In pursuit of treating Parkinson’s disease with cell replacement therapy, differentiated induced ... more In pursuit of treating Parkinson’s disease with cell replacement therapy, differentiated induced pluripotent stem cells (iPSC) are an ideal source of midbrain dopaminergic (mDA) cells. We previously established a protocol for differentiating iPSC-derived post-mitotic mDA neurons capable of reversing 6-hydroxydopamine-induced hemiparkinsonism in rats. In the present study, we transitioned the iPSC starting material and defined an adapted differentiation protocol for further translation into a clinical cell transplantation therapy. We examined the effects of cellular maturity on survival and efficacy of the transplants by engrafting mDA progenitors (cryopreserved at 17 days of differentiation, D17), immature neurons (D24), and post-mitotic neurons (D37) into immunocompromised hemiparkinsonian rats. We found that D17 progenitors were markedly superior to immature D24 or mature D37 neurons in terms of survival, fiber outgrowth and effects on motor deficits. Intranigral engraftment to th...
Recent reports have suggested that the reactivation of otherwise transcriptionally silent transpo... more Recent reports have suggested that the reactivation of otherwise transcriptionally silent transposable elements (TEs) might induce brain degeneration, either by dysregulating the expression of genes and pathways implicated in cognitive decline and dementia or through the induction of immune-mediated neuroinflammation resulting in the elimination of neural and glial cells. In the work we present here, we test the hypothesis that differentially expressed TEs in blood could be used as biomarkers of cognitive decline and development of AD. To this aim, we used a sample of aging subjects (age > 70) that developed late-onset Alzheimer’s disease (LOAD) over a relatively short period of time (12–48 months), for which blood was available before and after their phenoconversion, and a group of cognitive stable subjects as controls. We applied our developed and validated customized pipeline that allows the identification, characterization, and quantification of the differentially expressed (...
There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expressi... more There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer’s disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 (APOE ε4) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-β (Aβ)-positron emission tomography (Aβ-PET) and 18F-fluorodeoxyglucose-PET (18F-FDG-PET). We identified a set of six brain-enriched miRNAs—miRNA-125b, miRNA-146a, miRNA-15b, miRN...
Background: Altered plasma levels of sphingolipids, including sphingomyelins (SM), have been foun... more Background: Altered plasma levels of sphingolipids, including sphingomyelins (SM), have been found in mouse models of Alzheimer’s disease (AD) and in AD patient plasma samples. Objective: This study assesses fourteen plasma SM species in a late-onset AD (LOAD) patient cohort (n = 138). Methods: Specimens from control, preclinical, and symptomatic subjects were analyzed using targeted mass-spectrometry-based metabolomic methods. Results: Total plasma SM levels were not significantly affected by age or cognitive status. However, one metabolite that has been elevated in manifest AD in several recent studies, SM OHC14:1, was reduced significantly in pre-clinical AD and MCI relative to normal controls. Conclusion: We recommend additional comprehensive plasma lipidomics in experimental and clinical biospecimens related to LOAD that might advance the utility of plasma sphingomyelin levels in molecular phenotyping and interpretations of pathobiological mechanisms.
OBJECTIVE Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite o... more OBJECTIVE Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite of large investments over several decades. Following a large meeting of experts, this review article discusses the state of the science, possible reasons for past PD trials' failures to demonstrate disease-modifying benefit, and potential solutions. METHODS The National Institute of Neurological Disorders and Stroke (NINDS) convened a meeting including leaders in the field and representatives of key stakeholder groups to discuss drug therapy with the goal of disease modification in PD. RESULTS Important lessons can be learned from previous attempts, as well as from other fields. The selection process for therapeutic targets and agents differs among various organizations committed to therapeutic development. The areas identified as critical to target in future research include the development of relevant biomarkers, refinements of the targeted patient populations, considerations of novel trial designs, and improving collaborations between all stakeholders. CONCLUSIONS We identify potential barriers to progress in disease modification for Parkinson's and propose a set of research priorities that may improve the likelihood of success.
β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodil... more β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer’s disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction.In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction.The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance tha...
The maltase structural gene MAL6 of the yeast Saccharomyces carlsbergensis has been cloned by tra... more The maltase structural gene MAL6 of the yeast Saccharomyces carlsbergensis has been cloned by transformation of a maltose nonfermenting recipient strain with autonomously replicating chimeric recombinant plasmids. One recombinant plasmid, pMAL26, was shown by positive hybridization translation, as well as by Southern and Northern blot experiments, to carry the MAL6 structural gene.
Significant limitations and rapid declines in financial capacity are a hallmark of patients with ... more Significant limitations and rapid declines in financial capacity are a hallmark of patients with early‐stage Alzheimer's disease (AD). We use linked Health and Retirement Study and Medicare claims data spanning 1992–2014 to examine the effect of early‐stage AD, from the start of first symptoms to diagnosis, on household financial outcomes. We estimate household fixed‐effects models and examine continuous measures of liquid assets and net wealth, as well as dichotomous indicators for a large change in either outcome. We find robust evidence that early‐stage AD places households at significant risk for large adverse changes in liquid assets. Further, we find some, but more limited, evidence that early‐stage AD reduces net wealth. Our findings are consequential because financial vulnerability during the disease's early‐stage impacts the ability of afflicted individuals and their families to pay for care in the disease's later stage. Additionally, the findings speak to the v...
IntroductionObservational multimodal neuroimaging studies indicate sex differences in Alzheimer&#... more IntroductionObservational multimodal neuroimaging studies indicate sex differences in Alzheimer's disease pathophysiological markers.MethodsPositron emission tomography brain amyloid load, neurodegeneration (hippocampus and basal forebrain volumes adjusted to total intracranial volume, cortical thickness, and 2‐deoxy‐2‐[fluorine‐18]fluoro‐D‐glucose–positron emission tomography metabolism), and brain resting‐state functional connectivity were analyzed in 318 cognitively intact older adults from the INSIGHT‐preAD cohort (female n = 201, male n = 117). A linear mixed‐effects model was performed to investigate sex effects and sex∗apolipoprotein E genotype interaction on each marker as well as sex∗amyloid group interaction for non‐amyloid markers.ResultsMen compared with women showed higher anterior cingulate cortex amyloid load (P = .009), glucose hypometabolism in the precuneus (P = .027), posterior cingulate (P < .001) and inferior parietal (P = .043) cortices, and lower restin...
To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA... more To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10(-6), including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem t...
Purpose To explore whether arterial spin labeling (ASL) imaging in cognitively intact elderly ind... more Purpose To explore whether arterial spin labeling (ASL) imaging in cognitively intact elderly individuals may be used to predict subsequent early neuropsychological decline. Materials and Methods The local ethics committee approved this prospective study, and written informed consent was obtained from all participants. A total of 148 consecutive control subjects were included, 75 of whom had stable cognitive function (sCON) (mean age, 75.9 years ± 3.4 [standard deviation]; 43 female) and 73 of whom had deteriorated cognitive function (dCON) at 18-month clinical follow-up (mean age, 76.8 years ± 4.1; 44 female). An additional 65 patients with mild cognitive impairment (MCI) (mean age, 76.2 years ± 6.1; 25 female) were also included. Two-dimensional pulsed ASL was performed at the baseline visit. Statistical analysis included whole-brain voxelwise analysis of the ASL relative cerebral blood flow (CBF) data, receiver operating characteristic (ROC) curve analysis of the posterior cingul...
In pursuit of treating Parkinson’s disease with cell replacement therapy, differentiated induced ... more In pursuit of treating Parkinson’s disease with cell replacement therapy, differentiated induced pluripotent stem cells (iPSC) are an ideal source of midbrain dopaminergic (mDA) cells. We previously established a protocol for differentiating iPSC-derived post-mitotic mDA neurons capable of reversing 6-hydroxydopamine-induced hemiparkinsonism in rats. In the present study, we transitioned the iPSC starting material and defined an adapted differentiation protocol for further translation into a clinical cell transplantation therapy. We examined the effects of cellular maturity on survival and efficacy of the transplants by engrafting mDA progenitors (cryopreserved at 17 days of differentiation, D17), immature neurons (D24), and post-mitotic neurons (D37) into immunocompromised hemiparkinsonian rats. We found that D17 progenitors were markedly superior to immature D24 or mature D37 neurons in terms of survival, fiber outgrowth and effects on motor deficits. Intranigral engraftment to th...
Recent reports have suggested that the reactivation of otherwise transcriptionally silent transpo... more Recent reports have suggested that the reactivation of otherwise transcriptionally silent transposable elements (TEs) might induce brain degeneration, either by dysregulating the expression of genes and pathways implicated in cognitive decline and dementia or through the induction of immune-mediated neuroinflammation resulting in the elimination of neural and glial cells. In the work we present here, we test the hypothesis that differentially expressed TEs in blood could be used as biomarkers of cognitive decline and development of AD. To this aim, we used a sample of aging subjects (age > 70) that developed late-onset Alzheimer’s disease (LOAD) over a relatively short period of time (12–48 months), for which blood was available before and after their phenoconversion, and a group of cognitive stable subjects as controls. We applied our developed and validated customized pipeline that allows the identification, characterization, and quantification of the differentially expressed (...
There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expressi... more There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer’s disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 (APOE ε4) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-β (Aβ)-positron emission tomography (Aβ-PET) and 18F-fluorodeoxyglucose-PET (18F-FDG-PET). We identified a set of six brain-enriched miRNAs—miRNA-125b, miRNA-146a, miRNA-15b, miRN...
Background: Altered plasma levels of sphingolipids, including sphingomyelins (SM), have been foun... more Background: Altered plasma levels of sphingolipids, including sphingomyelins (SM), have been found in mouse models of Alzheimer’s disease (AD) and in AD patient plasma samples. Objective: This study assesses fourteen plasma SM species in a late-onset AD (LOAD) patient cohort (n = 138). Methods: Specimens from control, preclinical, and symptomatic subjects were analyzed using targeted mass-spectrometry-based metabolomic methods. Results: Total plasma SM levels were not significantly affected by age or cognitive status. However, one metabolite that has been elevated in manifest AD in several recent studies, SM OHC14:1, was reduced significantly in pre-clinical AD and MCI relative to normal controls. Conclusion: We recommend additional comprehensive plasma lipidomics in experimental and clinical biospecimens related to LOAD that might advance the utility of plasma sphingomyelin levels in molecular phenotyping and interpretations of pathobiological mechanisms.
OBJECTIVE Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite o... more OBJECTIVE Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite of large investments over several decades. Following a large meeting of experts, this review article discusses the state of the science, possible reasons for past PD trials' failures to demonstrate disease-modifying benefit, and potential solutions. METHODS The National Institute of Neurological Disorders and Stroke (NINDS) convened a meeting including leaders in the field and representatives of key stakeholder groups to discuss drug therapy with the goal of disease modification in PD. RESULTS Important lessons can be learned from previous attempts, as well as from other fields. The selection process for therapeutic targets and agents differs among various organizations committed to therapeutic development. The areas identified as critical to target in future research include the development of relevant biomarkers, refinements of the targeted patient populations, considerations of novel trial designs, and improving collaborations between all stakeholders. CONCLUSIONS We identify potential barriers to progress in disease modification for Parkinson's and propose a set of research priorities that may improve the likelihood of success.
β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodil... more β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer’s disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction.In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction.The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance tha...
The maltase structural gene MAL6 of the yeast Saccharomyces carlsbergensis has been cloned by tra... more The maltase structural gene MAL6 of the yeast Saccharomyces carlsbergensis has been cloned by transformation of a maltose nonfermenting recipient strain with autonomously replicating chimeric recombinant plasmids. One recombinant plasmid, pMAL26, was shown by positive hybridization translation, as well as by Southern and Northern blot experiments, to carry the MAL6 structural gene.
Significant limitations and rapid declines in financial capacity are a hallmark of patients with ... more Significant limitations and rapid declines in financial capacity are a hallmark of patients with early‐stage Alzheimer's disease (AD). We use linked Health and Retirement Study and Medicare claims data spanning 1992–2014 to examine the effect of early‐stage AD, from the start of first symptoms to diagnosis, on household financial outcomes. We estimate household fixed‐effects models and examine continuous measures of liquid assets and net wealth, as well as dichotomous indicators for a large change in either outcome. We find robust evidence that early‐stage AD places households at significant risk for large adverse changes in liquid assets. Further, we find some, but more limited, evidence that early‐stage AD reduces net wealth. Our findings are consequential because financial vulnerability during the disease's early‐stage impacts the ability of afflicted individuals and their families to pay for care in the disease's later stage. Additionally, the findings speak to the v...
IntroductionObservational multimodal neuroimaging studies indicate sex differences in Alzheimer&#... more IntroductionObservational multimodal neuroimaging studies indicate sex differences in Alzheimer's disease pathophysiological markers.MethodsPositron emission tomography brain amyloid load, neurodegeneration (hippocampus and basal forebrain volumes adjusted to total intracranial volume, cortical thickness, and 2‐deoxy‐2‐[fluorine‐18]fluoro‐D‐glucose–positron emission tomography metabolism), and brain resting‐state functional connectivity were analyzed in 318 cognitively intact older adults from the INSIGHT‐preAD cohort (female n = 201, male n = 117). A linear mixed‐effects model was performed to investigate sex effects and sex∗apolipoprotein E genotype interaction on each marker as well as sex∗amyloid group interaction for non‐amyloid markers.ResultsMen compared with women showed higher anterior cingulate cortex amyloid load (P = .009), glucose hypometabolism in the precuneus (P = .027), posterior cingulate (P < .001) and inferior parietal (P = .043) cortices, and lower restin...
To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA... more To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10(-6), including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem t...
Purpose To explore whether arterial spin labeling (ASL) imaging in cognitively intact elderly ind... more Purpose To explore whether arterial spin labeling (ASL) imaging in cognitively intact elderly individuals may be used to predict subsequent early neuropsychological decline. Materials and Methods The local ethics committee approved this prospective study, and written informed consent was obtained from all participants. A total of 148 consecutive control subjects were included, 75 of whom had stable cognitive function (sCON) (mean age, 75.9 years ± 3.4 [standard deviation]; 43 female) and 73 of whom had deteriorated cognitive function (dCON) at 18-month clinical follow-up (mean age, 76.8 years ± 4.1; 44 female). An additional 65 patients with mild cognitive impairment (MCI) (mean age, 76.2 years ± 6.1; 25 female) were also included. Two-dimensional pulsed ASL was performed at the baseline visit. Statistical analysis included whole-brain voxelwise analysis of the ASL relative cerebral blood flow (CBF) data, receiver operating characteristic (ROC) curve analysis of the posterior cingul...
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Papers by Howard Federoff