CURRENT CLINICAL NEUROLOGY - PART 8 doc

Mixed Dementia 245 245 From: Current Clinical Neurology Vascular Dementia: Cerebrovascular Mechanisms and Clinical Management Edited by: R. H. Paul, R. Cohen, B. R. Ott, and S. Salloway © Humana Press Inc., Totowa, NJ 17 Understanding Incidence and Prevalence Rates in Mixed Dementia John Gunstad and Jeffrey Browndyke 1. INTRODUCTION Countries throughout the world are reporting increased life-spans and lower birth rates. These sociodemographic changes result in the elderly, particularly the oldest old, comprising an increas- ingly larger segment of the population (1). Consequently, dementia is projected to be one of the major health-care problems of future decades (2). Alzheimer’s disease (AD) and vascular dementia (VaD) have long been considered the most preva- lent forms of dementia (3). More recently, increased attention has been given to the co-occurrence of AD and VaD, typically referred to as mixed dementia (MD). Although first described in the 1960s, MD has received relatively little attention until recently (4). It has been speculated that MD may be the most common form of dementia (5), but its “true” prevalence remains unknown. A growing number of studies report the frequency of MD within their samples of patients with dementia or in the community at large, but these studies were designed to detect AD or VaD, not MD. The goals of this chapter are to present the incidence/prevalence rates of MD reported in past studies, to identify possible methodological concerns of these studies, and to suggest future directions for MD studies. To accomplish these goals, this chapter has been divided into five sections: 2. RATES OF MIXED DEMENTIA 2.1. Terminology Review The prevalence of a disorder may be defined as the “fraction (proportion) of a group possessing a clinical outcome at a given point in time and is measured by a single examination or survey of a group” (6). Incidence rates refer to the “fraction or proportion of a group initially free of the outcome which develops the outcome over a given period of time” (6). To put these definitions into more concrete terms, incidence rates refer to the number of examined persons that develop MD within a particular time period, whereas prevalence rates refer to the number of individuals who develop MD and survive until the time of assessment. Incidence studies are typically longitudinal, requiring researchers to assess the same sample on at least two occasions. Prevalence studies assess partici- pants at a single time point, establishing a “point prevalence” for the condition of interest. 2.2. Incidence Rates Few studies have examined the incidence of MD. Reported incidence rates of MD and combined MD /VaD are presented in Tables 1 and 2. 246 Gunstad and Browndyke Standardized incidence rates were used to promote comparison across studies. Rates were stan- dardized by dividing the total number of incident cases by the average number of years to follow-up (13). This value was then standardized to incidence per 100 cases. It should be noted that this method assumes a constant incidence rate over time (e.g., 100 incident cases during 10 yr, 10 cases/yr), even though MD rates increase with age (14,15). Despite this potential statistical artifact, standardized incidence rates allow greater comparability across studies than cases per patient years (e.g., cases per 1000 patient yr) because of the differential influence of long-enrolled participants. Using this method, the incidence rates of any type of dementia range from 1.5 to 5.0 cases per 100 persons, with MD incidence ranging from 0.2 to 0.7 cases per 100 persons/yr. Overall dementia incidence rates for studies combining MD and VaD range from 1.7 to 5.7, with MD /VaD incidence ranging from 0.2 to 1.4 cases per 100 persons/yr. Not appearing in the tables, the Sydney Older Persons Study found incidence rates of 3.3 for mixed AD and 1.4 for mixed VaD during an average of 3-yr follow-up (16). It is unclear how these groups may overlap. Table 2 Standardized Incidence Rates of Dementia in Studies Including Mixed Dementia With Vascular Dementia Study Population n Age Follow-up (yr) Total a AD b VaD/MD c Tsolaki et al., Pylea d 380 70+ 2–4 5.7 4.0 1.4 1999 (11) Greece Kawas et al., Baltimore, 1236 55–97 2–13 1.7 1.2 0.2 2000 (12) United States a Number of dementia cases per 100 persons. b Number of dementia cases per 100 persons attributed to Alzheimer’s disease (AD). c Number of dementia cases per 100 persons attributed to vascular dementia (VaD) or mixed dementia (MD). d Unable to provide standardized rate. Table 1 Standardized Incidence Rates of Dementia in Studies Separating Mixed Dementia From Vascular Dementia Study Population n Age Follow-up (yr) Total a AD b VaD c MD d Aronson et al., New York City, 442 75–85 8 2.4 1.0 — 0.7 1991 (7) United States Fratiglioni et al., Stockholm, 987 75+ 3 5.0 3.7 0.8 0.2 1997 (8) Sweden Liu et al., Southern 2175 65+ 2 1.4 0.6 0.4 0.2 1998 (9) Taiwan Lopez et al., Multisite, 2831 65+ 11 2.3 1.6 0.3 0.4 2003 (10) United States a Number of dementia cases per 100 persons. b Number of dementia cases per 100 persons attributed to Alzheimer’s disease (AD). c Number of dementia cases per 100 persons attributed to vascular dementia (VaD). d Number of dementia cases per 100 persons attributed to mixed dementia (MD). Mixed Dementia 247 2.3. Prevalence Rates of Mixed Dementia Relative to other forms of dementia, few studies have examined the prevalence rates of MD. Reported prevalence rates of MD are presented in Table 3. Prevalence rates for all dementia range from 2.7 to 29.8 cases per 100 persons, with MD prevalence ranging from 0.0 to 4.5 cases per 100 persons. Table 4 presents studies that reported the prevalence rates of MD by age group. Results suggest that MD becomes more prevalent with age, with a possible decline in the oldest old. This decline may reflect an increased mortality risk in persons with vascular pathology. A similar pattern is found in those studies reporting the combined prevalence of MD and VaD across the age span (see Table 5). Table 3 Dementia Prevalence Rates Study Population n Age Total a AD b VaD c MD d Brayne et al., Cambridgeshire, 365 70–79 7.9 4.1 2.5 0.3 1989 (17) England O’Conner et al., Cambridge, 2311 75+ 10.5 7.9 2.2 0.3 1989 (18) England Rocca et al., Appignano, 751 60+ 6.2 2.6 2.2 0.8 1991 (19) Italy Skoog et al., Gothenberg, 494 85+ 29.8 13.0 11.5 2.4 1993 (20) Sweden White et al., Honolulu, 3734 71–93 6.0 2.1 1.8 0.6 1996 (21) United States Andersen et al., Odense, 3346 65–84 7.1 4.7 1.3 0.1 1997 (22) Denmark Shiba et al., Hanazono-mura, 201 65+ 8.5 3.5 3.0 1.8 1999 (23) Japan von Strauss et al., Stockholm, 1424 77+ 25.1 19.2 4.4 0.0 1999 (24) Sweden Wang et al., Beijing, 5003 60+ 2.7 1.4 1.0 .002 2000 (25) China Ikeda et al., Nakayama, 1162 65+ 5.2 1.8 2.4 0.1 2001 (26) Japan Yamada et al., Amino, 3715 65–99 3.8 2.1 1.0 0.2 2001 (27) Japan Benedetti et al., Buttapietra, 222 75+ 15.8 6.8 3.6 1.4 2002 (28) Italy Herrara et al., Catanduva, 1656 65–96 7.1 3.9 0.7 1.0 2002 (29) Brazil Yamada et al., Campo Grande, 157 70–100 12.1 5.7 0.6 4.5 2002 (30) Brazil a Number of dementia cases per 100 persons. b Number of dementia cases per 100 persons attributed to Alzheimer’s disease. c Number of dementia cases per 100 persons attributed to vascular dementia. d Number of dementia cases per 100 persons attributed to MD. 248 Gunstad and Browndyke 2.4. Rates of Mixed Dementia in Clinicopathological Studies Clinicopathological studies may be categorized as being either prospective or retrospective examinations of a disorder. Prospective studies select individuals and follow them over time to iden- tify the frequency of a given clinical outcome. Retrospective studies identify persons with a given clinical outcome and gather information about the past (13). MD clinicopathological rates are presented in Table 6 and range from 2.9 to 54.2%. MD rates in prospective studies range from 2.9 to 31.3%, whereas retrospective rates range from 6.0 to 54.2%. Table 5 Dementia Prevalence Rates by Age in Studies Combining Mixed Dementia and Vascular Dementia Study Population Age Total a AD b VaD/MD c Sulkava et al., 1985 (31) Finland 30–64 0.3 0.03 0.08 65–74 4.2 1.7 1.9 75–84 10.7 6.3 4.3 85+ 17.3 14.8 2.5 a Number of dementia cases per 100 persons. b Number of dementia cases per 100 persons attributed to Alzheimer’s disease (AD). c Number of dementia cases per 100 persons attributed to vascular dementia (VaD) or mixed dementia (MD). Table 4 Dementia Prevalence Rates by Age in Studies Separating Mixed Dementia and Vascular Dementia Study Population Age n Total a AD b VaD c MD d Manubens et al., 1995 (14) Pamplona, Spain 72–74 146 6.3 0.6 3.0 1.3 75–79 311 11.8 8.2 1.9 0.3 80–84 302 17.3 10.6 2.2 2.2 85–89 279 25.6 17.8 0.9 4.6 90–91 89 34.7 25.0 6.1 2.3 Vas et al., 2001 (15) Bombay, India <49 12,099 0.0 0.0 0.0 0.0 50–54 3,933 0.08 0.0 0.05 0.0 55–59 2,422 0.04 0.04 0.0 0.0 60–64 2,112 0.3 0.05 0.1 0.1 65–69 1,751 0.9 0.5 0.2 0.2 70–74 1,157 2.4 1.6 0.4 0.2 75–79 481 5.0 2.9 1.2 0.4 80–84 336 5.1 3.9 0.6 0.9 85+ 208 3.9 2.9 1.0 0.0 a Number of dementia cases per 100 persons. b Number of dementia cases per 100 persons attributed to Alzheimer’s disease (AD). c Number of dementia cases per 100 persons attributed to vascular dementia (VaD). d Number of dementia cases per 100 persons attributed to mixed dementia (MD). Mixed Dementia 249 3. METHODOLOGICAL ISSUES As shown in Section 2., recent years have seen a growing number of studies report MD incidence and/or prevalence rates. Despite this interest, few studies have been specifically designed to detect the presence of MD. As a result, methodological concerns specific to MD are not accounted for in these studies. Concerns including the absence of established definition for MD, limits of instrumentation, differential mortality rates, possible selection bias, and low incidence rate likely result in an underes- timation of the actual incidence and prevalence of MD. Each of these concerns is briefly discussed in the following sections. 3.1. Lack of Established Criteria for Mixed Dementia Although researchers more or less agree that MD is the co-occurrence of AD and VaD, operational definitions vary widely across studies. Past definitions include: • A clinical dementia syndrome consistent with AD but with history of stroke (8). • History of acute focal neurologic symptoms/signs without a clear temporal connection with the evolution of the dementia (20). • Clinical history and Hachinski score of 5 or 6 (46). • The Neuroepidemiology Branch of the National Institute of Neurological Disorders and Stroke-Associa- tion Internationale pour la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN) criteria for AD with cerebrovascular disease (CVD) (29). • Alzheimer’s Disease Diagnostic Treatment Center (ADDTC) criteria (21). Table 6 Mixed Dementia Prevalence Rates in Clinicopathological Studies Study Study type n AD a VaD b MD c Jellinger et al., 1990 (32) Retrospective 675 60.0 15.7 7.9 Mirra et al., 1991 (33) Retrospective 142 41.5 2.1 28.1 Gilleard et al., 1992 (34) Prospective 64 37.5 32.8 15.6 Mendez, 1992 (35) d Retrospective 650 60.0 — 6.0 Giannakopoulos et al., 1994 (36) Retrospective 127 45.7 8.7 45.7 Ince et al., 1995 (37) Prospective 69 60.9 5.8 2.9 Victoroff et al., 1995 (38) Retrospective 196 33.7 1.5 7.7 Snowdon et al., 1997 (39) Prospective 102 36.2 1.0 23.5 Bowler et al., 1998 (40) Prospective 122 38.5 4.1 18.0 Nolan et al., 1998 (41) Retrospective 87 50.5 0.0 36.8 Lim et al., 1999 (42) Prospective 134 25.3 3.0 31.3 Kammoun et al., 2000 (43) Retrospective 120 17.5 28.3 54.2 Barker et al., 2002 (44) Retrospective 382 41.6 3.1 11.3 Jellinger, 2003 (45) Prospective 950 33.0 8.6 3.6 a Percentage of dementia cases attributed to Alzheimer’s disease (AD). b Percentage of dementia cases attributed to vascular dementia (VaD). c Percentage of dementia cases attributed to mixed dementia (MD). d Rate for pure VaD unavailable. 250 Gunstad and Browndyke There are also no established criteria for the identification of MD in clinicopathological studies. It absence may be the largest limiting factor in using these studies to identify MD prevalence (47) and limits comparison across studies (40). Past definitions include: • The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) protocol for AD and more than 100 mL combined infarct volume (37). • Presence of senile plaques and neurofibrillary tangles in excess of 5 mm 2 in the hippocampal formation/ neocortex and the presence of multifocal cerebral infarcts (36). • The presence of moderate or severe concentrations of neuritic plaques in the neocortex and two or more gross cortical infarcts or two or more gross subcortical infarcts (35). Conclusions regarding clinicopathological studies are further complicated by the use of different criteria at various sites within the same study (38) or changing criteria over time (41). Further com- plicating these studies, many persons exhibit neuropathological changes at autopsy similar to those found in AD, VaD, or MD but do not meet clinical criteria for dementia (36,37). 3.2. Measurement Limitations The limitations of cognitive screening instruments in detecting dementia are well known (48). Instrument selection is critical, because different measures have different conceptualizations of cognitive impairment (49). Screening instruments also vary in their psychometric properties, often with less than desirable reliability/validity, sensitivity/specificity, and degree of regression to the mean over multiple assessments. Studies also use different cutoffs on similar instruments, further limiting comparison. For example, many dementia studies use a form of the Mini-Mental State Examination (MMSE) to screen participants, although cutoff scores for impairment range from 23 to 17 total correct (8,25). Concerns regarding instrumentation or measurement issues are not limited to incidence and preva- lence studies of MD. Standard practices in autopsy studies may also distort the prevalence rates of different forms of dementia. Korczyn (5) describes potential concerns in using pathological studies to detect dementia, including using only half the brain for analysis, failure to include myelin stains, and slicing at 5- to 10-mm intervals (perhaps missing lacunes between slices). 3.3. Differential Mortality for Mixed Dementia? Although unknown, the mortality rate of individuals with MD is likely elevated. All persons with dementia have a higher mortality rate than their counterparts without dementia (50), and individuals suffering from VaD are at greatest risk (51). If MD progression is more similar to VaD than AD (52), it is appropriate to assume an elevated mortality rate for MD. If so, more persons with MD would die before assessment than other types of dementia (i.e., AD) and thus underestimate its prevalence. Methodological and statistical procedures have been developed to allow researchers to estimate dementia in persons who die between assessment time points (53). However, these methods can distort observed rates, because a single source of information (e.g., death certificate or informant) rarely provides sufficient information to accurately diagnose antemortem dementia (53). 3.4. Selection Bias Obtaining a representative sample is a difficult task, because prevalence rates are influenced by many factors. One factor is the compliance rates of potential participants. Epidemiological studies often overrepresent younger, healthier individuals (6), perhaps reflecting the less positive attitude toward study participation in older persons with cognitive impairment (54). Another factor affecting sample composition is the method by which persons are enrolled. For example, dementia prevalence is higher in institutional settings than community-based samples (55). Rates of different kinds of dementia are also believed to vary by geographic region (19). Although these factors are well known, their effects on observed prevalence rates of MD remain unclear. Mixed Dementia 251 As in clinical studies of MD, recruiting a representative sample is important in clinicopathological studies. Neuropathological studies are often conducted on samples of persons originally referred to a memory disorders clinic, and higher rates of AD are found in memory clinic samples than in commu- nity samples (56). Furthermore, persons with AD may be more likely to participate in necropsy stud- ies (52). It remains unclear how these tendencies influence observed MD rates. 3.5. Low Incidence Rates Accurate determination of the incidence of disorders with low incidence rates is difficult. Although MD is not a rare condition (its incidence similar to stroke in the general population, 0.15 per 100 cases per year [57]), its incidence is much lower than AD or geriatric depression (4.6 per 100 persons per year [58]). A large sample size is required to compensate for this low incidence rate, typically larger than those employed in past studies. 4. DEVELOPMENT OF MIXED DEMENTIA Another obstacle in determining the true incidence and prevalence rates of MD is the development of the disorder, because MD may look different to the clinician or pathologist at different points in time (see Fig. 1). Persons identified as having MD at autopsy likely move from one diagnostic cat- Fig. 1. Possible clinical course of MD. 252 Gunstad and Browndyke egory to another in the years before death, reflecting the progression of neurodegenerative and vascu- lar pathology over time. For example, early in the disease course, a person may be diagnosed with mild cognitive impair- ment (MCI) or vascular cognitive impairment no dementia (VCI-ND) (59,60). With the passing of additional time and exacerbation of vascular problems, persons may be diagnosed with VaD (given the similarities between VaD and MD progression [52]). Finally, these vascular problems cause a proliferation of senile plaques and neurofibrillary tangles, resulting in the neuropathological changes consistent with MD. If this hypothesized development is accurate, an individual’s death at different stages of the disorder would result in different neuropathological findings, despite the possibility that all represent the same underlying disorder. Support for this progression may be found in clinical studies of persons with mild cognitive dys- function who later develop dementia. Persons with VCI-ND progress to MD, AD, or VaD (60). Indi- viduals with vascular problems and cognitive difficulties progress to AD at approximately the same rate as those with MCI (59). Persons with MCI progress to VaD at a higher rate than controls, not just AD (61). These findings may be interpreted in many ways. One interpretation is that these findings reflect the need for better diagnostic criteria and more sensitive instrumentation. Another, more optimistic, perspective is that these findings are accurate and hint at the “synergistic” interaction between vascu- lar and degenerative processes of the brain (62). Such optimism appears warranted, because both vascular and degenerative lesions influence cognitive performance in persons with dementia and controls and most demented persons exhibit mixed pathology at autopsy (63). 5. FUTURE DIRECTIONS Dementia researchers have devoted increased resources to cross-cultural and genetic studies in recent years. This attention is well-founded, because a better understanding of cross-cultural demen- tia rates and the likely genetic contribution to cognitive impairment may offer insight into the etiol- ogy of all dementia syndromes, including MD. 5.1. Cultural Issues in Mixed Dementia It is believed that nearly 75% of all persons with dementia in 2020 will reside in a developing nation (64). Despite the methodological difficulties involved in conducting studies in third-world regions (65), determination of the incidence and prevalence of dementia in various countries may yield important etiological clues (3). In addition to studying people in developing nations, further attention is also needed in examining underserved populations within developed nations. For example, relatively little is known about dementia rates in Native American populations (66). 5.2. Genetics and Mixed Dementia The search for possible genetic factors in dementia recently has received considerable attention. The presence of the apolipoprotein E4 (apo E4) allele is frequently associated with increased risk for AD (67). Studies also report a relationship between apo E4 and VaD (68), although this finding is inconsistent (69). Currently, no large studies have examined the relationship between apo E4 and MD. However, apo E4 has been linked to coronary heart disease (70) and atherosclerosis (71), suggesting the possibility of a common mechanism (72). Finally, no study has examined the possi- bility of the genetic factors associated with increased risk for vascular pathology (e.g., angiotensin peptide receptors) being associated with MD, AD, and VaD. 6. CONCLUSION Although it has been speculated that MD may be the most common form of dementia, its “true” prevalence remains unknown. MD incidence rates range from 0.2 to 0.7 cases per 100 persons per Mixed Dementia 253 year, with prevalence estimates ranging to 4.5% of the elderly population. 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The N-terminal portion of the molecule has a laminin-binding (NTA) domain, nine Kazel-type protease inhibitor repeats (shaded), a region homologous to domain III of laminin B chains (III), a serine- and threonine-rich domain (S), and a 3 8- amino acid hydrophobic region believed to be a signal sequence The C-terminal portion has four epidermal growth factor (EGF)-like cysteine repeats (E), a serine-threonine-rich... 2002;977:162–1 68 37 Shibata M, Yamada S, Kumar SR, et al Clearance of Alzheimer’s amyloid-ss( 1-4 0) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier J Clin Invest 2000;106:1 489 –1499 38 Bading JR, Yamada S, Mackic JB, et al Brain clearance of Alzheimer’s amyloid-beta40 in the squirrel monkey: a SPECT study in a primate model of cerebral amyloid angiopathy J Drug Target 2002;10:359–3 68. .. stroke involving large-vessel disease Arterioscler Thromb Vasc Biol 1007;17: 288 0– 288 4 9 Friedman G, Froom P, Sazbon L, et al Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury Neurology 1999;52:244–2 48 10 McCarron MO, Hoffmann KL, DeLong DM, et al Intracerebral hemorrhage outcome: apolipoprotein E genotype, hematoma, and edema volumes Neurology 1999;53:2176–2179... 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