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The predisposing factors, biological markers, neuroimaging techniques and medical complications associated with Alzheimer's disease.

The concept and terminology of dementia is changing. There is a proposal in DSM-V which will be published in the next few years to eliminate the word "dementia" and "mild cognitive disorder" and replace the diagnoses with minor and major neurocognitive disorders. (1) Over time, practitioners have recognized that pure Alzheimer's dementia is not as prevalent as once thought. The majority of the dementias we see, especially in the very elderly are often of a mixed variety involving degenerative and vascular factors. While it may be possible to differentiate dementias in the early phase of the dementing process with the so-called vascular prodrome of Alzheimer's disease, it is extremely difficult in the moderate to severe ranges. (2,3) Much of the research associated with Alzheimer's type dementia identified in this article have been found to be common both in Vascular and Alzheimer's Dementia. (4) The authors review the predisposing factors, the biological markers, neuroimaging techniques, and the medical complications associated with the diagnosis of Alzheimer's disease.

Predisposing Factors

Age and gender have been identified as factors that may be associated with dementia. As one ages, there is a greater probability of developing dementia. By the age of 85, approximately 50% of those individuals will have some form of dementia. Although questionable, some studies have also shown that people who do not develop cognitive impairments by the age of 85 are unlikely to develop it in later life. While the exact etiology is not clear, gender may also play a role in dementia. Dementia occurs more frequently in females. Hormone changes such as deficiencies of estrogen have been implicated; however, women tend to live seven to eight years longer than men, which may account for the greater prevalence rates. The evidence is not conclusive. (5,6)

Genetics have played a role in the development of Alzheimer's dementia especially when the cognitive deficits are seen below the age of 65. Deficits in chromosomes 14, 21 presenilin 1 and 2 genes have been identified. Individuals with Down 's syndrome (trisomy 21), who live beyond 40 develop both the clinical and histopathological changes seen in Alzheimer's dementia. (7)

Apolipoprotein E4 (APOE4) has been implicated in the development of dementia. Research has been shown that if one inherits this allele from both parents, the chances of developing dementia are significantly higher and earlier than in those who either inherit the allele from one parent or none at all. Free radicals play a role in the development of dementia through the oxidative process. The neuronal degradation of the cells through free radicals is still, however, debatable (ex. aluminum, zinc, iron, lead, etc). The APO-E4 carriers are more likely to develop Alzheimer's dementia if they have concomitant cerebrovascular disease, which suggests that carriers may reduce the risk through improved diet, exercise, blood pressure monitoring and avoidance of smoking. (8)

The Food and Drug Administration (FDA) has recently given the approval for Bryostatin to enter Phase II clinical trials for not only the treatment of Alzheimer's disease but also its underlying causes. (9) Bryostatins are potent modulators of protein Kinase C. The drug has shown positive results in enhancing and restoring memory destroyed in aging, stroke, or head trauma by rewiring connections in the brain. The results suggest Bryostatin promotes new synapses (synaptogenesis) and prevents the loss of dying neurons. (9)

Although controversial, psychiatric factors have been implicated in some epidemiological studies. The impact of head trauma on dementia depends on the severity and the functional reserve prior to the injury. In individuals with limited education, the functional reserve is less and the chances of developing dementia are higher as opposed to those with higher cognitive reserve. (10) Depression has also been identified as an independent risk factor in the development of Dementia of the Alzheimer's type. (4,11) When memory impairment is a symptom of depression, and although depression may improve with the treatment, it has been shown to be a harbinger for the development of dementia earlier than in those with no memory impairment as a part of the clinical depression. Although not clear, Brain Derived Neurotropic Factor (BDNF) affecting the hippocampal size has been linked to the depressive spectrum. (12) Alcohol abuse and substance abuse have been implicated in the development of dementia which is related to poor nutrition, lack of functional reserve and the prevalence of head trauma from falls or other altercations during intoxication. (13)

On the other hand, medical issues such as uncontrolled hypertension, diabetes mellitus, and lipid abnormalities have also been identified as predisposing (14) factors both in Alzheimer's and vascular dementias which have given support for the concept of mixed dementia. (11)

Biological Markers

Currently, there are no biological markers to prove with certainty that one has Alzheimer's type dementia except for brain biopsy. Brain imaging and spinal cord sampling has shown some promise especially in moderate dementia but both are expensive and cumbersome. The use of NMDA receptor antagonists and acetylcholinesterase has not been found to be helpful in stopping the progression of Alzheimer's dementia though it does modify the illness. The brain changes leading to the development of Alzheimer's dementia begin at least a decade before memory impairment symptoms emerge. (15)

Low AB42 and high phosphorylated TAU proteins in the spinal fluid have been shown to be consistent in the diagnosis of Alzheimer's. (16,17) Hyperphosphorylated TAU pairs with other threads of TAU forming neurofibrillary tangles inside the nerve cell bodies. The neuron's transport system collapses which results in malfunction in biochemical communication between neurons and eventually death of the cells. The results are found more in the amnestic variety than in those who remain healthy or develop other dementias. While the results have been encouraging, the routine use of this clinical procedure is not recommended.

APO-E4 genotyping can be helpful in certain cases, but it is still not recommended. The results may be helpful in the memory impaired elderly where the diagnosis is in doubt, however, 20% of people who have positive APO-E4 do not develop dementia. (18) Overall, drugs in current use have had abysmal results in modifying the course of the disease.

The amyloid theory of Alzheimer's disease has been challenged. (18,19) There is little question that the amyloid hypothesis explains the disease in families with mutations of the amyloid precursor protein and the presenilin genes, however, there are questions if the same process is at play in the typical Alzheimer's patient. Recent animal research suggests that oligomers (clumps of beta amyloid protein) are the main players in the rogue process attacking the brain. The amyloid plaques form in clumps to prevent the spread of oligomers and act as a defense mechanism. On the other hand, some studies have found no evidence of dementia in brains inundated with plaques. Currently, research designed to decrease the production of oligomers is underway and may eventually identify a remedy in the spread of this devastating illness.

Neuroimaging Techniques

Brain atrophy and decreased brain volume have been seen on routine CT scans of the head in younger patients and are thought to be predictors of dementia. Typically, SPECT and functional MRI will show hypoperfusion in the frontal, temporal and parietal areas of the brain in those with a diagnosis of dementia. The procedures are, however, experimental and expensive, and not recommended in routine clinical practice. Hippocampal atrophy, especially the rate and degree, correlates well in the conversion of MCI to dementia. (20) Although more costly, MRI has been found to be a better predictor than the CT scan in assessing brain and hippocampal atrophy including volume. The atrophy may begin several years before the clinical symptoms of memory impairment appear. On the other hand, 20% of the patients with hippocampal atrophy do not develop dementia of the Alzheimer's type. Moreover, the size of the hippocampus varies in different individuals with education playing a role. Unless longitudinal measurements are available, it is difficult to identify changes in the size of the hippocampus for a specific individual.

Medical Complications

Currently, 5.3 million have Alzheimer's disease and that number is expected to rise. Diabetes mellitus, hypertension, hyperlipidemia, and obesity have been identified as predisposing factors in dementia. Individuals with diabetes mellitus have a high risk of comorbid disease, disability, cognitive impairment, pain, and depression. Hypertension is associated with renal disease and high mortality. Hyperlipidemia has been associated with cerebrovascular accidents. Carrying excessive weight in the abdominal region is a risk factor for dementia later in life. (21) On the other hand, low BMI (body mass index) and weight loss are not early manifestations of dementia. Other physical causes have to be ruled out, especially malignancy. Changes in lifestyle can prevent or modify the onset of diabetes, cardiac problems, and lipid abnormalities. A diet comprised of healthier foods and regular exercise can reduce body mass. Lowering the BMI would be helpful not only in the prevention of dementia, but in improving the quality of life in all aspects. The best preventative practice would involve targeting youth. Research suggests that adverse early life experiences including lack of exercise (both physical and mental), poor nutrition especially vitamins such as folic acid, the use of aspirin or other anti-inflammatories, and cultural and educational deprivation may affect the development of dementia in later life. (22,23)

Summary

With increased longevity and increased prevalence of diabetes, hypertension, heart disease, and obesity, dementia is likely to raise three to fourfold. The diagnosis of the Alzheimer's type dementia is being challenged as the majority of the dementias appear to be of the mixed type. Biological and genetic factors combined with life style choices play a role in the development of the dementias. The drugs in current use to modify the symptoms have had little impact. Today's research challenges the long held amyloid theory of Alzheimer 's disease. Research has been inconsistent and more support is needed to help us identify preventable and modifiable factors of the disease.

Objectives

The authors review the predisposing factors, biological markers, and the neuroimaging techniques associated with Alzheimer's Type Dementia. Although no specific tests exists, research which attempts to identify the disease process are presented. The article also discusses some of the medical complications that impact the course of the illness.

References

(1.) Vayda, Sep., B.A., Patterson, Marian B., Ph.D., et al. The Future of Dementia: A case of Hardening of the Categories: Am J of Geriatric Psych, Editorial, Sept., 2010: 18.9.

(2.) Gustafson, L., England, E., Brunnstrom, H., et al. The Accuracy of Short Clinical Eating Scales in Neuropathologically Diagnosed Dementia. Am J Geriatric Psych, 2010: 18:810-820.

(3.) Alexopontos, G. S., et al. Vascular Depression Hypothesis. Arch Gen Psych, 1997, 54:915-922.

(4.) Smith, P.J., Blumenthal, et al. Cerebrovascular Risk Factors; Vascular Disease & Neuropsychological Outcomes in Adults with Major Depression. Psychosomatic Med, 2007, 60:578-586.

(5.) Hendrie HC. Epidemiology of Dementia and Alzheimer's Disease. AMJ Geriatric Psychology. 1998:6 (Suppl 1): S3-S18.

(6.) Shumaker, S. A. et al. Conjugated Equine Estrogens & Incidence of Probable Dementia & Mild Cognitive Impairment in Post Menopausal Women. Women's Health Initiative Memory Study. JAMA, 2006, 29(24): 2947-2958.

(7.) Waring SC, Rosenberg, RN, "Genome Wide Association Studies in "Alzheimer's Disease". Arch Neurol, March 2008, 65(3): 329-34.

(8.) Biomarkers for Alzheimer's Disease. Harvard Mental Health Letter, Nov 2010: Vol. 27, 5.

(9.) Clinical Trial at Blanchette Rockefeller Neurosciences Institute at West Virginia University--Clinical Trials, (2011) www.brni. org/scientific-research/clinical-trials.qspx.

(10.) Wilson, R. S., Li, Y., et al. Education and the Course of Cognitive Decline in Alzheimer's Disease. Neurology 2004, 63(7):1198-1202.

(11.) Flicker, L. Vascular Factors in Geriatric Psychiatry; Time to take a Second Look. Current Opin Psych, 2008, 21:551-554.

(12.) Berchfold, N. C. et al. Hippocampal Brain-derived Neurotrophic Factor Gene Regulation by Exercise and the Medial Septum. J Neuroscience Res, 2002, 68(5):511-521.

(13.) Laarson, E. B., et al. Exercise is Associated with Reduced/ or Incident Dementia Among Persons 65 years of Age and Older. Ann Intern Med, 2006, 144(2):75-81.

(14.) Farlow MR (2004) "NMDA Receptor Antagonists a New Therapeutic Approach for Alzheimer's Disease." Geriatrics 59 (6): p. 22-27

(15.) Dwnby, R.L., Crocco, E., Acevedo, A., John V. Loewenstein D. Depression and Risk for Alzheimer's Disease Systematic Review, Meta-Analysis and Meta-regression Analysis. Arch Gen Psychiatry. 2006; 63(5): 530-538.

(16.) Desai, A. K., et al. Tau Based Therapeutics for Alzheimer's Disease; Wave of the Future. Primary Psych, Vol. 16, Number 7, 2009.

(17.) Goedert M., Spillantini M. G., Crowther, R. A., "Tau Proteins and Neurofibrillary Degeneration". Brain Pathol, July 1999, 1 (4): 2079-86.

(18.) Holzman, D.C., From Vaccines to Genetics, Alzheimer's Research Moves Forward Towards Cure. CNS News, 2005, 7 (8): 4.

(19.) Grossberg, G. T., M. D. Innovative Treatment Approaches in Alzheimer's Disease. Primary Psych, Vol. 16, Number 7, 2009.

(20.) Menschik E.D. Finkel LH. Cholinergic Neuromodulation and Alzheimer's Disease: From Single Cells to Network Stimulations. Prog Brain Res. 1999: 121:19-45.

(21.) Luchsinger, J.A., et al. Measures of Adiposity and Dementia Risk in Elderly Persons. Arch Neurology, 2007, 66(3): 392-398.

(22.) Bassil, Nazem, Groisberg, George, T. Evidence Based Approaches to Preventing Alzheimer's Disease. Primary Psych, Vol. 16, Number 7, 2009.

(23.) Laarson, E. B., et al. Exercise is Associated with Reduced/ or Incident Dementia Among Persons 65 years of Age and Older. Ann Intern Med, 2006, 144(2):75-81

M. Khalid Hasan, MD, FAPA

Distinguished Fellow, American Board of Psychiatry and Neurology

Clinical Professor, WVU School of Medicine

Roger P. Mooney, MA, EdD

Psychologist

CME Post-Test

10. While the exact etiology is unclear, dementia is seen more often in females.

a. True

b. False

11. Education and culture play a role in the development of Alzheimer's type dementia.

a. True

b. False

12. Low BMI in late life and weight loss are risk factors for Alzheimer's type dementia.

a. True

b. False
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Title Annotation:Scientific Article: Special Issue
Author:Hasan, M. Khalid; Mooney, Roger P.
Publication:West Virginia Medical Journal
Article Type:Disease/Disorder overview
Geographic Code:1U5WV
Date:May 1, 2011
Words:2304
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