The Canadian Journal of Neurological Sciences, 2014
ABSTRACT Nitrous oxide (N2O), commonly referred to as laughing gas, is a colourless, non-flammabl... more ABSTRACT Nitrous oxide (N2O), commonly referred to as laughing gas, is a colourless, non-flammable, inorganic volatile with psychedelic effects. It has assorted uses among diverse fields: in medicine and dentistry, N2O provides a source of dissociative anaesthesia and analgesia; in the food and automobile industries, N2O serves as a propellant in whipped cream canisters and as an engine booster, respectively. Various cases of N2O abuse have surfaced in the literature, although isolated psychiatric presentations are uncommon. As cessation from N2O exposure and treatment with vitamin B12 usually lead to complete resolution of psychiatric symptoms, it is important to consider such a precipitant when a patient presents with neuropsychiatric manifestations of an uncertain etiology, especially when N2O use is obtained on history.
White matter hyperintensity (WMH) is commonly detected in patients with Alzheimer&amp... more White matter hyperintensity (WMH) is commonly detected in patients with Alzheimer's disease (AD), but its role in cortical impairment is unclear. This study investigated the effects of WMH on gray matter (GM) volume in patients with AD. We consecutively enrolled 84 patients with AD and 35 normal controls, who underwent brain MRI and were then classified according to WMH grade, based on a combination of deep white matter hyperintensity (DWMH) and periventricular white matter hyperintensity (PVWMH). The volume changes in GM were observed using voxel-based morphometry. It was found that global GM volume decreased with increasing WMH. Regional atrophies were in the dorsolateral frontal lobes, orbitofrontal gyri and insula (false discovery rate [FDR], p<0.01). After controlling for PVWMH, DWMH affected cortical atrophy in the frontal lobe, insula and precuneus (FDR, p<0.05), but PVWMH did not. Thus, WMH in AD is associated with GM volume reduction, especially in the frontal lobe, and DWMH is independently related to cortical atrophy.
Medial temporal atrophy (MTA) is a recognized marker of Alzheimer&amp... more Medial temporal atrophy (MTA) is a recognized marker of Alzheimer's disease (AD), and white matter hyperintensities (WMH) are frequently observed on MRI of AD. The purpose of this study was to understand the role of WMH in MTA. Subjects were 94 probable AD patients and 51 cognitively normal subjects. WMH was assessed based on the severity of deep WMH (DWMH) and periventricular WMH (PWMH). Each structural volume was evaluated using the Individual Brain Atlases from the Statistical Parametric Mapping Toolbox. There were no significant differences between subjects with and without WMH in terms of general cognitive function scales. Subjects with AD with WMH had decreased volume in the bilateral orbital frontal gyrus, frontal rectus gyrus, and olfactory gyrus, but not in the medial temporal lobes. After correcting for differences in DWMH, age and Clinical Dementia Rating Scale (CDR), AD with PWMH showed decreased volumes in the bilateral hippocampi. AD with PWMH showed worse scores on the Clinical Dementia Rating-Sum of Boxes and Barthel-ADL, and some frontal executive function tests. Those with DWMH did not show any reductions in the medial temporal lobes. WMH in AD is not associated with medial temporal lobe atrophy, but PWMH is independently correlated with hippocampal volume reduction.
Mixed pathology, particularly Alzheimer&a... more Mixed pathology, particularly Alzheimer's disease with cerebrovascular lesions, is reported as the second most common cause of dementia. Research on mixed dementia typically includes people with a primary AD diagnosis and hence, little is known about the effects of co-existing amyloid pathology in people with vascular cognitive impairment (VCI). The purpose of this study was to understand whether individual differences in amyloid pathology might explain variations in cognitive impairment among individuals with clinical subcortical VCI (SVCI). Twenty-two participants with SVCI completed an (11)C Pittsburgh compound B (PIB) position emission tomography (PET) scan to quantify global amyloid deposition. Cognitive function was measured using: 1) MOCA; 2) ADAS-Cog; 3) EXIT-25; and 4) specific executive processes including a) Digits Forward and Backwards Test, b) Stroop-Colour Word Test, and c) Trail Making Test. To assess the effect of amyloid deposition on cognitive function we conducted Pearson bivariate correlations to determine which cognitive measures to include in our regression models. Cognitive variables that were significantly correlated with PIB retention values were entered in a hierarchical multiple linear regression analysis to determine the unique effect of amyloid on cognitive function. We controlled for age, education, and ApoE ε4 status. Bivariate correlation results showed that PIB binding was significantly correlated with ADAS-Cog (p < 0.01) and MOCA (p < 0.01); increased PIB binding was associated with worse cognitive function on both cognitive measures. PIB binding was not significantly correlated with the EXIT-25 or with specific executive processes (p > 0.05). Regression analyses controlling for age, education, and ApoE ε4 status indicated an independent association between PIB retention and the ADAS-Cog (adjusted R-square change of 15.0 %, Sig F Change = 0.03). PIB retention was also independently associated with MOCA scores (adjusted R-Square Change of 27.0 %, Sig F Change = 0.02). We found that increased global amyloid deposition was significantly associated with greater memory and executive dysfunctions as measured by the ADAS-Cog and MOCA. Our findings point to the important role of co-existing amyloid deposition for cognitive function in those with a primary SVCI diagnosis. As such, therapeutic approaches targeting SVCI must consider the potential role of amyloid for the optimal care of those with mixed dementia. NCT01027858.
In addition to nonmodifiable genetic risk factors, potentially modifiable factors such as hyperte... more In addition to nonmodifiable genetic risk factors, potentially modifiable factors such as hypertension, hyperlipidemia and environmental exposures have been identified as risk factors for Alzheimer disease. In this article, we provide physicians with practical guidance on risk assessment and primary prevention of Alzheimer disease based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006. We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that met the following criteria: dementia (all-cause, Alzheimer disease or vascular dementia) as the outcome; longitudinal cohort study; study population broadly reflective of Canadian demographics; and genetic risk factors and general risk factors (e.g., hypertension, education, occupation and chemical exposure) identified. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care. Of 3424 articles on potentially modifiable risk factors for dementia, 1719 met our inclusion criteria; 60 were deemed to be of good or fair quality. Of 1721 articles on genetic risk factors, 62 that met our inclusion criteria were deemed to be of good or fair quality. On the basis of evidence from these articles, we made recommendations for the risk assessment and primary prevention of Alzheimer disease. For the primary prevention of Alzheimer's disease, there is good evidence for controlling vascular risk factors, especially hypertension (grade A), and weak or insufficient evidence for manipulation of lifestyle factors and prescribing of medications (grade C). There is good evidence to avoid estrogens and high-dose (> 400 IU/d) of vitamin E for this purpose (grade E). Genetic counselling and testing may be offered to at-risk individuals with an apparent autosomal dominant inheritance (grade B). Screening for the apolipoprotein E genotype in asymptomatic individuals in the general population is not recommended (grade E). Despite the personal and societal burden of dementia, our understanding of genetic predisposition to dementias and the contribution of other risk factors remains limited. More importantly, there are few data to explain the overall risks and benefits of prevention strategies or their impact of risk modification.
Brain iron elevation is implicated in Alzheimer&a... more Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.
The Canadian Journal of Neurological Sciences, 2014
ABSTRACT Nitrous oxide (N2O), commonly referred to as laughing gas, is a colourless, non-flammabl... more ABSTRACT Nitrous oxide (N2O), commonly referred to as laughing gas, is a colourless, non-flammable, inorganic volatile with psychedelic effects. It has assorted uses among diverse fields: in medicine and dentistry, N2O provides a source of dissociative anaesthesia and analgesia; in the food and automobile industries, N2O serves as a propellant in whipped cream canisters and as an engine booster, respectively. Various cases of N2O abuse have surfaced in the literature, although isolated psychiatric presentations are uncommon. As cessation from N2O exposure and treatment with vitamin B12 usually lead to complete resolution of psychiatric symptoms, it is important to consider such a precipitant when a patient presents with neuropsychiatric manifestations of an uncertain etiology, especially when N2O use is obtained on history.
White matter hyperintensity (WMH) is commonly detected in patients with Alzheimer&amp... more White matter hyperintensity (WMH) is commonly detected in patients with Alzheimer's disease (AD), but its role in cortical impairment is unclear. This study investigated the effects of WMH on gray matter (GM) volume in patients with AD. We consecutively enrolled 84 patients with AD and 35 normal controls, who underwent brain MRI and were then classified according to WMH grade, based on a combination of deep white matter hyperintensity (DWMH) and periventricular white matter hyperintensity (PVWMH). The volume changes in GM were observed using voxel-based morphometry. It was found that global GM volume decreased with increasing WMH. Regional atrophies were in the dorsolateral frontal lobes, orbitofrontal gyri and insula (false discovery rate [FDR], p<0.01). After controlling for PVWMH, DWMH affected cortical atrophy in the frontal lobe, insula and precuneus (FDR, p<0.05), but PVWMH did not. Thus, WMH in AD is associated with GM volume reduction, especially in the frontal lobe, and DWMH is independently related to cortical atrophy.
Medial temporal atrophy (MTA) is a recognized marker of Alzheimer&amp... more Medial temporal atrophy (MTA) is a recognized marker of Alzheimer's disease (AD), and white matter hyperintensities (WMH) are frequently observed on MRI of AD. The purpose of this study was to understand the role of WMH in MTA. Subjects were 94 probable AD patients and 51 cognitively normal subjects. WMH was assessed based on the severity of deep WMH (DWMH) and periventricular WMH (PWMH). Each structural volume was evaluated using the Individual Brain Atlases from the Statistical Parametric Mapping Toolbox. There were no significant differences between subjects with and without WMH in terms of general cognitive function scales. Subjects with AD with WMH had decreased volume in the bilateral orbital frontal gyrus, frontal rectus gyrus, and olfactory gyrus, but not in the medial temporal lobes. After correcting for differences in DWMH, age and Clinical Dementia Rating Scale (CDR), AD with PWMH showed decreased volumes in the bilateral hippocampi. AD with PWMH showed worse scores on the Clinical Dementia Rating-Sum of Boxes and Barthel-ADL, and some frontal executive function tests. Those with DWMH did not show any reductions in the medial temporal lobes. WMH in AD is not associated with medial temporal lobe atrophy, but PWMH is independently correlated with hippocampal volume reduction.
Mixed pathology, particularly Alzheimer&a... more Mixed pathology, particularly Alzheimer's disease with cerebrovascular lesions, is reported as the second most common cause of dementia. Research on mixed dementia typically includes people with a primary AD diagnosis and hence, little is known about the effects of co-existing amyloid pathology in people with vascular cognitive impairment (VCI). The purpose of this study was to understand whether individual differences in amyloid pathology might explain variations in cognitive impairment among individuals with clinical subcortical VCI (SVCI). Twenty-two participants with SVCI completed an (11)C Pittsburgh compound B (PIB) position emission tomography (PET) scan to quantify global amyloid deposition. Cognitive function was measured using: 1) MOCA; 2) ADAS-Cog; 3) EXIT-25; and 4) specific executive processes including a) Digits Forward and Backwards Test, b) Stroop-Colour Word Test, and c) Trail Making Test. To assess the effect of amyloid deposition on cognitive function we conducted Pearson bivariate correlations to determine which cognitive measures to include in our regression models. Cognitive variables that were significantly correlated with PIB retention values were entered in a hierarchical multiple linear regression analysis to determine the unique effect of amyloid on cognitive function. We controlled for age, education, and ApoE ε4 status. Bivariate correlation results showed that PIB binding was significantly correlated with ADAS-Cog (p < 0.01) and MOCA (p < 0.01); increased PIB binding was associated with worse cognitive function on both cognitive measures. PIB binding was not significantly correlated with the EXIT-25 or with specific executive processes (p > 0.05). Regression analyses controlling for age, education, and ApoE ε4 status indicated an independent association between PIB retention and the ADAS-Cog (adjusted R-square change of 15.0 %, Sig F Change = 0.03). PIB retention was also independently associated with MOCA scores (adjusted R-Square Change of 27.0 %, Sig F Change = 0.02). We found that increased global amyloid deposition was significantly associated with greater memory and executive dysfunctions as measured by the ADAS-Cog and MOCA. Our findings point to the important role of co-existing amyloid deposition for cognitive function in those with a primary SVCI diagnosis. As such, therapeutic approaches targeting SVCI must consider the potential role of amyloid for the optimal care of those with mixed dementia. NCT01027858.
In addition to nonmodifiable genetic risk factors, potentially modifiable factors such as hyperte... more In addition to nonmodifiable genetic risk factors, potentially modifiable factors such as hypertension, hyperlipidemia and environmental exposures have been identified as risk factors for Alzheimer disease. In this article, we provide physicians with practical guidance on risk assessment and primary prevention of Alzheimer disease based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006. We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that met the following criteria: dementia (all-cause, Alzheimer disease or vascular dementia) as the outcome; longitudinal cohort study; study population broadly reflective of Canadian demographics; and genetic risk factors and general risk factors (e.g., hypertension, education, occupation and chemical exposure) identified. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care. Of 3424 articles on potentially modifiable risk factors for dementia, 1719 met our inclusion criteria; 60 were deemed to be of good or fair quality. Of 1721 articles on genetic risk factors, 62 that met our inclusion criteria were deemed to be of good or fair quality. On the basis of evidence from these articles, we made recommendations for the risk assessment and primary prevention of Alzheimer disease. For the primary prevention of Alzheimer's disease, there is good evidence for controlling vascular risk factors, especially hypertension (grade A), and weak or insufficient evidence for manipulation of lifestyle factors and prescribing of medications (grade C). There is good evidence to avoid estrogens and high-dose (> 400 IU/d) of vitamin E for this purpose (grade E). Genetic counselling and testing may be offered to at-risk individuals with an apparent autosomal dominant inheritance (grade B). Screening for the apolipoprotein E genotype in asymptomatic individuals in the general population is not recommended (grade E). Despite the personal and societal burden of dementia, our understanding of genetic predisposition to dementias and the contribution of other risk factors remains limited. More importantly, there are few data to explain the overall risks and benefits of prevention strategies or their impact of risk modification.
Brain iron elevation is implicated in Alzheimer&a... more Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.
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