Major reviewVision function abnormalities in Alzheimer disease
Introduction
Alzheimer disease (AD) is a progressive, age-related, debilitating condition and a growing public health problem in the developed world. This most common form of dementia has two forms: early onset and late onset (International Classification of Diseases, 10th Revision). The early-onset form of the disease, diagnosed before the age of 65 years and accounting for ∼4% of all cases,1 is caused most often by mutations in three genes (amyloid precursor protein [APP], presenilin 1, and presenilin 2) and is often inherited in an autosomal-dominant pattern.25, 303 In the late-onset form, most cases do not have a clearly identifiable Mendelian pattern. Recent studies, however, confirm the presence of strong genetic risk factors, such as the inheritance of the ε4 allele of the APOE4 gene, both for the early-onset and the late-onset form of the disease.84, 186 Presently, no effective treatment is available and the median life expectancy is between 7 to 10 years for patients diagnosed in their 60s and early 70s, or less if they are diagnosed later.319
Changes in the visual system associated with AD have been of interest for many years, with extensive reviews available covering different aspects of the problem.117, 130, 143, 155, 197, 295 We summarize the accumulated evidence with an emphasis on vision changes that could be of practical importance to physicians. We evaluate which vision symptoms may appear early during the development of the disease, and, therefore, could have a diagnostic and perhaps predictive value, and consider the potential for certain tests to be diagnostic instruments.
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Epidemiology and public health importance
The prevalence of dementia in North America in people over age 60 years is about 6.4% of the population, and approximately 70% of those are attributed to AD.74 The reported incidence for North America is 10.5 per 1,000. The estimated number of Americans suffering from AD is 5.4 million, including 5.2 million people aged 65 years and older and 200,000 under the age of 65 years.1 Women are more likely than men to develop dementia at any given age. Presently, almost two-thirds of U.S. Alzheimer
Definition and diagnostic criteria
The current definition was established in 1984 based on the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria.194 According to these criteria AD can be diagnosed as definite, probable, or possible. Definite AD requires pathological evidence, and probable AD is the maximum level of certainty without pathological confirmation and requires a gradual onset and progressive decline in memory with involvement of
Pathophysiology of the disease relevant to the visual system
Two major factors are thought to contribute to the pathogenesis of AD: excessive formation of soluble and insoluble amyloid beta aggregates and accumulation of neurofibrillary tangles (NFTs), the result of hyperphosphorylation and aggregation of the tau protein.
Amyloid beta (Aβ), a peptide of variable length (from 36 to 43 amino acids), is expressed in most tissues in the body. Functions of the peptide include activation of kinases, protection against oxidative stress, and regulation of
Retinal ganglion cell (RGC) number
Hinton et al109 examined four eyes of AD patients and found RGC loss in three of them; they did not provide either quantitative results, or direct comparison with age-matched controls, however. In contrast, Curcio et al53 did not find any differences between RGC numbers in four autopsy-confirmed, severely demented patients with AD and four age- and sex-matched control subjects. Blanks et al23, 24 expanded the initial observation of Hinton et al and compared the ganglion cell numbers between 12
Slit lamp examination
Until recently, slit lamp examinations were considered of limited value in AD. Some types of cataract (i.e., equatorial supranuclear), however, may be more common in AD,88 which is expected due to similarities of biochemical aspects of the two conditions101 and based on epidemiological data.37 Further, cataracts were significantly associated with visual hallucinations in 20 AD patients.39 The potential link between cataract and AD was strengthened recently by the identification of an allele of
Psychophysical visual measures
Psychophysical testing in a disease like AD, where the results of the tests are heavily dependent on the patient's good understanding and memorization of the rules and requirements and compliance with the test instructions, may be challenging. Furthermore, some amount of vigilance on the part of the patient is required, which depends on their cognitive status. Therefore, without careful control of the potential impact of the cognitive status on testing, detected abnormalities interpreted as a
Testing of higher-order visual function
Psychophysical testing of higher-order visual function includes testing of visual memory, assessing the numerosity of complex patterns, texture discrimination, and so forth. These abilities result from a complex interaction between secondary visual processing pathways and other higher cortical functions. To what extent their decline is influenced by a decline in primary visual function (cortical and precortical) is still a matter of debate. Testing of these functions occurs in specialized
Pupillary light response in AD
The pupillary response is controlled by a balance between cholinergic and adrenergic innervation and is influenced directly or indirectly by central and autonomic nervous system inputs. As cholinergic system deficits are associated with dementia and AD78 the pupillary light reflex would be expected to be affected in AD.278 The development of a sensitive and specific pupillary response test for the clinical diagnosis of early AD, however, has proved to be challenging.
Ocular motor abnormalities in AD
Eye movements are controlled by a complex oculomotor control system involving input from the retina, processing in different parts of the brain, transmission of signals from the brain to the extraocular muscles and synchronized action of the extraocular muscles.255 Studies in autopsy cases have demonstrated that oculomotor brain nuclei are affected by the pathological processes associated with AD,26, 245 and therefore some negative effects on eye movements should be detectable.
Abnormalities of
Electrophysiological measures in AD
Changes in the bioelectrical response from parts of the visual system as a result of the presentation of visual stimuli can be measured electrophysiologically. These tests have the advantage of providing an objective measure of the functional capabilities of the visual pathways.
Overlap between AD and ocular conditions
An accurate diagnosis of AD is important and may be challenging, especially in the early stages of the disease.71, 83 We focus on similarities in pathophysiology and clinical presentation of two common ophthalmic conditions and AD.
Conclusion
Although precortical visual system abnormalities in AD have been questioned in the past, data emerging from more recent studies provide mounting evidence that they do exist. This is supported by findings in animal models of AD.221 Examples of human ocular abnormalities include optic nerve changes and retinal nerve fiber layer thinning. Future studies are needed to define whether or not retinal ganglion cell loss is present in cases of AD and, if so, to what extent this loss is related to
Method of literature search
The literature search was conducted through Medline, BioMed Central, and EMBASE. All years from 1950 to the present were included in the search. The following search terms were used: Alzheimer's disease, epidemiology, pathogenesis, retina, optic nerve, lateral geniculate nucleus, visual cortex, ophthalmolscopy, fundus photography, fluorescein angiography, optical coherence tomography, visual acuity, color vision, visual field, flicker fusion, contrast sensitivity, dark adaptation, depth
Disclosure
The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
Acknowledgments
We would like to thank Vernon Odom and Gregory Jackson for their detailed reading and comments on the manuscript.
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