James Vickers | University of Tasmania (original) (raw)

Papers by James Vickers

Cerebral Cortex, 2011

Accumulating evidence indicates that damage to the adult mammalian brain evokes an array of adapt... more Accumulating evidence indicates that damage to the adult mammalian brain evokes an array of adaptive cellular responses and may retain a capacity for structural plasticity. We have investigated the cellular and architectural alterations following focal experimental brain injury, as well as the specific capacity for structural remodeling of neuronal processes in a subset of cortical interneurons. Focal acute injury was induced by transient insertion of a needle into the neocortex of anesthetized adult male Hooded-Wistar rats and thy1 green fluorescent protein (GFP) mice. Immunohistochemical, electron microscopy, and bromodeoxyuridine cell proliferation studies demonstrated an active and evolving response of the brain to injury, indicating astrocytic but not neuronal proliferation. Immunolabeling for the neuron-specific markers phosphorylated neurofilaments, α-internexin and calretinin at 7 days post injury (DPI) indicated phosphorylated neurofilaments and α-internexin but not calretinin immunopositive axonal sprouts within the injury site. However, quantitative studies indicated a significant realignment of horizontally projecting dendrites of calretinin-labeled interneurons at 14 DPI. This remodeling was specific to calretinin immunopositive interneurons and did not occur in a subpopulation of pyramidal neurons expressing GFP in the injured mouse cortex. These data show that subclasses of cortical interneurons are capable of adaptive structural remodeling.

Objective. The Tasmanian Healthy Brain Project (THBP) is a long-term, longitudinal investigation ... more Objective. The Tasmanian Healthy Brain Project (THBP) is a long-term, longitudinal investigation into whether later-life tertiary education reduces ageing-related cognitive alterations and/or provides protection from dementia. Cognitive reserve (CR) has also been proposed to be protective for dementia, and brain derived neurotrophic factor (BDNF) has been implicated as having a significant role in mediating the effects of environmental enrichments in experimental studies. Method. We have investigated the THBP cohort at baseline to determine whether common allelic variation in BDNF Val66Met and APOE interact with CR to produce cognitive outcomes. This study involved 433 participants (66.7% female), aged 50-79 years (M = 62.16, SD = 6.81). A measure of CR was established through a principal components analysis (PCA) of THBP study variables (WTAR IQ, prior education and the Lifetime of Experiences Questionnaire) previously shown to contribute to the construct. Composite variables of ep...

Advances in Behavioral Biology, 1995

Assessment, Jan 16, 2015

The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a semiautomated computer inte... more The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a semiautomated computer interface for assessing cognitive function. We examined whether CANTAB tests measured specific cognitive functions, using established neuropsychological tests as a reference point. A sample of 500 healthy older (M = 60.28 years, SD = 6.75) participants in the Tasmanian Healthy Brain Project completed battery of CANTAB subtests and standard paper-based neuropsychological tests. Confirmatory factor analysis identified four factors: processing speed, verbal ability, episodic memory, and working memory. However, CANTAB tests did not consistently load onto the cognitive domain factors derived from traditional measures of the same function. These results indicate that five of the six CANTAB subtests examined did not load onto single cognitive functions. These CANTAB tests may lack the sensitivity to measure discrete cognitive functions in healthy populations or may measure other cognitive domains ...

Background: We have investigated the alterations in myelin associated with Aß plaques, a major pa... more Background: We have investigated the alterations in myelin associated with Aß plaques, a major pathological hallmark of Alzheimer's disease (AD), both in human tissue and relevant transgenic mice models. Methods: Human tissue examined included neocortical samples from pathologically aged (Braak Stage III) and end-stage AD. Transgenic animal tissue examined included Tg2576(APPSwe670/671) and APP/PS1 (APPSwe x PS1M146L)) lines as well as age-matched wildtype mice (n ¼ 5, for each type). Myelination was assessed using FluoroMyelin or a modified Gallyas silver stain. Flu-oroMyelin staining was combined with immunofluorescence for Aß and/or axonal/dystrophic neurite markers. Results: We determined that fibrillar Aß pathology in the grey matter of the neocortex was associated with focal demyelination in human preclinical and end-stage AD cases, as well as in two mouse transgenic models of AD, as compared to age-matched control tissue. This demyelination was most pronounced at the core of Aß plaques. In both human and transgenic mice, plaque-free neocortical regions did not demonstrate significant demyelination compared to controls. Dystrophic neurites associated with the plaques were also demyelinated. Diffuse plaques were not associated with demyelination. In both human cases and transgenic mice, plaque-free neocortical grey matter did not demonstrate significant demyelination compared to controls. Conclusions: Fibrillar Aß plaque formation results in focal demyelination in the neocortex. Furthermore, alterations in axons that result in dystrophic neurite formation involve a loss of myelin. This demyelination confirms that fibrillar plaques are sites of substantial neuropil disruption in AD.

Neurobiology of aging, 2015

The transactive response DNA-binding protein 43 (TDP-43) has been identified as a neurofilament l... more The transactive response DNA-binding protein 43 (TDP-43) has been identified as a neurofilament light (NF-L) messenger RNA (mRNA)-binding protein. Abnormally increased levels of TDP-43 are detected in patients with amyotrophic lateral sclerosis and a downregulation of NF-L mRNA. However, links between NF-L and TDP-43 expressions are unclear. In this study, we investigated whether the deficiency of NF-L protein can result in alterations in TDP-43 localization or protein expression and whether this is altered with aging. There was a significant increase in TDP-43 protein levels in the cortex and lumbar spinal cord in 12-month-old NF-L knockout (NF-L KO) mice, compared with wild-type (WT) C57BL/6 mice. However, there was no difference in either the phosphorylation of TDP-43 between WT and NF-L KO mice or the abnormal mislocalization of TDP-43 to the cytoplasm in NF-L KO animals. Our findings suggest that NF-L protein or mRNA may negatively affect the expression of TDP-43 in the central...

Frontiers in cellular neuroscience, 2014

Traumatic brain injury (TBI) from penetrating or closed forces to the cranium can result in a ran... more Traumatic brain injury (TBI) from penetrating or closed forces to the cranium can result in a range of forms of neural damage, which culminate in mortality or impart mild to significant neurological disability. In this regard, diffuse axonal injury (DAI) is a major neuronal pathophenotype of TBI and is associated with a complex set of cytoskeletal changes. The neurofilament triplet proteins are key structural cytoskeletal elements, which may also be important contributors to the tensile strength of axons. This has significant implications with respect to how axons may respond to TBI. It is not known, however, whether neurofilament compaction and the cytoskeletal changes that evolve following axonal injury represent a component of a protective mechanism following damage, or whether they serve to augment degeneration and progression to secondary axotomy. Here we review the structure and role of neurofilament proteins in normal neuronal function. We also discuss the processes that char...

Objective. The Tasmanian Healthy Brain Project (THBP) is a long-term, longitudinal investigation ... more Objective. The Tasmanian Healthy Brain Project (THBP) is a long-term, longitudinal investigation into whether later-life tertiary education reduces ageing-related cognitive alterations and/or provides protection from dementia. Cognitive reserve (CR) has also been proposed to be protective for dementia, and brain derived neurotrophic factor (BDNF) has been implicated as having a significant role in mediating the effects of environmental enrichments in experimental studies. Method. We have investigated the THBP cohort at baseline to determine whether common allelic variation in BDNF Val66Met and APOE interact with CR to produce cognitive outcomes. This study involved 433 participants (66.7% female), aged 50-79 years (M = 62.16, SD = 6.81). A measure of CR was established through a principal components analysis (PCA) of THBP study variables (WTAR IQ, prior education and the Lifetime of Experiences Questionnaire) previously shown to contribute to the construct. Composite variables of ep...

Objective Environmental enrichment (EE) has been proposed to reduce the risk of developing dement... more Objective Environmental enrichment (EE) has been proposed to reduce the risk of developing dementia in conditions such as Alzheimer’s disease (AD). The current project investigates the potential of different forms of later-life EE to ameliorate cognitive deterioration in ageing in wildtype (WT) mice as well as in a transgenic model (APP/PS1) of early-stage AD. Method Male transgenic (APPswe, PSEN1dE9) and WT mice entered differential housing from 6 – 12 months of age. Mice entered standard (SH) or EE housing. EE housing comprised a cage double the size of the SH cage, with various enrichment objects. A sub-set of EE mice (EE+) received additional stimulation by spending several hours a week in a larger cage with novel objects. Working memory (Y maze) was tested at 6 months, before entering differential housing, and at 9 and 12 months. At 12 months, mice were also tested for their long-term memory function on the Barnes maze. Results At 6 months, APP/PS1 mice demonstrated inferior Y ...

Experimental Neurology, 2015

Traumatic brain injury is a risk factor for Alzheimer&amp... more Traumatic brain injury is a risk factor for Alzheimer's disease (AD), however the effect of such neural damage on the onset and progression of beta-amyloid (Aβ) plaque pathology is not well understood. This study utilized an in vivo model of focal brain injury to examine how localized damage may acutely affect the onset and progression of Aβ plaque deposition as well as inflammatory and synaptic changes, in the APP/PS1 (APPSWE, PSEN1dE9) transgenic model of AD relative to wild-type (Wt) mice. Acute focal brain injury in 3- and 9-month-old APP/PS1 and Wt mice was induced by insertion of a needle into the somatosensory neocortex, as compared to sham surgery, and examined at 24h and 7d post-injury (PI). Focal brain injury did not induce thioflavine-S stained or (pan-Aβ antibody) MOAB-2-labeled plaques at either 24h or 7d PI in 3-month-old APP/PS1 mice or Wt mice. Nine-month-old APP/PS1 mice demonstrate cortical Aβ plaques but focal injury had no statistically significant (p>0.05) effect on thioflavine-S or MOAB-2 plaque load surrounding the injury site at 24h PI or 7d PI. There was a significant (p<0.001) increase in cross-sectional cortical area occupied by Iba-1 positive microglia in injured mice compared to sham animals, however this response did not differ between APP/PS1 and Wt mice (p>0.05). For both Wt and APP/PS1 mice alike, synaptophysin puncta near the injury site were significantly reduced 24h PI (compared to sites distant to the injury and the corresponding area in sham mice; p<0.01), but not after 7d PI (p>0.05). There was no significant effect of genotype on this response (p>0.05). These results indicate that focal brain injury and the associated microglial response do not acutely alter Aβ plaque deposition in the APP/PS1 mouse model. Furthermore the current study demonstrated that the brains of both Wt and APP/PS1 mice are capable of recovering lost synaptophysin immunoreactivity post-injury, the latter in the presence of Aβ plaque pathology that causes synaptic degeneration.

Journal of Neurochemistry, 2003

Recent data suggests that metallothioneins (MTs) are major neuroprotective proteins within the CN... more Recent data suggests that metallothioneins (MTs) are major neuroprotective proteins within the CNS. In this regard, we have recently demonstrated that MT-IIA (the major human MT-I/-II isoform) promotes neural recovery following focal cortical brain injury. To further investigate the role of MTs in cortical brain injury, MT-I/-II expression was examined in several different experimental models of cortical neuron injury. While MT-I/-II immunoreactivity was not detectable in the uninjured rat neocortex, by 4 days, following a focal cortical brain injury, MT-I/-II was found in astrocytes aligned along the injury site. At latter time points, astrocytes, at a distance up to several hundred microns from the original injury tract, were MT-I/-II immunoreactive. Induced MT-I/-II was found both within the cell body and processes. Using a cortical neuron/astrocyte co-culture model, we observed a similar MT-I/-II response following in vitro injury. Intriguingly, scratch wound injury in pure astrocyte cultures resulted in no change in MT-I/-II expression. This suggests that MT induction was specifically elicited by neuronal injury. Based upon recent reports indicating that MT-I/-II are major neuroprotective proteins within the brain, our results provide further evidence that MT-I/-II plays an important role in the cellular response to neuronal injury.

Molecular and cellular neurosciences, Jan 27, 2015

Multiple system atrophy (MSA) exhibits widespread astrogliosis together with α-synuclein (α-syn) ... more Multiple system atrophy (MSA) exhibits widespread astrogliosis together with α-synuclein (α-syn) glial cytoplasmic inclusions (GCIs) in mature oligodendrocytes. We quantified astrocyte activation by morphometric analysis of MSA cases, and investigated the correlation to GCI proximity. Using Imaris software, we obtained "skinned" three-dimensional models of GFAP-positive astrocytes in MSA and control tissue (n=75) from confocal z-stacks and measured the astrocyte process length and thickness and radial distance to GCI. Astrocytes proximal to GCI-containing oligodendrocytes (r<25μm) had significantly (p, 0.05) longer and thicker processes characteristic of activation than distal astrocytes (r>25μm), with a reciprocal linear correlation (m, 90μm(2)) between mean process length and radial distance to the nearest GCI (R(2), 0.7). In primary cell culture studies, α-syn addition caused ERK-dependent activation of rat astrocytes and perinuclear α-syn inclusions in mature (MO...

Acta Neuropathologica Communications, 2013

Background: Axon degeneration, a key pathological event in many neurodegenerative diseases and in... more Background: Axon degeneration, a key pathological event in many neurodegenerative diseases and injury, can be induced by somatodendritic excitotoxin exposure. It is currently unclear, however, whether excitotoxin-induced axon degeneration is mechanistically similar to Wallerian degeneration, which occurs following axon transection, but does not involve axonal caspase activation.

Cell and Tissue Research, 1991

Immunoreactivity for the neurofilament protein triplet was investigated in neurons of the dorsal ... more Immunoreactivity for the neurofilament protein triplet was investigated in neurons of the dorsal root ganglia of the guinea-pig by using a battery of antibodies. In unfixed tissue, nearly all neurons in these ganglia demonstrated some degree of neurofilament protein triplet immunoreactivity. Large neurons generally displayed intense immunoreactivity, whereas most small to medium-sized neurons showed faint to moderate immunoreactivity. Double-labelling immunofluorescence

Frontiers in Aging Neuroscience, 2014

Despite the abundance of research reporting the neurophysiological and behavioral effects of tran... more Despite the abundance of research reporting the neurophysiological and behavioral effects of transcranial direct current stimulation (tDCS) in healthy young adults and clinical populations, the extent of potential neuroplastic changes induced by tDCS in healthy older adults is not well understood. The present study compared the extent and time course of anodal tDCS-induced plastic changes in primary motor cortex (M1) in young and older adults. Furthermore, as it has been suggested that neuroplasticity and associated learning depends on the brain-derived neurotrophic factor (BDNF) gene polymorphisms, we also assessed the impact of BDNF polymorphism on these effects. Corticospinal excitability was examined using transcranial magnetic stimulation before and following (0, 10, 20, 30 min) anodal tDCS (30 min, 1 mA) or sham in young and older adults. While the overall extent of increases in corticospinal excitability induced by anodal tDCS did not vary reliably between young and older adults, older adults exhibited a delayed response; the largest increase in corticospinal excitability occurred 30 min following stimulation for older adults, but immediately post-stimulation for the young group. BDNF genotype did not result in significant differences in the observed excitability increases for either age group. The present study suggests that tDCS-induced plastic changes are delayed as a result of healthy aging, but that the overall efficacy of the plasticity mechanism remains unaffected.

Journal of Neurology Neurosurgery and Psychiatry, 1994

The distribution of neurofilament immunoreactivity in the substantia nigra was examined by immuno... more The distribution of neurofilament immunoreactivity in the substantia nigra was examined by immunohistochemistry in five patients dying with Parkinson's disease and six control patients dying without neurological disease. In controls, pigmented neurons in the substantia nigra were intensively labelled by SMI32, a monoclonal antibody to non-phosphorylated neurofilament protein. In the substantia nigra from patients who had Parkinson's disease, there was

Psychogeriatrics, 2014

The association between level of educational attainment and cognitive performance is well studied... more The association between level of educational attainment and cognitive performance is well studied. People with higher education perform better across a broad range of cognitive tasks. However, there is uncertainty as to whether education moderates the trajectory of age-related cognitive decline. This review paper addresses the potential link between education and age-related cognitive decline by evaluating relevant research published since 2000. Studies reporting data on education and its association with the rate of cognitive decline across various cognitive domains were reviewed. A total of 10 studies were identified with a mean follow-up period of 7.6 years; each contained a population-based, non-demented sample. In the majority of studies, results showed that education did not moderate age-associated cognitive decline. The few studies that did find an association between education and decline in specific cognitive functions should be interpreted with caution because of methodological issues. The literature reveals little consistent evidence that normal age-related cognitive decline is moderated by education attainment. This supports a passive theory of cognitive reserve: people with a higher level of education will continue to perform at a higher level of cognitive functioning than their lower educated peers, which may delay the onset of impairment in the future.

Alzheimer's & Dementia, 2014

Cerebral Cortex, 2011

Accumulating evidence indicates that damage to the adult mammalian brain evokes an array of adapt... more Accumulating evidence indicates that damage to the adult mammalian brain evokes an array of adaptive cellular responses and may retain a capacity for structural plasticity. We have investigated the cellular and architectural alterations following focal experimental brain injury, as well as the specific capacity for structural remodeling of neuronal processes in a subset of cortical interneurons. Focal acute injury was induced by transient insertion of a needle into the neocortex of anesthetized adult male Hooded-Wistar rats and thy1 green fluorescent protein (GFP) mice. Immunohistochemical, electron microscopy, and bromodeoxyuridine cell proliferation studies demonstrated an active and evolving response of the brain to injury, indicating astrocytic but not neuronal proliferation. Immunolabeling for the neuron-specific markers phosphorylated neurofilaments, α-internexin and calretinin at 7 days post injury (DPI) indicated phosphorylated neurofilaments and α-internexin but not calretinin immunopositive axonal sprouts within the injury site. However, quantitative studies indicated a significant realignment of horizontally projecting dendrites of calretinin-labeled interneurons at 14 DPI. This remodeling was specific to calretinin immunopositive interneurons and did not occur in a subpopulation of pyramidal neurons expressing GFP in the injured mouse cortex. These data show that subclasses of cortical interneurons are capable of adaptive structural remodeling.

Objective. The Tasmanian Healthy Brain Project (THBP) is a long-term, longitudinal investigation ... more Objective. The Tasmanian Healthy Brain Project (THBP) is a long-term, longitudinal investigation into whether later-life tertiary education reduces ageing-related cognitive alterations and/or provides protection from dementia. Cognitive reserve (CR) has also been proposed to be protective for dementia, and brain derived neurotrophic factor (BDNF) has been implicated as having a significant role in mediating the effects of environmental enrichments in experimental studies. Method. We have investigated the THBP cohort at baseline to determine whether common allelic variation in BDNF Val66Met and APOE interact with CR to produce cognitive outcomes. This study involved 433 participants (66.7% female), aged 50-79 years (M = 62.16, SD = 6.81). A measure of CR was established through a principal components analysis (PCA) of THBP study variables (WTAR IQ, prior education and the Lifetime of Experiences Questionnaire) previously shown to contribute to the construct. Composite variables of ep...

Advances in Behavioral Biology, 1995

Assessment, Jan 16, 2015

The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a semiautomated computer inte... more The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a semiautomated computer interface for assessing cognitive function. We examined whether CANTAB tests measured specific cognitive functions, using established neuropsychological tests as a reference point. A sample of 500 healthy older (M = 60.28 years, SD = 6.75) participants in the Tasmanian Healthy Brain Project completed battery of CANTAB subtests and standard paper-based neuropsychological tests. Confirmatory factor analysis identified four factors: processing speed, verbal ability, episodic memory, and working memory. However, CANTAB tests did not consistently load onto the cognitive domain factors derived from traditional measures of the same function. These results indicate that five of the six CANTAB subtests examined did not load onto single cognitive functions. These CANTAB tests may lack the sensitivity to measure discrete cognitive functions in healthy populations or may measure other cognitive domains ...

Background: We have investigated the alterations in myelin associated with Aß plaques, a major pa... more Background: We have investigated the alterations in myelin associated with Aß plaques, a major pathological hallmark of Alzheimer's disease (AD), both in human tissue and relevant transgenic mice models. Methods: Human tissue examined included neocortical samples from pathologically aged (Braak Stage III) and end-stage AD. Transgenic animal tissue examined included Tg2576(APPSwe670/671) and APP/PS1 (APPSwe x PS1M146L)) lines as well as age-matched wildtype mice (n ¼ 5, for each type). Myelination was assessed using FluoroMyelin or a modified Gallyas silver stain. Flu-oroMyelin staining was combined with immunofluorescence for Aß and/or axonal/dystrophic neurite markers. Results: We determined that fibrillar Aß pathology in the grey matter of the neocortex was associated with focal demyelination in human preclinical and end-stage AD cases, as well as in two mouse transgenic models of AD, as compared to age-matched control tissue. This demyelination was most pronounced at the core of Aß plaques. In both human and transgenic mice, plaque-free neocortical regions did not demonstrate significant demyelination compared to controls. Dystrophic neurites associated with the plaques were also demyelinated. Diffuse plaques were not associated with demyelination. In both human cases and transgenic mice, plaque-free neocortical grey matter did not demonstrate significant demyelination compared to controls. Conclusions: Fibrillar Aß plaque formation results in focal demyelination in the neocortex. Furthermore, alterations in axons that result in dystrophic neurite formation involve a loss of myelin. This demyelination confirms that fibrillar plaques are sites of substantial neuropil disruption in AD.

Neurobiology of aging, 2015

The transactive response DNA-binding protein 43 (TDP-43) has been identified as a neurofilament l... more The transactive response DNA-binding protein 43 (TDP-43) has been identified as a neurofilament light (NF-L) messenger RNA (mRNA)-binding protein. Abnormally increased levels of TDP-43 are detected in patients with amyotrophic lateral sclerosis and a downregulation of NF-L mRNA. However, links between NF-L and TDP-43 expressions are unclear. In this study, we investigated whether the deficiency of NF-L protein can result in alterations in TDP-43 localization or protein expression and whether this is altered with aging. There was a significant increase in TDP-43 protein levels in the cortex and lumbar spinal cord in 12-month-old NF-L knockout (NF-L KO) mice, compared with wild-type (WT) C57BL/6 mice. However, there was no difference in either the phosphorylation of TDP-43 between WT and NF-L KO mice or the abnormal mislocalization of TDP-43 to the cytoplasm in NF-L KO animals. Our findings suggest that NF-L protein or mRNA may negatively affect the expression of TDP-43 in the central...

Frontiers in cellular neuroscience, 2014

Traumatic brain injury (TBI) from penetrating or closed forces to the cranium can result in a ran... more Traumatic brain injury (TBI) from penetrating or closed forces to the cranium can result in a range of forms of neural damage, which culminate in mortality or impart mild to significant neurological disability. In this regard, diffuse axonal injury (DAI) is a major neuronal pathophenotype of TBI and is associated with a complex set of cytoskeletal changes. The neurofilament triplet proteins are key structural cytoskeletal elements, which may also be important contributors to the tensile strength of axons. This has significant implications with respect to how axons may respond to TBI. It is not known, however, whether neurofilament compaction and the cytoskeletal changes that evolve following axonal injury represent a component of a protective mechanism following damage, or whether they serve to augment degeneration and progression to secondary axotomy. Here we review the structure and role of neurofilament proteins in normal neuronal function. We also discuss the processes that char...

Objective. The Tasmanian Healthy Brain Project (THBP) is a long-term, longitudinal investigation ... more Objective. The Tasmanian Healthy Brain Project (THBP) is a long-term, longitudinal investigation into whether later-life tertiary education reduces ageing-related cognitive alterations and/or provides protection from dementia. Cognitive reserve (CR) has also been proposed to be protective for dementia, and brain derived neurotrophic factor (BDNF) has been implicated as having a significant role in mediating the effects of environmental enrichments in experimental studies. Method. We have investigated the THBP cohort at baseline to determine whether common allelic variation in BDNF Val66Met and APOE interact with CR to produce cognitive outcomes. This study involved 433 participants (66.7% female), aged 50-79 years (M = 62.16, SD = 6.81). A measure of CR was established through a principal components analysis (PCA) of THBP study variables (WTAR IQ, prior education and the Lifetime of Experiences Questionnaire) previously shown to contribute to the construct. Composite variables of ep...

Objective Environmental enrichment (EE) has been proposed to reduce the risk of developing dement... more Objective Environmental enrichment (EE) has been proposed to reduce the risk of developing dementia in conditions such as Alzheimer’s disease (AD). The current project investigates the potential of different forms of later-life EE to ameliorate cognitive deterioration in ageing in wildtype (WT) mice as well as in a transgenic model (APP/PS1) of early-stage AD. Method Male transgenic (APPswe, PSEN1dE9) and WT mice entered differential housing from 6 – 12 months of age. Mice entered standard (SH) or EE housing. EE housing comprised a cage double the size of the SH cage, with various enrichment objects. A sub-set of EE mice (EE+) received additional stimulation by spending several hours a week in a larger cage with novel objects. Working memory (Y maze) was tested at 6 months, before entering differential housing, and at 9 and 12 months. At 12 months, mice were also tested for their long-term memory function on the Barnes maze. Results At 6 months, APP/PS1 mice demonstrated inferior Y ...

Experimental Neurology, 2015

Traumatic brain injury is a risk factor for Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp... more Traumatic brain injury is a risk factor for Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD), however the effect of such neural damage on the onset and progression of beta-amyloid (Aβ) plaque pathology is not well understood. This study utilized an in vivo model of focal brain injury to examine how localized damage may acutely affect the onset and progression of Aβ plaque deposition as well as inflammatory and synaptic changes, in the APP/PS1 (APPSWE, PSEN1dE9) transgenic model of AD relative to wild-type (Wt) mice. Acute focal brain injury in 3- and 9-month-old APP/PS1 and Wt mice was induced by insertion of a needle into the somatosensory neocortex, as compared to sham surgery, and examined at 24h and 7d post-injury (PI). Focal brain injury did not induce thioflavine-S stained or (pan-Aβ antibody) MOAB-2-labeled plaques at either 24h or 7d PI in 3-month-old APP/PS1 mice or Wt mice. Nine-month-old APP/PS1 mice demonstrate cortical Aβ plaques but focal injury had no statistically significant (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;0.05) effect on thioflavine-S or MOAB-2 plaque load surrounding the injury site at 24h PI or 7d PI. There was a significant (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) increase in cross-sectional cortical area occupied by Iba-1 positive microglia in injured mice compared to sham animals, however this response did not differ between APP/PS1 and Wt mice (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;0.05). For both Wt and APP/PS1 mice alike, synaptophysin puncta near the injury site were significantly reduced 24h PI (compared to sites distant to the injury and the corresponding area in sham mice; p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01), but not after 7d PI (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;0.05). There was no significant effect of genotype on this response (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;0.05). These results indicate that focal brain injury and the associated microglial response do not acutely alter Aβ plaque deposition in the APP/PS1 mouse model. Furthermore the current study demonstrated that the brains of both Wt and APP/PS1 mice are capable of recovering lost synaptophysin immunoreactivity post-injury, the latter in the presence of Aβ plaque pathology that causes synaptic degeneration.

Journal of Neurochemistry, 2003

Recent data suggests that metallothioneins (MTs) are major neuroprotective proteins within the CN... more Recent data suggests that metallothioneins (MTs) are major neuroprotective proteins within the CNS. In this regard, we have recently demonstrated that MT-IIA (the major human MT-I/-II isoform) promotes neural recovery following focal cortical brain injury. To further investigate the role of MTs in cortical brain injury, MT-I/-II expression was examined in several different experimental models of cortical neuron injury. While MT-I/-II immunoreactivity was not detectable in the uninjured rat neocortex, by 4 days, following a focal cortical brain injury, MT-I/-II was found in astrocytes aligned along the injury site. At latter time points, astrocytes, at a distance up to several hundred microns from the original injury tract, were MT-I/-II immunoreactive. Induced MT-I/-II was found both within the cell body and processes. Using a cortical neuron/astrocyte co-culture model, we observed a similar MT-I/-II response following in vitro injury. Intriguingly, scratch wound injury in pure astrocyte cultures resulted in no change in MT-I/-II expression. This suggests that MT induction was specifically elicited by neuronal injury. Based upon recent reports indicating that MT-I/-II are major neuroprotective proteins within the brain, our results provide further evidence that MT-I/-II plays an important role in the cellular response to neuronal injury.

Molecular and cellular neurosciences, Jan 27, 2015

Multiple system atrophy (MSA) exhibits widespread astrogliosis together with α-synuclein (α-syn) ... more Multiple system atrophy (MSA) exhibits widespread astrogliosis together with α-synuclein (α-syn) glial cytoplasmic inclusions (GCIs) in mature oligodendrocytes. We quantified astrocyte activation by morphometric analysis of MSA cases, and investigated the correlation to GCI proximity. Using Imaris software, we obtained "skinned" three-dimensional models of GFAP-positive astrocytes in MSA and control tissue (n=75) from confocal z-stacks and measured the astrocyte process length and thickness and radial distance to GCI. Astrocytes proximal to GCI-containing oligodendrocytes (r<25μm) had significantly (p, 0.05) longer and thicker processes characteristic of activation than distal astrocytes (r>25μm), with a reciprocal linear correlation (m, 90μm(2)) between mean process length and radial distance to the nearest GCI (R(2), 0.7). In primary cell culture studies, α-syn addition caused ERK-dependent activation of rat astrocytes and perinuclear α-syn inclusions in mature (MO...

Acta Neuropathologica Communications, 2013

Background: Axon degeneration, a key pathological event in many neurodegenerative diseases and in... more Background: Axon degeneration, a key pathological event in many neurodegenerative diseases and injury, can be induced by somatodendritic excitotoxin exposure. It is currently unclear, however, whether excitotoxin-induced axon degeneration is mechanistically similar to Wallerian degeneration, which occurs following axon transection, but does not involve axonal caspase activation.

Cell and Tissue Research, 1991

Immunoreactivity for the neurofilament protein triplet was investigated in neurons of the dorsal ... more Immunoreactivity for the neurofilament protein triplet was investigated in neurons of the dorsal root ganglia of the guinea-pig by using a battery of antibodies. In unfixed tissue, nearly all neurons in these ganglia demonstrated some degree of neurofilament protein triplet immunoreactivity. Large neurons generally displayed intense immunoreactivity, whereas most small to medium-sized neurons showed faint to moderate immunoreactivity. Double-labelling immunofluorescence

Frontiers in Aging Neuroscience, 2014

Despite the abundance of research reporting the neurophysiological and behavioral effects of tran... more Despite the abundance of research reporting the neurophysiological and behavioral effects of transcranial direct current stimulation (tDCS) in healthy young adults and clinical populations, the extent of potential neuroplastic changes induced by tDCS in healthy older adults is not well understood. The present study compared the extent and time course of anodal tDCS-induced plastic changes in primary motor cortex (M1) in young and older adults. Furthermore, as it has been suggested that neuroplasticity and associated learning depends on the brain-derived neurotrophic factor (BDNF) gene polymorphisms, we also assessed the impact of BDNF polymorphism on these effects. Corticospinal excitability was examined using transcranial magnetic stimulation before and following (0, 10, 20, 30 min) anodal tDCS (30 min, 1 mA) or sham in young and older adults. While the overall extent of increases in corticospinal excitability induced by anodal tDCS did not vary reliably between young and older adults, older adults exhibited a delayed response; the largest increase in corticospinal excitability occurred 30 min following stimulation for older adults, but immediately post-stimulation for the young group. BDNF genotype did not result in significant differences in the observed excitability increases for either age group. The present study suggests that tDCS-induced plastic changes are delayed as a result of healthy aging, but that the overall efficacy of the plasticity mechanism remains unaffected.

Journal of Neurology Neurosurgery and Psychiatry, 1994

The distribution of neurofilament immunoreactivity in the substantia nigra was examined by immuno... more The distribution of neurofilament immunoreactivity in the substantia nigra was examined by immunohistochemistry in five patients dying with Parkinson's disease and six control patients dying without neurological disease. In controls, pigmented neurons in the substantia nigra were intensively labelled by SMI32, a monoclonal antibody to non-phosphorylated neurofilament protein. In the substantia nigra from patients who had Parkinson's disease, there was

Psychogeriatrics, 2014

The association between level of educational attainment and cognitive performance is well studied... more The association between level of educational attainment and cognitive performance is well studied. People with higher education perform better across a broad range of cognitive tasks. However, there is uncertainty as to whether education moderates the trajectory of age-related cognitive decline. This review paper addresses the potential link between education and age-related cognitive decline by evaluating relevant research published since 2000. Studies reporting data on education and its association with the rate of cognitive decline across various cognitive domains were reviewed. A total of 10 studies were identified with a mean follow-up period of 7.6 years; each contained a population-based, non-demented sample. In the majority of studies, results showed that education did not moderate age-associated cognitive decline. The few studies that did find an association between education and decline in specific cognitive functions should be interpreted with caution because of methodological issues. The literature reveals little consistent evidence that normal age-related cognitive decline is moderated by education attainment. This supports a passive theory of cognitive reserve: people with a higher level of education will continue to perform at a higher level of cognitive functioning than their lower educated peers, which may delay the onset of impairment in the future.

Alzheimer's & Dementia, 2014