Although the prenatal hippocampus displays deficits in cellular proliferation/migration and volum... more Although the prenatal hippocampus displays deficits in cellular proliferation/migration and volume, which are later associated with memory deficits, little is known about the effects of trisomy 21 on postnatal hippocampal cellular development in Down syndrome (DS). We examined postnatal hippocampal neuronal profiles from autopsies of DS and neurotypical (NTD) neonates born at 38-weeks’-gestation up to children 3 years of age using antibodies against non-phosphorylated (SMI-32) and phosphorylated (SMI-34) neurofilament, calbindin D-28k (Calb), calretinin (Calr), parvalbumin (Parv), doublecortin (DCX) and Ki-67, as well as amyloid precursor protein (APP), amyloid beta (Aβ) and phosphorylated tau (p-tau). Although the distribution of SMI-32-immunoreactive (-ir) hippocampal neurons was similar at all ages in both groups, pyramidal cell apical and basal dendrites were intensely stained in NTD cases. A greater reduction in the number of DCX-ir cells was observed in the hippocampal granule...
Cognitive composite scores are used as the primary outcome measures for Alzheimer's disease (... more Cognitive composite scores are used as the primary outcome measures for Alzheimer's disease (AD) prevention trials; however, the extent to which these composite measures correlate with AD pathology has not been fully investigated. Since many on-going AD prevention studies are testing therapies that target either amyloid or tau, we sought to establish an association between a cognitive composite score and the underlying pathology of AD. Data from 192 older deceased and autopsied persons from the Rush Religious Order Study were used in this study. All participants were classified at their initial evaluations with a clinical diagnosis of no cognitive impairment (NCI). Of these individuals, 105 remained NCI at the time of their death while the remaining 87 progressed to mild cognitive impairment (MCI) or AD. A cognitive composite score composed of eight cognitive tests was used as the outcome measure. Individuals were classified into groups based on Consortium to Establish a Registr...
Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic e... more Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic encephalopathy (CTE). Brain pathology in CTE includes intracellular accumulation of abnormally phosphorylated tau proteins (p-tau), the main constituent of neurofibrillary tangles (NFTs). Recently, we found that cholinergic basal forebrain (CBF) neurons within the nucleus basalis of Meynert (nbM), which provide the major cholinergic innervation to the cortex, display an increasing number of NFTs across the pathological stages of CTE.1 However, molecular mechanisms underlying nbM neurodegeneration post CTE remain unknown. Here, we assessed the genetic signature of nbM neurons containing the p-tau pretangle maker pS422 obtained from CTE subjects who came to autopsy and received a neuropathological CTE staging assessment (Stages II, III, and IV) using laser capture microdissection and custom-designed microarray analysis. Quantitative analysis revealed dysregulation of key genes in several ge...
Precuneus (PreC) cortex is affected with amyloid plaques early in Alzheimer's disease (AD), a... more Precuneus (PreC) cortex is affected with amyloid plaques early in Alzheimer's disease (AD), and this pathology may be associated with alterations in PreC synapses and cognitive impairment. We quantified the spinophilin-immunoreactive (ir) dendritic spine density and the intensity of spinophilin immunofluorescence, the latter as a measure of relative protein levels of spinophilin, in PreC lamina III from 33 subjects with clinical diagnoses of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or severe AD (sAD). Both measures of spinophilin were lower in mAD and sAD compared with NCI. The MCI group had higher protein levels of spinophilin compared with mAD and sAD, and higher spinophilin-ir dendritic spine density compared with sAD. Lower spinophilin-ir dendritic spine density and relative protein levels of spinophilin were associated with greater amyloid beta (Aβ) plaque burden, detected with a derivative of Pittsburgh compound-B (6-CN-PiB), ...
Journal of Alzheimer's disease : JAD, Jul 14, 2016
The presence of Alzheimer's disease (AD)-related neuropathology among cognitively normal indi... more The presence of Alzheimer's disease (AD)-related neuropathology among cognitively normal individuals has been well documented. It has been proposed that these individuals may represent a pre-clinical AD population. Previous studies have demonstrated a negative association between the presence of both amyloid-β (Aβ) plaques and neurofibrillary tangles with ante-mortem cognitive performance, a relationship which is likely influenced by a number of factors including age and APOE ɛ4 carrier status. The present study determined whether the presence of neuritic plaques (NPs) and diffuse plaques (DPs) are associated with performance in a number of cognitive domains after accounting for APOE ɛ4 carrier status and neurofibrillary tangle presence in a cohort of 123 older participants from the Rush Religious Order Study who died with a premortem clinical diagnosis of no cognitive impairment (NCI). After adjusting for age at death, education, gender, Braak stage, and APOE ɛ4 carrier status,...
Central cholinergic structures within the brain of the even‐toed hoofed Goettingen miniature dome... more Central cholinergic structures within the brain of the even‐toed hoofed Goettingen miniature domestic pig (Sus scrofa domesticus) were evaluated by immunohistochemical visualization of choline acetyltransferase (ChAT) and the low‐affinity neurotrophin receptor, p75NTR. ChAT‐immunoreactive (‐ir) perikarya were seen in the olfactory tubercle, striatum, medial septal nucleus, vertical and horizontal limbs of the diagonal band of Broca, and the nucleus basalis of Meynert, medial habenular nucleus, zona incerta, neurosecretory arcuate nucleus, cranial motor nuclei III and IV, Edinger‐Westphal nucleus, parabigeminal nucleus, pedunculopontine nucleus, and laterodorsal tegmental nucleus. Cholinergic ChAT‐ir neurons were also found within transitional cortical areas (insular, cingulate, and piriform cortices) and hippocampus proper. ChAT‐ir fibers were seen throughout the dentate gyrus and hippocampus, in the mediodorsal, laterodorsal, anteroventral, and parateanial thalamic nuclei, the fasc...
Posterior cingulate cortex (PCC) accumulates amyloid-β (Aβ) early in Alzheimer's disease (AD)... more Posterior cingulate cortex (PCC) accumulates amyloid-β (Aβ) early in Alzheimer's disease (AD). The relative concentrations of full-length Aβ and truncated, pyroglutamate-modified Aβ (NpE3) forms, and their correlations to cognitive dysfunction in AD, are unknown. We quantified AβNpE3-42, AβNpE3-40, Aβ1-42, and Aβ1-40 concentrations in soluble (nonfibrillar) and insoluble (fibrillar) pools in PCC from subjects with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment, or mild-moderate AD. In clinical AD, increased PCC concentrations of Aβ were observed for all Aβ forms in the insoluble pool but only for Aβ1-42 in the soluble pool. Lower Mini-Mental State Exam and episodic memory scores correlated most strongly with higher concentrations of soluble and insoluble Aβ1-42. Greater neuropathology severity by Consortium to Establish a Registry for Alzheimer's Disease and National Institute on Aging-Reagan pathologic criteria was associated with hig...
Amnestic mild cognitive impairment (aMCI) is considered to be one of the early stages in the prog... more Amnestic mild cognitive impairment (aMCI) is considered to be one of the early stages in the progression from no cognitive impairment (NCI) to Alzheimer's disease (AD). Individuals with aMCI have increased levels of AD-type neuropathology in multiple regions of the neocortex and hippocampus and demonstrate a loss of synaptic connectivity. Recent neuroimaging studies have reported increased levels of 11C-PiB (Pittsburgh, compound B) in regions of the neocortex including the precuneus region of the medial parietal lobe. This cortical region has been implicated in episodic memory, which is disrupted early in the progression of AD. In this study, unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the precuneus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI did not reveal a statistically significant decline in total syna...
ABSTRACTThe two major histopathologic hallmarks of Alzheimer's disease (AD) are amyloid beta ... more ABSTRACTThe two major histopathologic hallmarks of Alzheimer's disease (AD) are amyloid beta protein (Aβ) plaques and neurofibrillary tangles (NFT). Aβ pathology is a common feature in the aged nonhuman primate brain, whereas NFT are found almost exclusively in humans. Few studies have examined AD‐related pathology in great apes, which are the closest phylogenetic relatives of humans. In the present study, we examined Aβ and tau‐like lesions in the neocortex and hippocampus of aged male and female western lowland gorillas using immunohistochemistry and histochemistry. Analysis revealed an age‐related increase in Aβ‐immunoreactive plaques and vasculature in the gorilla brain. Aβ plaques were more abundant in the neocortex and hippocampus of females, whereas Aβ‐positive blood vessels were more widespread in male gorillas. Plaques were also Aβ40‐, Aβ42‐, and Aβ oligomer‐immunoreactive, but only weakly thioflavine S‐ or 6‐CN‐PiB‐positive in both sexes, indicative of the less fibrill...
The identification of individuals at risk for Alzheimer’s disease (AD) is essential for the timel... more The identification of individuals at risk for Alzheimer’s disease (AD) is essential for the timely administration of treatment approaches aimed at slowing the onset or progression of the disease. As amnestic forms of mild cognitive impairment (aMCI) may represent preclinical AD, the search for specific diagnostic biomarkers that characterize those with aMCI is a key research objective. Using surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDITOF-MS), we screened the cerebrospinal fluid (CSF) of Religious Orders Study participants with a clinical diagnosis of no cognitive impairment (NCI), aMCI, or mild/moderate AD for potential biomarkers. CSF was fractionated on immobilized metal affinity chromatography (IMAC) protein arrays preloaded with either gallium (IMAC-Ga), which binds phosphoproteins, or copper (IMAC-Cu) to isolate copper-binding proteins. SELDI TOF-MS analysis of the IMAC-Ga arrays revealed a phosphopeptide of 2490 Da that was selectively ...
Background: Fibers containing galanin (GAL) enlarge and hyperinnervate cholinergic basal forebrai... more Background: Fibers containing galanin (GAL) enlarge and hyperinnervate cholinergic basal forebrain (CBF) nucleus basalis (NB) neurons in late-stage Alzheimer’s disease (AD), yet the physiological consequences of this phenomenon are unclear. Objective: To determine whether GAL hyperinnervation of cholinergic NB neurons modulates the expression of genes critical to cholinergic transmission [e.g. acetylcholine (ACh) metabolism and ACh receptors] in AD. Methods: Single-cell gene expression profiling was used to compare cholinergic mRNA levels in non-GAL-hyperinnervated NB neurons in tissue autopsied from cases classified as having no cognitive impairment (NCI) or late-stage AD (AD/GAL–) and in GAL-hyperinnervated (AD/GAL+) NB neurons from the same AD subjects. Results: AD/GAL+ cells displayed a significant upregulation in choline acetyltransferase (ChAT) mRNA expression compared to NCI and AD/GAL– cells. Conclusion: GAL fiber hyperinnervation of cholinergic NB neurons upregulates the ex...
Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterize... more Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of extracellular amyloid-β peptide and intracellular tau. Here, we review data suggesting that prefibrillar tau oligomers mediate cognitive decline early in the disease. Objective: It was our aim to study the presence of tau-positive pretangle neurons and correlate findings with cognitive test scores. Methods: Pretangle antibodies (TOC1 and pS422) were applied to tissue containing cholinergic basal forebrain neurons from people who died with a premortem clinical diagnosis of no cognitive impairment, mild cognitive impairment and AD. Results: Data lend support to the concept that tau oligomers are the toxic form of tau, that non-fibillar tau relates to cognitive dysfunction and that the earliest pretangle pathology occurs in neuritic processes. Conclusions: Clinicopathological findings highlight the importance of studying tau modifications in neuronal soma and neurit...
Although the prenatal hippocampus displays deficits in cellular proliferation/migration and volum... more Although the prenatal hippocampus displays deficits in cellular proliferation/migration and volume, which are later associated with memory deficits, little is known about the effects of trisomy 21 on postnatal hippocampal cellular development in Down syndrome (DS). We examined postnatal hippocampal neuronal profiles from autopsies of DS and neurotypical (NTD) neonates born at 38-weeks’-gestation up to children 3 years of age using antibodies against non-phosphorylated (SMI-32) and phosphorylated (SMI-34) neurofilament, calbindin D-28k (Calb), calretinin (Calr), parvalbumin (Parv), doublecortin (DCX) and Ki-67, as well as amyloid precursor protein (APP), amyloid beta (Aβ) and phosphorylated tau (p-tau). Although the distribution of SMI-32-immunoreactive (-ir) hippocampal neurons was similar at all ages in both groups, pyramidal cell apical and basal dendrites were intensely stained in NTD cases. A greater reduction in the number of DCX-ir cells was observed in the hippocampal granule...
Cognitive composite scores are used as the primary outcome measures for Alzheimer's disease (... more Cognitive composite scores are used as the primary outcome measures for Alzheimer's disease (AD) prevention trials; however, the extent to which these composite measures correlate with AD pathology has not been fully investigated. Since many on-going AD prevention studies are testing therapies that target either amyloid or tau, we sought to establish an association between a cognitive composite score and the underlying pathology of AD. Data from 192 older deceased and autopsied persons from the Rush Religious Order Study were used in this study. All participants were classified at their initial evaluations with a clinical diagnosis of no cognitive impairment (NCI). Of these individuals, 105 remained NCI at the time of their death while the remaining 87 progressed to mild cognitive impairment (MCI) or AD. A cognitive composite score composed of eight cognitive tests was used as the outcome measure. Individuals were classified into groups based on Consortium to Establish a Registr...
Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic e... more Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic encephalopathy (CTE). Brain pathology in CTE includes intracellular accumulation of abnormally phosphorylated tau proteins (p-tau), the main constituent of neurofibrillary tangles (NFTs). Recently, we found that cholinergic basal forebrain (CBF) neurons within the nucleus basalis of Meynert (nbM), which provide the major cholinergic innervation to the cortex, display an increasing number of NFTs across the pathological stages of CTE.1 However, molecular mechanisms underlying nbM neurodegeneration post CTE remain unknown. Here, we assessed the genetic signature of nbM neurons containing the p-tau pretangle maker pS422 obtained from CTE subjects who came to autopsy and received a neuropathological CTE staging assessment (Stages II, III, and IV) using laser capture microdissection and custom-designed microarray analysis. Quantitative analysis revealed dysregulation of key genes in several ge...
Precuneus (PreC) cortex is affected with amyloid plaques early in Alzheimer's disease (AD), a... more Precuneus (PreC) cortex is affected with amyloid plaques early in Alzheimer's disease (AD), and this pathology may be associated with alterations in PreC synapses and cognitive impairment. We quantified the spinophilin-immunoreactive (ir) dendritic spine density and the intensity of spinophilin immunofluorescence, the latter as a measure of relative protein levels of spinophilin, in PreC lamina III from 33 subjects with clinical diagnoses of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or severe AD (sAD). Both measures of spinophilin were lower in mAD and sAD compared with NCI. The MCI group had higher protein levels of spinophilin compared with mAD and sAD, and higher spinophilin-ir dendritic spine density compared with sAD. Lower spinophilin-ir dendritic spine density and relative protein levels of spinophilin were associated with greater amyloid beta (Aβ) plaque burden, detected with a derivative of Pittsburgh compound-B (6-CN-PiB), ...
Journal of Alzheimer's disease : JAD, Jul 14, 2016
The presence of Alzheimer's disease (AD)-related neuropathology among cognitively normal indi... more The presence of Alzheimer's disease (AD)-related neuropathology among cognitively normal individuals has been well documented. It has been proposed that these individuals may represent a pre-clinical AD population. Previous studies have demonstrated a negative association between the presence of both amyloid-β (Aβ) plaques and neurofibrillary tangles with ante-mortem cognitive performance, a relationship which is likely influenced by a number of factors including age and APOE ɛ4 carrier status. The present study determined whether the presence of neuritic plaques (NPs) and diffuse plaques (DPs) are associated with performance in a number of cognitive domains after accounting for APOE ɛ4 carrier status and neurofibrillary tangle presence in a cohort of 123 older participants from the Rush Religious Order Study who died with a premortem clinical diagnosis of no cognitive impairment (NCI). After adjusting for age at death, education, gender, Braak stage, and APOE ɛ4 carrier status,...
Central cholinergic structures within the brain of the even‐toed hoofed Goettingen miniature dome... more Central cholinergic structures within the brain of the even‐toed hoofed Goettingen miniature domestic pig (Sus scrofa domesticus) were evaluated by immunohistochemical visualization of choline acetyltransferase (ChAT) and the low‐affinity neurotrophin receptor, p75NTR. ChAT‐immunoreactive (‐ir) perikarya were seen in the olfactory tubercle, striatum, medial septal nucleus, vertical and horizontal limbs of the diagonal band of Broca, and the nucleus basalis of Meynert, medial habenular nucleus, zona incerta, neurosecretory arcuate nucleus, cranial motor nuclei III and IV, Edinger‐Westphal nucleus, parabigeminal nucleus, pedunculopontine nucleus, and laterodorsal tegmental nucleus. Cholinergic ChAT‐ir neurons were also found within transitional cortical areas (insular, cingulate, and piriform cortices) and hippocampus proper. ChAT‐ir fibers were seen throughout the dentate gyrus and hippocampus, in the mediodorsal, laterodorsal, anteroventral, and parateanial thalamic nuclei, the fasc...
Posterior cingulate cortex (PCC) accumulates amyloid-β (Aβ) early in Alzheimer's disease (AD)... more Posterior cingulate cortex (PCC) accumulates amyloid-β (Aβ) early in Alzheimer's disease (AD). The relative concentrations of full-length Aβ and truncated, pyroglutamate-modified Aβ (NpE3) forms, and their correlations to cognitive dysfunction in AD, are unknown. We quantified AβNpE3-42, AβNpE3-40, Aβ1-42, and Aβ1-40 concentrations in soluble (nonfibrillar) and insoluble (fibrillar) pools in PCC from subjects with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment, or mild-moderate AD. In clinical AD, increased PCC concentrations of Aβ were observed for all Aβ forms in the insoluble pool but only for Aβ1-42 in the soluble pool. Lower Mini-Mental State Exam and episodic memory scores correlated most strongly with higher concentrations of soluble and insoluble Aβ1-42. Greater neuropathology severity by Consortium to Establish a Registry for Alzheimer's Disease and National Institute on Aging-Reagan pathologic criteria was associated with hig...
Amnestic mild cognitive impairment (aMCI) is considered to be one of the early stages in the prog... more Amnestic mild cognitive impairment (aMCI) is considered to be one of the early stages in the progression from no cognitive impairment (NCI) to Alzheimer's disease (AD). Individuals with aMCI have increased levels of AD-type neuropathology in multiple regions of the neocortex and hippocampus and demonstrate a loss of synaptic connectivity. Recent neuroimaging studies have reported increased levels of 11C-PiB (Pittsburgh, compound B) in regions of the neocortex including the precuneus region of the medial parietal lobe. This cortical region has been implicated in episodic memory, which is disrupted early in the progression of AD. In this study, unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the precuneus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI did not reveal a statistically significant decline in total syna...
ABSTRACTThe two major histopathologic hallmarks of Alzheimer's disease (AD) are amyloid beta ... more ABSTRACTThe two major histopathologic hallmarks of Alzheimer's disease (AD) are amyloid beta protein (Aβ) plaques and neurofibrillary tangles (NFT). Aβ pathology is a common feature in the aged nonhuman primate brain, whereas NFT are found almost exclusively in humans. Few studies have examined AD‐related pathology in great apes, which are the closest phylogenetic relatives of humans. In the present study, we examined Aβ and tau‐like lesions in the neocortex and hippocampus of aged male and female western lowland gorillas using immunohistochemistry and histochemistry. Analysis revealed an age‐related increase in Aβ‐immunoreactive plaques and vasculature in the gorilla brain. Aβ plaques were more abundant in the neocortex and hippocampus of females, whereas Aβ‐positive blood vessels were more widespread in male gorillas. Plaques were also Aβ40‐, Aβ42‐, and Aβ oligomer‐immunoreactive, but only weakly thioflavine S‐ or 6‐CN‐PiB‐positive in both sexes, indicative of the less fibrill...
The identification of individuals at risk for Alzheimer’s disease (AD) is essential for the timel... more The identification of individuals at risk for Alzheimer’s disease (AD) is essential for the timely administration of treatment approaches aimed at slowing the onset or progression of the disease. As amnestic forms of mild cognitive impairment (aMCI) may represent preclinical AD, the search for specific diagnostic biomarkers that characterize those with aMCI is a key research objective. Using surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDITOF-MS), we screened the cerebrospinal fluid (CSF) of Religious Orders Study participants with a clinical diagnosis of no cognitive impairment (NCI), aMCI, or mild/moderate AD for potential biomarkers. CSF was fractionated on immobilized metal affinity chromatography (IMAC) protein arrays preloaded with either gallium (IMAC-Ga), which binds phosphoproteins, or copper (IMAC-Cu) to isolate copper-binding proteins. SELDI TOF-MS analysis of the IMAC-Ga arrays revealed a phosphopeptide of 2490 Da that was selectively ...
Background: Fibers containing galanin (GAL) enlarge and hyperinnervate cholinergic basal forebrai... more Background: Fibers containing galanin (GAL) enlarge and hyperinnervate cholinergic basal forebrain (CBF) nucleus basalis (NB) neurons in late-stage Alzheimer’s disease (AD), yet the physiological consequences of this phenomenon are unclear. Objective: To determine whether GAL hyperinnervation of cholinergic NB neurons modulates the expression of genes critical to cholinergic transmission [e.g. acetylcholine (ACh) metabolism and ACh receptors] in AD. Methods: Single-cell gene expression profiling was used to compare cholinergic mRNA levels in non-GAL-hyperinnervated NB neurons in tissue autopsied from cases classified as having no cognitive impairment (NCI) or late-stage AD (AD/GAL–) and in GAL-hyperinnervated (AD/GAL+) NB neurons from the same AD subjects. Results: AD/GAL+ cells displayed a significant upregulation in choline acetyltransferase (ChAT) mRNA expression compared to NCI and AD/GAL– cells. Conclusion: GAL fiber hyperinnervation of cholinergic NB neurons upregulates the ex...
Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterize... more Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of extracellular amyloid-β peptide and intracellular tau. Here, we review data suggesting that prefibrillar tau oligomers mediate cognitive decline early in the disease. Objective: It was our aim to study the presence of tau-positive pretangle neurons and correlate findings with cognitive test scores. Methods: Pretangle antibodies (TOC1 and pS422) were applied to tissue containing cholinergic basal forebrain neurons from people who died with a premortem clinical diagnosis of no cognitive impairment, mild cognitive impairment and AD. Results: Data lend support to the concept that tau oligomers are the toxic form of tau, that non-fibillar tau relates to cognitive dysfunction and that the earliest pretangle pathology occurs in neuritic processes. Conclusions: Clinicopathological findings highlight the importance of studying tau modifications in neuronal soma and neurit...
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Papers by Elliott Mufson