Surgery – Diagnostic testing – Eye or testing by visual stimulus
Reexamination Certificate
1999-09-16
2002-04-02
Winakur, Eric F. (Department: 3736)
Surgery
Diagnostic testing
Eye or testing by visual stimulus
C351S200000, C128S898000
Reexamination Certificate
active
06364845
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for diagnosing visuospatial disorientation or assessing visuospatial orientation capacity and their use in diagnosing neurodegenerative diseases. The present invention also relates to a method for enhancing visuospatial orientation in a subject.
BACKGROUND OF THE INVENTION
Visuospatial disorientation is the inability to perceive, recall, or navigate through the structured environment surrounding, the individual. It includes topographagnosia (the failure to recognize environmental structure) (Holmes, “Disturbances of Vision by Cerebral Lesions,”
British J. of Ophthalmology
, 2:353-384 (1918); Brain, “Visual Disorientation With Special Reference to Lesions of the Right Cerebral Hemisphere,”
Brain
, 64:244-272 (1941); Critchley,
The Parietal Lobes
, New York, Hafner Publishing Co. (1953)) and is thought to rely on dorsal stream occipito-parietal visual pathways (Mountcastle et al.,
The Mindful Brain: Cortical Organization and the Group-Selective Theory of Higher Brain Function
, Cambridge, Mass., MIT Press (1978); Ungerleider et al., “Two Cortical Visual Systems,” In:
Analysis of Visual Behavior
, Ingle et al., eds., Cambridge, MIT Press, pp. 549-586 (1982)).
Damage to parieto-occipital cortex has long been associated with the syndrome of visuospatial disorientation (Holmes, “Disturbances of Vision By Cerebral Lesions,”
British Journal of Ophthalmology
, 2:353-384(1918), Critchley, “The Parietal Lobes,” New York, Hafner Publishing Co., (1953)). More recently, this syndrome has been recognized as a common component of behavioral impairment in Alzheimer's disease (“AD”) (Cogan, “Visual Disturbances With Focal Progressive Dementing Disease,”
American Journal of Ophthalmology
, 100:68-72 (1985), Levine et al., “The Visual Variant of Alzheimer's Disease: A Clinicopathologic Case Study,”
Neurology
, 305-313 (1993)). AD patients with prominent visuospatial disorientation show neuropathological evidence of greater disease impact on parieto-occipital areas (Hof et al., “Balint's Syndrome in Alzheimer's Disease: Specific Disruption of the Occipito-Parietal Visual Pathway,”
Brain Research
, 493:368-375 (1989), Hof et al., “Quantitative Analysis of a Vulnerable Subset of Pyramidal Neurons in Alzheimer's Disease: II. Primary and Secondary Visual Cortex,”
The Journal of Comparative Neurology
, 301:55-64 (1990)). In addition, functional imaging studies have linked the visuospatial disorientation of AD to metabolic changes in parieto-occipital cortex (Kiyosawa et al., “Alzheimer's Disease with Prominent Visual Symptoms Clinical and Metabolic Evaluation,”
Ophthalmology
, 96:1077-1086 (1989), Pietrini et al., “A Longitudinal Positron Emission Tomography Study of Cerebral Glucose Metabolism in Patients With Alzheimer's Disease and Prominent Visual Impairment,”
Advances in the Biosciences
, 87:69-71 (1993)).
Visuospatial disorientation can occur either as an isolated syndrome in a distinct presentation of AD (Cogan, “Visual Disturbances With Focal Progressive Dementing Disease,”
American J. of Ophthalmology
, 11:68-72 (1985)), or with other impairments in the context of typical AD (Becker et al., “Neuropsychological Function In Alzheimer's Disease. Pattern of Impairment and Rates of Progression,”
Arch. Neurology
, 45:263-268 (1988); Levine et al., “The Visual Variant of Alzheimer's Disease: A Clinicopathologic Case Study,”
Neurology
, 43:305-313 (1993)). While some normal elderly subjects show aspects of visuospatial disorientation (Flicker et al., “Equivalent Spatial-Rotation Deficits in Normal Aging and Alzheimer's Disease,”
J. of Clinical
&
Exp. Neuropsychology
, 10:294-300 (1988); Lipman et al., “Adult Age Differences in Memory Routes: Effects of Instruction and Spatial Diagram,”
Psychology and Aging
, 7:434-442 (1992)), it is a robust finding in 39% of patients with AD (Henderson et al., “Spatial Disorientation in Alzheimer's Disease,”
Arch. Neurol
., 46:391-394 (1989)) who often first complain of spatial confusion and at autopsy have posterior cortical atrophy (PCA) (Benson et al., “Posterior Cortical Atrophy,”
Arch. Neurol
., 45:789-793 (1988)). Convincing evidence of this disorder comes from studies of patients with visuospatial disorientation but no memory impairment, who later develop typical AD (Kaskie et al., “Visuospatial Deficit in Dementia of the Alzheimer Type,”
Arch. Neurol
., 52:422-425 (1995); Butter et al., “Visual-Spatial Deficits Explain Visual Symptoms in Alzheimer's Disease,”
Am. J. Ophthalmology
, 122:97-105 (1996)). These patients can be contrasted to AD without visual complaints and verbal, but not spatial, impairments (Binetti et al., “Disorders of Visual and Spatial Perception of the Early Stage of Alzheimer's Disease,”
Annals of the NY Academy of Sciences
, 777:221-225 (1996)).
Visuospatial AD must be distinguished from primary visual dysfunction in the setting of AD. AD associated losses of visual acuity, contrast sensitivity, and visual fields are associated with optic atrophy with abnormal visual evoked potentials (VEPs) (Sadun et al., “Assessment of Visual Impairment in Patients With Alzheimer's Disease,”
Am. J. of Ophthalmology
, 104:113-120 (1987)). But many AD patients with prominent visual complaints have normal electroretinograms (ERGs) and VEPs (Rizzo et al., “A Human Visual Disorder Resembling Area V4 Dysfunction in the Monkey,”
Neurology
, 42:1175-1180 (1992)) and profiles of visual impairment that suggest dysfunction in visual association cortex (Cronin-Golomb et al., “Visual Dysfunction in Alzheimer's Disease Relation to Normal Aging,”
Annals of Neurology
, 29:41-52 (1991)). These patients have visuospatial impairments, in the absence of verbal-memory impairments, and fit the neuropsychological profile of posterior cerebral involvement with the preservation of other areas (Furey-Kurkjian et al., “Visual Variant of Alzheimer's Disease: Distinctive Neuropsychological Features,”
Neuropsychology
, 10:294-300 (1996)).
The histopathology of AD is most evident in limbic areas, but the greatest cortical involvement is in parietotemporal association areas (Brun et al., “Distribution of Cerebral Degeneration in Alzheimer's Disease,”
Arch. Psychiat. Nervenkr
., 223:15-33 (1976); Brun et al., “Region Pattern of Degeneration in Alzheimer's Disease: Neuronal Loss and Histopathological Grading,”
Histopathology
, 5:549-564 (1981); Mountjoy et al., “Cortical Neuronal Counts in Normal Elderly Controls and Demented Patients,”
Neurobiology of Aging
, 4:1-11 (1983)) with neurofibrillary tangles (NFTs) increasing from primary to tertiary visual areas especially effecting corticocortical projection neurons (Lewis et al., “Laminar and Regional Distributions of Neurofibrillary Tangles and Neuritic Plaques in Alzheimer's Disease: A Quantitative Study of Visual and Auditory Cortices,”
The Journal of Neuroscience
, 7:1799-1808 (1987); Arnold et al., “The Topographical and Neuroanatomical Distribution of Neurofibrillary Tangles and Neuritic Plaques in the Cerebral Cortex of Patients With Alzheimer's Disease,” 1:103-116 (1991)). In visual AD the pathology is more concentrated in visual areas (Hof et al., “Balint's Syndrome in Alzheimer's Disease: Specific Disruption of the Occipito-Parietal Visual Pathway,”
Brain Research
, 493 :368-375 (1989); Hof et al., “Quantitative Analysis of a Vulnerable Subset of Pyramidal Neurons in Alzheimer's Disease: II. Primary and Secondary Visual Cortex,”
The Journal of Comparative Neurology
, 301:55-64 (1990)), especially in neurons with intracortical projections to visual association areas, potentially creating a functional disconnection in the occipito-parietal visual pathway (Hof et al., “Quantitative Analysis of a Vulnerable Subset of Pyramidal Neurons in Alzheimer's Disease: II. Primary and Secondary Visual Cortex,”
The Journal of Comparative Neurology
, 301:55-64 (1990)). This posterior cortical localization is confirmed by 18-fluo
Duffy Charles J.
Tetewsky Sheldon J.
Marmor II Charles
University of Rochester
Winakur Eric F.
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