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Advance Access publication July 16, 2008 Dementia of the Alzheimer Type Jessica J. Jalbert1, Lori A. Daiello1,2, and Kate L. Lapane1 1 Department of Community Health – Epidemiology, Warren Alpert School of Medicine at Brown University, Providence, RI.
2 Alzheimer's Disease and Memory Disorders Center, Rhode Island Hospital, Providence, RI.
Accepted for publication May 12, 2008.
Dementia of the Alzheimer type is a progressive, fatal neurodegenerative condition characterized by deterioration in cognition and memory, progressive impairment in the ability to carry out activities of daily living,and a number of neuropsychiatric symptoms. This narrative review summarizes the literature regardingdescriptive epidemiology, clinical course, and characteristic neuropathological changes of dementia of theAlzheimer type. Although there are no definitive imaging or laboratory tests, except for brain biopsy, for diagnosis,brief screening instruments and neuropsychiatric test batteries used to assess the disease are discussed.
Insufficient evidence exists for the use of biomarkers in clinical practice for diagnosis or disease management, butpromising discoveries are summarized. Optimal treatment requires both nonpharmacological and pharmacolog-ical interventions, yet none have been shown to modify the disease's clinical course. This review describes thecurrent available options and summarizes promising new avenues for treatment. Issues related to the care ofpersons with dementia of the Alzheimer type, including caregiver burden, long-term care, and the proliferation ofdementia special care units, are discussed. Although advances have been made, more research is needed toaddress the gaps in our understanding of the disease.
Alzheimer disease; dementia; drug therapy; review Abbreviations: APOE, apolipoprotein E; DAT, dementia of the Alzheimer type; DSM-IV-TR, Diagnostic and Statistical Manualof Mental Disorders, fourth edition text revision; MMSE, Mini-Mental State Examination; NINCDS/ADRDA, National Institute ofNeurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association.
dition if current trends persist and no preventive treatmentsbecome available (4). The cognitive, behavioral, and func- Dementia of the Alzheimer type (DAT) is a progressive, tional decline in patients with DAT places a considerable fatal neurodegenerative condition characterized by deterio- burden on the health care system and caregivers (5). DAT is ration in cognition and memory, progressive impairment in therefore a growing medical, social, and economic problem.
the ability to carry out activities of daily living, and a number Despite the urgency of the situation, many questions re- of neuropsychiatric and behavioral symptoms (1). DAT is main unanswered in DAT research. For instance, although the most common form of dementia among elderly persons advanced age, female gender, carrying the apolipoprotein E and accounts for approximately two thirds of cases of de- (APOE) e4 allele, current smoking, family history of DAT or mentia and between 60 percent and 70 percent of cases of other dementia, fewer years of formal education, lower in- progressive cognitive impairment in older adults (2, 3). The come, and lower occupational status have been associated prevalence of DAT is expected to increase as the population with an increased risk of developing the condition, the path- ogenesis of Alzheimer's disease is still largely unknown (6–8).
In 2000, approximately 4.5 million people in the United Although progress is being made in developing new therapies States were living with DAT; by 2050, more than 13 million for DAT, no therapeutic interventions to cure or substantially older Americans are projected to be afflicted with the con- modify disease progression currently exist.
Correspondence to Jessica J. Jalbert, Department of Community Health – Epidemiology, Warren Alpert School of Medicine at Brown University,121 South Main, Box G, Providence, RI 02912 (e-mail: [email protected]).
Epidemiol Rev 2008;30:15–34 Jalbert et al.
This review provides an update on the current state of In the United States, 12 percent of the population is at knowledge on DAT. With a focus on findings generated from least 65 years of age (13). By 2020, 16 percent of the pop- studies conducted in the United States, it describes the ep- ulation will be 65 years of age or older, and adults over 80 idemiology of DAT, its characteristic clinical course, neuro- years of age are expected to account for 3.7 percent of the psychiatric symptoms, factors associated with accelerated population (14, 15). Growth will occur in all racial and ethnic cognitive decline, characteristic neuropathological changes groups (4). By 2050, the number of persons with DAT is of Alzheimer's disease, diagnostic tools to assess DAT, and expected to increase to 13.2 million, and it is estimated that biomarkers and neuroimaging, and it provides an overview more than 8.0 million cases will be older than age 85 years (4).
of pharmacological and nonpharmacological treatments. Wealso summarize the ramifications of DAT for caregivers anddiscuss long-term care.
Patients with DAT are likely to exhibit neuropsychiatric symptoms, also commonly referred to in the literature as The following definitions were adapted from the position behavioral and psychological symptoms of dementia, such statement of the American Association for Geriatric Psychi- as aggression/agitation, depression, apathy, anxiety, delu- sions, and hallucinations at some point during the course Dementia is a clinical syndrome characterized by global of the illness. Neuropsychiatric symptoms are common in cognitive decline with memory and one other area of cog- all stages of dementia with prevalence estimates between 60 nition affected that interfere significantly with the person's percent and 80 percent, depending on whether patients are ability to perform the tasks of daily life and meet the community dwelling or institutionalized, and a lifetime risk Diagnostic and Statistical Manual of Mental Disorders, of nearly 100 percent (16–20). The prevalence of neuropsy- fourth edition text revision (DSM-IV-TR) criteria.
chiatric symptoms in persons with DAT or dementia is Dementia resulting from Alzheimer's disease or DAT is greater than the background prevalence in the general pop- characterized by decline primarily in cortical aspects of ulation (16, 17, 21–24). Those symptoms most commonly cognition (i.e., memory, language, praxis) and follows a char- seen in patients with DAT or dementia are apathy, depres- acteristic time course of gradual onset and progression.
sion, anxiety, aggression/agitation, and psychosis (delusions Alzheimer's disease is a specific degenerative brain disease and hallucinations). The prevalence of apathy ranges from characterized by senile plaques, neuritic tangles, and progres- 20 percent to 51 percent and the 5-year prevalence is esti- sive loss of neurons, the presumptive cause of Alzheimer's mated as 71 percent (16, 18, 21, 23); the respective preva- lences are 15–54 percent and 77 percent for depression(16, 18, 21, 22, 24–27) and 10–59 percent and 62 percent GLOBAL INCIDENCE AND PREVALENCE OF DAT for anxiety (16, 18, 21, 23, 28). The prevalence estimates foraggression/agitation and psychosis range from 13 percent to Data documenting the incidence of DAT indicate that it is 30 percent and from 12 percent to 74 percent, respectively a global problem that will become more severe as the pop- (16, 18, 21, 29, 30). The considerable variation in the prev- ulation ages. Table 1 summarizes population-based studies alence estimates results from the different operational def- estimating the incidence and prevalence of DAT. Studies initions of dementia and neuropsychiatric symptoms, the from different parts of the world (North America, Europe, different types of dementia studied, and the heterogeneity Asia, and Africa) were selected if they were population of the study populations. Other less-common and less- based and large. The estimates from the Delphi Consensus studied neuropsychiatric symptoms include irritability, ela- Study are for dementia rather than DAT but were included tion, disinhibition, wandering, and aberrant motor behavior.
because prevalence/incidence estimates were generated Neuropsychiatric symptoms in DAT may be better cap- from a systematic review of population-based studies.
tured by grouping individual symptoms into various clusters Regardless of country of origin, age-specific incidence rates (20, 31–34). The motivation behind identifying symptom of DAT increase exponentially with advancing age. In the clusters is that they may form syndromes, with each DAT– United States, the incidence rate of DAT is 1 per 1,000 neuropsychiatric symptom subtype having a different prev- person-years among individuals aged 60–64 years and 25 alence and time course as well as distinct biologic correlates per 1,000 person-years among those older than age 85 years and psychosocial determinants (32). If neuropsychiatric (10). Although DAT is not a normal part of the aging pro- symptom clusters reflect differences in brain regions af- cess, the prevalence of DAT also increases with advancing fected by the disease, pharmacological and nonpharmaco- age. While less than 1 percent of individuals aged 60–64 logical treatment opportunities could be optimized (20, 32).
years are deemed to be affected, it is estimated that up to 40 Neuropsychiatric symptoms in DAT may be classified into percent of those over the age of 85 years have the condition three groups: an affective syndrome, a psychotic syndrome, (11). Similar trends were observed in a population-based and other neuropsychiatric disturbances (20). Diagnostic European study of persons aged 65 years or older. The criteria for DAT-associated affective disorder and DAT- age-standardized prevalence of DAT was 4.4 percent, and associated psychotic disorder have been proposed (34). Other the prevalence increased with age (0.6 percent for those neuropsychiatric symptom classification systems, all of aged 65–69 years; 22.2 percent for those aged 90 years or which have identified clusters of mood or psychotic neuro- older) (12).
psychiatric symptoms, have also been advanced (17, 35–39).
Epidemiol Rev 2008;30:15–34 Dementia of the Alzheimer Type NEUROPATHOLOGICAL FEATURES OF ALZHEIMER'S retrospectively determined symptom onset and 5.7 years (standard deviation, 0.1) from initial clinic presentation(79). Baseline level of cognition may not predict mortality, Alzheimer's disease can be definitively diagnosed only at but mortality is strongly related to rate of cognitive decline brain autopsy or biopsy, when neuritic plaques reach a cer- (76). Indeed, the lack of effective predictors of the rate of tain number in the most severely affected regions of the deterioration extends to the earliest stages of dementia (80).
neocortex (40, 41). More stringent research criteria require In the early clinical stage, deficits occur in episodic mem- the presence of neuritic plaques and neurofibrillary tangles ory, verbal abilities, visuospatial functions, attention, and in the neocortex (42–44).
executive functions (81). Sensory-motor performance and Neuritic plaques consist of a central core of beta-amyloid procedural memory seem to be intact, and only slight im- peptides clumped together with fibrils of beta-amyloid, dys- pairment may be seen in primary memory (81). Cognitive trophic neurites, reactive astrocytes, phagocytic cells, and decline stems from unifunctional to global deficits (81).
other proteins and protein fragments derived from degener- Performance falls off rapidly in all areas of cognitive func- ating cells or liberated from neurons (45, 46). The accumu- tioning, but abilities thought to be subserved by the medial lation of beta-amyloid seen in Alzheimer's disease brains may and lateral temporal lobes (episodic and semantic memory, be the result of faulty beta-amyloid clearance (47), cleaving respectively) appear to be substantially more impaired than of the amyloid precursor protein by enzymes to yield free those abilities thought to be subserved by the frontal lobes beta-amyloid peptides (48), or overproduction of beta- (82). Yearly cognitive decline varies from a loss of 2.7–4.5 amyloid peptides caused by mutations in the amyloid pre- points on the Mini-Mental State Examination (MMSE), 1.8– cursor protein or the presenilins (49–54) or in the presence 4.2 points on the Blessed Dementia Scale, and 12–13 points of the APOE e4 genotype (55, 56). Beta-amyloid fibrils on the Cambridge Cognitive Examination to a gain of 2.6– aggregate and neuritic plaques form, triggering a locally 4.5 points on the Blessed Test of Information, Memory, and induced, non-immune-mediated, chronic inflammatory re- Concentration (83).
sponse involving microglial cell activation and stimulation The presence of one or more APOE e4 alleles is a signif- of a cerebral acute-phase reaction (57) (figure 1). Activated icant predictor of the incidence of delusions during the microglial cells release potentially neurotoxic proinflamma- course of DAT (84). The frequency and intensity of neuro- tory cytokines (e.g., interleukin-6), reactive oxygen and ni- psychiatric symptoms may increase with declining cognitive trogen species, and proteolytic enzymes that may exacerbate function in patients with DAT (76, 85–87) or may simply be neuronal damage (58, 59). Beta-amyloid fibrils also appear correlated with duration of disease (88). Curvilinear associ- to exert direct neurotoxic effects (60–62).
ations between dementia severity and neuropsychiatric Oxidative stress resulting from free radical damage may symptoms such as forgetfulness and emotional and impul- also be caused when soluble, aggregated amyloid fibrils are sive behaviors have been reported (89, 90). Consensus has inserted into neuronal membranes, inducing lipid perioxida- yet to be reached on whether the prevalence of individual tion, protein oxidation, and formation of reactive oxygen neuropsychiatric symptoms remains constant at all stages of and nitrogen species (63). APOE may, in e4 allele carriers, dementia or whether it varies systematically depending on exacerbate oxidative stress through its association with the the stage of the disease (21, 30, 91–94).
catabolism of polyunsaturated fatty acids (63). Oxidative Some DAT patients appear to have neuropsychological stress results in loss of cell potential, accumulation of ex- deficits more prominent in one domain than in other do- citotoxic molecules, and decreased neuronal viability (61).
mains (95). Language impairment in DAT may be associ- Healthy neurons have microtubules stabilized by the tau ated with two distinct neuropsychological abnormalities: protein; in Alzheimer's disease, this protein is hyperphos- 1) a lexical/semantic impairment unrelated to onset or phorylated and aggregates as paired helical filaments, caus- 2) progression of symptoms and a syntactic impairment that ing the dissociation of microtubules and the formation of may be associated with earlier onset and more rapid pro- neurofibrillary tangles that result in neurotransmitter deficits gression of dementia (96, 97). The annual decline in lan- and neuronal cell death (45, 64–66). Beta-amyloid deposits guage composite score was approximately 0.71 standard may accelerate the formation of neurofibrillary tangles in units, which did not differ by gender (98).
brain areas associated with Alzheimer's disease (67, 68).
Declining cholinergic function (69–71), reductions in syn-aptic density (71, 72), and the loss of neurons (71, 73–75) CORRELATES OF MORE RAPID COGNITIVE DECLINE are also consistent features of Alzheimer's disease.
CHARACTERISTICS AND CLINICAL COURSE OF DAT Progressive cognitive decline is the principal clinical manifestation of DAT, and a faster rate of decline is strongly DAT is associated with increased mortality, but survival associated with mortality (76). The rates at which people among those with the disease varies widely (76, 77). Esti- decline, however, differ substantially between affected per- mates of mean survival time are hampered by lack of de- sons, are difficult to predict, and are still not well understood finitive onset-of-disease dates. In a study that followed persons with DAT for an average of 4 years, 54 percent were The APOE e4 allele, a strong genetic risk factor for DAT, is institutionalized and 49 percent died (78). Median survival associated with a greater risk of developing DAT (odds ratio 5 is estimated at 11.8 years (standard deviation, 0.6) since 14.9, 95 percent confidence interval: 10.8, 20.6 for persons Epidemiol Rev 2008;30:15–34 Jalbert et al.
Summary of studies estimating incidence and prevalence of DAT* and dementia Population/study design Measure of disease frequency Incidence studies Canadian Study of Health and Population-based Canadian cohort study Women 65–69 years of age: 1.4 per 1,000 person-years Aging, Canadian Study of of 5,432 community-dwelling and 210 (95% CI*: 0.1, 3.3); men 65–69 years of age: 0; women Health and Aging Working institutionalized persons 65 years of 85 years of age or older: 49.0 per 1,000 person-years (95% CI: 40.7, 57.2); men 85 years of age or older:44.2 per 1,000 person-years (95% CI: 31.0, 57.5);women all ages: 7.4 per 1,000 person-years (95% CI:4.4, 10.4); men all ages: 5.9 per 1,000 person-years(95% CI: 2.0, 9.8) Cache County Study, Miech US population-based cohort study of 68 years of age or less: 2.2 per 1,000 person-years; 3,308 persons aged 65 years or older 84–86 years of age: 57.9 per 1,000 person-years;all ages: 16.8 per 1,000 person-years Monongahela Valley US population-based cohort study of 65–69 years of age: 2.1 per 1,000 person-years Independent Elders Survey 1,298 rural persons aged 65 years (95% CI: 0.6, 7.8); 90 years of age or older: 50.9 per (MoVIES), Ganguli et al.
1,000 person-years (95% CI: 23.3, 111.0); all ages: 11.6 per 1,000 person-years (95% CI: 9.5, 14.2) North America/Africa Hendrie et al. (294) 2,459 Yoruba residents of Ibadan, Annual age-standardized incidence rate of DAT: Nigeria, aged 65 years or older; 2,147 Nigeria: 1.15% (95% CI: 0.96, 1.35); Indiana: African Americans residing in 2.52% (95% CI: 1.4, 3.64) Indianapolis, Indiana, aged 65 yearsor older Fratiglioni et al. (295) Estimates of DAT incidence in persons 65–69 years of age: 1.2 per 1,000 person-years 65 years of age or older obtained by (95% CI: 0.6, 2.3); over 90 years of age: pooling population-based data from 53.5 per 1,000 person-years (95% CI: 36.5, 55.8) European population-based studies Neurologic Disorders in Population-based Spanish survey of 65–69 years of age: 1.5 per 1,000 person-years Central Spain Survey, 3,891 persons aged 65–90 years (95% CI: 0.3, 4.4); 90 years of age or older: 52.6 per Bermejo-Pareja et al. (296) 1,000 person-years (95% CI: 31.7, 82.2); age-adjustedincidence rate: 7.4 per 1,000 person-years (95% CI:6.0, 8.8) Conselice Study of Brain Italian prospective population-based 65–74 years of age: 11.3 per 1,000 person-years Imaging, Ravaglia et al.
study of 927 persons aged 65 years (95% CI: 7.1, 17.9); 85–94 years of age: 75.8 per 1,000 person-years (95% CI: 49.4, 116.2); all ages:23.8 per 1,000 person-years (95% CI: 17.3, 31.7) Rotterdam Study, Ruitenberg Population-based Dutch study of 7,046 65–69 years of age: 1.3 per 1,000 person-years persons aged 55 years or older (95% CI: 0.7, 2.3); 85–89 years of age: 34.8 per1,000 person-years (95% CI: 27.7, 43.9); all ages:7.2 per 1,000 person-years (95% CI: 6.4, 8.1) Chinese cohort of 1,593 persons aged All ages: 5.4 per 1,000 person-years 60 years or older residing in Beijing Indo-US Cross-National Population-based Indian study of 5,126 65–74 years of age: 1.2 per 1,000 person years Dementia Epidemiology persons aged 55 years or older (95% CI: 0.25, 3.57); 85 years of age or older: Study, Chandra et al. (300) 24.8 per 1,000 person-years (95% CI: 5.1, 72.5);65 years of age or older: 3.24 per 1,000person-years (95% CI: 1.48, 6.14) homozygous for the e4 genotype; persons with only one process regarding development of DAT and that cognitive copy of e4 are also at increased risk—odds ratio 5 2.6, 95 decline should progress more rapidly in these patients (102), percent confidence interval: 1.6, 4.0 for those with an e2/e4 but studies have provided conflicting evidence on whether genotype; odds ratio 5 3.2, 95 percent confidence interval: the APOE e4 allele is associated with an accelerated rate of 2.8, 3.8 for those with an e3/e4 genotype, relative to persons cognitive decline (102–107).
with an e3/e3 genotype) (100). Earlier age at onset is ob- High educational attainment is also associated with an served in a dose-dependent fashion (the average age at onset accelerated rate of cognitive deterioration in DAT patients for persons with genotype e4/e4, only one e4 allele, and no (108, 109), and the cognitive reserve hypothesis has been e4 allele is 68 years, 76 years, and 84 years, respectively) proposed to explain this association. For instance, someone (101). These findings have led to the hypothesis that APOE e4 with a higher number of neuronal synapses or neurons could allele carriers may experience a more rapid degenerative withstand a higher degree of neuropathological change Epidemiol Rev 2008;30:15–34 Dementia of the Alzheimer Type Population/study design Measure of disease frequency Delphi Consensus Study, Estimates of annual incidence of North America: 10.5; Latin America: 9.2; western Ferri et al. (301) dementia (per 1,000) in persons Europe: 8.8; eastern Europe: 7.7–8.1; North Africa 60 years of age or older derived by and Middle Eastern Crescent: 7.6; Africa: 3.5; India using the Delphi consensus approach and south Asia: 4.3; Indonesia, Thailand, and and guided by a systematic review of Sri Lanka: 5.9; China and developing western Pacific: 8.0; developed western Pacific: 7.0; worldannual incidence: 7.5 Prevalence studies Health and Retirement Study, Nationally representative sample of the 71–79 years of age: 5.0%; 90 years of age or Plassman et al. (302) US population (N 5 856) aged 71 older: 37.4%; all ages: 9.7% Framingham Study, Bachman US population-based cohort study Men: 1.17%; women: 3.01% North America/Africa Hendrie et al. (304) 2,494 Yoruba residents of Ibadan, Age-adjusted prevalence in Nigeria: 1.41%; Nigeria, aged 65 years or older; age-adjusted prevalence in Indiana for community- 2,212 African Americans residing in dwelling persons: 3.69%; age-adjusted prevalence in Indianapolis, Indiana, aged 65 years Indiana for persons living in the community and in nursing homes: 6.24% Farrag et al. (305) Population-based Egyptian study of 4.5% (95% CI: 3.6, 5.4) persons older than age 60 years Prevalence estimate for DAT in persons Age-standardized prevalence: 4.4%; 65–69 years of 65 years of age or older obtained by age: 0.6%; 90 years of age or older: 22.2% pooling population-based data fromEuropean population-based studies Rotterdam Study, Ott Population-based study of Dutch 55–64 years of age: 0.20%; 85 years of age or older: persons aged 55 years or older 26.8%; all ages: 4.5% Gurvit et al. (307) Population-based Turkish study of 11.0% (95% CI: 7.0, 15.0) persons older than age 70 years Dong et al. (308) Estimate of prevalence of DAT in 1.6% (95% CI: 1.0, 2.7) China among persons aged 60 yearsor older derived from systematicanalysis of work published between1980 and 2004 Zhang et al. (309) Prevalence of DAT among persons 65 years of age or older across fourregions in China: Beijing, Xian,Shanghai, Chengdu Delphi Consensus Study, Estimates of prevalence of dementia in North America: 6.4%; Latin America: 4.6%; western Ferri et al. (301) persons 60 years of age or older Europe: 5.4%; eastern Europe: 3.8%23.9%; derived by using the Delphi North Africa and Middle Eastern Crescent: 3.6%; consensus approach and guided by Africa: 1.6%; India and south Asia: 1.9%; Indonesia, a systematic review of published work Thailand, and Sri Lanka: 2.7%; China and developingwestern Pacific: 4.0%; developed western Pacific:4.3%; world prevalence 2001: 3.9% * DAT, dementia of the Alzheimer type; CI, confidence interval.
before becoming symptomatic (45, 109, 110). If patients toms such as aggression/agitation, depression, psychosis, with higher educational levels also have a higher cognitive delusions, and hallucinations (30, 78, 111–113), but these reserve, then, when DAT symptoms become apparent, the findings have been challenged (114–118). The neurobiology pathological burden will already be more severe and wide- underlying the emergence of neuropsychiatric symptoms is spread, and, with the cognitive reserve depleted, the patient far from being understood, as is the mechanism by which would appear to experience cognitive decline at a more these symptoms may accelerate cognitive decline (119–123).
rapid rate (45, 109). Rapid cognitive decline has also been Antipsychotic medications, widely used to treat neuro- observed among patients exhibiting neuropsychiatric symp- psychiatric symptoms (124, 125), have also been identified Epidemiol Rev 2008;30:15–34

Jalbert et al.
Cascade of neuropathological events leading to the behavioral and cognitive features of dementia. Reproduced with permission from primary author J. L. Cummings and from JAMA 2002;287:2335–2338. Copyright ª 2002, American Medical Association. All rights reserved.
as a factor accelerating cognitive decline (114, 126).
to 96 percent and that the specificity of these criteria for Although it is possible that antipsychotics could exacerbate DAT against other dementia ranges from 23 percent to 88 cognitive deficits through their anticholinergic effects (117), some studies have failed to corroborate the findings that Table 2 briefly summarizes the screening instruments antipsychotic medications are associated with more rapid used to determine the need for further evaluation. The cognitive decline in DAT patients (117, 127–129). Although MMSE (140), consisting of a brief assessment of language, there is little information on the effects of other commonly memory, praxis, and orientation, is the most widely used and used psychotropic medications on cognition in patients with has been the most extensively studied with respect to its DAT (125, 129), a positive association between certain psy- accuracy and validity (141–146). MMSE scores are affected chotropic medications (sedatives and anxiolytics) and cogni- by gender, educational attainment, age, and cultural back- tive deterioration has been reported (129).
ground (143, 147, 148); the sensitivity of the MMSE is poorfor patients with mild dementia (2, 149); the instrument isconsidered too time-consuming to administer in routine ASSESSMENT METHODS clinical practice (150, 151); not all changes in MMSE scoresnecessarily reflect true clinical improvement or decline In practice and in research, DAT is diagnosed by applying (152, 153); and the MMSE exhibits floor effects in patients the DSM-IV-TR criteria (130) and/or those of the National with severe impairment and ceiling effects in those who are Institute of Neurological and Communicative Diseases and mildly impaired (154). Modifications, alternatives, and sup- Stroke/Alzheimer's Disease and Related Disorders Associ- plements to the MMSE such as the modified version of the ation (NINCDS/ADRDA) (40). Whereas the DSM-IV-TR MMSE (155); the Montreal Cognitive Assessment (156); criteria require the presence of memory impairment and the Memory Impairment Screen (157); the Blessed Test of cognitive deterioration in one other domain such as lan- Information, Memory, and Concentration (158) and its guage, perception, or motor skills, or disturbances in exec- abridged version, the Short Blessed Test (159); the One- utive functioning (130), the NINCDS/ADRDA criteria Minute Verbal Fluency Test for Animals; and the Clock classify the likelihood of DAT into one of three categories: Drawing Test (160) have been advanced.
definite (clinical diagnosis coupled with a histologic confir- Although the lines between screening instruments and mation of Alzheimer's disease), probable (clinical diagnosis neuropsychological battery tests are sometimes blurred, without a histologic confirmation), and possible (atypical generally the former are much less time-consuming and de- symptoms with no apparent alternative diagnosis in the ab- tailed than the latter; battery tests often combine multiple sence of a histologic confirmation) (40). The NINCDS/ screening tests so that more cognitive symptoms in DAT can ADRDA clinical diagnostic criteria, similar to those of the be covered in one assessment; and battery tests may allow DSM-IV-TR, require a subtle onset and a gradual worsening for discrimination between DAT and other illnesses affect- of cognitive function and that other etiologies (e.g., thyroid ing cognitive function. One of the most commonly used diseases) be ruled out. Studies validating the NINCDS/ neuropsychological instruments in clinical trials of antide- ADRDA and DSM-IV-TR against a variety of ‘‘gold stand- mentia medications in the United States is the Alzheimer's ards'' have found that the sensitivity ranges from 65 percent Disease Assessment Scale-Cognitive Subscale (161, 162).
Epidemiol Rev 2008;30:15–34 Dementia of the Alzheimer Type Summary of commonly used DAT* screening instruments Cognitive domains assessed Language, memory, praxis, 8–13 minutes in duration (310), covers Sensitivity poor in those with mild a wide variety of cognitive domains dementia (2, 149); performance in a brief test, reliable (149, 311) affected by age, educationalattainment, gender, and culturalbackground (2, 143, 148); too long toadminister routinely in clinical practice(150, 151); ceiling effects in mildimpairment and floor effects in severeimpairment (154) Language, memory, praxis, 10–15 minutes in duration (310), samples Takes longer to administer than the orientation, executive a broader variety of cognitive domains than the MMSE (155), enhanced reliability and validity relative to theMMSE (155, 312) Language, memory, praxis, High specificity and sensitivity for mild Useful primarily for mild cognitive cognitive impairment and mild DAT impairment and mild DAT (156), abilities, attention, (156), can detect mild cognitive longer to administer than the MMSE concentration, executive impairment (156), reliable (156) 4 minutes in duration (310); performance Covers few cognitive domains in DAT not affected by age, education, or patients, sensitivity influenced by severity of dementia (157) Performance not correlated with Covers few cognitive domains in DAT educational background (151), does patients, demonstrates intermediate not require a specific form to administer sensitivity (151) 5 minutes in duration (310), reliable Covers few cognitive domains in DAT (314, 315), can differentiate between patients, should be used in conjunction mild cognitive impairment and normal with other screens subjects (159), highly sensitive andspecific for dementia (313), highcorrelation with the MMSE (163, 314) Language, semantic 1 minute in duration, less time-consuming Covers few cognitive domains in DAT than most screens, correlates well with patients, demonstrates intermediate the MMSE (163), demonstrates good sensitivity (151), should be used in discrimination between persons with conjunction with other screens dementia and normal controls (316),does not require a specific form toadminister Praxis, executive 2 minutes in duration (310), less Covers few cognitive domains in DAT functioning, attention, time-consuming than most screens, patients, subjective interpretation of visuospatial abilities high interrater reliability (317) clock drawing, intermediate sensitivityand specificity (313, 317), should beused in conjunction with other screens * DAT, dementia of the Alzheimer type; MMSE, Mini-Mental State Examination.
This instrument assesses memory, language, praxis, and ori- calculation, and perception). Screening instruments, partic- entation with a total score ranging from zero (no impair- ularly the MMSE, and more in-depth neuropsychological ment) to 70 (severely impaired). The Neuropsychological tests are also often used to chart the rate of cognitive Battery of the Consortium to Establish a Registry for Alzheimer's Disease (163) consists of seven tests, includingthe MMSE and three others adapted from the Alzheimer'sDisease Assessment Scale-Cognitive Subscale (162) and BIOMARKERS AND NEUROIMAGING measures memory, language, praxis, and orientation. Otherneuropsychological tests used in dementia include, but are Disease-modifying drugs are likely to be more efficacious not limited to, the Syndrom-Kurztest (164) (assessing mem- in the early or preclinical stage of the disease (168, 169).
ory, attention, naming, and object arrangement), the Seven- Promising biomarkers and neuroimaging could have a sub- Minute Neurocognitive Screening Battery (165) (assessing stantial public health impact if new drug candidates, such as memory, orientation, visual abilities, praxis, and language beta-amyloid immunotherapy or beta-sheet breakers, were skills), the Addenbrooke's Cognitive Examination (166) found to have disease-arresting effects (170). Evidence is (assessing orientation, attention, memory, language, and vi- currently insufficient to support or direct the use of bio- suospatial abilities), and the Cambridge Cognitive Exami- markers (table 3) in usual clinical practice for dementia di- nation (167) (assessing orientation, language, memory, praxis, agnosis or disease management purposes.
Epidemiol Rev 2008;30:15–34 Jalbert et al.
Summary of the rationale and the disadvantages of selected CSF* and plasma biomarkers Decreased levels of beta-amyloid in CSF may Requires a lumbar puncture; invasive and uncomfortable reflect increased deposition of beta-amyloid procedure; despite availability of a commercial test in the brain (171).
with high sensitivity and specificity, this biomarker isunderutilized (318).
tau is released from dying neurons, so total tau Requires a lumbar puncture; invasive and uncomfortable concentration in the CSF is thought to reflect procedure; nonspecific for Alzheimer's disease because the intensity of the neuronal damage and elevated levels of tau are observed in other degeneration (168).
degenerative CNS* conditions (168); despite theavailability of a commercial test with high sensitivityand specificity, this biomarker is underutilized (318).
Concentration of phosphorylated tau in the Requires a lumbar puncture; invasive and uncomfortable CSF may reflect the formation of tangles in procedure; despite the availability of a commercial test the brain because there is no increase in with high sensitivity and specificity, this biomarker is phosphorylated tau in other diseases with intense neuronal degeneration (e.g.,Creutzfeldt-Jakob disease) (168).
Plasma beta-amyloid Beta-amyloid is produced in the brain and Plasma beta-amyloid levels do not correlate well with cleared to the plasma via the CSF and the biochemical or pathological measures of cerebral blood brain barrier (319).
beta-amyloid deposition (181); there is broad overlapin the plasma levels of beta-amyloid peptides inpersons with DAT* and controls, making discriminationof persons with and without Alzheimer's diseasedifficult (171).
Plasma amyloid-beta Antibodies against neuritic plaques may Titer of beta-amyloid antibodies has been found to be protect against Alzheimer's disease significantly higher in healthy controls than in patients with DAT (322); some studies have found nocorrelation between antibody titer and prevalence ofDAT (323); immune response to beta-amyloid 40 andtolerance of beta-amyloid 42 occurs naturally inhumans and is not related to the neuritic plaqueburden in the brain (171).
The APOE e4 allele is associated with Studies of levels of APOE in DAT have been increased neuritic plaque load and elevated contradictory; some have reported elevated APOE levels of beta-amyloid in the brain levels in DAT (328), no difference (329–331), or (324–326); the APOE e4 allele is associated reduced (332, 333) levels compared with controls.
with less APOE protein in plasma (327).
Plasma isoprostanes Increased levels of lipid oxidation in the Isoprostanes appear to be elevated in DAT patients Alzheimer's disease brain support a role for relative to controls (334), but these findings have been oxidative stress in DAT (171); free-radical- challenged (335).
mediated peroxidation of polyunsaturatedfatty acids creates isoprostanes (171).
Inflammatory molecules Amyloid deposition in the Alzheimer's disease Many of the proteins involved in the inflammatory such as interleukin-6 brain elicits a range of inflammatory response do not cross the blood-brain barrier (188); responses (57, 336); interleukin-6 is a controversy exists regarding the levels of cytokine and cytokine implicated in inflammation.
acute-phase reaction reactants in the blood followingan inflammatory response (187); findings from studiescomparing the levels of plasma interleukin-6 in peoplewith DAT and in healthy controls have been inconsistent(182, 185, 186, 337).
* CSF, cerebrospinal fluid; CNS, central nervous system; DAT, dementia of the Alzheimer type; APOE, apolipoprotein E.
Beta-amyloid 42, a more aggregate-prone peptide derived Plasma levels of beta-amyloid peptides in persons with from the amyloid precursor protein, a key molecule in DAT overlap those found in controls (171, 178–180) and do Alzheimer's disease pathology (171), total tau, and phosphor- not reflect neuropathological or neurochemical measures of ylated tau in the cerebrospinal fluid are biomarkers with the levels of beta-amyloid deposition in the brain (181).
high diagnostic sensitivity and specificity for Alzheimer's Some studies reported increased levels of interleukin-6, a cy- disease (172, 173). The decrease in beta-amyloid 42 in the tokine implicated in inflammation, in serum and plasma of cerebrospinal fluid, presumably a result of its decreased persons with DAT (182, 183), whereas others did not (184– clearance from the brain into the cerebrospinal fluid (174), 186). Cytokine and acute-phase-reaction reactant levels in has recently been added as one of the supportive features of the plasma or serum remain controversial (187), and many the proposed revisions of NINCDS/ADRDA criteria for of these proteins do not cross the blood-brain barrier (188).
Alzheimer's disease (131). Cerebrospinal fluid biomarkers Cerebrospinal fluid measures of beta-amyloid, total tau, and may be able to identify preclinical Alzheimer's disease even hyperphosphorylated tau are currently the best biomarkers before the onset of mild cognitive impairment (175–177).
Epidemiol Rev 2008;30:15–34 Dementia of the Alzheimer Type Within the medial temporal lobe, the disease consistently quent use in clinical practice, few have been studied in manifests itself through atrophy of the hippocampus and controlled trials. Much of the published evidence is charac- parahippocampal gyrus (189), which can be visualized by terized by a number of limitations such as inadequate sample using structural magnetic resonance imaging (190). Mag- sizes, short study duration, use of nonstandardized evaluation netic resonance imaging measurements of the medial tem- methods, and lack of information on persistence of treatment poral lobe include the qualitative appraisal of atrophy in the effects (209). Although short-term adverse consequences of hippocampal formation (191) as well as quantitative tech- nonpharmacological interventions, such as agitation and cat- niques analyzing tissue segmentation and computing cerebral astrophic reactions, have been reported in some studies, these volume (192). Sensitivity ranges from 80 percent to 100 outcomes have not been a focus of research (210).
percent (193–195) and specificity is over 90 percent (194) The 2007 American Psychiatric Association guidelines when magnetic resonance imaging–based estimates of the for treatment of patients with DAT and other dementias volume of various regions of the medial temporal lobe are categorize nonpharmacological or psychosocial treatments used to discriminate between patients with Alzheimer's dis- into four broad areas: emotion oriented (reminiscence ther- ease and normal controls. Functional magnetic resonance apy, validation therapy, supportive psychotherapy, sensory imaging may also allow for earlier detection of Alzheimer's integration, and simulated-presence therapy), stimulation ori- disease (189).
ented (recreational activities, art therapies, exercise), cogni- Single-photon emission computed tomography has been tion oriented (reality orientation, cognitive retraining, skills used to measure regional cerebral blood flow, which corre- training), and behavior oriented (211). The growing interest lates well with severity of DAT (196, 197) and prognosis in newer, nonpharmacological interventions such as cognitive (198), although its diagnostic accuracy for distinguishing rehabilitation and retraining techniques in the early stages of between DAT and non-DAT in studies including healthy DAT is focused on developing therapies that enhance present controls is quite low (pooled weighted sensitivities ranged capabilities and possibly augment the effects of cholinester- from 65 percent to 71 percent with a specificity of 79 per- ase inhibitors (212, 213). While some studies have reported cent) (199). Computed tomography, the oldest technique for treatment-related improvements in specific cognitive do- scanning the brain, is generally used to exclude other causes mains, well-designed, randomized trials of these interven- of dementia (e.g., subdural hematomas) (189) but is worse tions are lacking, and the effect on real-life skills, required than cognitive screening in identifying dementia (200).
for independent living, is largely unknown (214).
Positron emission tomography can assess hypometabo- Nonpharmacological interventions for dementia-related lism and hypoperfusion and, when conducted with fluoro- neuropsychiatric symptoms have been more widely studied deoxyglucose, can measure the regional cerebral metabolic and target predominantly neuropsychiatric symptoms in rate of glucose (201). Approved in the United States as a di- mild to moderate stages of dementia (e.g., communication agnostic tool, fluorodeoxyglucose2positron emission to- techniques, environmental alterations) (215). Studies of mography is highly sensitive and specific in detecting patient-centered behavioral interventions such as sensory Alzheimer's disease in its early stages (202). Positron emis- stimulation or music therapy have reported positive, but sion tomography techniques in combination with use of an short-lived effects on agitation and other symptoms (216).
amyloid-specific tracer may also provide in vivo visualiza- Caregiver interventions may have long-term benefits be- tion of neuritic plaques. Studies using the Pittsburgh Com- cause several well-designed trials of psychoeducation pro- pound B, a molecule that binds preferentially to beta- grams for caregivers of persons with dementia reported amyloid fibrils (203), demonstrated that brains of DAT pa- a decrease in the frequency of neuropsychiatric symptoms tients had a two- to threefold greater Pittsburgh Compound and a delay in the time to institutionalization (217, 218).
B retention on positron emission tomography scans relative The currently available DAT pharmacotherapeutic agents to cognitively intact age-matched controls, and retention was are symptomatic rather than disease-modifying treatments.
consistent with Alzheimer's disease pathology (204–206).
Symptomatic treatments such as cholinesterase inhibitors Pittsburgh Compound B–positron emission tomography im- and memantine, an N-methyl-D-aspartate receptor antago- aging of amyloid deposits may have the potential to increase nist, may stabilize or slow the progression of DAT, but these diagnostic accuracy of DAT and could serve as a tool for effects are lost after discontinuation (219, 220). Disease- monitoring the changes in beta-amyloid pathology over the modifying therapies are being designed to target various course of DAT (206).
aspects of DAT neuropathology and confer benefits thatpersist beyond the course of treatment. The three broad in-vestigational classes of disease-modifying treatments are TREATMENTS FOR DAT antiamyloid agents, neuroprotective agents that reduce orprotect against neuronal injury associated with amyloid de- Optimal treatment of DAT requires both nonpharmaco- position, and neurorestorative strategies such as nerve logical and pharmacological interventions (207). Given the growth factors and cell transplantation (221). Experts in progressive nature of the illness, interventions must be pe- the field have theorized that the most effective DAT medi- riodically reviewed and revised to meet the changing needs cation regimens of the future will combine symptomatic and of the patient.
disease-modifying agents (221, 222).
Nonpharmacological methods are appropriately used Cholinesterase inhibitors have been the cornerstone of throughout the severity spectrum of DAT and are used alone contemporary DAT pharmacotherapy for over a decade or in combination with pharmacotherapy (208). Despite fre- and were developed based on the cholinergic hypothesis Epidemiol Rev 2008;30:15–34 Jalbert et al.
of memory dysfunction (223). Degeneration of cholinergic controlled trials of mild-moderate disease, however, have neurons in the basal forebrain and declining levels of cho- failed to show conclusive evidence of benefit (231, 232).
line acetyltransferase, the enzyme responsible for acetyl- In a 6-month, placebo-controlled, monotherapy trial, mem- choline synthesis, are associated with progressive decline antine was associated with improvements in cognition and of cholinergic transmission in the cerebral cortex and hip- function (233). In addition, memantine or placebo added to pocampus (223). Cholinesterase inhibitors block the degra- a stable regimen of donepezil resulted in significant treat- dation of acetylcholine and are associated with modest ment effects favoring memantine in cognitive, functional, benefits in the domains of cognition, function, and behavior neuropsychiatric, and global outcomes over a 6-month period in DAT clinical trials (224). Two drugs in this class, donep- (234). To our knowledge, no head-to-head trials comparing ezil and galantamine, inhibit acetylcholinesterase, whereas memantine monotherapy with cholinesterase inhibitors tacrine and rivastigmine block both acetylcholinesterase and therapy in moderate-to-severe DAT have been conducted.
butyrylcholinesterase, an enzyme that plays a lesser role in Adverse-effect rates from placebo-controlled dementia the breakdown of acetylcholine (225). Galantamine is also trials indicate that memantine is generally well tolerated an allosteric nicotinic receptor modulator and enhances the effect of acetylcholine on nicotinic receptors (226). Donepezil, Considerable debate over the value of the pharmacolog- rivastigmine, and galantamine have supplanted tacrine because ical treatment of DAT continues and is fueled by difficulties of more convenient dosing, greater tolerability, and the in translating the modest effects observed in controlled trials absence of significant hepatotoxicity (224).
into meaningful clinical and economic benefits (235). The A recent meta-analysis of 13 double-blind, placebo- United Kingdom's National Institute for Health and Clinical controlled trials using donepezil, rivastigmine, or galant- Excellence recently revised its previous position and ap- amine treatments for 6 months to 1 year in patients with proved the use of cholinesterase inhibitors for moderate- mild, moderate, or severe DAT reported improvements over stage DAT only (235). Memantine is not recommended as placebo in cognition averaging 2.7 points (95 percent con- a treatment for DAT under the guidelines, except for patients fidence interval: 23.0, 22.3) on the 70-point Alzheimer's participating in clinical trials. Without solid evidence to Disease Assessment Scale-Cognitive Subscale and 1.37 points elucidate the optimal duration of therapy, the impact of (95 percent confidence interval: 1.13, 1.61) on the 30-point treatment on outpatient and institutional caregiver burden, MMSE scale (227). Modest, but statistically significant bene- and the effects of therapy on patient and caregiver quality of fits were also observed for global clinical ratings, activities of life, payers will continue to question the utility of treating daily living functioning, and neuropsychiatric symptoms.
DAT with the currently available agents.
More patients dropped out of cholinesterase inhibitor treat- Another area of controversy in DAT pharmacotherapy is ment groups because of adverse effects (29 percent) than what constitutes appropriate treatment of neuropsychiatric placebo-treated patients (18 percent), and fewer patients symptoms. Pharmacological treatment of neuropsychiatric experienced adverse events with donepezil compared with symptoms may be warranted when nonpharmacological in- terventions fail or when the nature or severity of neuropsy- Despite the structural differences between various cholin- chiatric symptoms endangers the safety of the patient or esterase inhibitors, there is no evidence to suggest clinical others (211). Before considering any pharmacological ther- differentiation in efficacy trials (227, 228). Of the four cho- apy to treat neuropsychiatric symptoms, it is essential that linesterase inhibitor comparative clinical trials that have physiologic (hunger, thirst, need to void) and medical causes been conducted, there is only one double-blind study: a of the behavior be investigated and treated because these 2-year comparison of donepezil with rivastigmine in patients antecedents can trigger or exacerbate neuropsychiatric with moderate DAT (range of MMSE scores: 10–20) (229).
symptoms (236, 237).
No significant treatment differences were observed be- Pharmacotherapeutic management of neuropsychiatric tween donepezil and rivastigmine regarding ratings of cog- symptoms poses complex challenges for clinicians and care- nitive function, activities of daily living performance, and givers because an increasing body of evidence has revealed neuropsychiatric symptoms (229). However, compared with that the potential ‘‘cost'' in the form of adverse effects may rivastigmine-treated patients, fewer donepezil patients dis- offset marginal therapeutic benefits for many patients (238).
continued treatment (odds ratio 5 0.64, 95 percent confi- A recent meta-analysis of antipsychotic, antidepressant, and dence interval: 0.50, 0.83) (229).
anticonvulsant clinical trials for dementia-related neuropsy- More recently, dysregulation of glutamatergic neurotrans- chiatric symptoms concluded that these medications offer mission in DAT was hypothesized to play a role in abnormal modest benefits and a considerable risk of adverse effects information processing, storage, and retrieval (230). Meman- (239). No medication has been approved by the US Food tine, a low-to-moderate-affinity, noncompetitive, N-methyl- and Drug Administration to treat dementia-related neuro- D-aspartate glutamate receptor antagonist, blocks excitotoxic neuronal toxicity associated with excessive release of gluta- The second generation of antipsychotics, atypical antipsy- mate (230). Memantine has been used in the treatment of chotics, is the best-studied and most commonly prescribed a variety of neurologic disorders for more than 25 years in class of psychoactive medications for neuropsychiatric symp- Europe and, in 2003, was approved in the United States to toms. A number of recent placebo-controlled clinical trials of treat moderate-to-severe DAT.
atypical antipsychotics for neuropsychiatric symptoms have Studies of memantine in patients with more advanced reported small treatment effects coupled with adverse effects DAT have reported favorable treatment effects; randomized, at rates that exceed those observed among placebo-treated Epidemiol Rev 2008;30:15–34 Dementia of the Alzheimer Type patients (238, 240). Results from some randomized con- stage of the illness (254). Increasing dependency, personality trolled trials in dementia and subsequent meta-analyses have changes, and neuropsychiatric symptoms such as aggression/ identified an increased risk of mortality and cerebrovascular- agitation and depression are also highly distressing to the adverse events associated with atypical antipsychotic treat- caregiver (255, 256). Providing assistance to a loved one ment (241, 242). Conventional antipsychotics may not be afflicted with DAT comes at a considerable emotional, psy- safer than atypical antipsychotics; subsequent analyses have chological, and physical cost to the caregiver. Informal care- reported an elevated risk of mortality associated with the use givers report higher levels of depression and anxiety (255– of older antipsychotics in patients with dementia and other 259), lower overall life satisfaction (257, 260), and engaging psychiatric illnesses (243, 244). These developments have in fewer preventive health behaviors (261), and they are at fueled an ongoing debate over the appropriate prescribing increased risk of illness (262–265) and mortality (266).
of antipsychotics (242, 245).
Informal caregivers also often experience social isolation Better understanding of the safety issues associated with (256), financial strain (251, 259, 267), employment compli- antipsychotic therapy and the lack of safer and more effec- cations (258, 268), and disruption of relationships (258).
tive alternatives have stimulated interest in the effects of Research has predominantly focused on the negative and dementia-specific medication on neuropsychiatric symp- deleterious aspects of caregiving, but some studies have toms. Modest reductions in neuropsychiatric symptoms found that caregivers of persons with dementia perceive have been reported from trials of cholinesterase inhibitors, their caregiving as providing them with positive and satis- fying experiences (269–272).
donepezil in DAT patients (227, 246). Studies of small num- The decision to institutionalize a loved one afflicted with bers of patients in open trials of cholinesterase inhibitors DAT is difficult and complex but has been found to be as- (donepezil, rivastigmine, galantamine) and in one double- sociated with the patient's manifestation of neuropsychiatric blind, placebo-controlled trial with rivastigmine have re- symptoms, caregiver exhaustion, and the increased need for ported varying degrees of improvement of neuropsychiatric patient supervision (273–276). As many as 90 percent of symptoms and psychosis in dementia with Lewy bodies patients with dementia will be institutionalized before death (247). Delusions, hallucinations, apathy, and agitation/ (277). Among new admissions to nursing homes, the prev- aggression are the symptoms most likely to show significant alence of dementia is nearly 70 percent (278); in 1999, improvement in trials of DAT or dementia with Lewy bodies approximately 214,200 nursing home residents were living (246), but there is considerable intertrial heterogeneity in with DAT (279).
neuropsychiatric symptoms domains showing the greatest In the last few decades, there has been a rapid prolifera- response to treatment. Current treatment guidelines suggest tion of dementia special care units in nursing homes (280).
a trial of a cholinesterase inhibitor and/or memantine in Approximately 10 percent of nursing homes had a special the management of nonacute neuropsychiatric symptoms unit for people with dementia in the 1990s; this figure has risen to 20 percent (281, 282). There is no consensus defi- A substantial number of patients with dementia experi- nition of what constitutes ‘‘special care'' for dementia, but ence severe and persistent neuropsychiatric symptoms that a modified physical environment, special programs for res- may require the use of medication for varying periods of idents and families, and additional staff training and cover- time throughout the course of DAT (248). The optimal treat- age have become standard features (283). Studies evaluating ment of neuropsychiatric symptoms is an essential research the impact of living in a special care unit on improved focus. More thoughtfully designed randomized controlled resident outcomes (slower cognitive and functional decline trials of pharmacological agents as monotherapy and in and fewer neuropsychiatric symptoms) have been contradic- combination with innovative nonpharmacological interven- tory (284–287). In contrast, research has shown that the use tions are urgently needed.
of psychotropic medications is higher among residents ofspecial care units (288–290).
CAREGIVING AND LONG-TERM CARE As persons with DAT become more cognitively and func- tionally impaired, many lose the ability to care for them- Alzheimer's disease is a complex neurodegenerative ill- selves and become dependent on others for their care (249).
ness, but much progress has been made in understanding it.
The majority of informal DAT caregivers are caring for Research on the use of neuroimaging and biomarkers is a relative, usually a parent, because the spouse of a DAT promising and may allow for earlier and more accurate de- patient may be deceased or unable to provide the level of tection of Alzheimer's disease cases. Most studies across the care needed without substantial help from his or her children world indicate that the incidence and prevalence of DAT are (250, 251). The burden of care is often borne by one in- increasing. The majority of persons afflicted with DAT will dividual (252).
exhibit neuropsychiatric symptoms, but symptom-specific Caregiving generally requires a significant investment of prevalence estimates vary widely and it is unclear how time, energy, and money that often needs to be sustained and if stage-specific prevalence of individual symptoms over a period of years (252, 253). The number of hours per changes. Current pharmacological treatments for DAT ap- week spent providing care increases from 13.1 for patients pear to slow progression of the disease but are not disease with mild dementia to 46.1 for those in the more advanced modifying. Further research on disease-modifying therapies Epidemiol Rev 2008;30:15–34 Jalbert et al.
is needed if the prevalence and clinical course of the condition Rockville, MD: Agency for Healthcare Research and Quality, are to be altered. This review underscores that much more 2000. (Fact sheet; AHRQ publication no. 00-P012).
needs to be done before the mystery of DAT is unraveled.
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Isolation and characterisation of a novel angiotensin i-converting enzyme (ace) inhibitory peptide from the algae protein waste

Food Chemistry 115 (2009) 279–284 Contents lists available at Isolation and characterisation of a novel angiotensin I-converting enzyme(ACE) inhibitory peptide from the algae protein waste I.-Chuan Sheih a, Tony J. Fang a,1, Tung-Kung Wu b,* a Department of Food Science and Biotechnology, National Chung Hsing University, 250 Kuokuang, Taichung 40227, Taiwan, ROCb Department of Biological Science and Technology, National Chiao Tung University,75 Po-Ai Street, Hsin-Chu 30068, Taiwan, ROC

20 Medizin Medical Tribune · 45. Jahrgang · Nr. 6 · 12. Februar 2010 Westerwälder Hausärzte verschreiben sich dem RennsportSieg im Cockpit – darüber entscheidet auch der Doktor MONTABAUR – Extreme Ge- Herzfrequenz und auch Luftschad- falls gibt es ein Nickerchen schwindigkeiten, massive Er- stoffe, wie sie etwa beim Abrieb der zwischendurch, da wo ge-