Can we improve care for patients with dementia?

the Journal of Nutrition, Health & Aging© Volume 15, Number 7, 2011

JNHA: NutRitioN

EDITORIAL Can We Improve Care for patIents WIth DementIa? J.e. morley Division of Geriatric medicine, saint louis University school of medicine, 1402 s. Grand Blvd., m238, st. louis, mo 63104, email: [email protected]

since the original pathological descriptions of alzheimer’s disease by alzheimer in munich and fischer in prague over a century ago, we have seen a number of stuttering steps forward in the recognition and management of persons with dementia. Dementia markedly increases both the direct costs of care but also has marked indirect costs and burden through the activation of an informal carer network (1-4). the utility of the available disease modifying drugs is minor at the best (5, 6). Drugs available for the treatment of behavior disturbances lack strong evidence of efficacy in double-blind trials and have a myriad of severe side effects (7, 8). the ability of general practitioners and internists to recognize persons with early stages of dementia is poor (9, 10). the mini-mental status examination which has been classically used to detect dementia, has very poor ability to detect mild cognitive impairment (mCI) (11). tests that do detect mCI, such as the montreal Cognitive assessment and the st. louis mental status examination are not widely used (12, 13). most patients seeing a general practitioner are not screened for functional ability which allows targeting of early interventions (14). It has been recommended that all clinicians be taught to screen for dementia (15). there are over a hundred causes of dementia, the majority of which are unknown to the average physician. Curable dementias, e.g., those caused by drugs, vitamin B12 and folate deficiency, hypothyroidism and other metabolic disorders, infections, depression, normal pressure hydrocephalus and space occupying lesions, are often not recognized until late in the course of the disease process. even the diagnosis of the more common dementias (alzheimer’s disease, lewy Body disease, vascular Dementia, pick’s disease and Dementia associated with parkinson’s disease) are fraught with difficulty. many persons have more than one of these diseases co-existing and the clinician and/or pathologist arbitrarily assign them to one or another diagnosis. Increasing recognition of some more recently recognized dementias, such as fragile X syndrome dementia (essential tremor associated dementia) creates further diagnostic quandaries (16). superimposed delirium or subsyndromal delirium further create diagnostic difficulties (17-19).

and memantine – have focused on trying to alter end stage events in the pathophysiology of the disease and, on the whole, results have been disappointing. some studies have shown small effects which may improve quality of life in a subset of patients (24). the primary pathology in alzheimer’s disease has been considered to be the overproduction of amyloid-beta protein with the development of amyloid plaques (25). While much focus has been on the plaques the primary process would appear to be the overproduction of amyloid-beta protein in many forms. amyloid-beta protein in high doses inhibits memory, produces oxidative damage and leads to activation of GsK-3 resulting in phosphorylation of tau and the production of neurofibrillary tangles (26-29). recently it has been shown that amyloid-beta protein in low doses is a mimetic (30). this may explain the problem with some drugs that were developed to inhibit amyloid-beta protein production. thus, amyloid-beta, should be though of as being like thyroid hormone with both low doses (hypo disease) and high doses (hyper disease) resulting in memory problems. thus, developing drugs, such as antisenses that do not completely reduce amyloid-beta protein may be a more suitable alternative (31). It is important to recognize that, like diabetes mellitus, it is likely that there are a number of different types of alzheimer’s disease, all of which have similar end stage symptoms and pathology. such a classification has been developed for neurodegenerative dementia and parkinson’s (32). It is clear that a central focus of many end stage patients is a high degree of oxidative metabolism (33-35). the analogy with diabetes mellitus is an excellent one as diabetes mellitus leads to memory disturbances by a number of different mechanisms (36-38) and insulin has been implicated in the pathophysiology of alzheimer’s disease due to the fact that the insulin degrading enzyme is also responsible for degradation of amyloid-beta protein in the brain (39). finally, like diabetes mellitus, alzheimer’s disease has been associated with multiple genes, altering multiple different systems (40, 41). a number of biomarkers for alzheimer’s disease are being developed (42, 43). the most promising are low levels of amyloid-beta protein and high levels of tau in the cerebrospinal fluid (Csf) (44, 45). the low levels of amyloid-beta are Alzheimer’s Disease thought to be due to the fact that amyloid-beta toxicity damages alzheimer’s disease is the most common dementia and has the blood brain barrier trapping the amyloid-beta protein in the had the most focus in the attempt to develop disease modifying brain (46). recently, the combination of low amyloid-beta and drugs (20-23). the drugs developed – cholinesterase inhibitors high tau has been related to the level of memory disturbance in normal humans and those with early dementia (47). Received June 18, 2011 Accepted for publication June 20, 2011 523


CAN We impRoVe CARe foR pAtieNts WitH DemeNtiA? Imaging techniques are moving rapidly forward as both diagnostic techniques and possible biomarkers. magnetic resonance Imaging (mrI) with a focus on hippocampal size is proving to be an excellent measure of determining whether persons with amnestic mCI will go on to develop alzheimer’s disease (48). functional mrI’s are slowly becoming useful to distinguish between different types of dementia (49). the new high resolution mrI machines can detect amyloid-beta protein. positron emissions tomography (pet) scanning with glucose proved a useful early technique that differentiated between alzheimer’s fronto-temporal dementia and normal individuals (50). the pittsburgh B agent pet scanning is excellent at detecting amyloid-beta protein (51). It demonstrates increased amyloid deposits in persons with normal memory prior to the development of alzheimer’s disease (52). low bioavailable testosterone in males has been shown to be a predictor of rapid progression of mCI to alzheimer’s disease (53, 54). Exercise and Dementia It is now clear that regular exercise slows the rate of cerebral atrophy and improves cognitive function (55, 56). regular exercise has been associated with a slower rate of development of alzheimer’s disease in older populations (57). In persons in a nursing home, a regular exercise program delays the rate of functional deterioration (58). exercise also decreases agitated behaviors in person with dementia (59-61). Nutrition and Dementia It has long been recognized that severe protein energy malnutrition or vitamin deficiencies lead to cognitive dysfunction. In the 1980s it was recognized that food had more subtle effects on memory. feeding an animal after it has learned a task, but not before enhanced memory (62). this was shown to be due to the release of a gut hormone, cholecystokinin, which stimulated the ascending fibers of the vagus to send messages to the hippocampus (63). more recently, ghrelin, a stomach hormone which is elevated during starvation, has been shown to cross the blood-brain barrier and facilitate memory recall (64). fat stores also modulate memory. the fat hormone, leptin, has been shown to enhance memory (65). Cytokines, which can be derived from fat, have been demonstrated to inhibit memory (66). high triglyeride levels block the entry of leptin into the brain and produce cognitive decline both in animals and humans (67-69). numerous epidemiological studies have shown that vitamins with antioxidant activity are associated with a lower incidence of alzheimer’s disease (70). Unfortunately, intervention studies have failed to reproduce these findings. alpha-lipoic acid, a potent antioxidant, reverses cognitive defects and oxidative damage in animals (71), but there is only one poorly controlled study in humans (72). a few studies have found small effects of 524

colostrinin and vitamin mixtures (73-76). eating fish has been shown to be associated with lower levels of dementia in the population (77). animal studies have supported the effect of docosahexanoic and eicosapentaenoic acid on cognition (78). human studies have, however, been disappointing (79), though a recent longer term study found less cognitive complaints in persons with a high long chain n-3 fatty acid intake (80). persons who eat a mediterranean diet appear to be less likely to develop alzheimer’s disease (81). overall, a prudent diet high in fruit and vegetables and with fish 3 to 4 times a week would appear to be a reasonable recommendation to reduce the incidence of alzheimer’s disease and vascular dementia. Weight Loss and Dementia early in alzheimer’s disease persons tend to increase their food intake. however, persons with moderate and more severe dementia almost always lose weight (82, 83). Weight loss is a major component of frailty and is associated with severe morbidity and mortality (84, 85). programs are being developed to try and limit weight loss (86). persons with dementia should regularly be screened with the mininutritional assessment (mna)(87-89). Behavioral and Psychological Symptoms in Dementia all persons with dementia should be screened for depression using the Cornell Depression Inventory (90). Depression represents a highly treatable cause of dementia and even in persons with depression co-existing with dementia, treatment can improve function and quality of life (91). apathy associated with dementia needs to be distinguished from depression (92). resistiveness to care is often difficult to treat and requires training in behavior modification for the nursing staff (93, 94). similarly, aggressive behavior is best treated by working around the behavior. Use of quiet room or “snoezelen” techniques prove useful for some (95, 96). antipsychotic drugs have been heavily utilized to “control” behavioral outbursts in person with dementia (97, 98). there is no evidence that these drugs are effective for this indication (99). antipsychotics cause hip fractures, aspiration pneumonia, stroke, myocardial infarction, diabetes mellitus and increased mortality (100-102). antipsychotics in low doses are useful for hallucinations, illusions, delusions and paranoia. they should not be used when these conditions are not present. numerous other drugs have been used in an attempt to control negative behavior symptoms. some have been found to be effective in small, often poorly controlled trials. sleep disturbances are common in persons with alzheimer’s disease. there is a disruption of the circadian rhythm in alzheimer’s disease (103). this leads to a phase advancement, with patients with alzheimer’s disease being more awake at night (104, 105). Use of bright light, possibly together with melatonin has been shown to decrease behavior disturbances.


JNHA: NutRitioN Conclusions

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While we have learned much about the pathophysiology of alzheimer’s disease and other dementias, we are still in our infancy as far as developing disease modifying drugs. It is hoped that over the next decade, a number of disease modifying drugs will be developed. at present, prevention of alzheimer’s disease should focus on utilizing a mediterranean type diet with fish 3 to 4 times a week. Use of curries (curcumin) might also decrease the development of alzheimer’s disease (106). this should be coupled with regular aerobic exercise at least 3 times a week. Cognitive intervention programs should also be included in the regimen (107-109). adequate control of hypertension and hypercholesterolemia in middle age will decrease vascular dementia and possibly alzheimer’s disease. maintaining an interest in meaningful activities such as playing a musical instrument, chess or dancing also decrease the chance of developing dementia (110). appropriate end-of-life care programs should be established for those with end stage alzheimer’s disease (111). there is a need to move from the overuse of drugs for behavior modification to using behavioral modification techniques. exercise clearly decreases behavioral outbursts. Utilizing wander gardens and other meaningful activities can further improve behaviors (112). Improvement in the care of patients with dementia is going to require an increase in innovative research. this will require strong partnerships between academia and industry. It is recommended that multidisciplinary memory clinics are developed to enhance the care of person with dementia and coordinate future clinical trials (113).

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