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Papers by Robert Friedland
Human Molecular Genetics, 2003
Journal of The Neurological Sciences, 1997
Few European families have been reported with cerebral autosomal dominant arteriopathy with subco... more Few European families have been reported with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We describe four patients from two independent American families. All four cases underwent comprehensive clinical, neuropsychological and pathological examination. Pathological data were correlated with clinical features. Dementia was a prominent and constant feature in all subjects. The families differed in phenotypical presentation and
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2002
There is currently no method for noninvasive imaging of amyloid beta (Abeta) deposition in Alzhei... more There is currently no method for noninvasive imaging of amyloid beta (Abeta) deposition in Alzheimer's disease (AD). Because Abeta plaques are characteristic of AD and Abeta deposits contain abundant heparan sulfate proteoglycans that can bind basic fibroblast growth factor (bFGF) and serum amyloid P component (SAP), we investigated a novel route of ligand delivery to the brain to assess Abeta deposition in a transgenic (Tg) mouse model overexpressing Abeta-protein precursor. The biodistribution of bFGF injected intranasally was studied using (125)I-bFGF in Tg and wild-type control mice and by unlabeled bFGF and SAP immunocytochemistry with light and electron microscopy. Three- to 5-fold higher amounts of (125)I-bFGF were found in the brain of Tg mice than that of wild-type mice (P < 0.05). bFGF or SAP given intranasally labeled cerebral Abeta plaques in the cortex and microvessels of Tg mice but not in wild-type mice. Weak bFGF staining and no SAP staining were detected in T...
Parkinson's Disease
Nonmotor symptoms (NMS) in Parkinson’s disease (PD) can start up to a decade before motor manifes... more Nonmotor symptoms (NMS) in Parkinson’s disease (PD) can start up to a decade before motor manifestations and strongly correlate with the quality of life. Understanding patterns of NMS can provide clues to the incipient site of PD pathology. Our goal was to systematically characterize the progression of NMS in PD (n = 489), compared to healthy controls, HC (n = 241), based on the sex of the subjects and laterality of motor symptom onset. Additionally, NMS experienced at the onset of PD were also compared to subjects with scans without dopaminergic deficit, SWEDD (n = 81). The Parkinson’s Progression Markers Initiative (PPMI) database was utilized to analyze several NMS scales. NMS experienced by PD and SWEDD cohorts were significantly higher than HC and both sex and laterality influenced several NMS scales at the onset of motor symptoms. Sex Differences. PD males experienced significant worsening of sexual, urinary, sleep, and cognitive functions compared to PD females. PD females re...
International Journal of Molecular Sciences
Despite the enormous literature documenting the importance of amyloid beta (Ab) protein in Alzhei... more Despite the enormous literature documenting the importance of amyloid beta (Ab) protein in Alzheimer's disease, we do not know how Ab aggregation is initiated and why it has its unique distribution in the brain. In vivo and in vitro evidence has been developed to suggest that functional microbial amyloid proteins produced in the gut may cross-seed Ab aggregation and prime the innate immune system to have an enhanced and pathogenic response to neuronal amyloids. In this commentary, we summarize the molecular mechanisms by which the microbiota may initiate and sustain the pathogenic processes of neurodegeneration in aging.
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 6, 2017
Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry... more Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10(-8)) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the APOE ɛ4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10(-6)) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10(-6)). Our findings highlight...
Neurobiol Aging, 2004
The relationship between leisure activities and development of cognitive impairment in aging has ... more The relationship between leisure activities and development of cognitive impairment in aging has been the subject of recent research. We examined television viewing in association with risk of developing Alzheimer's disease (AD) in a case-control study. ...
Journal of Alzheimer's disease : JAD, 2013
Many studies have documented the role of risk and protective factors for late life dementing illn... more Many studies have documented the role of risk and protective factors for late life dementing illnesses, particularly Alzheimer's disease. A "Systematic Review" from the US Agency for Healthcare Research and Quality and the National Institute on Aging concluded that because the overall quality of evidence was low, recommendations for public health could not be made. In order to gain evidence for the efficacy of lifestyle interventions, we propose a "Modest Proposal" to study 10,000 subjects over 40 years randomly assigned to groups of low or high saturated fat in the diet, head injury, and high or low levels of mental activity, physical activity, or inactivity as well as smoking or non-smoking. This proposed study cannot be accomplished. The "Modest Proposal" illustrates that the absence of definitive evidence should not restrict physicians from making reasonable recommendations based on the evidence that is available.
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, 1986
Dementia of the Alzheimer type (DAT) has proven to be difficult to diagnose using computerized X-... more Dementia of the Alzheimer type (DAT) has proven to be difficult to diagnose using computerized X-ray tomography (CT). To improve the identification of DAT with CT, several different quantitative approaches have been tried. Brain parenchymal density measurements and a variety of linear indices of ventricular size have failed to reliably separate DAT patients from age matched controls. Measures of ventricular volume improve discrimination, but overlap with controls persists. The inadequacy of a single CT study to diagnose DAT is clearly related to the overlap of brain atrophy in DAT and healthy aging, a finding which has also been noted in post-mortem studies. Estimating the rate of ventricular enlargement from quantitative measurements of ventricular size on successive CT scans may allow the physician to take advantage of the progressive nature of DAT, improving separation of DAT patients from healthy controls.
Neurology, 1988
We measured monoamine metabolites and biopterin in the CSF of 37 patients with dementia of the Al... more We measured monoamine metabolites and biopterin in the CSF of 37 patients with dementia of the Alzheimer type (DAT), with or without extrapyramidal signs, and in 14 age-matched healthy controls. Compared with concentrations in DAT and controls, the concentrations of homovanillic acid (HVA) and biopterin were significantly decreased in DAT with extrapyramidal signs (EDAT). CSF 3-methoxy-4-hydroxy-phenethyleneglycol and 5-hydroxyindoleacetic acid did not differ significantly among these groups. Age at onset of dementia was positively correlated with CSF HVA (r = 0.49, p less than 0.05). The two dementia groups did not differ significantly in the extent of ventricular dilation as measured by quantitative CT, but EDAT patients had lower Mini-Mental State Examination scores than did DAT patients. When patients were matched for age and dementia severity, CSF HVA and biopterin concentrations remained significantly lower in EDAT than in DAT patients. These results indicate that EDAT patients form a distinct subgroup of DAT with evidence of central monoamine dysfunction.
Neurobiology of Aging, 2004
Journal of Animal Science, 2013
To assess lumbar puncture (LP) stress as measured by Hypothalamic-Pituitary-Adrenal axis response... more To assess lumbar puncture (LP) stress as measured by Hypothalamic-Pituitary-Adrenal axis response, serum cortisols were measured before and after LP in Alzheimer's disease (AD) and healthy elderly individuals. There were no differences in baseline serum cortisol. AD group had significantly higher cortisols at 165 minutes post-LP. Growth curve analysis confirmed these findings and showed significant differences in cortisol levels overall. The AD males had higher cortisols at 105 minutes post-LP, but no other consistent gender differences emerged. The findings are consistent with the relative reduction in HPA negative feedback seen in AD. Overall, LP induces little change in group mean cortisol levels relative to inter-individual variation, indicating that while LP is an interesting model of neuroendocrine challenge, it needs to be tested in larger populations.
Nature communications, Nov 20, 2017
Myoblast fusion is an indispensable step for skeletal muscle development, postnatal growth, and r... more Myoblast fusion is an indispensable step for skeletal muscle development, postnatal growth, and regeneration. Myeloid differentiation primary response gene 88 (MyD88) is an adaptor protein that mediates Toll-like receptors and interleukin-1 receptor signaling. Here we report a cell-autonomous role of MyD88 in the regulation of myoblast fusion. MyD88 protein levels are increased during in vitro myogenesis and in conditions that promote skeletal muscle growth in vivo. Deletion of MyD88 impairs fusion of myoblasts without affecting their survival, proliferation, or differentiation. MyD88 regulates non-canonical NF-κB and canonical Wnt signaling during myogenesis and promotes skeletal muscle growth and overload-induced myofiber hypertrophy in mice. Ablation of MyD88 reduces myofiber size during muscle regeneration, whereas its overexpression promotes fusion of exogenous myoblasts to injured myofibers. Our study shows that MyD88 modulates myoblast fusion and suggests that augmenting its ...
Human Molecular Genetics, 2003
Journal of The Neurological Sciences, 1997
Few European families have been reported with cerebral autosomal dominant arteriopathy with subco... more Few European families have been reported with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We describe four patients from two independent American families. All four cases underwent comprehensive clinical, neuropsychological and pathological examination. Pathological data were correlated with clinical features. Dementia was a prominent and constant feature in all subjects. The families differed in phenotypical presentation and
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2002
There is currently no method for noninvasive imaging of amyloid beta (Abeta) deposition in Alzhei... more There is currently no method for noninvasive imaging of amyloid beta (Abeta) deposition in Alzheimer's disease (AD). Because Abeta plaques are characteristic of AD and Abeta deposits contain abundant heparan sulfate proteoglycans that can bind basic fibroblast growth factor (bFGF) and serum amyloid P component (SAP), we investigated a novel route of ligand delivery to the brain to assess Abeta deposition in a transgenic (Tg) mouse model overexpressing Abeta-protein precursor. The biodistribution of bFGF injected intranasally was studied using (125)I-bFGF in Tg and wild-type control mice and by unlabeled bFGF and SAP immunocytochemistry with light and electron microscopy. Three- to 5-fold higher amounts of (125)I-bFGF were found in the brain of Tg mice than that of wild-type mice (P < 0.05). bFGF or SAP given intranasally labeled cerebral Abeta plaques in the cortex and microvessels of Tg mice but not in wild-type mice. Weak bFGF staining and no SAP staining were detected in T...
Parkinson's Disease
Nonmotor symptoms (NMS) in Parkinson’s disease (PD) can start up to a decade before motor manifes... more Nonmotor symptoms (NMS) in Parkinson’s disease (PD) can start up to a decade before motor manifestations and strongly correlate with the quality of life. Understanding patterns of NMS can provide clues to the incipient site of PD pathology. Our goal was to systematically characterize the progression of NMS in PD (n = 489), compared to healthy controls, HC (n = 241), based on the sex of the subjects and laterality of motor symptom onset. Additionally, NMS experienced at the onset of PD were also compared to subjects with scans without dopaminergic deficit, SWEDD (n = 81). The Parkinson’s Progression Markers Initiative (PPMI) database was utilized to analyze several NMS scales. NMS experienced by PD and SWEDD cohorts were significantly higher than HC and both sex and laterality influenced several NMS scales at the onset of motor symptoms. Sex Differences. PD males experienced significant worsening of sexual, urinary, sleep, and cognitive functions compared to PD females. PD females re...
International Journal of Molecular Sciences
Despite the enormous literature documenting the importance of amyloid beta (Ab) protein in Alzhei... more Despite the enormous literature documenting the importance of amyloid beta (Ab) protein in Alzheimer's disease, we do not know how Ab aggregation is initiated and why it has its unique distribution in the brain. In vivo and in vitro evidence has been developed to suggest that functional microbial amyloid proteins produced in the gut may cross-seed Ab aggregation and prime the innate immune system to have an enhanced and pathogenic response to neuronal amyloids. In this commentary, we summarize the molecular mechanisms by which the microbiota may initiate and sustain the pathogenic processes of neurodegeneration in aging.
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 6, 2017
Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry... more Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10(-8)) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the APOE ɛ4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10(-6)) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10(-6)). Our findings highlight...
Neurobiol Aging, 2004
The relationship between leisure activities and development of cognitive impairment in aging has ... more The relationship between leisure activities and development of cognitive impairment in aging has been the subject of recent research. We examined television viewing in association with risk of developing Alzheimer's disease (AD) in a case-control study. ...
Journal of Alzheimer's disease : JAD, 2013
Many studies have documented the role of risk and protective factors for late life dementing illn... more Many studies have documented the role of risk and protective factors for late life dementing illnesses, particularly Alzheimer's disease. A "Systematic Review" from the US Agency for Healthcare Research and Quality and the National Institute on Aging concluded that because the overall quality of evidence was low, recommendations for public health could not be made. In order to gain evidence for the efficacy of lifestyle interventions, we propose a "Modest Proposal" to study 10,000 subjects over 40 years randomly assigned to groups of low or high saturated fat in the diet, head injury, and high or low levels of mental activity, physical activity, or inactivity as well as smoking or non-smoking. This proposed study cannot be accomplished. The "Modest Proposal" illustrates that the absence of definitive evidence should not restrict physicians from making reasonable recommendations based on the evidence that is available.
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, 1986
Dementia of the Alzheimer type (DAT) has proven to be difficult to diagnose using computerized X-... more Dementia of the Alzheimer type (DAT) has proven to be difficult to diagnose using computerized X-ray tomography (CT). To improve the identification of DAT with CT, several different quantitative approaches have been tried. Brain parenchymal density measurements and a variety of linear indices of ventricular size have failed to reliably separate DAT patients from age matched controls. Measures of ventricular volume improve discrimination, but overlap with controls persists. The inadequacy of a single CT study to diagnose DAT is clearly related to the overlap of brain atrophy in DAT and healthy aging, a finding which has also been noted in post-mortem studies. Estimating the rate of ventricular enlargement from quantitative measurements of ventricular size on successive CT scans may allow the physician to take advantage of the progressive nature of DAT, improving separation of DAT patients from healthy controls.
Neurology, 1988
We measured monoamine metabolites and biopterin in the CSF of 37 patients with dementia of the Al... more We measured monoamine metabolites and biopterin in the CSF of 37 patients with dementia of the Alzheimer type (DAT), with or without extrapyramidal signs, and in 14 age-matched healthy controls. Compared with concentrations in DAT and controls, the concentrations of homovanillic acid (HVA) and biopterin were significantly decreased in DAT with extrapyramidal signs (EDAT). CSF 3-methoxy-4-hydroxy-phenethyleneglycol and 5-hydroxyindoleacetic acid did not differ significantly among these groups. Age at onset of dementia was positively correlated with CSF HVA (r = 0.49, p less than 0.05). The two dementia groups did not differ significantly in the extent of ventricular dilation as measured by quantitative CT, but EDAT patients had lower Mini-Mental State Examination scores than did DAT patients. When patients were matched for age and dementia severity, CSF HVA and biopterin concentrations remained significantly lower in EDAT than in DAT patients. These results indicate that EDAT patients form a distinct subgroup of DAT with evidence of central monoamine dysfunction.
Neurobiology of Aging, 2004
Journal of Animal Science, 2013
To assess lumbar puncture (LP) stress as measured by Hypothalamic-Pituitary-Adrenal axis response... more To assess lumbar puncture (LP) stress as measured by Hypothalamic-Pituitary-Adrenal axis response, serum cortisols were measured before and after LP in Alzheimer's disease (AD) and healthy elderly individuals. There were no differences in baseline serum cortisol. AD group had significantly higher cortisols at 165 minutes post-LP. Growth curve analysis confirmed these findings and showed significant differences in cortisol levels overall. The AD males had higher cortisols at 105 minutes post-LP, but no other consistent gender differences emerged. The findings are consistent with the relative reduction in HPA negative feedback seen in AD. Overall, LP induces little change in group mean cortisol levels relative to inter-individual variation, indicating that while LP is an interesting model of neuroendocrine challenge, it needs to be tested in larger populations.
Nature communications, Nov 20, 2017
Myoblast fusion is an indispensable step for skeletal muscle development, postnatal growth, and r... more Myoblast fusion is an indispensable step for skeletal muscle development, postnatal growth, and regeneration. Myeloid differentiation primary response gene 88 (MyD88) is an adaptor protein that mediates Toll-like receptors and interleukin-1 receptor signaling. Here we report a cell-autonomous role of MyD88 in the regulation of myoblast fusion. MyD88 protein levels are increased during in vitro myogenesis and in conditions that promote skeletal muscle growth in vivo. Deletion of MyD88 impairs fusion of myoblasts without affecting their survival, proliferation, or differentiation. MyD88 regulates non-canonical NF-κB and canonical Wnt signaling during myogenesis and promotes skeletal muscle growth and overload-induced myofiber hypertrophy in mice. Ablation of MyD88 reduces myofiber size during muscle regeneration, whereas its overexpression promotes fusion of exogenous myoblasts to injured myofibers. Our study shows that MyD88 modulates myoblast fusion and suggests that augmenting its ...