Closing the gap between research techniques and clinical practice in the treatment of dementia
Alissa H Wicklund1, Moises Gaviria2
1 Neurobehavioral Associates, P.C., Chicago, USA
2 Department of Psychiatry, University of Illinois, Chicago, IL, USA
|Date of Submission||14-Jul-2011|
|Date of Acceptance||20-Oct-2011|
|Date of Web Publication||19-Nov-2011|
Alissa H Wicklund
Neurobehavioral Associates, P.C., Chicago
© 2011 Wicklund et al; This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
|How to cite this article:|
Wicklund AH, Gaviria M. Closing the gap between research techniques and clinical practice in the treatment of dementia. Surg Neurol Int 2011;2:168
Alzheimer's disease (AD) and vascular disease represent the most common causes of dementia in the elderly, with estimates of over 35 million individuals suffering from dementia, primarily of the Alzheimer's type, worldwide.  In the past 30 years, there has been a proliferation of imaging techniques to examine structural and functional brain changes associated with dementia as well as to identify the biomarkers indicative of molecular pathology and neuronal injury in neurologic disease. Advancements in magnetic resonance imaging (MRI; i.e. diffusion tensor imaging, fractional anisotropy, anatomic volumetric renderings) and nuclear medicine [i.e. F-18 fluorodeoxyglucose (FDG)-positron emission tomography, single-photon emission computed tomography (SPECT), β-amyloid labeled tracers Pittsburg compound B (PIB)] have presented researchers with tools to scaffold on their existing knowledge of the clinical and pathological hallmarks of dementia. Goals of imaging techniques include tracking and staging of the disease process, differential diagnosis, identification of prodromal stages of neurodegeneration and the detection of co-morbid conditions in the elderly, such as idiopathic normal pressure hydrocephalus (INPH). Examination of biomarkers can identify individuals at risk for developing dementia, aid in differential diagnosis, and provide confirmation of molecular pathology and neuronal injury. However, currently, advanced imaging tools and biomarker analyses are reserved primarily for research, with limited clinical application. ,
The pathology of AD, amyloid plaques and neurofibrillary tangles has an initial affinity for limbic regions that are involved in the cognitive processes of episodic memory.  With advancement of the disease process, pathology progresses to other cortical regions, resulting in additional cognitive, behavioral and psychiatric symptoms. Recent advancements in clinical diagnostic procedures, imaging and biomarker identification have led to a revision of the research and clinical diagnostic criteria for AD.  The revision incorporates both overt clinical symptoms of AD, as well as the spectrum of intermediate stages of the disease, such as the identification of positive biomarkers in asymptomatic individuals and individuals with mild cognitive impairment (MCI; a condition of focal cognitive changes without significant disruption to functional ability).
Neuroimaging increasingly plays a role in the identification of prodromal stages of AD dementia for research purposes. For example, MRI is utilized to analyze cortical thickness and gray matter atrophy in specified regions of interest such as temporal and parietal brain areas that subserve memory function and can be compared between individuals with AD, MCI and cognitively normal healthy older adults. ,,, Increasingly, histopathologic changes, such as deposition of cerebral amyloid-β peptide, are being visualized with tracers such as PIB, with the goal of clinical correlation to cognitive function in individuals who may be asymptomatic or on the spectrum from normal aging to a clinical diagnosis of AD dementia. ,, The value of these techniques in diagnosis and early intervention is being examined. However, standardization of techniques must be performed before they can be integrated clinically.
Vascular dementia (VaD) (in the literature, also referred to as multi-infarct dementia and subcortical ischemic vascular disease,  for review) occurs in individuals with white matter ischemic disease, lacunar infarcts and cerebrovascular accidents, and results in a progressive change in cognition and functional ability. The clinical picture of VaD can be distinct, or when concomitant with AD, is characterized clinically by a profile of mixed dementia (VaD + AD). Imaging techniques primarily describe brain structure in VaD, rather than examining molecular changes. However, recent studies are examining amyloid imaging in individuals with subcortical vascular dementia to more closely assess the presence or absence of specific pathological processes, which could help the clinicians guide pharmacologic interventions, for example. 
The disparity between research and clinical implementation of imaging and biomarkers as diagnostic tools in dementia is being addressed through clinical trial outcome studies. Programs such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), , have goals of validating neuroimaging techniques and biomarkers for use in clinical trials. The development of standards for such techniques, with validation in multiple countries, and across ethnicities and cultural settings represents the initial pathway to offer worldwide access to novel diagnostic tools. These goals represent an exciting first step toward the eventual clinical utility of such techniques. Even with advancement in the validation of the methodology, barriers continue to exist to prevent widespread use of neuroimaging for the clinical diagnosis of dementia syndromes.
One issue is the lack of imaging tools commercially available to clinicians. For example, hippocampal and entorhinal volumetric measurements on MRI have been shown to be useful in identifying incipient dementia and tracking volumetric change over time using voxel-based morphometry. , A study using diffusion tensor imaging (DTI) showed subtle axonal loss and gliosis in anterior frontal white matter in a small group of elderly individuals with idiopathic normal pressure hydrocephalus.  The DTI results provide advanced information about possible neural disruption to frontal subcortical circuitry implicated in gait disturbance and cognitive changes in INPH. However, at this time, validation studies are not at the point to implement tools commercially. Additional limitations include the need for lengthy analysis, advanced computer software and individuals specifically trained to perform such techniques, which may be cost prohibitive for individual clinics and unavailable in developing and rural countries.
Another barrier in applying neuroimaging techniques to clinical practice is that even if the techniques could improve diagnostic accuracy, there is currently a lack of pharmacologic treatments available for dementia. However, increased diagnostic accuracy can still be useful in the tracking and staging of illness caused by neurodegenerative disease and measuring outcomes of neurosurgical procedures in dementia resulting from INPH. Acknowledging the level of the disease process can inform decisions regarding the patients' functional abilities and psychiatric treatment, and provide information for family education and intervention.
As described, current research is focusing more on the early stages of neurodegeneration by examining the biomarkers and risk factors for dementia that may present even decades before clinical symptoms appear.  Baseline neuroimaging could be useful in tracking disease progression in individuals with risk factors and/or identified positive biomarkers of dementia. Neuroimaging may also be useful in the selection of elderly individuals with neurosurgical needs to help identify those who may have the most positive response and outcome to surgical intervention. The consequences of acknowledgment of risk factors and early identification of the possible clinical disease trajectory have yet to be determined. Researches typically do not inform patients and research subjects of the results of tests specifying positive biomarkers or structural abnormalities, for example. In addition, techniques have not been implemented into clinical practice, as they are not standardized diagnostic tools. Aside from guiding clinical treatment with this information, there are psychological implications for individuals and families accepting and utilizing genetic information. Genetic counseling will be integral, and the assessment of value added in knowing such information will need to be assessed.
Another barrier to bridging the gap between research and clinical practice is in the area of insurance and healthcare coverage, particularly in the United States healthcare system. Healthcare does not yet recognize many of these techniques for early stage diagnosis and treatment planning, as to date many of the techniques are still in experimental stages. If imaging could be applied to track and stage a future neurodegenerative condition, earlier intervention may be possible. Even for those individuals with suspected clinical dementia syndromes, insurance coverage for currently approved imaging techniques is not universal. For example, some insurance plans cover the cost of PET in the differential diagnosis of AD versus frontotemporal lobar degeneration (a neurodegenerative disease typically presenting in individuals before the age of 65, characterized by symptoms of progressive decline in behavior and/or language). Other insurance carriers have limitations on the age group or diagnostic categories in which they determine advanced imaging to be clinically useful.
New neuroimaging techniques continue to emerge and advance our tools for the assessment, diagnosis, tracking and staging of dementia. Programs such as ADNI have an impact by validating the utility of these techniques for clinical trials. With organized large-scale validation trials, clinicians can remain hopeful that imaging vendors may also see the utility of such techniques and prepare more readily available commercial software for image analysis. The insurance industry will also need to make strides to offer reimbursement for such techniques. However, a gap to implementation still exists in countries without resources to fund such advanced tools. Thus, developing countries will continue to rely on clinical acumen and cognitive screening batteries, which are ultimately the most readily available and applied tools, and most useful in terms of guiding treatment planning, family education and assessing functional ability in individuals with dementia.
With collective support from imaging vendors, insurance companies, researchers and organized professional societies, such as the International Neuropsychiatric Association, American Neuroradiological Society, Society for Nuclear Medicine, American Association of Neurological Surgeons, the Alzheimer's Association and others, we can see individual patients benefit through more comprehensive clinical care, with the goal of diminishing the gap between research techniques and clinical practice.
| References|| |
|1.||Acosta D, Wortmann M. Alzheimer′s Disease International World Alzheimer Report (2009). In: Prince M, Jackson J, editors. London, UK: Alzheimer′s Disease International; 2009.p. 1-92. |
|2.||Albert M, DeCarli C, DeKosky S, De Leon M, Foster NL, Fox N, et al. The use of MRI and PET for clinical diagnosis of dementia and investigation of cognitive impairment: A consensus report. Neuroimaging Work Group of the Alzheimer′ Association; 2004. Available from: http://www.alz.org. [Last accessed on 2011 Jun 30]. |
|3.||Baron JC, Chételat G, Desgranges B, Perchey G, Landeau B, de la Sayette V, et al. In vivo mapping of gray matter loss with voxel-based morphometry in mild Alzheimer′s disease. Neuroimage 2001;14:298-309. |
|4.||Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239-59. |
|5.||Dickerson BC, Bakkour A, Salat DH, Feczko E, Pacheco J, Greve DN, et al. The cortical signature of Alzheimer′s disease: Regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid-positive individuals. Cereb Cortex2009;19:497-510. |
|6.||Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA 2000;97:11050-5. |
|7.||Jack CR Jr, Bernstein MA, Borowski BJ, Gunter JL, Fox NC, Thompson PM, et al. Update on the magnetic resonance imaging core of the Alzheimer′s disease neuroimaging initiative. Alzheimers Dement 2010;6:212-20. |
|8.||Jack CR Jr, Petersen RC, O′Brien PC, Tangalos EG. MR-based hippocampal volumetry in the diagnosis of Alzheimer′s disease. Neurology 1992;42:183-8. |
|9.||Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer′s disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306-19. |
|10.||Kowalski J, Gaviria M, Horowitz S. Neuroimaging in dementia: From research to clinical practice. Denver, CO: American Neuropsychiatric Association; 2011. |
|11.||Lee JH, Kim SH, Kim GH, Seo SW, Park HK, Oh SJ, et al. Identification of pure subcortical vascular dementia using 11C-Pittsburgh com- pound B. Neurology 2011;77:18-25. |
|12.||Lenfeldt N, Larsson A, Nyberg L, Birgander R, Eklund A, Malm J. Diffusion tensor imaging reveals supplementary lesions to frontal white matter in idiopathic normal pressure hydrocephalus. Neurosurgery 2011;68:1586-93; discussion 1593. |
|13.||Lockhart A, Lamb JR, Osredkar T, Sue LI, Joyce JN, Ye L, et al. PIB is a non-specific imaging marker of amyloid-beta peptide-related cerebral amyloidosis. Brain2007;130:2607-15. |
|14.||McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer′s disease: Recommendations from the National Institiute on Aging-Alzheimer′s Association workgroups on diagnostic guidelines for Alzheimer′s disease. Alzheimers Dement 2011;7:263-9. |
|15.||Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer′s disease: Recommendations from the National Institute on Aging and the Alzheimer′s Association workgroup. Alzheimers Dement 2011;7:280-92. |
|16.||Storandt M, Mintun MA, Head D, Morris JC. Cognitive decline and brain volume loss as signatures of cerebral amyloid- β peptide deposition identified with Pittsburgh Compound B. Arch Neurol 2009;66:1476-81. |
|17.||Weiner MW, Aisen PS, Jack CR Jr, Jagust WJ, Trojanowski JQ, Shaw L, et al. The Alzheimer′s disease neuroimaging initiative: Progress report and future plans. Alzheimers Dement2010;6:202-11.e7. |
|18.||Wiederkehr S, Simard M, Fortin C, van Reekum R. Comparability of the clinical diagnostic criteria for Vascular Dementia: A critical review. Part I. J Neuropsychiatry Clin Neurosci 2008;20:150-61. |