Neuropathological changes in Alzheimer’s disease

by | Oct 22, 2020 | Alzheimer's Disease, Medical Officers, Prescribers | 0 comments

Alzheimer’s Disease (AD) is a neurodegenerative disease that gradually worsens over time. (1) In fact, it is the most common neurodegenerative disease and constitutes about two-thirds of cases of dementia overall. (2) Millions of Americans are affected by this disease, and as of now, there is no cure for AD. Current research is working on understanding the progression of neuropathological changes that occur in the brain. With greater understanding of these biomarkers, earlier diagnosis and treatment can be used to slow the development of AD. (10)

AD is a progressive disease that results in the irreversible loss of neurons, particularly in the cortex and hippocampus. (2) Alterations in the function of neural systems that release glutamate, norepinephrine, and serotonin are a few of the physiological changes that the body undergoes from Alzheimer’s. (1) AD, unlike Parkinson’s Disease, does not involve the degradation of a single neurotransmitter but is instead highly heterogeneous. (3) The main changes the brain undergoes are to the β-amyloid plaques and neurofibrillary tangles. (4)

β-amyloid plaques are hard, insoluble accumulations of β-amyloid proteins that clump together between the neurons in the brain. (5) They are extracellular and are found in a high proportion of all elderly people. (4) Evidence suggests that amyloid deposition in AD can precede structural changes in the brain, including hippocampal volume loss and decreased glucose metabolism. (7) Amyloid plaques alone do not seem to be a sufficient substrate for advanced clinical AD dementia. (4) However, in contrast to neurofibrillary (tau) pathology, there seems to be a stronger association between AD genetics and Aβ plaque formation. (4)

Neurofibrillary tangles, on the other hand, are insoluble twisted fibers composed of the protein tau that block the neuron’s transport system and form thick bundles near the cell surface of affected neurons. (6, 7) These lesions throughout the brain result in the loss of synapses and neurons, leading to the symptoms commonly associated with AD. (7) A neuropathologic diagnosis of AD requires both amyloid plaques and neurofibrillary tangles composed of filamentous tau proteins. (7) There is evidence that suggests that the neurofibrillary tangles are a better indicator of cognitive impairment than the amyloid deposits. (7) Neurofibrillary tangles occur in three stages beginning as “pretangles” containing abnormal conformers of tau in the cell body and dendrites of neurons. (7) Once they mature, the tangles then displace the nucleus and other vital cellular components, and eventually the neurons die. (8)

The pathological diagnosis of AD recognizes that any amount of Alzheimer neuropathological change is abnormal. (9) The main way to diagnose Alzheimer’s disease is through brain scans. Brain scans are able to rule out other conditions such as hemorrhages, brain tumours or stroke. They are also able to distinguish between different types of degenerative disease. However, the problem with diagnosing Alzheimer’s disease is that there is overlap between what doctors would consider normal age-related changes and abnormal change in the brain. (10) Recently, technological advances in PET scans, positron emission tomography, have been developed to detect clusters of amyloid proteins. (10) These tests have only been done in research settings, and more research must be done before being introduced in clinical settings. Additionally, research and diagnostic tests are being done to investigate the effect of genes, disease-related proteins, and imaging procedures which may accurately predict whether you have AD and how much the disease has progressed.

These diagnostic tools do not diagnose early AD very effectively (8), but new research is finding better ways to do this. Brain diseases affect the eyes since the optic nerve and retina are actually brain tissue that extends outside the brain. Research shows that patients with Alzheimer’s have changes in their eyes’ saccadic movements. Saccadic eye latency declines with age, but delays become more pronounced in patients with AD. Additionally, saccadic eye movements are reduced, and the degree of the reduction is correlated with the severity of dementia. (11)

Esurgi is currently developing a product, EyeAD, as an early diagnosis and ongoing monitor adjunct for Alzheimer’s disease. This product will be a real-time eye monitor device for Alzheimer’s disease that is cost effective and non-invasive. EyeAD, a portable pair of glasses that patients can use at home, monitors saccadic eye movement. It will act as an early diagnosis tool and ongoing monitoring adjunct. The glasses are connected to an app that senses and reads the information and shares it with patients’ physicians. How would EyeAD help you monitor patients for early signs of AD?

Citations

  1. Wenk, G. L. (2003). Neuropathologic changes in Alzheimer’s disease. The Journal of clinical psychiatry.
  2. Nussbaum, R. L., & Ellis, C. E. (2003). Alzheimer’s disease and Parkinson’s disease. New england journal of medicine, 348(14), 1356-1364.
  3. Selkoe, D. J. (2001). Alzheimer’s disease: genes, proteins, and therapy. Physiological reviews.
  4. Nelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., … & Duyckaerts, C. (2012). Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. Journal of Neuropathology & Experimental Neurology, 71(5), 362-381.
  5. Meadowcroft, M. D., Connor, J. R., Smith, M. B., & Yang, Q. X. (2009). MRI and histological analysis of beta‐amyloid plaques in both human Alzheimer’s disease and APP/PS1 transgenic mice. Journal of Magnetic Resonance Imaging: An Official Journal of the International Society for Magnetic Resonance in Medicine, 29(5), 997-1007.
  6. Lewis, J., McGowan, E., Rockwood, J., Melrose, H., Nacharaju, P., Van Slegtenhorst, M., … & Duff, K. (2000). Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nature genetics, 25(4), 402-405. 
  7. DeTure, M. A., & Dickson, D. W. (2019). The neuropathological diagnosis of Alzheimer’s disease. Molecular neurodegeneration, 14(1), 1-18.
  8. Perl, D. P. (2010). Neuropathology of Alzheimer’s disease. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine: A Journal of Translational and Personalized Medicine, 77(1), 32-42.
  9. Hyman, B. T., Phelps, C. H., Beach, T. G., Bigio, E. H., Cairns, N. J., Carrillo, M. C., … & Mirra, S. S. (2012). National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimer’s & dementia, 8(1), 1-13.
  10. Khachaturian, Z. S. (1985). Diagnosis of Alzheimer’s disease. Archives of neurology, 42(11), 1097-1105.
  11. Armstrong, R. A. (2009). Alzheimer’s disease and the eye. Journal of Optometry, 2(3), 103-111.


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