The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reduct... more The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reductions in brain phosphoCr and Cr kinase, yet no studies have examined the neurobehavioral effects of Cr supplementation in AD, including the 3xTg mouse model. This studied investigated the effects of Cr supplementation on spatial cognition, plasticity- and disease-related protein levels, and mitochondrial function in the 3xTg hippocampus. Here, 3xTg mice were fed a control or Cr-supplemented (3% Cr (w/w)) diet for 8–9 weeks and tested in the Morris water maze. Mitochondrial oxygen consumption (Seahorse) and protein levels (Western blots) were measured in the hippocampus in subsets of mice. Overall, 3xTg females exhibited impaired memory as compared to males. In females, Cr supplementation decreased escape latency and was associated with increased spatial search strategy use. In males, Cr supplementation decreased the use of spatial search strategies. Pilot data indicated mitochondrial enha...
Alcohol use problems among older adults have been called the "invisible epidemic." As the populat... more Alcohol use problems among older adults have been called the "invisible epidemic." As the population of older adults continues to grow, there is an increased need to reexamine alcohol use in this population. The authors provide an overview on alcohol use in the over-60 age group. The main areas of focus included research on the prevalence of drinking in that population, as well as comments on the best practices in assessment and psychological treatment. Several screening assessments have been recommended for use with older adults, such as the CAGE questionnaire, Michigan Alcohol Screening Test-Geriatric version, Alcohol-Related Problems Survey, and the Alcohol Use Disorders Identification Test. The authors note age-appropriate psychological treatment interventions that include brief interventions, family interventions, motivational counseling, and cognitive behavioral therapies. Barriers to assessment and treatment are also discussed.
We sought to identify a level of alcohol consumption representing the boundary between health pro... more We sought to identify a level of alcohol consumption representing the boundary between health protective and hazardous drinking. The Winnipeg Health and Drinking Survey began in 1990-91 (n = 1257). Seven years later, a third wave of interviews (n = 785) expanded questions on heavy episodic drinking (HED) and assessed the consumption of ≥ 3, ≥ 5, ≥ 8, and ≥ 12 drinks at a sitting for each of wine, beer and liquor (equivalent to about 40 g, 65 g, 105 g and 155 g of ethanol). Cox proportional hazards models were based on seven years of illness and mortality data following the Wave 3 interview, and were stratified by gender and HED definition. For HED of ≥ 40 g, ≥65 g, ≥ 105 g, or ≥ 155 g per occasion, the hazard ratios for morbidity and mortality from all causes were 1.06, 1.09, 1.17, and 1.16 respectively in women, and 1.00, 0.98, 1.02, and 1.02 in men. Most of these hazard ratios were significant in women, whereas none was significant in men. This study did not provide support for a definition of HED that could divide protective from hazardous alcohol consumption.
Participant attrition and attendance at follow-up were examined in a multicenter, randomized, cli... more Participant attrition and attendance at follow-up were examined in a multicenter, randomized, clinical trial. The Lung Health Study (LHS) enrolled a total of 5, 887 adults to examine the impact of smoking cessation coupled with the use of an inhaled bronchodilator on chronic obstructive pulmonary disease (COPD). Of the initial LHS 1 volunteers still living at the time of enrolment in LHS 3 (5,332), 4,457 (84%) attended the LHS 3 clinic visit, a follow-up session to determine current smoking status and lung function. The average period between the beginning of LHS 1 and baseline interview for LHS 3 was 11 years. In univariate analyses, attenders were older, more likely female, more likely to be married, smoked fewer cigarettes per day, and were more likely to have children who smoked at the start of LHS 1 than non-attenders. Attenders were also less likely to experience respiratory symptoms, such as cough, but had decreased baseline lung function compared with non-attenders. Volunteers recruited via mass mailing were more likely to attend the long-term follow-up visit. Those recruited by public site, worksite, or referral methods were less likely to attend. In multivariate models, age, gender, cigarettes smoked per day, married status, and whether participants' children smoked were identified as significant predictors of attendance versus non-attendance at LHS 3 using stepwise logistic regression. Treatment condition (smoking intervention or usual care) was not a significant predictor of attendance at LHS 3. Older females who smoked less heavily were most likely to participate. These findings may be applied to improve participant recruitment and retention in future clinical trials.
... to the following parents, families and organizations for their ongoing commitment to the GROW... more ... to the following parents, families and organizations for their ongoing commitment to the GROW program: Karyn, Mel and Jordan Lazareck; Jewish ... Maiya Kogan volunteered to read the translated text to check for accuracy and verify that the translated version upheld the intended ...
over time. Methods:We used dMRI data from healthy elderly subjects from the Alzheimer’s Disease N... more over time. Methods:We used dMRI data from healthy elderly subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI: 23/73 APOE4 carriers/non-carriers; 2-4 time-points) and Singapore Longitudinal Ageing Brain Study (S-LABS: 21/73 APOE4 carriers/non-carriers; 2-3 time-points). We derived subject-specific FW and FAt maps from dMRI data and averaged over the whole-brain WM and 18 major WM fibres traced using the TRACULAmethod (Yendiki et al., 2016). Linear mixed models assessed the contribution of cross-sectional age, time and APOE genotype (E4 carrier/non-carrier) on FW and FAt longitudinal trajectories. Covariates included gender, years of education and estimated total intracranial volume. Results: APOE4 carriers exhibited larger increases in average FW over time than non-carriers in ADNI (APOE4*age*time; p<0.05) and S-LABS (APOE4*time; p<0.05; Fig.1). Specifically, APOE4 carriers had greater FW increases in the right cingulum angular bundle (CAB) for S-LABS (p1⁄40.003; Fig.2) and bilateral CAB for ADNI (p<0.05). APOE4 carriers that were older at baseline showed steeper reduction in left CAB FAt over time in S-LABS (APOE4*age*time; p<0.05; Fig.3). Moreover, APOE4 carriers had faster FAt decline (S-LABS) and greater age-dependent FW increases (ADNI) in the right inferior longitudinal fasciculus (p<0.05; Fig.4). Conclusions:Across the two datasets, we consistently demonstrated that the presence of APOE4 allele in healthy elderly appears to be associated with greater neuroinflammation, mild vascular changes and excessive WM degeneration over time in temporal-parietal and temporal-occipital fibres.
Besides mental dysfunctions, Alzheimer's disease (AD) may impair muscle function. Creatine su... more Besides mental dysfunctions, Alzheimer's disease (AD) may impair muscle function. Creatine supplementation (CR) can enhance skeletal muscle mass and function in sarcopenia and muscular dystrophies,...
Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp... more 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) is the most common late onset neurodegenerative disorder with indications that women are disproportionately affected. Mitochondrial dysfunction has been one of the most discussed hypotheses associated with the early onset and progression of AD, and it has been attributed to intraneuronal accumulation of amyloid β (Aβ). It was suggested that one of the possible mediators for Aβ-impaired mitochondrial function is the nuclear factor kappa B (NF-κB) signaling pathway. NF-κB plays important roles in brain inflammation and antioxidant defense, as well as in the regulation of mitochondrial function, and studies have confirmed altered NF-κB signaling in AD brain. In this study, we looked for sex-based differences in impaired bioenergetic processes and NF-κB signaling in the AD-like brain using transgenic (Tg) CRND8 mice that express excessive brain Aβ, but without tau pathology. Our results show that mitochondrial dysfunction is not uniform in affected brain regions. We observed increased basal and coupled respiration in the hippocampus of TgCRND8 females only, along with a decreased Complex II-dependent respiratory activity. Cortical mitochondria from TgCRND8 mice have reduced uncoupled respiration capacity, regardless of sex. The pattern of changes in NF-κB signaling was the same in both brain structures, but was sex specific. Whereas in females there was an increase in all three subunits of NF-κB, in males we observed increase in p65 and p105, but no changes in p50 levels. These results demonstrate that mitochondrial function and inflammatory signaling in the AD-like brain is region- and sex-specific, which is an important consideration for therapeutic strategies.
A diagnosis of Alzheimer's disease (AD), a neurodegenerative disorder accompanied by severe f... more A diagnosis of Alzheimer's disease (AD), a neurodegenerative disorder accompanied by severe functional and cognitive decline, is based on clinical findings, with final confirmation of the disease at autopsy by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles. Given that microstructural brain alterations occur years prior to clinical symptoms, efforts to detect brain changes early could significantly enhance our ability to diagnose AD sooner. Diffusion tensor imaging (DTI), a type of MRI that characterizes the magnitude, orientation, and anisotropy of the diffusion of water in tissues, has been used to infer neuropathological changes in vivo. Its utility in AD, however, is still under investigation. The current study used DTI to examine brain regions susceptible to AD-related pathology; the cerebral cortex, entorhinal cortex, and hippocampus, in 12-14-month-old 3xTg AD mice that possess both Aβ plaques and neurofibrillary tangles. Mean diffusivity did not differ...
Although, better known for its role in inflammation, the transcription factor nuclear factor kapp... more Although, better known for its role in inflammation, the transcription factor nuclear factor kappa B (NF-κB) has more recently been implicated in synaptic plasticity, learning, and memory. This has been, in part, to the discovery of its localization not just in glia, cells that are integral to mediating the inflammatory process in the brain, but also neurons. Several effectors of neuronal NF-κB have been identified, including calcium, inflammatory cytokines (i.e., tumor necrosis factor alpha), and the induction of experimental paradigms thought to reflect learning and memory at the cellular level (i.e., long-term potentiation). NF-κB is also activated after learning and memory formation in vivo. In turn, activation of NF-κB can elicit either suppression or activation of other genes. Studies are only beginning to elucidate the multitude of neuronal gene targets of NF-κB in the normal brain, but research to date has confirmed targets involved in a wide array of cellular processes, including cell signaling and growth, neurotransmission, redox signaling, and gene regulation. Further, several lines of research confirm dysregulation of NF-κB in Alzheimer's disease (AD), a disorder characterized clinically by a profound deficit in the ability to form new memories. AD-related neuropathology includes the characteristic amyloid beta plaque formation and neurofibrillary tangles. Although, such neuropathological findings have been hypothesized to contribute to memory deficits in AD, research has identified perturbations at the cellular and synaptic level that occur even prior to more gross pathologies, including transcriptional dysregulation. Indeed, synaptic disturbances appear to be a significant correlate of cognitive deficits in AD. Given the more recently identified role for NF-κB in memory and synaptic transmission in the normal brain, the expansive network of gene targets of NF-κB, and its dysregulation in AD, a thorough understanding of NF-κB-related signaling in AD is warranted and may have important implications for uncovering treatments for the disease. This review aims to provide a comprehensive view of our current understanding of the gene targets of this transcription factor in neurons in the intact brain and provide an overview of studies investigating NF-κB signaling, including its downstream targets, in the AD brain as a means of uncovering the basic physiological mechanisms by which memory becomes fragile in the disease.
The notion that the cerebellum is a central regulator of motor function is undisputed. There exis... more The notion that the cerebellum is a central regulator of motor function is undisputed. There exists, however, considerable literature to document a similarly vital role for the cerebellum in the regulation of various non-motor domains, including emotion. Research from numerous avenues of investigation (i.e., neurophysiological, behavioural, electrophysiological, imagining, lesion, and clinical studies) have documented the importance of the cerebellum, in particular, the vermis, in affective processing that appears preserved across species. The cerebellum possesses a distinct laminar arrangement and highly organized neuronal circuitry. Moreover, the cerebellum forms reciprocal connections with several brain regions implicated in diverse functional domains, including motor, sensory, and emotional processing. It has been argued that these unique neuroanatomical features afford the cerebellum with the capacity to integrate information about an organism, its environment, and its place wi...
The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reduct... more The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reductions in brain phosphoCr and Cr kinase, yet no studies have examined the neurobehavioral effects of Cr supplementation in AD, including the 3xTg mouse model. This studied investigated the effects of Cr supplementation on spatial cognition, plasticity- and disease-related protein levels, and mitochondrial function in the 3xTg hippocampus. Here, 3xTg mice were fed a control or Cr-supplemented (3% Cr (w/w)) diet for 8–9 weeks and tested in the Morris water maze. Mitochondrial oxygen consumption (Seahorse) and protein levels (Western blots) were measured in the hippocampus in subsets of mice. Overall, 3xTg females exhibited impaired memory as compared to males. In females, Cr supplementation decreased escape latency and was associated with increased spatial search strategy use. In males, Cr supplementation decreased the use of spatial search strategies. Pilot data indicated mitochondrial enha...
The transcription factor nuclear factor kappa B (NF-κB) is highly expressed in almost all types o... more The transcription factor nuclear factor kappa B (NF-κB) is highly expressed in almost all types of cells. NF-κB is involved in many complex biological processes, in particular in immunity. The activation of the NF-κB signaling pathways is also associated with cancer, diabetes, neurological disorders and even memory. Hence, NF-κB is a central factor for understanding not only fundamental biological presence but also pathogenesis, and has been the subject of intense study in these contexts. Under healthy physiological conditions, the NF-κB pathway promotes synapse growth and synaptic plasticity in neurons, while in glia, NF-κB signaling can promote pro-inflammatory responses to injury. In addition, NF-κB promotes the maintenance and maturation of B cells regulating gene expression in a majority of diverse signaling pathways. Given this, the protein plays a predominant role in activating the mammalian immune system, where NF-κB-regulated gene expression targets processes of inflammatio...
Alzheimer’s disease (AD) is a major public health concern worldwide. Advanced age and female sex ... more Alzheimer’s disease (AD) is a major public health concern worldwide. Advanced age and female sex are two of the most prominent risk factors for AD. AD is characterized by progressive neuronal loss, especially in the cortex and hippocampus, and mitochondrial dysfunction has been proposed to be an early event in the onset and progression of the disease. Our results showed early perturbations in mitochondrial function in 3xTg mouse brain, with the cortex being more susceptible to mitochondrial changes than the hippocampus. In the cortex of 3xTg females, decreased coupled and uncoupled respiration were evident early (at 2 months of age), while in males it appeared later at 6 months of age. We observed increased coupled respiration in the hippocampus of 2-month-old 3xTg females, but no changes were detected later in life. Changes in mitochondrial dynamics were indicated by decreased mitofusin (Mfn2) and increased dynamin related protein 1 (Drp1) (only in females) in the hippocampus and c...
Abstract Purpose: This mixed-methods systematic review synthesized findings from studies publishe... more Abstract Purpose: This mixed-methods systematic review synthesized findings from studies published between January 1, 2006 and July 31, 2018 on the social inclusion experiences of children with and without disabilities, as viewed from their own perspective, with a focus on how typically developing peers promote social inclusion. Method: Forty-five studies met the inclusion criteria. Data from included studies were synthesized by means of content analysis. Results: The findings detail the inner social inclusion experiences (e.g., feeling included, different) of children with disabilities and provide information regarding the influence of disability type (e.g., physical, social, affective) on typically developing peers’ responses (e.g., acceptance vs. rejection), peers’ explanations for social inclusion/exclusion, and peers’ relationships with children with disabilities. Barriers to social inclusion, supports, as well as strategies used to promote social inclusion, as perceived by peers and children with disabilities, are also reported. Conclusion: The findings of this review provide evidence that despite society’s efforts to promote social inclusion, children with disabilities continue to report feeling lonely and excluded, having limited contact socially outside of home, and encountering systemic barriers (e.g., bullying, discrimination). More research on the social inclusion experiences of children with disabilities beyond educational settings is needed, such as in the contexts of recreation and leisure, community, and employment. Implications for rehabilitation The perspectives of children with and without disabilities need to be integrated in activities and programs aimed at promoting social inclusion. Teaching social inclusion strategies to children with and without disabilities is needed to help them deal with barriers. In addition to educational settings, rehabilitation clinicians need to promote social inclusion strategies in other contexts such as recreation and leisure, community, and employment contexts.
Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease. Although neu... more Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease. Although neurofibrillary tangles and amyloid beta are classic hallmarks of AD, the earliest deficits in AD progression may be caused by unknown factors. One suspected factor has to do with brain energy metabolism. To investigate this factor, brain metabolic activity in 3xTg-AD mice and age-matched controls were measured with FDG-PET. Significant hypometabolic changes (p < .01) in brain metabolism were detected in the cortical piriform and insular regions of AD brains relative to controls. These regions are associated with olfaction, which is a potential clinical marker for AD progression as well as neurogenesis. The activity of the terminal component of the mitochondrial respiratory chain (complex IV) and the expression of complex I-V were significantly decreased (p < .05), suggesting that impaired metabolic activity coupled with impaired oxidative phosphorylation leads to decreased mitochondrial bioenergetics and subsequent Neurodegeneration. Although there is an association between neuroinflammatory pathological markers (microglial) and hypometabolism in AD, there was no association found between neuropathological (Aβ, tau, and astrocytes) and functional changes in AD sensitive brain regions, also suggesting that brain hypometabolism occurs prior to AD pathology. Therefore, targeting metabolic mechanisms in cortical piriform and insular regions at early stages may be a promising approach for preventing, slowing, and/or blocking the onset of AD and preserving neurogenesis.
The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reduct... more The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reductions in brain phosphoCr and Cr kinase, yet no studies have examined the neurobehavioral effects of Cr supplementation in AD, including the 3xTg mouse model. This studied investigated the effects of Cr supplementation on spatial cognition, plasticity- and disease-related protein levels, and mitochondrial function in the 3xTg hippocampus. Here, 3xTg mice were fed a control or Cr-supplemented (3% Cr (w/w)) diet for 8–9 weeks and tested in the Morris water maze. Mitochondrial oxygen consumption (Seahorse) and protein levels (Western blots) were measured in the hippocampus in subsets of mice. Overall, 3xTg females exhibited impaired memory as compared to males. In females, Cr supplementation decreased escape latency and was associated with increased spatial search strategy use. In males, Cr supplementation decreased the use of spatial search strategies. Pilot data indicated mitochondrial enha...
Alcohol use problems among older adults have been called the "invisible epidemic." As the populat... more Alcohol use problems among older adults have been called the "invisible epidemic." As the population of older adults continues to grow, there is an increased need to reexamine alcohol use in this population. The authors provide an overview on alcohol use in the over-60 age group. The main areas of focus included research on the prevalence of drinking in that population, as well as comments on the best practices in assessment and psychological treatment. Several screening assessments have been recommended for use with older adults, such as the CAGE questionnaire, Michigan Alcohol Screening Test-Geriatric version, Alcohol-Related Problems Survey, and the Alcohol Use Disorders Identification Test. The authors note age-appropriate psychological treatment interventions that include brief interventions, family interventions, motivational counseling, and cognitive behavioral therapies. Barriers to assessment and treatment are also discussed.
We sought to identify a level of alcohol consumption representing the boundary between health pro... more We sought to identify a level of alcohol consumption representing the boundary between health protective and hazardous drinking. The Winnipeg Health and Drinking Survey began in 1990-91 (n = 1257). Seven years later, a third wave of interviews (n = 785) expanded questions on heavy episodic drinking (HED) and assessed the consumption of ≥ 3, ≥ 5, ≥ 8, and ≥ 12 drinks at a sitting for each of wine, beer and liquor (equivalent to about 40 g, 65 g, 105 g and 155 g of ethanol). Cox proportional hazards models were based on seven years of illness and mortality data following the Wave 3 interview, and were stratified by gender and HED definition. For HED of ≥ 40 g, ≥65 g, ≥ 105 g, or ≥ 155 g per occasion, the hazard ratios for morbidity and mortality from all causes were 1.06, 1.09, 1.17, and 1.16 respectively in women, and 1.00, 0.98, 1.02, and 1.02 in men. Most of these hazard ratios were significant in women, whereas none was significant in men. This study did not provide support for a definition of HED that could divide protective from hazardous alcohol consumption.
Participant attrition and attendance at follow-up were examined in a multicenter, randomized, cli... more Participant attrition and attendance at follow-up were examined in a multicenter, randomized, clinical trial. The Lung Health Study (LHS) enrolled a total of 5, 887 adults to examine the impact of smoking cessation coupled with the use of an inhaled bronchodilator on chronic obstructive pulmonary disease (COPD). Of the initial LHS 1 volunteers still living at the time of enrolment in LHS 3 (5,332), 4,457 (84%) attended the LHS 3 clinic visit, a follow-up session to determine current smoking status and lung function. The average period between the beginning of LHS 1 and baseline interview for LHS 3 was 11 years. In univariate analyses, attenders were older, more likely female, more likely to be married, smoked fewer cigarettes per day, and were more likely to have children who smoked at the start of LHS 1 than non-attenders. Attenders were also less likely to experience respiratory symptoms, such as cough, but had decreased baseline lung function compared with non-attenders. Volunteers recruited via mass mailing were more likely to attend the long-term follow-up visit. Those recruited by public site, worksite, or referral methods were less likely to attend. In multivariate models, age, gender, cigarettes smoked per day, married status, and whether participants' children smoked were identified as significant predictors of attendance versus non-attendance at LHS 3 using stepwise logistic regression. Treatment condition (smoking intervention or usual care) was not a significant predictor of attendance at LHS 3. Older females who smoked less heavily were most likely to participate. These findings may be applied to improve participant recruitment and retention in future clinical trials.
... to the following parents, families and organizations for their ongoing commitment to the GROW... more ... to the following parents, families and organizations for their ongoing commitment to the GROW program: Karyn, Mel and Jordan Lazareck; Jewish ... Maiya Kogan volunteered to read the translated text to check for accuracy and verify that the translated version upheld the intended ...
over time. Methods:We used dMRI data from healthy elderly subjects from the Alzheimer’s Disease N... more over time. Methods:We used dMRI data from healthy elderly subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI: 23/73 APOE4 carriers/non-carriers; 2-4 time-points) and Singapore Longitudinal Ageing Brain Study (S-LABS: 21/73 APOE4 carriers/non-carriers; 2-3 time-points). We derived subject-specific FW and FAt maps from dMRI data and averaged over the whole-brain WM and 18 major WM fibres traced using the TRACULAmethod (Yendiki et al., 2016). Linear mixed models assessed the contribution of cross-sectional age, time and APOE genotype (E4 carrier/non-carrier) on FW and FAt longitudinal trajectories. Covariates included gender, years of education and estimated total intracranial volume. Results: APOE4 carriers exhibited larger increases in average FW over time than non-carriers in ADNI (APOE4*age*time; p<0.05) and S-LABS (APOE4*time; p<0.05; Fig.1). Specifically, APOE4 carriers had greater FW increases in the right cingulum angular bundle (CAB) for S-LABS (p1⁄40.003; Fig.2) and bilateral CAB for ADNI (p<0.05). APOE4 carriers that were older at baseline showed steeper reduction in left CAB FAt over time in S-LABS (APOE4*age*time; p<0.05; Fig.3). Moreover, APOE4 carriers had faster FAt decline (S-LABS) and greater age-dependent FW increases (ADNI) in the right inferior longitudinal fasciculus (p<0.05; Fig.4). Conclusions:Across the two datasets, we consistently demonstrated that the presence of APOE4 allele in healthy elderly appears to be associated with greater neuroinflammation, mild vascular changes and excessive WM degeneration over time in temporal-parietal and temporal-occipital fibres.
Besides mental dysfunctions, Alzheimer's disease (AD) may impair muscle function. Creatine su... more Besides mental dysfunctions, Alzheimer's disease (AD) may impair muscle function. Creatine supplementation (CR) can enhance skeletal muscle mass and function in sarcopenia and muscular dystrophies,...
Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp... more 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) is the most common late onset neurodegenerative disorder with indications that women are disproportionately affected. Mitochondrial dysfunction has been one of the most discussed hypotheses associated with the early onset and progression of AD, and it has been attributed to intraneuronal accumulation of amyloid β (Aβ). It was suggested that one of the possible mediators for Aβ-impaired mitochondrial function is the nuclear factor kappa B (NF-κB) signaling pathway. NF-κB plays important roles in brain inflammation and antioxidant defense, as well as in the regulation of mitochondrial function, and studies have confirmed altered NF-κB signaling in AD brain. In this study, we looked for sex-based differences in impaired bioenergetic processes and NF-κB signaling in the AD-like brain using transgenic (Tg) CRND8 mice that express excessive brain Aβ, but without tau pathology. Our results show that mitochondrial dysfunction is not uniform in affected brain regions. We observed increased basal and coupled respiration in the hippocampus of TgCRND8 females only, along with a decreased Complex II-dependent respiratory activity. Cortical mitochondria from TgCRND8 mice have reduced uncoupled respiration capacity, regardless of sex. The pattern of changes in NF-κB signaling was the same in both brain structures, but was sex specific. Whereas in females there was an increase in all three subunits of NF-κB, in males we observed increase in p65 and p105, but no changes in p50 levels. These results demonstrate that mitochondrial function and inflammatory signaling in the AD-like brain is region- and sex-specific, which is an important consideration for therapeutic strategies.
A diagnosis of Alzheimer's disease (AD), a neurodegenerative disorder accompanied by severe f... more A diagnosis of Alzheimer's disease (AD), a neurodegenerative disorder accompanied by severe functional and cognitive decline, is based on clinical findings, with final confirmation of the disease at autopsy by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles. Given that microstructural brain alterations occur years prior to clinical symptoms, efforts to detect brain changes early could significantly enhance our ability to diagnose AD sooner. Diffusion tensor imaging (DTI), a type of MRI that characterizes the magnitude, orientation, and anisotropy of the diffusion of water in tissues, has been used to infer neuropathological changes in vivo. Its utility in AD, however, is still under investigation. The current study used DTI to examine brain regions susceptible to AD-related pathology; the cerebral cortex, entorhinal cortex, and hippocampus, in 12-14-month-old 3xTg AD mice that possess both Aβ plaques and neurofibrillary tangles. Mean diffusivity did not differ...
Although, better known for its role in inflammation, the transcription factor nuclear factor kapp... more Although, better known for its role in inflammation, the transcription factor nuclear factor kappa B (NF-κB) has more recently been implicated in synaptic plasticity, learning, and memory. This has been, in part, to the discovery of its localization not just in glia, cells that are integral to mediating the inflammatory process in the brain, but also neurons. Several effectors of neuronal NF-κB have been identified, including calcium, inflammatory cytokines (i.e., tumor necrosis factor alpha), and the induction of experimental paradigms thought to reflect learning and memory at the cellular level (i.e., long-term potentiation). NF-κB is also activated after learning and memory formation in vivo. In turn, activation of NF-κB can elicit either suppression or activation of other genes. Studies are only beginning to elucidate the multitude of neuronal gene targets of NF-κB in the normal brain, but research to date has confirmed targets involved in a wide array of cellular processes, including cell signaling and growth, neurotransmission, redox signaling, and gene regulation. Further, several lines of research confirm dysregulation of NF-κB in Alzheimer's disease (AD), a disorder characterized clinically by a profound deficit in the ability to form new memories. AD-related neuropathology includes the characteristic amyloid beta plaque formation and neurofibrillary tangles. Although, such neuropathological findings have been hypothesized to contribute to memory deficits in AD, research has identified perturbations at the cellular and synaptic level that occur even prior to more gross pathologies, including transcriptional dysregulation. Indeed, synaptic disturbances appear to be a significant correlate of cognitive deficits in AD. Given the more recently identified role for NF-κB in memory and synaptic transmission in the normal brain, the expansive network of gene targets of NF-κB, and its dysregulation in AD, a thorough understanding of NF-κB-related signaling in AD is warranted and may have important implications for uncovering treatments for the disease. This review aims to provide a comprehensive view of our current understanding of the gene targets of this transcription factor in neurons in the intact brain and provide an overview of studies investigating NF-κB signaling, including its downstream targets, in the AD brain as a means of uncovering the basic physiological mechanisms by which memory becomes fragile in the disease.
The notion that the cerebellum is a central regulator of motor function is undisputed. There exis... more The notion that the cerebellum is a central regulator of motor function is undisputed. There exists, however, considerable literature to document a similarly vital role for the cerebellum in the regulation of various non-motor domains, including emotion. Research from numerous avenues of investigation (i.e., neurophysiological, behavioural, electrophysiological, imagining, lesion, and clinical studies) have documented the importance of the cerebellum, in particular, the vermis, in affective processing that appears preserved across species. The cerebellum possesses a distinct laminar arrangement and highly organized neuronal circuitry. Moreover, the cerebellum forms reciprocal connections with several brain regions implicated in diverse functional domains, including motor, sensory, and emotional processing. It has been argued that these unique neuroanatomical features afford the cerebellum with the capacity to integrate information about an organism, its environment, and its place wi...
The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reduct... more The creatine (Cr) energy system has been implicated in Alzheimer’s disease (AD), including reductions in brain phosphoCr and Cr kinase, yet no studies have examined the neurobehavioral effects of Cr supplementation in AD, including the 3xTg mouse model. This studied investigated the effects of Cr supplementation on spatial cognition, plasticity- and disease-related protein levels, and mitochondrial function in the 3xTg hippocampus. Here, 3xTg mice were fed a control or Cr-supplemented (3% Cr (w/w)) diet for 8–9 weeks and tested in the Morris water maze. Mitochondrial oxygen consumption (Seahorse) and protein levels (Western blots) were measured in the hippocampus in subsets of mice. Overall, 3xTg females exhibited impaired memory as compared to males. In females, Cr supplementation decreased escape latency and was associated with increased spatial search strategy use. In males, Cr supplementation decreased the use of spatial search strategies. Pilot data indicated mitochondrial enha...
The transcription factor nuclear factor kappa B (NF-κB) is highly expressed in almost all types o... more The transcription factor nuclear factor kappa B (NF-κB) is highly expressed in almost all types of cells. NF-κB is involved in many complex biological processes, in particular in immunity. The activation of the NF-κB signaling pathways is also associated with cancer, diabetes, neurological disorders and even memory. Hence, NF-κB is a central factor for understanding not only fundamental biological presence but also pathogenesis, and has been the subject of intense study in these contexts. Under healthy physiological conditions, the NF-κB pathway promotes synapse growth and synaptic plasticity in neurons, while in glia, NF-κB signaling can promote pro-inflammatory responses to injury. In addition, NF-κB promotes the maintenance and maturation of B cells regulating gene expression in a majority of diverse signaling pathways. Given this, the protein plays a predominant role in activating the mammalian immune system, where NF-κB-regulated gene expression targets processes of inflammatio...
Alzheimer’s disease (AD) is a major public health concern worldwide. Advanced age and female sex ... more Alzheimer’s disease (AD) is a major public health concern worldwide. Advanced age and female sex are two of the most prominent risk factors for AD. AD is characterized by progressive neuronal loss, especially in the cortex and hippocampus, and mitochondrial dysfunction has been proposed to be an early event in the onset and progression of the disease. Our results showed early perturbations in mitochondrial function in 3xTg mouse brain, with the cortex being more susceptible to mitochondrial changes than the hippocampus. In the cortex of 3xTg females, decreased coupled and uncoupled respiration were evident early (at 2 months of age), while in males it appeared later at 6 months of age. We observed increased coupled respiration in the hippocampus of 2-month-old 3xTg females, but no changes were detected later in life. Changes in mitochondrial dynamics were indicated by decreased mitofusin (Mfn2) and increased dynamin related protein 1 (Drp1) (only in females) in the hippocampus and c...
Abstract Purpose: This mixed-methods systematic review synthesized findings from studies publishe... more Abstract Purpose: This mixed-methods systematic review synthesized findings from studies published between January 1, 2006 and July 31, 2018 on the social inclusion experiences of children with and without disabilities, as viewed from their own perspective, with a focus on how typically developing peers promote social inclusion. Method: Forty-five studies met the inclusion criteria. Data from included studies were synthesized by means of content analysis. Results: The findings detail the inner social inclusion experiences (e.g., feeling included, different) of children with disabilities and provide information regarding the influence of disability type (e.g., physical, social, affective) on typically developing peers’ responses (e.g., acceptance vs. rejection), peers’ explanations for social inclusion/exclusion, and peers’ relationships with children with disabilities. Barriers to social inclusion, supports, as well as strategies used to promote social inclusion, as perceived by peers and children with disabilities, are also reported. Conclusion: The findings of this review provide evidence that despite society’s efforts to promote social inclusion, children with disabilities continue to report feeling lonely and excluded, having limited contact socially outside of home, and encountering systemic barriers (e.g., bullying, discrimination). More research on the social inclusion experiences of children with disabilities beyond educational settings is needed, such as in the contexts of recreation and leisure, community, and employment. Implications for rehabilitation The perspectives of children with and without disabilities need to be integrated in activities and programs aimed at promoting social inclusion. Teaching social inclusion strategies to children with and without disabilities is needed to help them deal with barriers. In addition to educational settings, rehabilitation clinicians need to promote social inclusion strategies in other contexts such as recreation and leisure, community, and employment contexts.
Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease. Although neu... more Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease. Although neurofibrillary tangles and amyloid beta are classic hallmarks of AD, the earliest deficits in AD progression may be caused by unknown factors. One suspected factor has to do with brain energy metabolism. To investigate this factor, brain metabolic activity in 3xTg-AD mice and age-matched controls were measured with FDG-PET. Significant hypometabolic changes (p < .01) in brain metabolism were detected in the cortical piriform and insular regions of AD brains relative to controls. These regions are associated with olfaction, which is a potential clinical marker for AD progression as well as neurogenesis. The activity of the terminal component of the mitochondrial respiratory chain (complex IV) and the expression of complex I-V were significantly decreased (p < .05), suggesting that impaired metabolic activity coupled with impaired oxidative phosphorylation leads to decreased mitochondrial bioenergetics and subsequent Neurodegeneration. Although there is an association between neuroinflammatory pathological markers (microglial) and hypometabolism in AD, there was no association found between neuropathological (Aβ, tau, and astrocytes) and functional changes in AD sensitive brain regions, also suggesting that brain hypometabolism occurs prior to AD pathology. Therefore, targeting metabolic mechanisms in cortical piriform and insular regions at early stages may be a promising approach for preventing, slowing, and/or blocking the onset of AD and preserving neurogenesis.
Uploads
Papers by Wanda Snow