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Roger L Albin

Publications and source records attributed to Roger L Albin.

At least 19 recordsLinked to original sources
PubMed2025

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

BACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.

Humans↗
PubMed2006

Recent advances in Tourette syndrome research.

Tourette syndrome (TS) is a developmentally regulated neurobehavioral disorder characterized by involuntary, stereotyped, repetitive movements. Recent anatomical and neuroimaging studies have provided evidence for abnormal basal ganglia and dopaminergic function in TS. Basic research on striatal inhibitory mechanisms and dopaminergic function complements the recent neuroimaging and anatomical data. Parallel studies of basal ganglia participation in the normal performance and learning of stereotyped repetitive behaviors or habits has provided additional insight. These lines of research have provided new pieces to the TS puzzle, and their increasing convergence is showing how those pieces can be put together.

Basal Ganglia↗
PubMed2006

Positron emission tomography of monoaminergic vesicular binding in aging and Parkinson disease.

The type-2 vesicular monoamine transporter (VMAT2) might serve as an objective biomarker of Parkinson disease (PD) severity. Thirty-one subjects with early-stage PD and 75 normal subjects underwent continuous intravenous infusion of (+)-[(11)C]dihydrotetrabenazine (DTBZ) and positron emission tomography (PET) imaging to estimate the striatal VMAT2 binding site density with equilibrium tracer modeling. Parkinson disease patients were evaluated clinically in the practically defined 'off' state with the Unified Parkinson Disease Rating Scale (UPDRS), the Hoehn and Yahr Scale (HY), and the Schwab and England Activities of Daily Living Scale (SE). In normal subjects there was age-related decline in striatal DTBZ binding, approximating 0.5% per year. In PD subjects, specific DTBZ binding was reduced in the caudate nucleus (CD; -44%), anterior putamen (-68%), and posterior putamen (PP; -77%). The PP-to-CD ratio of binding was reduced significantly in PD subjects. Dihydrotetrabenazine binding was also reduced by approximately 50% in the PD substantia nigra. Striatal binding reductions correlated significantly with PD duration and SE scores, but not with HY stage or with UPDRS motor subscale (UPDRS(III)) scores. Striatal and midbrain DTBZ binding was asymmetric in PD subjects, with greatest reductions contralateral to the most clinically affected limbs. There was significant correlation between asymmetry of DTBZ binding and clinical asymmetry measured with the UPDRS(III). In HY stage 1 and 1.5 subjects (n=16), PP DTBZ binding contralateral to the clinically unaffected body side was reduced by 73%, indicating substantial preclinical nigrostriatal pathology in PD. We conclude that (+)-[(11)C]DTBZ-PET imaging displays many properties necessary of a PD biomarker.

Adult↗
PubMed2006

Parkinson's disease: background, diagnosis, and initial management.

Parkinson's disease is a common neurodegenerative disorder associated with aging. After essential tremor, it is the most common movement disorder of the elderly. Parkinson's disease is the most common disabling movement disorder. This article reviews the major clinical features, differential diagnosis, approach to diagnosis, and initial management of Parkinson's disease.

Humans↗
PubMed2006

Neuroimaging of Tourette syndrome.

Traditional neuropathologic methods have provided only limited insight into the central nervous system abnormalities underlying Tourette syndrome. In the past 20 years, investigators have turned increasingly to in vivo neuroimaging approaches to localize, quantify, and characterize neuroanatomic, functional, and neurochemical distinctions in living subjects with Tourette syndrome. Research methods have included aggregate measures of cerebral energy metabolism, assessments of cerebral structure and size, and highly specific assessments of neurochemical markers of select neurons and synapses. Although the available data have important limitations, an encouraging convergence of findings implicates abnormal function in the Tourette syndrome striatum and in associated limbic and frontal cortical systems.

Brain↗
PubMed2006

Abnormalities of germ cell maturation and sertoli cell cytoskeleton in androgen receptor 113 CAG knock-in mice reveal toxic effects of the mutant protein.

An unresolved question in the study of the polyglutamine neurodegenerative disorders is the extent to which partial loss of normal function of the mutant protein contributes to the disease phenotype. To address this, we studied Kennedy disease, a degenerative disorder of lower motor neurons caused by a CAG/glutamine expansion in the androgen receptor (Ar) gene. Signs of partial androgen insensitivity, including testicular atrophy and decreased fertility, are common in affected males, although the underlying mechanisms are not well understood. Here, we describe a knock-in mouse model that reproduces the testicular atrophy, diminished fertility, and systemic signs of partial androgen insensitivity that occur in Kennedy disease patients. Using this model, we demonstrate that the testicular pathology in this disorder is distinct from that mediated by loss of AR function. Testes pathology in 113 CAG knock-in mice was characterized by morphological abnormalities of germ cell maturation, decreased solubility of the mutant AR protein, and alterations of the Sertoli cell cytoskeleton, changes that are distinct from those produced by AR loss-of-function mutation in testicular feminization mutant mice. Our data demonstrate that toxic effects of the mutant protein mediate aspects of the Kennedy disease phenotype previously attributed to a loss of AR function.

Age Factors↗
PubMed2005

Genetics of subthalamic nucleus in development and disease.

The subthalamic nucleus (STN) is a crucial node in the basal ganglia. Clinical success in targeting the STN for deep brain stimulation in Parkinson's disease patients has prompted increased interest in understanding STN biology. In this report, we discuss recent evidence for transcription factor mediated regulation of STN development. We also review STN developmental neurobiology and known patterns of gene expression in the developing and mature STN.

Animals↗
PubMed2005

11C-DTBZ and 18F-FDG PET measures in differentiating dementias.

UNLABELLED: Accurate, early differentiation of dementias will become increasingly important as new therapies are introduced. Differential diagnosis by standard clinical criteria has limited accuracy. PET offers the potential to increase diagnostic accuracy. (18)F-FDG studies detect metabolic abnormalities in demented patients, but with limited specificity. PET also offers the ability to quantify other biochemical markers that can yield additional useful diagnostic information. We demonstrate that (+)-(11)C-dihydrotetrabenazine ((11)C-DTBZ) studies, which provide an index of nigrostriatal terminal density (distribution volume; DV), also provide a measure of transport (K(1)) that produces information comparable to the metabolic measure of (18)F-FDG. METHODS: Fifty-two patients and 19 control subjects underwent both (11)C-DTBZ and (18)F-FDG PET scans. Seven had the clinical diagnosis of frontotemporal dementia (FTD), 25 had Alzheimer's disease (AD), and 20 had dementia with Lewy bodies (DLB). DTBZ scans provided maps of K(1) and DV, whereas (18)F-FDG scans provided maps of glucose metabolism. Correlation analyses were performed between the different PET measures both within and across subjects. Discriminant analysis using logistic regression compared the performance of (11)C-DTBZ K(1) and (18)F-FDG in differentiating subject groups. Three experienced PET researchers participated in an interrater reliability study using both (11)C-DTBZ K(1) and (18)F-FDG images. RESULTS: Within-subject correspondence between (11)C-DTBZ K(1) and (18)F-FDG measures was high, with correlations averaging 0.92. Correlations between the (11)C-DTBZ DV and either K(1) or (18)F-FDG were far lower, averaging 0.37 and 0.31, respectively, indicating the much higher degree of similarity in information provided by K(1) and (18)F-FDG compared with the very different information provided by (11)C-DTBZ DV. Discriminant analysis demonstrated that (11)C-DTBZ K(1) and (18)F-FDG yielded similar levels of sensitivity and specificity for differentiating the subjects in this study. Including (11)C-DTBZ DV in addition to either K(1) or (18)F-FDG improved discrimination between groups. The raters classified PET scans nearly equivalently using K(1) and (18)F-FDG. CONCLUSION: Multiple PET measures, whether 2 parameters from a single PET study such as (11)C-DTBZ K(1) and DV, or 2 parameters from different studies such as (18)F-FDG and (11)C-DTBZ DV, offer complementary information useful for diagnosing dementias. K(1) and DV images generated from a single (11)C-DTBZ scan provide as much diagnostic information as 2-scan studies using both (11)C-DTBZ and (18)F-FDG.

Aged↗
PubMed2004

Embryonic stem cells expressing expanded CAG repeats undergo aberrant neuronal differentiation and have persistent Oct-4 and REST/NRSF expression.

Nine neurodegenerative disorders are caused by CAG/polyglutamine (polyQ) repeat expansions. The molecular mechanisms responsible for disease-specific neurodegeneration remain elusive. We developed an embryonic stem (ES) cell-based model to probe the role of polyQ tract expansion in neuronal degeneration. ES cells containing expanded CAG repeats in the hypoxanthine phosphoribosyltransferase (Hprt) gene develop features typical of CAG-mediated neuropathology, exhibit length-dependent decrease in survival, undergo aberrant neuronal differentiation as well as persistent Oct-4 and Repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF) expression. This novel model will allow analysis of the molecular pathogenesis of neuronal degeneration and can be used to rapidly screen therapeutic interventions for these fatal diseases.

Cell Differentiation↗
PubMed2003

Genomic medicine.

Explore the source record for details and available documents.

Eugenics↗
PubMed2003

Hprt(CAG)146 mice: age of onset of behavioral abnormalities, time course of neuronal intranuclear inclusion accumulation, neurotransmitter marker alterations, mitochondrial function markers, and susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

We reported previously a model of polyglutamine repeat disorders with insertion of 146 CAG repeats into the murine hypoxanthine phosphoribosyl transferase locus (Hprt(CAG)146; Ordway et al. [1997] Cell 91:753-763), which does not normally contain polyglutamine repeats. These mice develop an adult-onset neurologic phenotype of incoordination, involuntary limb clasping, seizures, and premature death. Histologic analysis demonstrates widespread ubiquinated neuronal intranuclear inclusions (NIIs). We now report characterization of the age of onset of behavioral abnormalities, correlated with the time course of occurrence of NIIs in several brain regions, and the occurrence of NIIs in non-neuronal tissues. Onset of behavioral abnormalities occurred at approximately 22 weeks of age. There was variable time course of expression of NIIs in several brain regions. Assessment of several non-neuronal tissues revealed nuclear inclusions in hepatocytes and choroid plexus epithelium. Gamma-aminobutyric acid (GABA)/benzodiazepine receptors, dopamine D1-like and D2-like receptors, and type 2 vesicular monoamine transporter (VMAT2) binding sites were assayed before and after the onset of behavioral abnormalities. GABA/benzodiazepine receptors were unchanged either before or after the onset of behavioral abnormalities in any region analyzed, whereas striatal D1-like and D2-like receptors were diminished after but not before the onset of symptoms. Dorsal striatal VMAT2 binding sites were decreased before the onset of behavioral changes. Mitochondrial electron transport chain components were assayed with histochemical methods before and after the onset of behavioral changes. There was no change in behaviorally presymptomatic or symptomatic animals. Hprt(CAG)146 mice did not exhibit increased susceptibility to the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Hprt(CAG)146 mice are a useful model for studying polyglutamine repeat disorders.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse.

Cayman ataxia is a recessive congenital ataxia restricted to one area of Grand Cayman Island. Comparative mapping suggested that the locus on 19p13.3 associated with Cayman ataxia might be homologous to the locus on mouse chromosome 10 associated with the recessive ataxic mouse mutant jittery. Screening genes in the region of overlap identified mutations in a novel predicted gene in three mouse jittery alleles, including the first mouse mutation caused by an Alu-related (B1 element) insertion. We found two mutations exclusively in all individuals with Cayman ataxia. The gene ATCAY or Atcay encodes a neuron-restricted protein called caytaxin. Caytaxin contains a CRAL-TRIO motif common to proteins that bind small lipophilic molecules. Mutations in another protein containing a CRAL-TRIO domain, alpha-tocopherol transfer protein (TTPA), cause a vitamin E-responsive ataxia. Three-dimensional protein structural modeling predicts that the caytaxin ligand is more polar than vitamin E. Identification of the caytaxin ligand may help develop a therapy for Cayman ataxia.

Amino Acid Sequence↗
PubMed2003

Nucleocytoplasmic transport signals affect the age at onset of abnormalities in knock-in mice expressing polyglutamine within an ectopic protein context.

In order to better understand the role of nuclear localization of polyglutamine in the human CAG repeat disorders, gene targeting was used to add either nuclear localization (NLS) or nuclear export (NES) signals to versions of the mouse Hprt protein containing expanded polyglutamine (HprtQ150). The NLS increased levels of nuclear HprtQ150 protein in the mouse brain and hastened both the presentation of neuronal intranuclear inclusions (NIIs) and the onset of behavioral abnormalities. The NES reduced levels of nuclear HprtQ150 protein in mouse brain and delayed both the presentation of NIIs and the onset of behavioral abnormalities. Together these results indicate the nucleus is the primary site of toxicity in HprtQ150 mice. Furthermore, the signals did not alter the relative regional distribution of NIIs, suggesting that factors other than nuclear access dictate the regional specificity of NII formation in this mouse model.

Active Transport, Cell Nucleus↗
PubMed2003

Mice lacking phosphatidylinositol transfer protein-alpha exhibit spinocerebellar degeneration, intestinal and hepatic steatosis, and hypoglycemia.

Phosphatidylinositol transfer proteins (PITPs) regulate the interface between lipid metabolism and cellular functions. We now report that ablation of PITP alpha function leads to aponecrotic spinocerebellar disease, hypoglycemia, and intestinal and hepatic steatosis in mice. The data indicate that hypoglycemia is in part associated with reduced proglucagon gene expression and glycogenolysis that result from pancreatic islet cell defects. The intestinal and hepatic steatosis results from the intracellular accumulation of neutral lipid and free fatty acid mass in these organs and suggests defective trafficking of triglycerides and diacylglycerols from the endoplasmic reticulum. We propose that deranged intestinal and hepatic lipid metabolism and defective proglucagon gene expression contribute to hypoglycemia in PITP alpha-/- mice, and that hypoglycemia is a significant contributing factor in the onset of spinocerebellar disease. Taken together, the data suggest an unanticipated role for PITP alpha in with glucose homeostasis and in mammalian endoplasmic reticulum functions that interface with transport of specific luminal lipid cargoes.

Adenosine Triphosphate↗