Executive Control Function and Vascular Disease: Should We Pay More Attention to Frontal System Deficits in Patients With MCI?
Mark B. Detweiler, MD, MS, David Trinkle, MD, and Martha S. Anderson, MS, RN, CS
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From the Dept. of Psychiatric Medicine, Edward Via Virginia College of Osteopathic Medicine, Blacksburg, VA, the University of Virginia and Veterans Affairs Medical Center, Salem; and the Carilion Center for Healthy Aging, Dept. of Psychiatric Medicine, University of Virginia Roanoke-Salem Program.

Introduction

The observation that memory and functional capacity often erode with age is not new. However, the study of the variables contributing to early memory and functional impairment are receiving more attention as the elderly population increases in size and longevity.1 The cost of memory impairment and dementia to society in terms of lost productivity and reduced quality of life is a present and future concern. It is estimated that approximately one-half of the population reaching age 85 years will develop dementia.2 In addition to the human cost of memory disorders to society in the form of lost quality of life, institutionalization and caregiver burden, national health care costs are continually increasing.3,4 This cost is predicted to increase substantially with the future treatment of memory problems and dementia as the post-World War II generation ages.5 Not including the costs secondary to early memory deficits, the present cost of treating dementia patients is estimated to be $100 billion per year in the United States.

Alzheimer’s disease (AD) is presently considered the largest dementia subcategory.6 The number of patients with AD alone is expected to increase to 14 million by 2050.7 Knopman8 reported that non–Alzheimer’s dementias may constitute 20-40% of all dementias. With improved diagnostic techniques and the identification of other dementia syndromes, the prevalence of AD may be in the lower end of its estimated range.9

Memory impairment is a ubiquitous clinical presentation in late middle age and thereafter. Memory changes have been reported to be a major index for predicting future dementia.10,11 The early diagnosis of dementia is one of clinicians’ most challenging tasks. Until recently, AD has been the focus of most dementia research and clinical investigation, based on its estimated prevalence.12 Within the last decade, the role of the frontal system and executive control function (ECF) in cognition, global function, and memory disorders has been the subject of a growing body of research.13-17 Without adequate screening tools, a reasonably secure presumptive dementia diagnosis requires longitudinal observation since mild executive control dysfunction and memory deficits may represent what is presently considered “normal aging” rather than a progressive step toward possible dementia.1,18-21

With the relatively recent understanding that mild cognitive impairment (MCI) is a high risk factor for dementia, early memory complaints have gained a higher level of suspicion for primary care and geriatrics clinicians.1,22,23 In today’s time-constrained practices, early memory complaints may get overlooked due to the necessity of treating only those problems triaged to be the most pressing clinical presentations. Even if MCI is identified, there is presently no consensus on etiology, clinical course, or treatment.1,24 Clinically, the patient may be in the early posterior cortical stages of Alzheimer’s disease, having frontal system disruptions such as Pick’s disease, experiencing an early mixed dementia process, or merely presenting with the cognitive sequelae of “normal aging.” With the risk of MCI conversion to dementia presenting considerable future morbidity, mortality, and stress on the health care costs of the aging population, the need for more effective early diagnosis and treatment of MCI is undeniable.

The data of Petersen,22,23 demonstrating that about 48% of patients with MCI convert to dementia in 4 years, suggests that initiating treatment at the earliest MCI signs may offer the best outcome. As the diagnosis and treatment of MCI is still controversial, several areas need exploration. First, we need to differentiate the predementia syndromes from “normal aging” cognitive impairments. Second, the patients with MCI who will convert to a particular type of dementia need to be differentiated from those who will not convert. Third, it needs to be determined if MCI subgroups have diverse physiopathology. Fourth, a cost-effective diagnostic protocol for each MCI subgroup needs to be developed for use in the time-constrained primary care clinics. Fifth, once the converter and nonconverter subgroups have been identified, what is the best treatment for each subgroup? Sixth, for those subgroups determined to benefit from early intervention, how early should treatment be started? And finally, while improved understanding of MCI and its subgroups will undoubtedly lead to new medications and broad treatment protocols, an understanding of the most effective use of present medications and treatment strategies is needed.

Executive Control Function and the Case for Frontal System Assessment

ECF is associated with frontal system function (frontal lobe, basal ganglion, thalamus, and connecting subsystems) and regulates the central nervous system’s capacity to integrate multiple cognitive functions for the purpose of complex decision-making.15,25 Deficits in the capacity to abstract, manage multiple tasks, maintain relationships, drive, cook, and remain independent may occur with executive control dysfunction. Frontal lobe syndromes are frequently accompanied by apathy, which also influences ECF and the patient’s affective state.26 Affect may present in a wide spectrum of moods ranging from abulia and apathy to silliness and euphoria or impulsivity, irritability, and rage.26 Consequently, in addition to the loss of baseline cognitive and functional capacities, ECF and affect impairment such as that seen in frontotemporal dementias can lead to behavioral manifestations that increase risk of injury secondary to aggression, disinhibition, and falls.27

Given the association of ECF with cognition, function, and affect, ECF is gaining interest as an index of frontal system integrity.28-31 This index crosses many diagnoses such as major depression, schizophrenia, Parkinson’s disease and subcortical strokes. 14,32,33 Isolated ECF deficits have been associated with major depression and behavioral problems in the elderly.21,34 Reflecting the importance of frontal system function to mental status, in 1994 the American Psychiatric Association suggested that ECF assessment be part of the dementia work-up.35 At this time, there is a dearth of literature reporting the success of evaluating ECF impairment in daily clinical practice as suggested by the APA mandate.

The question has been raised as to whether all dementias are associated with vascular lesions or rather to the disease processes that contribute to the stroke phenomenon.36 Better understanding of the precise role of vascular disease in frontal system and posterior cortical memory syndromes is essential as preventive lifestyle changes and more aggressive early therapeutic interventions may be the most effective prophylaxis of future cognitive and functional impairment. Multiple diseases such as hypertension, diabetes mellitus, hyperlipidemia, and homocystinemia may be associated with vascular phenomena. It may in turn be that vascular impairment increases the risk of frontal system syndromes accompanied by ECF decline as cerebrovascular lesions have been shown to increase the risk of AD.14,36-41

Vascular Disease and Dementia

It is thought that vascular disease may constitute from one-tenth to one-third of all dementias, with mixed dementias being more common than reported.36,42 Establishing the role of vascular disease to ECF and MCI as Snowdon et al36 have done for AD would be a significant contribution to understanding memory disorders. If vascular disease is shown to have a role in the development of executive control dysfunction, MCI, and dementias, it will have significant treatment implications in terms of preventive medicine and lifestyle changes, in addition to the implementation of present and future medication protocols.

There is growing evidence that vascular disease is more debilitating to cognition and ECF than previously thought.25,43-50 While major stroke phenomena are routinely diagnosed and treated, more attention is being devoted to the role of hypoperfusion, microangiopathy, silent infarcts, and white matter disease in affect and mild cognitive changes.51 Historically, one of the first useful models for understanding the role of vascular supply on mood and cognition was the poststroke syndrome.51-55 Results indicated that acute poststroke lesions could be associated with clinically significant emotional and cognitive problems.56,57 Often, the symptoms of post-frontal stroke depression, particularly from a left frontal stoke, cannot be clinically distinguished from functional mood disorders.58,59

Vascular hypoperfusion of the basal ganglia and periventricular white matter (eg, Binswanger’s encephalitis, thalamic infarction, and lacunar state syndrome) may present clinically with apathy.20,60-70 Thus, apathy may be an index of subcortical vascular lesions associated with structures involved with executive control dysfunction.

Changes in the Normal Aging Brain

A precise understanding of what constitutes the boundaries of ECF, cognition, and function in normal aging have not been determined.1,56,57 A measurable decline in ECF has been reported in healthy age- and education-matched adults.37 Normal aging may include memory changes congruent with frontal system dementia syndromes without clinical signs of vascular disease or posterior cortical disease.71-75 For example, magnetic resonance imaging studies in the elderly without hypertension or vascular disease have demonstrated a disproportionate age-related frontal cortical atrophy compared to hippocampal, parietal, and temporal regions.29 Also, healthy volunteers from 19-78 years of age have been reported to have disproportional age-related frontal metabolic defects.28 Age-related subcortical hyperintensities in the putamen and caudate may cause increased frontal atrophy, decreased frontal lobe metabolism, and spare posterior cortical function.29 The progressive slowing of cognitive task performance with normal aging may result in part from ECF decline secondary to vascular and metabolic alterations.76,77

Mild Cognitive Impairment

Mild cognitive impairment is one of the newer concepts of age-related memory decrement. MCI can be described generally as an intermediary or transitional stage between “normal aging” and dementia. The early cognitive deficits that bring the patient to the clinic are usually not significant enough to markedly interfere with daily cognitive and functional activities. Most observers of the patient with MCI will not notice changes in work or social activities that warrant concern. The reported cognitive deficits do not meet dementia criteria.1 Studies suggest that such patients do not provoke a high level of clinical suspicion as the most commonly used cognitive screen, the Mini-Mental State Examination (MMSE), is not markedly altered in this clinical state (MMSE > 24/30).1,22,23 It is only with more specific testing for logical memory, visual reproductions, cognitive flexibility, and speeded processing, etc, that the subtle cognitive and functional MCI deficits can be documented.1,13,15,20,21,78-81

Within the variable diagnostic criteria of MCI, the estimated incidence ranges from 1-38% per year.82-84 This has considerable significance considering the finding of Jonker and associates85 that memory complaints in persons with and without MCI were suggestive of conversion to “dementia” after 2 years. Also, memory complaints in the highly educated elderly population that do not show evidence of cognitive impairment using short bedside screening tools may also be an index of early dementia.22,23,85 Petersen22,23 reported that 10-15% of his MCI group converted to AD each year compared with a 1-2% conversion rate for patients without MCI. After 4 years, 48% of the MCI group were diagnosed with AD.22,23 Petersen defines MCI as having five components: (1) self-reported, family corroborated, memory complaint; (2) objective memory impairment); (3) normal cognitive function; (4) capacity to drive, balance a checkbook, and attend to normal activities of daily living; and (5) absence of dementia.1,22,23 One may want to know more about the MCI subgroups, such as what percentage of MCI patients will convert to mixed dementia or have significant frontal system and ECF deficits before their MMSE falls into the mild dementia range.

With increasing public awareness of the morbidity of MCI,86,87 the incidence of memory deficits of varying degrees may precipitate more clinical visits from a younger population in the near future. Numerous studies indicate that early memory disorders have been recognized in primary and specialty clinics for many years.33,88-92 These past initiatives have not yielded consensus diagnostic protocols that enable the clinician to identify which early memory patients will convert to Alzheimer’s disease or other cognitively impairing dementia syndromes.

Presently, the clinical conundrum includes the initial diagnosis of MCI and the differentiation among the MCI subgroups, such as posterior cortical dementia syndrome (eg, AD), frontal system syndromes, mixed dementia syndromes, and normal aging.13 Several studies have identified MCI subclusters that may eventually lead to the development of diagnostic subgroups. One MCI cluster includes persons who do not have dementia with cognitive decline (13.8%). The other subcluster includes persons showing a correlation between cognitive decline and nerve growth factor serum level.93 Future studies are needed to identify consensus MCI subgroups including the MCI population who will not convert to dementia.

The Dilemma of Frontal System Diagnosis in Patients With MCI

Inquires about the short- and long-term significance of the memory impairment of MCI are likely to increase with the education of the public about early dementia symptoms. Several problems presently hinder primary care clinicians when patients with MCI present in the clinic for evaluation.

Royall and Polk20 reported a tendency of some dementia screening tests to be biased toward posterior cortical features of AD and to underestimate frontal system deficits such as ECF impairment. In the case of MCI where subgroup distinction is even less clear, the clinician may decide to expand the differential diagnosis. Neuropsychology testing has more diagnostic tools than are commonly utilized in most primary care and geriatric clinics to help identify early frontal, posterior cortical, and mixed-state syndromes in MCI. However, referring all patients with MCI to neuropsychology may be economically prohibitive, as this population will continue to increase with heightened awareness of MCI and improved use of presently available bedside diagnostic tools. What is the primary care clinician to do in the time-constrained practices in which MCI is suspected by the clinician or patient but is not necessarily presented as the primary or secondary problem for the visit?

The MMSE is routinely utilized to identify abnormal cognitive functioning. However, it is biased to identifying posterior cortical function, thus underestimating frontal system deficits with executive control dysfunction and mixed dementia syndromes.20,94,95 Royall et al78 reported that ECF and functional status related to frontal system deficits significantly decline before the MMSE is impaired. Also, the MMSE has been criticized for poor sensitivity in early dementias and in the elderly who are poorly educated.96 Moreover, the effect of ECF on cognitive and functional decline may be masked by the trend to correct psychometric testing for age.15

The advantages of early diagnosis are frequently lost for patients with MCI who have only frontal system memory deficits unless their cognition is evaluated with tests that complement the MMSE. In general, as long as the MMSE score remains greater or equal to 24 out of 30, ECF decline may continue without drawing clinical attention, despite patient complaints of increasing disruption of their work and social life. This common clinical presentation highlights the APA’s call for ECF assessment at the presentation of cognitive and functional decline.

Clock drawing tests (CDTs) are often used to complement the MMSE in screening for cognitive impairment.97-104 CDTs are rapid and assist in identifying frontal system deficits. Of the various CDTs, the authors have found the CLOX test of Royall and Polk13 to be helpful in screening for ECF and frontal system deficits in patients with MCI and dementia. The CLOX is a 2-part test with the first part (CLOX 1) screening for ECF deficits and the second part (CLOX 2) screening for posterior cortical impairments. The CLOX is practical in a busy clinic, requiring about 3-5 minutes for administration and scoring. In the authors’ memory disorders clinics, it has been helpful in screening for ECF deficits that the patient and family are often worried about but which were not identified by the MMSE (MBD, unpublished data, 2002). For example, the Figure illustrates the CLOX test findings for an elderly person with a frontal system memory syndrome without significant posterior cortical signs. Note that the MMSE and CLOX 2 scores are within normal range and that the MMSE is insensitive to the marked ECF deficits in this case. Isolated ECF deficits have been associated with adult-onset diabetes mellitus.19 In the authors’ memory disorders clinic, we have also found frontal system impairment in some of our MCI patients with diabetes mellitus.

Other bedside tests help differentiate frontal from posterior cortical dementias. Perhaps the oldest is the Hachinski Ischemic Score (HIS).105 It consists of a 2-minute checklist based on clinical presentation, natural history, and stroke factors.106 A prospective validation indicated that HIS could differentiate AD (posterior cortical dementia) from multi-infarct and mixed dementias in 84.4% of cases.106 The Dementia Alzheimer’s Type-Inventory (DAT-1) of Cummings107 is also a checklist test to differentiate AD from non-AD. Excluding mixed cases, it correctly classified 94% of AD and vascular disease cases.108 Finally, the Qualitative Evaluation of Dementia94 differentiates between hypothesized cortical and subcortical dementia characteristics as originally described by McHugh.109 With a 95% blinded rater accuracy, it also employs a checklist to distinguish between cortical deficits and behavior disinhibition and subcortical disease with apathy.94

As mentioned above, major depression is thought to be more frequently found in frontal system dementias than in posterior cortical syndromes by a ratio of about 15:1.110 In addition, the presence of apathy may suggest vascular disease, especially with subcortical lesions. Some studies indicate that depression in mild dementia is more frequent than in elderly persons without dementia.111,112 Thus, the authors’ patients who have MCI are screened with both the Geriatric Depression Scale and the Marin’s Modified Apathy Scale113 in the effort to improve our understanding of these two factors in the MCI subgroup differential diagnosis.

Conclusions

There is growing awareness in the medical community of the importance of MCI as a probable prodrome for future dementia syndromes. While the public is still largely unaware of MCI, it is only a matter of time before the connection between progressive memory lapses and dementia will be the stimulus for requests of memory work-ups in primary care and geriatrics clinics. The risk of 48% of MCI patients converting to AD within 4 years has and will have an enormous social impact. What part non-Alsheimer’s dementias and “normal aging” play in this population is unknown. Given that frontal system syndromes may have an earlier onset and more rapid disease course, it can be hypothesized that this MCI subgroup also presents significant long-term morbidity, reduced quality of life, and loss of independence.

With the incidence and prevalence of all dementias increasing with progressing longevity and the aging of the post-World War II population, time-constrained clinical practices need a rapid, cost-effective diagnostic protocol to identify the MCI subgroups at the earliest possible stages. Assessing the roles of demographic data such as family histories, medical histories, psychiatric histories, laboratory tests, imaging studies, genetic and serum markers may lead to the formulation of such MCI subgroup protocols.

The American Academy of Neurology recommends monitoring patients with MCI for functional and cognitive decline. Rapid screening tests with high sensitivity and specificity for frontal system deficits and vascular disease are also needed for the patient subgroups of both MCI and dementia. As some patients with MCI do not convert to dementia, establishing MCI subgroup protocols should aid in more clearly defining the boundaries between normal aging and MCI. Moreover, until there are consensus diagnostic and treatment protocols, pharmacologic intervention will be less than precise.

With a large part of adult cognition and function resting on intact ECF, it would be beneficial if primary care clinicians had a rapid, sensitive screening tool for MCI subgroups, with emphasis on early detection of ECF deficits. The associations of vascular disease with apathy, depression, and ECF dementia seem to be important elements in understanding the complex etiologies of the MCI subgroups. Assessing apathy, depression, and ECF in MCI may alert the clinician to unrecognized vascular lesions such as basal ganglion infarcts, thalamic infarcts, and periventricular white matter lesions. Treatment of the MCI syndromes should offer the possibility of forestalling or reversing some cognitive and functional deficits, whether they are frontal system, posterior cortical, or mixed MCI syndromes.

The establishment of a rapid diagnostic protocol for patients with MCI may increase their productivity and quality of life and decrease the risks of loss of independence and institutionalization. Also, early MCI diagnosis and treatment may reduce long-term national health care costs and caregiver burden. Therefore, the possibility of the substantial long-term social and economic gain should validate research funding to find consensus protocols for the early diagnosis and treatment of MCI subgroups.

Acknowledgment

The authors gratefully thank Jonna G. Detweiler for her contributions to the manuscript.

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Annals of Long-Term Care - ISSN: 1524-7929 - Volume 12 - Issue 01 - January 2004