Mild cognitive impairment: new neuropsychological and ...

Archives of Clinical Neuropsychology 19 (2004) 11–27

Mild cognitive impairment: new neuropsychological and pharmacological target Rafael A. Rivas-Vazquez a,b,∗ , Cecilia Mendez b , Gustavo J. Rey b,c,d , Enrique J. Carrazana c a

Neurologic Center of South Florida, Psy. D. 8940 N. Kendall Drive, Suite 802-E, Miami, FL 33176, USA b Miami Research Associates, Neuroscience Division, Miami, FL 33176, USA c Department of Neurology, University of Miami, Miami, FL 33176, USA d Neuroscience and Behavioral Medicine, Miami Children’s Hospital, Miami, FL 33176, USA Accepted 15 July 2002

Abstract Mild cognitive impairment (MCI) is increasingly being conceptualized in the literature as a cognitive disturbance representing a transitional phase between normal aging and dementia. The operational definitions of MCI provide an opportunity for neuropsychologists to detect subtle deficit and monitor cognitive status sequentially in order to determine rate and degree of progression. More importantly, clinical and neuropsychological studies are needed that can better characterize which MCI patients are at greatest risk for conversion to dementia. Preliminary data has also designated MCI as a potential indicator for initiation of pharmacotherapy, with the objective of decelerating rate of progression to dementia. Current criteria and clinical issues related to MCI are discussed, with the objective of better familiarizing clinicians with this syndrome and fostering ongoing investigations. © 2002 National Academy of Neuropsychology. Published by Elsevier Ltd. All rights reserved. Keywords: Mild cognitive impairment; Alzheimer’s disease; Prodromal Alzheimer’s disease

Concern regarding the projected prevalence of Alzheimer’s disease (AD) over the next several decades has stimulated a great deal of clinical and research effort aimed at developing and implementing therapeutic interventions for this illness. One investigative approach has focused on enhancing the detection of AD in its earliest stages and determining the feasibility of decreasing its rate of progression. In this vein, interest has developed regarding the relevance ∗

Corresponding author. Tel.: +1-305-595-4041x208. E-mail address: [email protected] (R.A. Rivas-Vazquez).

0887-6177/$ – see front matter © 2002 National Academy of Neuropsychology. PII: S 0 8 8 7 - 6 1 7 7 ( 0 2 ) 0 0 1 6 7 - 1

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R.A. Rivas-Vazquez et al. / Archives of Clinical Neuropsychology 19 (2004) 11–27

Fig. 1. Number of articles appearing in the literature from 1996 through 2001 in which the term MCI was used as a specific clinical entity preceding dementia.

of a clinical entity being referred to as mild cognitive impairment (MCI). Although this term has been used descriptively in the literature for decades, there has been a notable trend over the last several years to define MCI as a transitional phase between normal aging and early AD (Petersen, Doody et al., 2001). To determine this, we conducted a literature search of MEDLINE and PsychInfo databases from 1996 through 2001 using the search term “mild cognitive impairment.” All citations identified through this search were reviewed to determine whether the term was being used descriptively and non-specifically (e.g., to describe the severity of cognitive deficit following a head trauma) or as a specific reference to this boundary zone between normal aging and dementia (Fig. 1). Essentially, there appears to be growing consensus in the use of this term to define individuals evidencing this transitional stage of cognitive functioning. Proponents for establishing MCI as a separate nosological entity believe that such a consensus will increase awareness of this syndrome and consolidate clinical and research efforts (Ritchie & Touchon, 2000). The relevance of improved identification and characterization of MCI is based on findings that these individuals are at higher risk for developing dementia (compared to individuals without MCI) and are potential candidates for initiation of pharmacological intervention (Bozoki, Giordani, Heidebrink, Berent, & Foster, 2001). In addition to the clinical, functional and psychosocial implications, it has been noted that if patients identified with MCI were successfully treated so as to delay progression to AD by only one year, the dollar cost savings would be quite substantial (Petersen, Stevens et al., 2001). Given this, increased understanding as to the clinical and neurobiological aspects of MCI, as well as the current status of potential therapeutic interventions, will allow clinicians to better detect and manage this syndrome.

1. Clinical characteristics and course of MCI The concept of MCI needs to be placed in the proper historical context. One of the first terms used to describe non-demented patients evidencing some form of cognitive dysfunction was that of benign senescent forgetfulness (Kral, 1962). Since then, several terms have been utilized, oftentimes in confusing and interchangeable fashion, including age-associated


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memory impairment, late-life forgetfulness, and aging-related cognitive decline (see Ritchie & Touchon, 2000; Tuokko & Frerichs, 2000). The conceptual problem underlying these terms has been the implication that the observed cognitive change may very well be part of the normal aging process and does not represent a pathological entity with a high risk of progression to dementia. This is at variance with the objective of establishing conceptual and clinical criteria with sufficient predictive validity so as to efficiently identify pathological states and justify initiation of effective treatments. For example, the criteria for age-associated memory impairment have been criticized for being too overinclusive and representing a risk for misidentifying healthy elderly individuals as being impaired (Bozoki et al., 2001). One longitudinal study found that only 29 of 176 (16.5%) individuals who had received a diagnosis of age-associated memory impairment had progressed to greater impairment, represented by either MCI or dementia criteria, over a period of 3.6 years (Hanninen et al., 1995). The term cognitive impairment no dementia (CIND), referring to patients identified by virtue of clinical and neuropsychological examination (Graham et al., 1997), implies the presence of a pathological state. However, the underlying etiologies producing the impairment can be quite broad, and as such, limit the specificity of the term. The primary concept of MCI has principally involved the detection of memory impairment in individuals who are otherwise cognitively and functionally intact, and thereby do not meet criteria for dementia. Specific criteria are listed in Table 1 and essentially consist of a subjective complaint of memory decline (preferably corroborated by a family member or other informant), objective memory impairment, unaffected general cognition, normal capacity to perform activities of daily living (ADL), and absence of dementia (Petersen, Stevens et al., 2001). We have found the mnemonic “SOUND” to be helpful in retaining the current criteria for MCI: Subjective memory complaints, Objective memory deficit, Unaffected overall cognition, Normal capacity to perform of ADL’s, and Dementia criteria not met. Applying this criteria, it has been noted that individuals diagnosed with MCI converted to AD at an annual rate of approximately 12% per year, compared to the normal elderly population that demonstrates a conversion rate of approximately 1–2% per year (Petersen, Stevens et al., 2001). Following these patients over a longer period, it was noted that 50% had developed AD in 3–4 years, and 80% had developed AD by 6 years (Petersen, Stevens et al., 2001). However, this criteria have fallen under criticism primarily due to its inability to identify a homogenous syndrome with clear temporal stability (Ritchie, Artero, & Touchon, 2001). It is possible that the MCI criteria are too stringent, and that restricting the detected impairment to only memory may not be clinically useful, as studies have shown that patients who would otherwise meet the criteria for MCI also exhibit difficulty with language, orientation and praxis (Ritchie Table 1 “SOUND” mnemonic for mild cognitive impairment Self-reported memory complaint, preferably corroborated by a collateral informant Objective memory impairment (at approximately 1.5 standard deviations below the age norm) Unaffected general cognitive functioning (aside from memory) Normal capacity to perform activities of daily living (such as driving a car and balancing a checkbook) Dementia criteria not currently met Based on criteria from Petersen et al. (1999).

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et al., 2001). This is corroborated by Bozoki et al. (2001) who evaluated 48 non-demented patients, 17 of whom had pure MCI and 31 of whom had memory impairment plus additional deficit (designated by “M+”) in at least one of the following areas: Attention, word retrieval, visuospatial construction, or verbal fluency. The investigators found that patients in the M+ group were twice as likely as the impaired memory group to develop AD over a period of 2–5 years, with 50% of this group converting to AD within 2 years. The investigators concluded that expanding the domains of impairment beyond memory would facilitate increased accuracy in detecting patients who are at greatest risk for AD (Bozoki et al., 2001). The criterion requiring intact capacity to perform ADLs has also been called into question, particularly since functional ability has been noted to be reduced in patients with MCI (Albert et al., 1999). It has been suggested that developing guidelines for specific types of activities, defining the degree of ability (or disability) that would constitute “intact” functioning, and possibly allowing for some mild dysfunction in ADL performance would enhance sensitivity and specificity (Ritchie et al., 2001). Does MCI represent a risk factor for AD? This point has been the source of some controversy. In addition to the conversion studies noted above, pooled results from several other small hospital-based series of patients meeting criteria for MCI demonstrated estimated conversion rates of 10–15% within 1 years, 40% within 2 years, 20–53% within 3 years, and as many as 100% within 4.5 years (Ritchie & Touchon, 2000). Although individuals with MCI are noted to be at increased risk for dementia, there appears to be a semantic difference between that particular observation and the description of MCI itself as a risk factor for AD. Given the high rates of conversion, some researchers contend that MCI is not a separate nosological entity but rather a state representing early-stage AD (Milwain, 2000; Morris et al., 2001). In fact, the term “prodromal AD” has been suggested as a potentially more useful concept than MCI (Dubois, 2000). Nonetheless, MCI does exhibit heterogeneity, and the point has been made that not all patients with MCI will progress to AD (Almkvist et al., 1998; Jack et al., 2000; Lautenschlager, Riemenschneider, Drzega, & Kurz, 2001). Consequently, the issue of prodrome versus risk factor will most likely continue to be the source of ongoing debate. To date, identified risk factors for AD are increased age and possession of the ε4 gene allele of apolipoprotein E (APOE), a protein that participates in lipid transport (Ghebremedhin et al., 2001). Within patients who are demonstrating MCI, risk factors for progression to AD include higher age, APOE-ε4 genotype, fewer years of education, informant’s observation of memory deficit, fewer years of education and lower premorbid IQ (Hogan & Ebly, 2000; Kawas, Gray, Brookmeyer, Fozard, & Zonderman, 2000; Ritchie et al., 2001). Interestingly, losses in olfactory threshold, odor identification and odor memory—deficits that are demonstrated by AD patients and that appear to share an association with APOE-ε4—have been detected during MCI and may suggest increased risk for ongoing progression to AD (Devanand et al., 2000). Rate of progression to AD appears to be dependent on the level of cognitive impairment at the time of diagnosing the patient with MCI (Morris et al., 2001). The risk factors for developing MCI itself, although presumably similar to those for AD, have not been well characterized and more longitudinal studies are needed to determine the exact prevalence rate and predisposing factors for MCI. Several studies have found that APOE-ε4 is a risk factor for MCI (Smith et al., 1998; Zill et al., 2001). A longitudinal study of 1168 subjects evidencing no cognitive impairment found that subjects who were APOE-ε4 allele


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carriers demonstrated a greater rate of cognitive decline at follow-up assessment 6 years later (Dik et al., 2001). The highest rate of decline was noted for subjects with the APOE-ε4 allele who also developed subjective memory complaints, suggesting that these two variables serve as important risk factors for potential dementia (Dik et al., 2001). Other factors are currently under exploration. For example, based on preliminary data that vascular risk factors (e.g., blood pressure, serum cholesterol levels) may share a relationship with the development of AD, Kivipelto et al. (2001) examined the role of vascular risk factors in a sample of 1449 subjects with an average follow-up interval of 21 years. Eighty-two subjects (6.1%) met criteria for MCI. Midlife elevation of serum cholesterol was found to be a significant risk factor for MCI, while midlife systolic blood pressure approached significance as a risk factor (Kivipelto et al., 2001). This association was corroborated by DeCarli et al. (2001), who noted that elevated midlife blood pressure was found to increase the risk for MCI at least to the same degree as the APOE-ε4 genotype. 2. Neuropsychological features While there is an extensive body of neuropsychological literature documenting the phenotypic expression of cognitive changes in preclinical AD, there has been a relative dearth of neuropsychological studies in which the clinical entity of MCI has served as the explicit target. This distinction, although possibly appearing artificial, may be the most conservative, amidst the ongoing view of some researchers that not all MCI will progress to AD (Lautenschlager et al., 2001). Consequently, a battery of neuropsychological measures that can best characterize MCI and can predict those that will convert has yet to be formally proposed. In part, this may be due to the heterogeneity and variability in psychometric test performance that appears to increase with advancing age (Ylikoski et al., 1999). In characterizing MCI at a gross level, the operationalized criteria that have been proposed involve a score of 24 or more on the Mini-Mental Status Examination (MMSE; Folstein, Folstein, & McHugh, 1975), a score of 0.5 on the Clinical Dementia Rating (Morris, 1993), and an objective memory deficit (e.g., an impaired score on paragraph recall task; Geula et al., 2000). However, these criteria, which also function as the inclusion criteria for MCI clinical drug trials, appear to be excessively narrow, particularly for clinical practice. Cognitive impairment—most likely extending beyond isolated memory deficit—remains the measurable hallmark for MCI, indicating that this syndrome represents an ideal target for neuropsychological investigation (Tuokko & Frerichs, 2000). As such, the proposed objectives for neuropsychological studies would appear to be two-fold: (1) development and standardization of a battery and profile that discriminates MCI from cognitively-intact aged individuals with a high degree of sensitivity and specificity, and (2) determination of which measures of cognitive impairment are the best determinants of conversion to dementia within the MCI group (Hobson & Meara, 1998). When MCI is more specifically defined as a prodromal state to AD, the body of research overlaps directly with the several studies that have addressed cognitive predictors of incipient AD. In general, this research has demonstrated a close relationship between the neuropathological alterations associated with early AD and the nature of cognitive decline during this phase of the disorder. Specifically, the early involvement of subcortical cholinergic projection

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nuclei, the hippocampal formation, and the anterior and posterior association cortices result in a characteristic neuropsychological profile. However, some controversy still exists in this regard. While some studies indicate that AD can be predicted on the basis of performance on a battery of neuropsychological measures (Tierney et al., 1996), other researchers have found that neuropsychological test scores were not able to predict conversion to AD (Bowen et al., 1997; Goldman et al., 2001). Despite this discrepancy, there is a general sense that neuropsychological studies can, in fact, be very useful in identifying at-risk individuals (Albert, Moss, Tanzi, & Jones, 2001; Petersen, Doody et al., 2001). Longitudinal investigations of elderly community-based samples indicate that preclinical manifestations of AD may appear 5–10 years prior to reaching threshold for dementia (Almkvist et al., 1998; Linn et al., 1995; Small, Viitanen, & Backman, 1997; Small, Fratiglioni, Viitanen, Winblad, & Backman, 2000). A consistent finding is that measures of episodic memory and executive functioning are the most sensitive to detecting individuals who will go on to develop dementia (Backman, Small, & Fratiglioni, 2001; Chen et al., 2001). Traditionally, brief global measures, such as the MMSE, have been used to detect early changes and track progression. However, this approach may lack specificity, particularly very early in the disease process or when assessing premorbidly high functioning individuals. Loewenstein et al. (2000) administered a modified version of the MMSE to 102 elderly subjects who had been diagnosed, on the basis of neurological and neuropsychological examination, as being either cognitively normal (n = 52), MCI (n = 24), or demented (n = 26). By incorporating three extended delayed recall trials (for the three MMSE recall items) at 5-min intervals, they were able to enhance sensitivity and specificity in differentiating MCI from cognitively normal subjects, suggesting that this modification may be more useful for detection than the standard MMSE (Loewenstein et al., 2000). A brief battery assessing more specific cognitive dysfunction may have greater accuracy, however, than a single broad measure (Chen et al., 2001). For example, Drebing, Van Gorp, Stuck, Mitrushina, & Beck (1994) reported on a brief screening battery consisting of four standard neuropsychological tests (measuring psychomotor speed, verbal and visual memory, visual spatial and perceptual ability, and cognitive flexibility and set shifting) that exhibited a relatively high degree of accuracy for detecting early dysfunction. (This battery, however, has not been specifically applied to MCI patients in order to determine which characteristics will best discriminate those patients that will progress to dementia.) In addition to pure cognitive assessment, results from a study assessing psychomotor functioning in subjects classified into cognitively intact, MCI, and early AD suggested that changes in this domain may have discriminant value (Kluger, Gianutsos, Golomb, Ferris, & Reisberg, 1997). Performance on tests categorized as gross, fine or complex psychomotor measures indicated that, relative to the intact group, MCI patients performed as poorly on fine and complex motor measures as they did on cognitive measures (Kluger et al., 1997). The investigators concluded that performance on fine and complex measures of psychomotor functioning may be as useful as traditional cognitive tests for detecting MCI, and should be incorporated in screening batteries. Longitudinal studies afford the best chance at determining which test (or tests) should be included in a battery in order to detect dysfunction as well as high risk for progression (Petersen, Doody et al., 2001). For example, Ritchie et al. (2001) used a computerized battery assessing primary and secondary memory (verbal and visuospatial memory), language skills (naming, fluency, and syntax comprehension), visuospatial performance (ideational, ideomotor,


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and constructional praxis, visual reasoning, form perception, and functional and semantic categorization of visual data), and focused and divided attention (in both auditory and visual modalities). At 3-year follow-up, they found that the tests which were able to differentiate normal subjects from those with preclinical dementia two years before conversion were reaction time (on simple and dual attention task), semantic category fluency, recall of name–face pairs, narrative recall, copying of a complex figure, and—the most predictive tests—delayed free verbal recall and delayed cued verbal recall (Ritchie et al., 2001). The finding that delayed verbal recall was the most accurate measure is consistent with results from other studies (Kluger, Ferris, Golomb, Mittelman, & Reisberg, 1999; Touchon & Ritchie, 1999). Chen et al. (2000) compared the cognitive performance of 120 non-demented subjects who subsequently developed AD within 1.5 years with that of 483 controls that remained non-demented over a 10-year follow-up period. Of the 16 cognitive tests used as predictor variables, they found that, in addition to delayed recall, executive dysfunction was also a discriminating variable between the groups. More specifically, they observed that Word List Delayed Recall (Morris et al., 1989) discriminated best between cognitive decliners and cognitively stable subjects, followed by performance on the Word List Third Learning Trial, Word List First Learning Trial, and Trail-making Test B (Reitan, 1955). All of these variables were more accurate than the MMSE (Chen et al., 2000). This is generally consistent with results from Albert et al. (2001) who followed 42 normal subjects and 123 subjects with mild memory dysfunction (that met criteria for questionable AD) for 3 years with a comprehensive neuropsychological battery to determine which measures served as the best predictors of conversion to probable AD. In addition to immediate non-verbal memory and executive functioning, these investigators found that learning efficiency and consistency (as measured by the total number of words retained from a word list over five learning trials) differentiated controls from patients who converted to probable AD with 89% accuracy (Albert et al., 2001). Selection of a battery to appropriately assess the presence of MCI should also provide discriminative data that distinguishes this condition from both normal aging and a clinical presentation that meets criteria for dementia. Based on the existing literature, a proposed battery comprised of sensitive, well-normed, and readily available instruments would include assessment of (1) general cognition with the Folstein MMSE (Folstein et al., 1975); (2) language functions with the Boston Naming Test (Kaplan, Goodglass, & Weintraub, 1983) and Controlled Oral Word Association Test (Benton & Hamsher, 1989; Goodglass & Kaplan, 1983); (3) conceptual reasoning with the WAIS-III Similarities subtest (Wechsler, 1997); (4) constructional praxis with the WAIS-III Block Design subtest (Wechsler, 1997) and the Rey–Osterrieth Complex Figure drawing (Osterrieth, 1944); (5) working memory with the WAIS-III Letter–Number Sequencing subtest (Wechsler, 1997); (6) verbal and visual immediate and delayed recall with WMS-III Logical Memory and Visual Reproduction subtests (Wechsler, 1997) and the Rey Auditory Verbal Learning test (Rey, 1964); (7) executive functioning with the Trail Making Test A and B (Reitan, 1955). The sensitivity of these measures in MCI and preclinical AD has been demonstrated empirically, and is conceptually logical in that these cognitive domains are mediated by brain systems that seem to be affected in earliest stages of the disease. Conducting a large multicenter trial in which this battery is applied longitudinally, first to detect MCI and then to track progression to dementia criteria, would represent an important step in determining which neuropsychological instruments have the greatest sensitivity in this regard.

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3. Neurobiological aspects Confirmation of MCI as a valid clinical entity is bolstered by numerous neurobiological studies demonstrating that these patients exhibit structural, anatomical and functional changes that can be differentiated from both normal aging and dementia (Ritchie & Touchon, 2000). A review of the articles identified through our initial search indicated a significant amount of research being conducted specifically with patients having been classified as MCI. These studies have used neuropathological examinations, various imaging techniques, and different neurochemical markers, all with the objective of better characterizing MCI and identifying patients within this group who are at greatest risk for progression to dementia. In AD, the underlying pathology causing cell death is the development of senile neuritic plaques (SNPs), formed by an aggregation of ␤-amyloid protein, and neurofibrillary tangles (NFTs), produced when fibers of the substance tau protein become hyperphosphorylated and twisted due to faulty metabolism (Schneider, 1998). These neuropathological alterations are present in the brains of cognitively normal older adults as well, albeit in varying densities and distributions when compared to AD (Schmitt et al., 2000). Individuals with MCI exhibit pathological changes in the hippocampal region and diffuse SNPs in neocortical areas, although insufficient to constitute a neuropathological diagnosis of AD (Friedrich, 1999). Layer II of the entorhinal cortex, a brain region that contains cells of origin for the perforant path (projecting from the entorhinal cortex to the dentate gyrus of the hippocampus) and that plays a critical role in memory processing, appears susceptible to the development of NFTs, even during normal brain aging. In a large review of clinicopathological examinations of over 1000 cases, non-demented cases were compared to MCI and AD cases (Hof, Glannakopoulos, & Bouras, 1996). Results indicated that individuals who had been classified with MCI had already begun to demonstrate increased NFTs densities in layer II of the entorhinal cortex (Hof et al., 1996). In a smaller series of autopsied individuals who had been classified as either cognitively intact, MCI, or mild to moderate AD, significant atrophy and volume loss of the entorhinal cortex was noted in the MCI and AD groups relative to the cognitively intact group (Kordower et al., 2001). Moreover, atrophy of the entorhinal cortex was noted to be significantly correlated with performance on the MMSE. Du et al. (2001) found that volume change of the entorhinal cortex was better than hippocampal changes for discriminating between MCI and AD. The nucleus basalis of Meynert, a basal forebrain region that is rich in acetylcholine (ACh) and affected early in the pathogenesis of AD, also appears to be compromised in MCI. Mufson et al. (2000) conducted autopsies on 30 subjects, all of whom had been cognitively evaluated within 12 months of their death and classified as either cognitively intact (n = 9), MCI (n = 12), or probable AD (n = 9). Compared to the cognitively intact group, the MCI and AD groups demonstrated a significant reduction in nucleus basalis neurons, specifically those containing receptors for nerve growth factor (Mufson et al., 2000). These histopathological alterations have been confirmed by a growing series of neuroimaging studies using various techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). A review of studies using these imaging procedures indicated that these


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techniques were helpful in identifying structural and functional abnormalities in the temporal and parietal lobes of MCI patients (Bottino & Almeida, 1997). MRI-measured temporal lobe volume of MCI patients indicated atrophy at a follow-up period of 3.2 years, with changes in the medial occipitotemporal and middle and inferior temporal gyri demonstrating the best predictive value for conversion to dementia (Convit et al., 2000). Many studies have also focused on measuring hippocampal atrophy, using this index as a discriminating variable to identify at-risk MCI patients. For example, the CT and MRI scans of patients with MCI (n = 72), mild AD (n = 73), and moderate to severe AD (n = 130) were compared to scans of normal elderly subjects to determine the frequency of hippocampal atrophy (de Leon et al., 1997). Results indicated that presence of hippocampal atrophy was noted in 29% of the control subjects, in 78% of the MCI patients, and in 96% of the patients in the AD groups. This linear progression in hippocampal atrophy was replicated in a longitudinal study in which 129 subjects, divided into normal controls, MCI, and probable AD, were followed for a period ranging from 2 to 4 years. MRI and clinical examinations were performed at baseline and follow-up. At the follow-up period, the control group and MCI group were further subdivided into those who had remained cognitively stable or those who had declined to a lower level of cognitive functioning. MRI examinations indicated that at follow-up, annualized rates of hippocampal volume loss were greatest for the cognitively declining MCI group and the AD group. Percentage rates of atrophy per group were as follows: 1.73% for the control-stable group (n = 48), 2.81% for the control-declining group (n = 10), 2.55% for the MCI-stable group (n = 25), 3.69% for the MCI-declining group (n = 18), and 3.5% for the AD group (n = 28; Jack et al., 2000). Jack et al. (1999) obtained MRI-based measures of hippocampal volume on a series of 80 MCI patients and followed them clinically for an average of 32 months. Results indicated that degree of baseline hippocampal atrophy was predictive of conversion to AD (Jack et al., 1999). Early volume loss of the entorhinal cortex during MCI has also been noted on MRI-based measurements, although measurements of the hippocampus may be preferable due to better anatomical delineations (Xu et al., 2000). Finally, white matter abnormalities appreciated on CT or MRI scans—in MCI patients with no signs of cerebrovascular disease—were noted to correlate with conversion to AD, prompting the investigators to suggest a possible predictive role for any white matter pathology that is noted during MCI (Wolf, Ecke, Bettin, Dietrich, & Gertz, 2000). In addition to structural studies, techniques allowing for functional imaging, such as PET, SPECT and functional MRI (fMRI), are also being investigated for predictive value and practical application in MCI patients. These techniques, which can measure cerebral blood flow, receptor characteristics (e.g., density or affinity), or metabolic rates of glucose and oxygen, appear ideal for early detection strategies, as they can depict neuronal dysfunction prior to cell death (Small & Leiter, 1998). For example, PET scans on cognitively intact individuals who are at risk for AD by virtue of demonstrating the APOE-ε4 genotype exhibit reduced glucose metabolism in parietal, temporal, prefrontal and posterior cingulate regions when compared to an age-matched, non-APOE-ε4 control group (Reiman et al., 1996). When applied specifically to the MCI population, reduced glucose metabolism and hypoperfusion in bilateral temporoparietal areas, left possibly greater than right, have been documented using PET and SPECT techniques (Arnaiz et al., 2001; Celsis et al., 1997). Using SPECT, a reduction in blood perfusion has also been noted in the posterior cingulate gyrus, the

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hippocampal–amygdaloid complex and the anterior thalamus in MCI (Johnson et al., 1998; Okamura et al., 2000). Quantitative electroencephalography (QEEG) studies have also been able to detect patterns of alterations that emerge during MCI and serve to differentiate this group from normal elderly individuals, particularly in temporoparietal coherence and alpha and theta relative power (Jelic et al., 1996). In a longitudinal study, Jelic et al. (2000) followed 27 MCI patients over an average of 21 months, comparing baseline and follow-up QEEGs to those obtained from a normal elderly group (n = 16) and an AD group (n = 15). At follow-up, 14 MCI patients (52%) had progressed to AD. Logistical regression of baseline QEEGs indicated that alpha and theta relative power, as well as mean frequency from left temporo-occipital derivation, were the best predictors of classification (Jelic et al., 2000). Combined alpha and theta global field power has also been shown to discriminate AD and MCI patients from normal controls (Huang et al., 2000). In this study, MCI patients that progressed to AD could be distinguished from those who remained stable by decreased alpha global field power, antero-posterior localization of alpha frequency, and more anterior localization of theta, alpha and beta frequency (Huang et al., 2000). Biochemical studies have been under investigation in order to characterize early chemical alterations and identify potentially useful markers. Entorhinal cortex tissue was obtained from individuals who had been classified as either cognitively intact, MCI, or AD, and immunostained for ␤-amyloid, the protein that aggregates to form neuritic plaques (Mufson et al., 1999). Results indicated that the AD group had a significantly greater ␤-amyloid load than the control group, with the MCI group occupying an intermediary position. Immunocytochemistry of basal forebrain tissue to determine levels of choline acetyltransferase, a synthetic enzyme for acetylcholine that decreases as dementia severity progresses, revealed no such detectable reduction during MCI, suggesting that this will not be a useful marker (Gilmor et al., 1999). Cerebrospinal fluid (CSF) may provide a useful tool for analysis, as abnormal levels of soluble ␤-amyloid and protein tau have been isolated in patients with MCI (Andreasen et al., 1999; Arai et al., 2000; Maruyama et al., 2001). In a 1-year, prospective, community-based study of 241 patients demonstrating AD, MCI, vascular dementia and other neurologic disorders, CSF levels of tau and ␤-amyloid were found to have the highest predictive value for AD, at greater than 90% (Andreasen et al., 2001). The investigators commented that CSF is readily obtainable through lumber puncture, which they report is easy to perform and with low risk of complications; in combination with other clinical data, these investigators believe that CSF-tau and CSF-A␤42 can help identify MCI patients who will develop AD (Andreasen et al., 2001). Recently, Okamura et al. (2002) combined CSF data from lumbar puncture and measures of regional cerebral blow flow (CBF) from SPECT scans to derive a CSF-CBF index. Dividing CSF tau levels by CBF in the posterior cingulate cortex proved to be useful in discriminating MCI that progressed to AD from MCI that did not (Okamura et al., 2002). Finally, magnetic resonance spectroscopy (MRS), an imaging technique that produces quantitative data on various chemicals in the brain, has recently been applied to the AD population. A preliminary profile is beginning to emerge demonstrating reduced levels of N-acetylaspartate (felt to reflect neuronal loss or dysfunction) and increased levels of myoinositol (possibly reflecting proliferation of glial cells that accompany neuronal death) in the brains of AD patients (Kantarci et al., 2000). When MRS has been specifically applied


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to MCI with the objective of obtaining discriminating profiles, excessive biochemical overlap has prevented differentiation between normal controls, MCI and AD patients, indicating that this imaging technique has limited diagnostic or predictive value at this time (Kantarci et al., 2000).

4. Pharmacological studies The primary objective in better characterizing MCI and detecting those at risk for progression to AD is to identify patients who can benefit from treatment. The only agents currently approved by the Food and Drug Administration for the treatment of AD are the cholinesterase inhibitors (ChEIs). The rationale for the development and use of these agents is based on the documented association between cognitive deterioration and decreased cholinergic availability secondary to cholinergic cell loss and decreased ACh production. The ChEIs increase the availability of synaptic ACh by inhibiting acetylcholinesterase (AChE), the enzyme responsible for degrading ACh following its release into the synapse from presynaptic nerve terminals. These agents are neither curative nor preventive treatment, but geared to decrease the rate of cognitive and functional decline. Data indicates that the ChEIs can potentially attenuate progression, as evidenced by formal measures of cognitive functioning or psychosocial markers, such as prolonging time to placement in nursing home or residential facilities. At first, this was attributed to the stabilizing effect on cognitive and functional status produced by enhanced cholinergic transmission. However, recent findings have raised the possibility that ChEIs may demonstrate neuroprotective effects by various mechanisms. By increasing cholinergic activity, particularly at cholinergic muscarinic receptors, neurotrophic regeneration may be facilitated (Schneider, 1998). Furthermore, PET scans have indicated that treatment with ChEIs is associated with restoration of activity at cholinergic nicotinic receptor sites (Nordberg et al., 1992). Enhanced activity at nicotinic receptors should not only improve cognition, but may also cause cholinergic neurons to release more ACh (Stahl, 2000). Finally, increased levels of ACh may inhibit the formation of ␤-amyloid plaques. ␤-Amyloid protein originates from a larger parent protein, amyloid precursor protein (APP). Certain forms of APP are found in disproportionate ratios in AD, possibly accounting for the pathological formation and aggregation of ␤-amyloid that form plaques. Evidence now suggests that ChEIs may regulate processing and secretion of APP (Schneider, 1998). For examples, patients treated with donepezil (Aricept) for 30 days demonstrated significant alterations in the quantity of specific forms of APP compared to untreated AD patients (Borroni et al., 2001). The investigators concluded that ChEIs, by virtue of modifying levels of APP, may mitigate the process by which plaques are formed. There is clear consensus that once the diagnosis of AD is made, ChEI treatment should be initiated as soon as possible, given that lengthy delays may not allow patients to derive maximal benefits due to more advanced disease (Doody, Geldmacher, Gordon, Perdomo, & Pratt, 2001). However, MCI has now become a clinical and research target for ChEI treatment initiation, based on the premise that intervention during this stage may slow clinical progression of illness and increase the time latency to reach formal criteria for dementia. Empirical evidence for this hypothesis is presently being collected. For example, the beneficial effects of

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rivastigmine (Exelon) in delaying progression is currently being investigated in a large, multicenter, placebo-controlled trial referred to as the Delay to Diagnosis of Alzheimer’s disease with Exelon (InDDEx) study that has enrolled over a 1000 patients to date (Geula et al., 2000). Clinical trials with the other ChEIs are also underway. Several other compounds are also under current investigation for efficacy in MCI (see Sramek, Veroff, & Cutler, 2001). Antioxidant compounds (e.g., Vitamin E and selegeline) are being studied, amidst evidence that oxidative stress plays a role in the pathogenesis of AD and data that these compounds may delay disease progression in patients with moderate to severe illness. The herbal preparation Ginkgo biloba is purported to exhibit antioxidant properties, and there are plans to initiate an MCI study with this compound. Given data that inflammatory or immune mechanisms may play a role in the pathophysiology of AD, the application of anti-inflammatory agents to MCI is also in the initial stages of investigation. Recently, Nagaraja and Jayashree (2001) reported on a series of 30 patients with MCI who were randomly assigned either to placebo or to piribedil, a dopamine receptor agonist. This study was based on observations from imaging research that age-related decline in dopamine receptors correlated impaired performance on cognitive measures. Results indicated that piribedil-treated patients demonstrated improved cognitive performance, as measured by the MMSE, suggesting a role for further investigation for dopamine agonists for this population (Nagaraja & Jayashree, 2001).

5. Summary Despite the divergent views of whether MCI represents prodromal AD or not, there appears to be consensus that the increased use of the term MCI has been beneficial in that it has facilitated the identification of individuals with poor memory who may benefit from treatment (Milwain, 2000). Detection of MCI is critical, and it should be quite clear that memory complaints that are corroborated by neuropsychological examination should not be considered as benign or a normal manifestation of aging (Ritchie et al., 2001). However, it is also clear that the definition and characteristics of MCI need to be further refined in order to enhance clinical utility. While patients with MCI are at increased risk for developing AD, not all MCI patients progress to full criteria for dementia, implying that distinguishing elements between stable MCI and progressive MCI need to be better characterized. To this end, standardizing a neuropsychological battery that would detect MCI and predict patients at risk for progression are needed. Development of biomarkers and profiles from other diagnostic sources is also being actively explored, in order to develop protocols that are clinically and practically useful. Correlating neuropsychological measures with biochemical and neuroimaging indices would also prove beneficial. Once detected, the goal of the pharmacological agents that are under current investigation is to delay progression to the more debilitating stages of dementia. Although theoretical and preliminary data appear to support their use during MCI, the ChEIs have not yet been approved by the FDA for this syndrome. Pending the results from clinical trials currently being conducted, the decision to initiate ChEI therapy during MCI requires clinical judgement applied on a case-by-case basis following a risk-benefit analysis.


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