Mild Cognitive Impairment A Brief Overview

Mild Cognitive Impairment A Brief Overview - Transcript

Mild Cognitive Impairment

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Mild Cognitive Impairment A Brief Overview Geetika Agarwal University of Missouri Columbia Columbia Missouri 65211

Mild Cognitive Impairment Introduction There is a current interest in diagnosing Mild Cognitive Impairment MCI described as the transitional state between normal ageing and dementia As simplistic as it might sounds the wide variations in the criteria concepts and natural history indicate that this might not necessarily be the case MCI is not an established diagnosis but a concept for which different criteria have been proposed and furthermore then modified over time Although still an evolving concept prevalence rates for age associated memory impairment in various studies range from 17 to 34 Crook Bartus Ferris Whitehouse Cohen Gershon 1986 Coria Gomez de Caso Minguez RodriquezArtalej Claveria 1993 Larrabee Crook 1994 Smith Ivnik Peterson Malec Kokmen Tangalos 1991 while age associated cognitive decline has been estimated as having a prevalence of 26 Levy 1994

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The paper is an attempt to give a brief historic overview of the development of the concept along with a discussion on one of the diagnostic criterion for MCI A homogeneous as it might appear the paper will highlight the existing heterogeneity in the population often categorized as MCI This will be followed by a discussion on the various assessments used for diagnosing MCI This will include the use of rating scales informant rating scales and neuropsychological assessment The paper will conclude with a highlight on the limitations and future implications for neuropsychological assessment so that to better diagnose MCI leading to an accurate medical and psychological management of the patient

Mild Cognitive Impairment

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Historic overview The observation that some older individuals become mildly forgetful as they age dates back to the earliest medical writings In the modern era the first epidemiological study of dementia carried out in the northern English city of Newcastle Upon Tyne identified a group of individuals who did not fit clearly into the cognitively normal group of the dementia group In 1970s the Canadian psychiatrist V A Kral described a group of patients suffering from what he called benign semescent forgetfulness These patients complained of memory decline and had subtle changes on memory testing that he believed were compatible with normal aging However on a long term follow up he found that a significant proportion 90 had developed dementia leading him to conclude that the condition was not so benign after all In the 1980s the neurologist Ronald Peterson began studying a group of individuals who he concluded could be categorized as suffering from MCI a condition that was a precursor or an early manifestation of dementia At the same time a population based survey called the Canadian Study of Aging labeled a similar group as having CIND The CIND group was defined as having a decline in any are of cognition and not just memory but did not meet the criteria for dementia Rabins Lyketsos Steele 2006 At present most researchers and clinicians agree that there is a group of patients who have suffered some decline in cognition but who do not meet criteria of dementia Additionally there is no consensus on what criteria should be used to identify such individuals Further there is no consensus on whether these individuals suffer from the

Mild Cognitive Impairment earliest form of dementia or have symptoms that is a risk factor of developing dementia Rabins Lyketsos Steele 2006

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The most common presentation of cognitive decline that does not meet criteria for dementia is decline only in memory It is this group that has been studies the most and is referred to as Mild Cognitive Impairment MCI because the criteria proposed for this syndrome include decline in memory without other cognitive impairments Rabins Lyketsos Steele 2006

Mild Cognitive Impairment The field of aging and dementia is focusing on this characteristic of the earliest stages of cognitive impairment Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer s disease AD known as Mild Cognitive Impairment MCI Mild Cognitive Impairment refers to the clinical condition between normal aging and AD in which persons experience memory loss to a greater extent than one would expect for age yet they do not meet currently accepted criteria for clinically probably AD at a considerably accelerated rate compared with healthy agematched individuals Consequently this condition has been recognized as suitable for possible therapeutic intervention and several multicenter international treatment trials are under way Peterson et al 2001 Mild Cognitive Impairment MCI can be defined as a subtle but measurable memory disorder where a person with MCI experiences memory problems greater than normally expected with aging but does not show other symptoms of dementia such as impaired judgment or reasoning Reference In 2001 the American Academy of

Mild Cognitive Impairment Neurology ANN published practice guidelines for the early detection of memory problems The AAN identified the following criteria for an MCI diagnosis An individual s report of his or her own memory problems preferable confirmed by another person Measurable greater than memory impairment detected with standard memory assessment tests Normal general thinking and reasoning skills Ability to perform normal daily activities

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This type of MCI is termed amnestic MCI because its definition emphasizes memory loss Most of these subjects will progress to AD at a rate of 10 to 15 per year compared with healthy control subjects who convert at a rate of 1 to 2 per year Peterson et al 1999 Tierney Szalai Snow 1996 Data from Mayo Alzheimer s Disease Research Center Rochester Minnesota which has been observing a group of these subjects for more than 10 years have demonstrated a conversion of AD of up to 80 during approximately 6 years

Heterogeneity in Mild Cognitive Impairment All individuals who present clinically with mild cognitive symptoms may not share the same fate ultimately Some may go on to develop AD while others may progress to another dementia It is possible that some of the subjects will never progress to any significant extent This broad group of individuals with mild cognitive complaints could be considered as having MCI Recognizing that there are multiple sources of

Mild Cognitive Impairment heterogeneity in such a classification it is desirable to further specify criteria for subsets of MCI Peterson et al 2001 It has become apparent that heterogeneity of MCI is derived from differences in causes clinical symptoms and research methods For clarity it is recommended that the

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term MCI be qualified with an appropriate modifier such as amnestic MCI to inform the readers as to the specific criteria being used to characterize the condition and its most likely outcome The current studies suggest that there are two forms of MCI one with predominant impairment of memory for example MCI age associated memory impairment AAMI and the other with a wider range of cognitive impairments for example age associated cognitive decline AACD age related cognitive decline ARCD Population studies have showed that the cases with predominant impairment of memory constituted a relatively small group compared with all individuals with a much broader form of mild cognitive deficit This other presentation of cognitive decline not meeting criteria for dementia almost as common as amnestic MI characterizes individuals with cognitive impairments in non memory realms such as executive function visuospatial function and language Some individuals in this group have mild decline in multiple areas of cognitive function including memory but do not meet criteria for dementia because of declines are mild Although MCI syndrome is based on a neuropsychological pattern of impairment and no impaired function there are still some discrepancies over how to classify these patients Whether all subjects with memory deficits should be considered MCI amnestic type or whether there should be a clear differentiation between those with an isolated

Mild Cognitive Impairment memory deficit and those whose memory deficits are associated with abnormalities in other cognitive domains

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Assessment for Mild Cognitive Impairment With the advent of specific anti dementia drugs there is an increasing need to improve the specificity of screening tools for early diagnosis of dementia In the field of neuropsychology efforts to identify subjects with mild cognitive impairment and to estimate their risk of conversion to dementia have mainly focused on the search for a direct measure of current cognitive status that is sensitive enough to detect minor impairments and with memory tests usually showing the best discriminative and predictive power at least for the amnestic forms of MCI The paper will discuss rating scales used while assessing for MCI rating scales and questionnaires for caregivers for the screening of dementia Isella Villa Regazzoni Ferrarese Appollonio 2006 and also some of the neuropsychological assessment used while assessing dementia

Rating Scales Mild Cognitive Impairment refers to a transitional state between the cognition of normal aging and mild dementia There are several useful rating scales available for characterizing subject along a continuum from normal aging through various stages of dementia Morris 1993 Reisberg Ferns DeLeon Crook 1986 The CAMDEX informant interview the Clinical Dementia Rating Scale the Brief Cognitive Scale the Functional Activities Questionnaire and the Global Deterioration Scale have shown

Mild Cognitive Impairment satisfactory discriminative and predictive ability in the preclinical stages of Alzheimer s

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Disease AD Although these scales are useful for describing subjects at various levels of involvement they do not necessarily coincide with the clinically relevant condition of normal aging MCI and mild AD The Clinical Dementia Rating CDR is a popular scale used to classify subjects along a continuum from normal aging through AD Morris 1993 This scale describes a continuum from normal CDR 0 through questionable dementia CDR 0 5 to mild CDR 1 moderate CDR 2 and severe CDR 3 dementia Although some investigators believe that CDR 0 5 actually describes a broader population that includes subjects with MCI and mild AD Peterson 2000 Another instrument the Global Deterioration Scale GDR stages normal subjects from GDS 1 normal to GDS 2 normal with subjective memory impairment GDS 3 mild dementia and GDS 4 through 7 more severe stages of dementia Reisberg Ferns DeLeon Crook 1986 Within this rating scale subjects with MCI could correspond to a GDS of either 2 or 3 Peterson 2000 Because the amnestic form of MCI is an identifiable entity that does not necessarily map to a specific stage on these rating scales separate terminology is thereby justified

Informant Rating Scale In addition to accuracy scales for caregivers also display a series of strengths with respect to neuropsychological tests Jorm 1997 Jorm 1996 such as more direct correspondence with everyday functioning independence from educational and premorbid intellectual level better tolerability for patients and applicability to noncompliant or non testable cases Of the informant based tools the Informant

Mild Cognitive Impairment Questionnaire on Cognitive Decline in the Elderly IQCODE Jorm Korten 1988 is one of the most well known and widely used It comprises of 26 self administered items and requires relatives and friends to compare the patient s current cognitive and functional performance in everyday life with their level of functioning 10 years previously A meta analysis of studies comparing the IQCODE with Mini Mental Status Examination MMSE Folstein Folstein McHugh 1976 showed that the two scales have equivalent effectiveness at screening for dementia with sensitivity and specificity values ranging from 69 to 89 and from 65 to 96 respectively Jorm 1997

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Thanks to its retrospective character the IQCODE presents the additional advantage of allowing assessment of cognitive and functional decline In an investigation assessed the contribution of the IQCODE to the diagnostic and prognostic investigation in a larger sample while comparing it with the discriminative and predictive power of the two standards for the screening ad prediction of dementia the MMSE and an episodic verbal memory measure the Rey s Auditory Verbal Learning Test RAVLT showed that the IQCODE is a valid instrument for differentiating between normal elderly subjects and patients with subtle cognitive disturbances and for early prediction of the future development of dementia in MCI The level of discriminative accuracy obtained by the IQCODE was basically identical to that of the MMSE ad high IQCODE scores also showed the instruments to be a very sensitive and specific marker of progression to dementia The questionnaire even yielded a slightly higher predictive accuracy than immediate and delayed recall scores mainly due to the low specificity displayed by both memory measures

Mild Cognitive Impairment 10 A meta analysis performed of 10 studies Jorm 1997 in addition to the one described above indicate towards the significant of informants feedback and their importance in arriving at correct diagnostic conclusions leading to a correct and well matched pharmacological management

Neuropsychological Predictors of Preclinical AD and MCI Neuropsychological testing has the potential to increase the discriminative diagnostic capacity for isolated memory impairment and cognitive impairment associated with vascular disease Alzheimer s disease AD and other forms of dementia Verhey et al 1993 Neuropsychological measures are routinely used to quantify the degree to cognitive impairment in patients with dementia and are likely to be particularly helpful early in the course of a dementing illness when functional and behavioral disturbances are absent The value of neuropsychological measures in helping to identify very early cases of dementia has been documented by both cross sectional and longitudinal studies More specifically deficits in measures of verbal episodic are commonly reported in these patients while other cognitive functions e g language praxis and executive functions seem to be spared Arnaiz Almkvist 2003 Longitudinal Clinical Studies A review of literature observed that neuropsychological measures found to be predictors of AD are not completely homogeneous across studies and some of the most important longitudinal studies found different cognitive predictors in preclinical AD Arnaiz Almkvist 2003 Masur et al 1994 found that verbal episodic memory measured with delayed recall visual episodic memory measured with WAIS Digit

Mild Cognitive Impairment 11 Symbol Weschler 1955 and semantic memory measured by verbal fluency were the best predictors in their Bronx cohort Jacobs et al 1995 used only verbal episodic measured by immediate recall in the Selective Reminding Test and Boston naming Test Goodglass Wingfield Hyde 1986 were significantly and independently associated with increased risk of subsequent AD diagnosis In a recent stuffy on MCI subjects Peterson 2000 reported impairments that were as severe as those seen in mild AD However the same MCI group s performance on measures assessing other cognitive domains naming executive functioning etc was equivalent to that of healthy older controls This study also provided support for the hypothesis that verbal memory is the initial domain of cognitive to be affected in the AD process Some other MCI studies reported cognitive deficits similar to those described by Peterson and colleagues 1996 2000 Results from epidemiological longitudinal studies on incipient AD have also demonstrated that a variety of measures of episodic memory performance could help to clearly detect early cognitive changes in those patients who ultimately may develop dementia Masur Sliwinski Lipton 1994 Jacobs Sano Donneief 1995 Goodglass Wingfield Hyde 1986 Elias Beiseries Wolf et al 2000 Peterson 2000 Blesa Adroer Santacruz 1996 Small Fratiglioni Vitanen 2000 Grober Kawas 1984 Small Herlitz Backman et al 1997 These results showed that consideration of cognitive domains other than memory could significantly improve the predictive value of neuropsychological testing in non demented patients with a memory complaint The majority of these results follow from the hypothesis that subjects with evidence of

Mild Cognitive Impairment 12 impairments extending beyond memory are more likely to have AD than those with only memory deficits Bozoki Giordani Heidebrink et al 2001 Cross sectional Clinical Studies According to the literature the most salient predictors of AD appear to be different measures of episodic memory and learning This finding is in concordance with cross sectional studies that also found episodic memory to best discriminate between AD preclinical AD and controls However it is important to mention that psychometric discrimination of AD has been shown to be less accurate in community dwelling population that in clinic based samples as shown in cross validation studies Peterson 2000 Although episodic memory tasks appear to have the best predictive power for indicating early dementia development it is still unclear which aspect of episodic memory is most vulnerable to dementia Moreover neuropsychological tests may differ in terms of sensitivity and because of varying task difficulty rather than specific processes tapped by the memory task

Limitation of Neuropsychological Studies The apparent heterogeneity in some of the studies could be because of the following three methodological reasons 1 The lag time between the evaluations of cognitive performance varies considerably between studies 2 The specific properties of various test commonly used are not fully understood and

Mild Cognitive Impairment 13 3 Test scores are often strongly collinear essentially because common cognitive components are involved in different test e g attention Therefore it is expected that the best approach for identifying persons at high risk of having future dementia is to show the presence of memory impairments that is not caused by other cognitive deficits i e attention Therefore it is expected that the best approach for identifying persons at high risk of having future dementia is to show the presence of a memory impairment that is not caused by other cognitive deficits In addition cultural educational and attention related factors can also have an impact on neuropsychological testing Arnaiz Almkvist 2003 Additionally neuropsychological measures cannot fully distinguish between different types of dementia because there is a substantial overlap in neuropsychological profiles This problem could be partly avoided through the use of longitudinal studies in which the decrease in cognitive test scores that are observed can be more reliable attributed to age related cognitive deterioration Arnaiz Almkvist 2003 There is some debate as to whether cognitive data should be corrected for age and education because these variables are also predictors of AD It is argued that if data are not corrected for age and education then the specificity will decrease because there is ample evidence that age education and gender affect cognitive performance Arnaiz Almkvist 2003

Future Recommendations for Neuropsychological Studies in MCI Patients In a review paper Arnaiz Almkvist 2003 made following methodological recommendations for the future research in preclinical AD The combination of cross

Mild Cognitive Impairment 14 sectional and longitudinal data might be the best solution in tracing the sequential development of cognitive deficits in aging preclinical dementia and dementia Conversely because longitudinal cognitive deterioration is a defining characteristic of AD follow up cognitive test results could be used to validate baseline diagnoses retrospectively and thus help to determine optimal diagnostic criteria and behavioral predictors of future cognitive loss He further suggests that studies that investigate preclinical AD in subjects with MCI should have a follow up period of at least 5 years although secondary endpoints such as cognitive assessment can be used Cognitive performance and functional impairment should not be used as inclusion or exclusion criteria because both are highly variable in subjects with preclinical AD this could then lead to a circular diagnosis effect Finally further studies are needed to determine whether the group that does not develop dementia represents a completely different entity and if it is possible to characterize its cognitive phenotype

Conclusion Mild Cognitive Impairment is becoming an increasingly recognized clinical entity Most clinicians are aware of patients who appear to have a mild deficit in memory of some other aspect of cognitive but why are not demented There are however important differences between clinical practice and research settings For example researchers use comprehensive neuropsychological testing to document that memory loss is clinically significant and to make certain there are no other domains of significant cognitive impairment that might mimic criteria for mild AD Clinicians should be wary about designating a patient as having MCI in the absence of specific criteria Although

Mild Cognitive Impairment 15 therapies are being developed that might prevent progression of amnestic MCI to AD there is no evidence to support prescribing therapeutic agents to patients with MCI at this time MCI does deserves recognition and further study because as preventive treatments for AD becomes available it will become incumbent on clinicians to identify persons at risk for AD and those with the earliest signs of clinical impairments Such an evolution will be stimulated by evidence that pharmacological therapy is beneficial at this stage and by the clinician s ability to recognize earlier forms of AD

Mild Cognitive Impairment 16 References Arnaiz E Almkvist O 2003 Neuropsychological features of mild cognitive impairment and preclinical Alzheimer s disease Acta Neurologic Scandinavica 107 Suppl 179 34 41 Blesa R Adroer R Santacruz et al 1996 High Apolipoprotein e episilon 4 allele frequency in age related memory decline Annuals of Neurology 39 548551 Bozoki A Giordani B Heidebrink J L et al 2001 Mild cognitive impairment predicts dementia in non demented elderly patients with memory loss Archive of Neurology 58 411 6 Coria F Gomez de Caso J A Minguez F Rodriquez Artalej F Claveria L E 1993 Prevalence of age associated memory impairment and dementia in a rural community Journal of Neurology Neurosurgery and Psychiatry 56 642 648 Crook T Bartus R T Ferris S H Whitehouse P Cohen G D Gershon S 1986 Age associated memory impairment proposed diagnostic criteria and measures of clinical change Developmental Neuropsychology 2 261 276 Elias M F Beiseries A Wolf P A et al 2000 The preclinical phase of Alzheimer s disease Archive of Neurology 57 808 813 Folsetin M F Folstein S E McHugh P R 1976 Mini Mental State a practical guide for grading the cognitive sate of patients for the clinician Journal of Psychiatry Research 12 189 198

Mild Cognitive Impairment 17 Goodglass H Wingfield A Hyde M R et al 1986 Category specific dissociation in naming and recognition by aphasic patients Cortex 22 87 102 Isella V Villa L Russo A Regazzoni R Ferrarese C Appollonio I M 2006 Discriminative and predictive power of an informant report in mild cognitive impairment Journal of Neurology Neurosurgery and Psychiatry 77 166 171 Jacob D M et al 1995 Neuropsychological detection and characterization of preclinical Alzheimer s disease Neurology 45 957 962 Jorm A F 1997 Methods of screening for dementia a meta analysis of studies comparing informant questionnaire with a brief cognitive test Alzheimer disease and associated disorders 11 158 162 Jorm A F 1996 Assessment of cognitive impairment and dementia using informant reports Clinical Psychology Review 16 51 75 Jorm A F Korten A E 1988 Assessment of cognitive decline in the elderly by informant interview British Journal of Psychiatry 152 209 213 Krishnan K R Levy R M Wagner H R et al 2001 Informant rated cognitive symptoms in normal aging mild cognitive impairment and dementia Initial development of an informant rated screen Brief Cognitive Scale for mild cognitive impairment and dementia Psychopharmacology Bulletin 35 79 88 Larrabee G J Crook T H 1994 Estimated prevalence of age associated memory impairment derived from standardized tests of memory function International Psychogeriatric 6 95 104

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Mild Cognitive Impairment 19 Tierney M C Szalai J P Snow W G et al 1996 Prediction of probable Alzheimer s disorder in memory impaired patients a prospective longitudinal study Neurology 46 661 665 Verhey F R J et al 1993 Diagnosing dementia a comparison between a monodisciplinary and a multidisciplinary approach Journal of Neuropsychiatry and Clinical Neuroscience 5 78 85 Weschler D 1955 Weschler Adult Intelligence Scale WAIS Manual New York The Psychological Corporation