitive impairments, so there was no baseline assessment of cognitive per formance. Any effect of statin intake was therefore not measurable. Furthermore, the age range in the HPS was so wide, encompassing middle-aged as well as elderly persons, that the age-dependent influence of cholesterol may have been neutralized. Moreover, recent findings point to differences in the individual fractions of cholesterol. In analogy to coronary heart disease, a high proportion of HDL cholesterol may have a protective function, and future statin studies should take this into account.
A Mediterranean diet (a high proportion of fish, fruit, vegetables, cereals, and unsaturated fatty acids and a low proportion of dairy products, meat, and saturated fatty acids) could potentially exert a protective effect with regard to cognitive decline via improved carbo hydrate metabolism coupled with antioxidative and anti-inflammatory mechanisms. The only two prospective cohort studies carried out to date differed in some aspects of study design (observation period, composition of diet, etc.), but agreed in suggesting a dose-dependent protective effect of a Mediterranean diet. An American study of 1393 persons with initially normal cognitive function found a 28% reduction in the risk of MCI after 4.5 years among those with a high proportion of Mediterranean-style diet. A Cochrane Review of the value of omega-3 fatty acids in the prevention of dementia published in 2006 found insufficient evidence because of the lack of randomized trials at that time.
Various mechanisms (reduction of cardiovascular diseases, improved cerebral perfusion, induction of cortical angiogenesis, etc.) have been discussed for the postulated neuroprotective effect of physical activity. Recent cohort studies have revealed an association between regular exercise and a considerable reduction in the risk of developing MCI. A new meta-analysis of 15 prospective cohort studies embracing a total of 33 816 persons without dementia shows that both intense and moderate exercise reduce the risk of the occurrence of MCI by at least 35%. Various interventional trials in recent years have confirmed this effect; however, the numbers of participants were low (<150) and the observation times short (=1 year). Larger interventional trials are now under way, so more precise recommendations can be expected. It is already clear, however, that not all types of physical activity are suitable; boxing, for example, increases the risk of cognitive impairment.
The results of recent studies confirm that the symptoms and course of MCI and dementia can be influenced by somatic illnesses and other modifiable risk factors, although the current data originate largely from not entirely conclusive cross-sectional or longitudinal studies. Despite the current lack of positive interventional trials, we are of the opinion that an association with the classic cardiovascular risk factors—hypertension, diabetes mellitus, and hyperlipidemia – is biologically plausible. Measures to ameliorate these factors would simultaneously represent effective prevention of other vascular diseases (myocardial infarction, stroke). In recent years renal failure has also been identified as a somatic risk factor, though no evidence – based treatment strategies have yet emerged. With regard to MCI, the current data do not support the general recommendation of substitution therapy in the case of vitamin B12, vitamin D, or testosterone deficiency, hyperhomocysteinemia, or subclinical thyroid dysfunction. Purely estrogen-based hormone replacement therapy can be contemplated for improvement of verbal retentiveness in women under 65 after careful consideration of potential contraindications, but no other postmenopausal hormone replacement therapy should be given. Epidemiological data indicate a protective action of Mediterranean diet, physical activity, and moderate alcohol consumption, so these can be encouraged or— in the case of alcohol consumption—tolerated. Smoking increases the risk of developing MCI and should be stopped.
Dr. Thorleif Etgen
Deutsches Aerzteblatt International