- Email: [email protected]
P3-369 Decreased resting motor threshold in elderly with varying degrees of subcortical white matter hyperintensity volume change is associated with performance on tests of cognitive function
$460
Poster Session P3: Related Neurodegenerative Conditions - Others
data showed that hypometabolism centred on the lateral and medial parietal associative cortex, with variable involvement of the adjacent temporal and occipital associative cortex. There was considerable asymmetry in three cases. Oculomotor areas of the frontal lobes were involved, presumably due to deafferentation following parietal degeneration. Conclusions: Aetiology and nosology of PCA remain unclear. The early presence of memory deficits, the trend towards generalised cognitive decline, and autopsy findings suggest a close relationship of PCA to AD. However, location and asymmetry of atrophy, as well as the presenile onset and slow course in a subset of patients, suggest that PCA is a biologically separable, rather than merely localisational variant of AD.
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N E U R O N A L AND G L I A L F I B R I L L A R Y TANGLES IN PARKINSONISM DEMENTIA OF GUAM ARE MORE EXTENSIVE AND SEVERE THAN IN ALZHEIMER DISEASE AND OTHER TAUOPATHIES
Jndit Miklossy* l, Tetsu Arai 1, Claudia Schwab 1, John C. Steele 2, Patrick L. McGeer I . 1 University of BC, Vancouver, BC, Canada; 2Guam Memorial Hospital, Tamuning, GU, USA. Contact e-mail: [email protected]
Background: Parkinsonism Dementia of Guam (PDC) is a tangle forming disorder that has many clinical and pathological features that are observed in other dementias, including Alzheimer disease (AD), progressive supranuclear palsy (PSP), and less prevalent tauopathies such as corticobasal degeneration (CBD), and pallido-ponto-nigral degeneration (PPND). Objectives: To describe the anatomical distribution of neurofibrillary tangles (NFTs), glial fibrillary tangles (GFTs), and amyloid deposits in a series of PDC cases compared with PSP, AD PPND and CBD. Methods Immunohistochemical staining was carried out using a panel of anti-tan and anti A[3 antibodies covering the N-terminal, mid range, and C-terminal regions of both molecules. Results: Typical PDC cases had extensive NFTs in the allocortex reminiscent of AD, and in the superficial layers of the isocortex reminiscent of PSR These cortical degenerative changes explain the dementing features of the disorder. PDC cases also had extensive NFTs in the basal glanglia, substantia nigra, and brain stem nuclei reminiscent of PSP, CBD and PPND, which explains the parkinsonian features of the disease. The most distinctive feature of PDC may be the appearance of GFTs throughout the brain, especially in white matter including even the cerebellum. These appeared as coiled bodies in oligodendroglia, tufts in astrocytes, and curly fibers and threads of uncertain origin. Some PDC cases also demonstrated extensive A~ deposition which differed from that of AD senile plaques. Conclusions: We conclude that PDC is the most severe of the tanopathies that we have examined in term of intensity and distribution of both NFTs and GFTs. It demonstrates pathology typical of 4R tauopathies such as PSP and CBD, as well as mixed 4R and 3R tanopathies such as AD. We also conclude that a significant deposition of beta amyloid protein may occur in PDC.
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DECREASED RESTING MOTOR THRESHOLD IN ELDERLY WITH VARYING DEGREES OF SUBCORTICAL WHITE MATTER HYPERINTENSITY V O L U M E CHANGE IS ASSOCIATED WITH PERFORMANCE ON TESTS OF COGNITIVE FUNCTION
Lisa Silbert*, Sean Holman, Barry Oken, Jan-Shin Lou, Jeffrey Kaye. OHSU, Portland, OR, USA. Contact e-mail: [email protected] Background: Advanced age and age-related subcortical white matter hyperintensity (WMH) change is associated with impaired performance on speeded tests of cognitive function. It has been proposed that slowing of CNS processing may account for these changes. Alternatively, alterations in cortical inhibition may lead to disorganized CNS processing that manifests as slowed performance on tests of cognitive function. Functional impairment of the white matter, manifested as subcortical MRI WMH, may be one basis for the change in CNS processing that contributes to age-related cognitive decline. Objective(s): To determine the effects of transcranial magnetic stimulation (TMS)-derived measures of cortical excitability on cognitive
processing in the Elderly with varying degrees of MRI WMH. Methods: Cognitively intact elderly men and women age 65 and older (mean 89.2) were recruited from longitudinal aging studies in which subjects undergo yearly neuroimaging, neuropsychological, and neurological assessments. MRI's were analyzed for WMH volumes using a semi-automated computer program (REGION). Entry criteria included moderate to high (n = 9) or low (n = 9) subcortical WMH volume. Subjects had CDR = 0, MMSE > 24, and no history of seizure. All were right-handed. A figure-eight coil (Magstim 200) was used to elicit a motor evoked potential from the first dorsal interosseous muscle. Results: Higher subcortical WMH volume was associated with decreased right hemisphere resting motor threshold (RMT) (R2 = 0.245, p = 0.043, regression) but not left hemisphere RMT (p > 0.05, regression). Right hemisphere RMT was associated with poorer performance on Trails B (R2 = 0.339, p = 0.014, regression) and choice reaction time (R2 = 0.378, p = 0.011, regression). There was a trend of slower performance on Trails A and lower right hemisphere RMT (R2 = 0.201, p = 0.081, regression). There was no significant relationship between age and right hemisphere RMT (p > 0.05, regression). Conclusions: Increased cortical excitability disrupts CNS processing efficiency and may contribute to age-related slowing of cognitive function commonly observed in elderly with subcortical white matter signal change.
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L O N G - T E R M A C C U M U L A T I O N OF AMYLOID-O IN AXONS W I T H O U T P R O L O N G E D A M Y L O I D P L A Q U E F O R M A T I O N A F T E R BRAIN TRAUMA IN HUMANS
Xiao-Han Chen* 1, David I. Graham 2, Kunihiro Uryu 1, John Q. Trojanowskil, Douglas H. Smith1. I University of Pennsylvania, Philadelphia, PA, USA; 2Southern General Hospital, Glasgow, United Kingdom. Contact e-mail: xiaochen @mail.reed. upenn, edu
Background: Plaques composed of amyloid-~ (A~), a hallmark pathology of Alzheimer's disease (AD), have been found shortly following brain trauma in humans. We have previously found that a potential source of A~ is from extensive accumulation in damaged axons. Objective: To evaluate the temporal evolution of A~ accumulation from hours to years following brain trauma. Methods: Utilizing the Glasgow head injury brain bank, brains from 34 brain trauma patients with survival from 18 hours to 10 years following injury as well as brains from 4 control patients were examined. Subjects' ages at death ranged from 16 to 79 years. Immunohistochemistry was performed on paraffin-embedded sections using antibodies specific for neurofilaments (NF), amyloid precursor protein (APP), A~, beta site APP cleaving enzyme (BACE) and presenilin-1 (PS-1). Results: In 33 injured patients, NF and APP imrnunoreactivity revealed varying densities of axonal bulbs and axonal swelling, with a relatively high density of axonal injury occurring in 14 patients. In 30 of the 34 cases, we also found extensive accumulation of A~ in damaged axons and neurons as early as 18 hours and as late as 10 years postinjury. Most of this A~ staining co-localized with BACE and PS-1. In addition, A[~ plaque-like profiles were identified in the cortex and white matter in 8 brain-injured patients at relatively early time points following trauma. However, no A[~ plaques were found in any brains from patient long postinjury survival. Conclusions: These data suggest that following brain trauma (1) there is long-term production and accumulation of A[~ in damaged axons; and (2) despite this persistent source of A~, there may be a regression of A[3 plaque pathology over time. Supported by NIH grants AG21527, NS38104, NS08803 (DHS), and AG10124 and AG11542 (JQT)
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HIV.1 TAT INHIBITS NEPRILYSIN AND ELEVATES A M Y L O I D BETA
Lynn Pulliam* 1,2, Hans Rempel 2. ~University of California, San Francisco, San Francisco, CA, USA; 2VA Medical Center, San Francisco, San Francisco, CA, USA. Contact e-mail: [email protected] Background: Aging is a risk factor for amyloid beta (A[3) accumulation and dementia. For individuals infected with HIV-1, highly active antiretroviral therapies (HAART) have effectively lengthened their life expectancy putting
Poster Session P3: Related Neurodegenerative Conditions - Others
data showed that hypometabolism centred on the lateral and medial parietal associative cortex, with variable involvement of the adjacent temporal and occipital associative cortex. There was considerable asymmetry in three cases. Oculomotor areas of the frontal lobes were involved, presumably due to deafferentation following parietal degeneration. Conclusions: Aetiology and nosology of PCA remain unclear. The early presence of memory deficits, the trend towards generalised cognitive decline, and autopsy findings suggest a close relationship of PCA to AD. However, location and asymmetry of atrophy, as well as the presenile onset and slow course in a subset of patients, suggest that PCA is a biologically separable, rather than merely localisational variant of AD.
~
N E U R O N A L AND G L I A L F I B R I L L A R Y TANGLES IN PARKINSONISM DEMENTIA OF GUAM ARE MORE EXTENSIVE AND SEVERE THAN IN ALZHEIMER DISEASE AND OTHER TAUOPATHIES
Jndit Miklossy* l, Tetsu Arai 1, Claudia Schwab 1, John C. Steele 2, Patrick L. McGeer I . 1 University of BC, Vancouver, BC, Canada; 2Guam Memorial Hospital, Tamuning, GU, USA. Contact e-mail: [email protected]
Background: Parkinsonism Dementia of Guam (PDC) is a tangle forming disorder that has many clinical and pathological features that are observed in other dementias, including Alzheimer disease (AD), progressive supranuclear palsy (PSP), and less prevalent tauopathies such as corticobasal degeneration (CBD), and pallido-ponto-nigral degeneration (PPND). Objectives: To describe the anatomical distribution of neurofibrillary tangles (NFTs), glial fibrillary tangles (GFTs), and amyloid deposits in a series of PDC cases compared with PSP, AD PPND and CBD. Methods Immunohistochemical staining was carried out using a panel of anti-tan and anti A[3 antibodies covering the N-terminal, mid range, and C-terminal regions of both molecules. Results: Typical PDC cases had extensive NFTs in the allocortex reminiscent of AD, and in the superficial layers of the isocortex reminiscent of PSR These cortical degenerative changes explain the dementing features of the disorder. PDC cases also had extensive NFTs in the basal glanglia, substantia nigra, and brain stem nuclei reminiscent of PSP, CBD and PPND, which explains the parkinsonian features of the disease. The most distinctive feature of PDC may be the appearance of GFTs throughout the brain, especially in white matter including even the cerebellum. These appeared as coiled bodies in oligodendroglia, tufts in astrocytes, and curly fibers and threads of uncertain origin. Some PDC cases also demonstrated extensive A~ deposition which differed from that of AD senile plaques. Conclusions: We conclude that PDC is the most severe of the tanopathies that we have examined in term of intensity and distribution of both NFTs and GFTs. It demonstrates pathology typical of 4R tauopathies such as PSP and CBD, as well as mixed 4R and 3R tanopathies such as AD. We also conclude that a significant deposition of beta amyloid protein may occur in PDC.
~
DECREASED RESTING MOTOR THRESHOLD IN ELDERLY WITH VARYING DEGREES OF SUBCORTICAL WHITE MATTER HYPERINTENSITY V O L U M E CHANGE IS ASSOCIATED WITH PERFORMANCE ON TESTS OF COGNITIVE FUNCTION
Lisa Silbert*, Sean Holman, Barry Oken, Jan-Shin Lou, Jeffrey Kaye. OHSU, Portland, OR, USA. Contact e-mail: [email protected] Background: Advanced age and age-related subcortical white matter hyperintensity (WMH) change is associated with impaired performance on speeded tests of cognitive function. It has been proposed that slowing of CNS processing may account for these changes. Alternatively, alterations in cortical inhibition may lead to disorganized CNS processing that manifests as slowed performance on tests of cognitive function. Functional impairment of the white matter, manifested as subcortical MRI WMH, may be one basis for the change in CNS processing that contributes to age-related cognitive decline. Objective(s): To determine the effects of transcranial magnetic stimulation (TMS)-derived measures of cortical excitability on cognitive
processing in the Elderly with varying degrees of MRI WMH. Methods: Cognitively intact elderly men and women age 65 and older (mean 89.2) were recruited from longitudinal aging studies in which subjects undergo yearly neuroimaging, neuropsychological, and neurological assessments. MRI's were analyzed for WMH volumes using a semi-automated computer program (REGION). Entry criteria included moderate to high (n = 9) or low (n = 9) subcortical WMH volume. Subjects had CDR = 0, MMSE > 24, and no history of seizure. All were right-handed. A figure-eight coil (Magstim 200) was used to elicit a motor evoked potential from the first dorsal interosseous muscle. Results: Higher subcortical WMH volume was associated with decreased right hemisphere resting motor threshold (RMT) (R2 = 0.245, p = 0.043, regression) but not left hemisphere RMT (p > 0.05, regression). Right hemisphere RMT was associated with poorer performance on Trails B (R2 = 0.339, p = 0.014, regression) and choice reaction time (R2 = 0.378, p = 0.011, regression). There was a trend of slower performance on Trails A and lower right hemisphere RMT (R2 = 0.201, p = 0.081, regression). There was no significant relationship between age and right hemisphere RMT (p > 0.05, regression). Conclusions: Increased cortical excitability disrupts CNS processing efficiency and may contribute to age-related slowing of cognitive function commonly observed in elderly with subcortical white matter signal change.
•]
L O N G - T E R M A C C U M U L A T I O N OF AMYLOID-O IN AXONS W I T H O U T P R O L O N G E D A M Y L O I D P L A Q U E F O R M A T I O N A F T E R BRAIN TRAUMA IN HUMANS
Xiao-Han Chen* 1, David I. Graham 2, Kunihiro Uryu 1, John Q. Trojanowskil, Douglas H. Smith1. I University of Pennsylvania, Philadelphia, PA, USA; 2Southern General Hospital, Glasgow, United Kingdom. Contact e-mail: xiaochen @mail.reed. upenn, edu
Background: Plaques composed of amyloid-~ (A~), a hallmark pathology of Alzheimer's disease (AD), have been found shortly following brain trauma in humans. We have previously found that a potential source of A~ is from extensive accumulation in damaged axons. Objective: To evaluate the temporal evolution of A~ accumulation from hours to years following brain trauma. Methods: Utilizing the Glasgow head injury brain bank, brains from 34 brain trauma patients with survival from 18 hours to 10 years following injury as well as brains from 4 control patients were examined. Subjects' ages at death ranged from 16 to 79 years. Immunohistochemistry was performed on paraffin-embedded sections using antibodies specific for neurofilaments (NF), amyloid precursor protein (APP), A~, beta site APP cleaving enzyme (BACE) and presenilin-1 (PS-1). Results: In 33 injured patients, NF and APP imrnunoreactivity revealed varying densities of axonal bulbs and axonal swelling, with a relatively high density of axonal injury occurring in 14 patients. In 30 of the 34 cases, we also found extensive accumulation of A~ in damaged axons and neurons as early as 18 hours and as late as 10 years postinjury. Most of this A~ staining co-localized with BACE and PS-1. In addition, A[~ plaque-like profiles were identified in the cortex and white matter in 8 brain-injured patients at relatively early time points following trauma. However, no A[~ plaques were found in any brains from patient long postinjury survival. Conclusions: These data suggest that following brain trauma (1) there is long-term production and accumulation of A[~ in damaged axons; and (2) despite this persistent source of A~, there may be a regression of A[3 plaque pathology over time. Supported by NIH grants AG21527, NS38104, NS08803 (DHS), and AG10124 and AG11542 (JQT)
- ~
HIV.1 TAT INHIBITS NEPRILYSIN AND ELEVATES A M Y L O I D BETA
Lynn Pulliam* 1,2, Hans Rempel 2. ~University of California, San Francisco, San Francisco, CA, USA; 2VA Medical Center, San Francisco, San Francisco, CA, USA. Contact e-mail: [email protected] Background: Aging is a risk factor for amyloid beta (A[3) accumulation and dementia. For individuals infected with HIV-1, highly active antiretroviral therapies (HAART) have effectively lengthened their life expectancy putting