John Trojanowski - Academia.edu (original) (raw)
Papers by John Trojanowski
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 2019
IntroductionConventional Z‐scores are generated by subtracting the mean and dividing by the stand... more IntroductionConventional Z‐scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these “adjusted” Z‐scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z‐scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency.MethodsIn this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance).ResultsCorrected Z‐scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted‐R2.DiscussionNonlinearly corrected Z‐scores with respect to age, sex, and education with age‐va...
Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2019
1Over the last few years, as more and more sequencing studies have been performed, it has become ... more 1Over the last few years, as more and more sequencing studies have been performed, it has become apparent that the identification of pathogenic mutations is, more often than not, a complex issue. Here, with a focus on neurodegenerative diseases, we have performed a survey of coding genetic variability that is unlikely to be pathogenic.We have performed whole-exome sequencing in 478 samples derived from several brain banks in the United Kingdom and the United States of America. Samples were included when subjects were, at death, over 60 years of age, had no signs of neurological disease and were subjected to a neuropathological examination, which revealed no evidence of neurodegeneration. This information will be valuable to studies of genetic variability as a causal factor for neurodegenerative syndromes. We envisage it will be particularly relevant for diagnostic laboratories as a filter step to the results being produced by either genome-wide or gene-panel sequencing. We have made...
The Lancet Neurology, 2018
Annals of clinical and translational neurology, 2017
Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variabl... more Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression. We screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein (SNCA) expression in the GTEx (Genotype-Tissue Expression project) consortium database. Genotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) an...
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2004
The +16 exon 10 splice mutation of the tau gene (microtubule‐associated protein tau, MAPT) has be... more The +16 exon 10 splice mutation of the tau gene (microtubule‐associated protein tau, MAPT) has been reported in numerous families with frontotemporal dementia (FTD). To date, the majority of these families are from England and Wales in the UK, although families with this mutation have been reported from Australia and the USA. Our own analysis has identified eight families with the +16 MAPT splice mutation from around the Manchester and North Wales areas of the UK. Given the proximity of the UK families to one another it is likely that they are related and represent a single extended pedigree. In order to investigate this possibility, and the possibility that the families with this mutation from London, the USA, and Australia are related, we genotyped 11 microsatellite markers around the tau locus. In most cases (20/25, 80%), a common haplotype, approximately 3 cM in size, was identified. In the remaining cases, this haplotype appears to have been varyingly reduced in size by recombi...
Alzheimer's & Dementia, 2012
Alzheimer's & Dementia, 2012
Alzheimer's & Dementia, 2012
Background: A new ultra performance 2D-LC method with tandem mass spectrometric detection was dev... more Background: A new ultra performance 2D-LC method with tandem mass spectrometric detection was developed for accurate, reliable and efficient quantification of three amyloid beta peptides, 1-38, 1-40 and 1-42 in human CSF following an initial extraction step using 5M guanidine HCL (GUCL). Methods: An API 5000 triple quadrupole instrument (ABSciex) with an ESI ion source, interfaced with an ACQUITY UPLC (Waters), was used. Artificial CSF containing 4mg/mL bovine serum albumin was used as a matrix for standards and quality control samples. The analytes were isolated from CSF using Oasis MCX m Elution 96-well plates (Waters) after an initial extraction/denaturation step using 5M GUCL. During the first step of chromatography 50 m L of sample extracts undergo on-line dilution/cleaning, using an Xbridge BEH C18 column (Waters). After desalting with a highly aqueous solvent the valve was switched and analytes were transferred to the analytical column (BEH-300, C18, 2.1x150mm, 1.7 mm; Waters). An isocratic gradient of 0.1% ammonia in water and a mixture of organic solvents was used for efficient separation of the three peptides and their internal standards (isotopically labeled). The mass spectrometer was operated in the positive ion mode and MRM scanning. The quadrupoles were set to detect the 4+ molecular ions and their fragments: m/z 1033.9/1001.0 (A b 1-38), m/z 1083.5/1054.3 (A b 1-40) and m/z 1129.5/1079.1 (A b 1-42), m/z 1046.0/1012.5 (15 N-A b 1-38), m/z 1096.0/1066.5 (15 N-A b 1-40) and m/z 1142.5/1091.5 (15 N-A b 1-42). Results: The lower limit of quantification was 100pg/mL for all three peptides (Table 1). The upper limit of quantification was 7500pg/mL for A b 1-38 and 1-40, and 3000pg/mL for A b 1-42. For 4 quality control samples between-day precision varied from 11.1-12.8% (A b 1-38), 7.3-13.2% (A b 1-40) and 10-14.9% (A b 1-42) (Table 2). Mean analytical recovery of the abeta peptides for QC samples was 101.8% (A b 1-38), 100.2% (A b 1-40) and 97.3% (A b 142). Between-day precision for all calibrators not including LLOQ ranged from 4.6% to 16.3% and accuracy ranged from 92 to 109%. Under these conditions no ion suppression of the detection of any ion was found and no carry over effects were observed. Conclusions:We believe this newly developed and validated assay confirms its potential utility for the direct measurement of Abeta peptides in CSF samples and further analyses are underway to demonstrate this. Acknowledgments: We thank Rand Jenkins 1 from PPD Inc. for sharing his extensive experience in development and optimization of the 2-D liquid chromatography tandem mass spectrometry method and Erin Chambers from Waters for Table 2 Precision and accuracy of Ab38, Ab40, Ab42, pTau181 and Total Tau measurements
Alzheimer's & Dementia, 2012
SUBJECTS WITH ALZHEIMER’S DISEASE Alexey Nefedov, Juan Toledo, Yuk Yee Leung, Nandini Raghavan, S... more SUBJECTS WITH ALZHEIMER’S DISEASE Alexey Nefedov, Juan Toledo, Yuk Yee Leung, Nandini Raghavan, Sharon Xie, Robi Polikar, Michael Farnum, Tim Schultz, Young Baek, Victor Lobanov, Allitia DiBernardo, Vaibhav Narayan, Virginia Lee, Steven Arnold, John Trojanowski, Li-San Wang, Gayle Wittenberg, 1 University of Pennsylvania, Philadelphia, Pennsylvania, United States; 2 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; University of Pennsylvania, Philadelphia, Pennsylvania, United States; Janssen Pharmaceuticals, Raritan, New Jersey, United States; 5 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 6 Rowan University, Glassboro, New Jersey, United States; Janssen Pharmaceuticals, Spring House, Pennsylvania, United States; Janssen Pharmaceuticals, Spring House, Pennsylvania, United States; 9 Janssen Pharmaceuticals, Titusville, New Jersey, United States; Janssen Pharmaceuticals, Titusville, Pennsylvania, United States.
Alzheimer's & Dementia, 2012
Different inflammatory and metabolic pathways have been associated with Alzheimers disease (AD). ... more Different inflammatory and metabolic pathways have been associated with Alzheimers disease (AD). However, only recently multi-analyte panels to study a large number of molecules in well characterized cohorts have been made available. These panels could help identify molecules that point to the affected pathways. We studied the relationship between a panel of plasma biomarkers (Human DiscoveryMAPH) and presence of AD-like brain atrophy patterns defined by a previously published index (SPARE-AD) at baseline in subjects of the ADNI cohort. 818 subjects had MRI-derived SPARE-AD scores, of these subjects 69% had plasma biomarkers and 51% had CSF tau and Ab measurements. Significant analyte-SPARE-AD and analytes correlations were studied in adjusted models. Plasma cortisol and chromogranin A showed a significant association that did not remain significant in the CSF signature adjusted model. Plasma macrophage inhibitory protein-1a and insulinlike growth factor binding protein 2 showed a significant association with brain atrophy in the adjusted model. Cortisol levels showed an inverse association with tests measuring processing speed. Our results indicate that stress and insulin responses and cytokines associated with recruitment of inflammatory cells in MCI-AD are associated with its characteristic AD-like brain atrophy pattern and correlate with clinical changes or CSF biomarkers.
Alzheimer's & Dementia, 2012
Alzheimer's & Dementia, 2013
Alzheimer's & Dementia, 2013
Alzheimer's & Dementia, 2013
lower brain volumes in the frontal and occipital lobes 2. We examined the influence of the obesit... more lower brain volumes in the frontal and occipital lobes 2. We examined the influence of the obesity associated SNP rs17817449 in FTO on longitudinal changes in brain volume in non-demented older individuals within the Baltimore Longitudinal Study of Aging (BLSA). We hypothesized that obesityassociated risk allele carriers of the FTO gene would show faster rates of brain atrophy relative to non-carriers. Methods: Non-demented individuals (N¼120; mean baseline age 70.5 years) received annual volumetric MRI (826 MRI scans in total) over a mean six-year interval and underwent genome-wide genotyping. Linear mixed effects models were used in a region of interest approach to examine differences in longitudinal rates of change in brain volumes between obesity-associated risk allele carriers and non-carriers of rs17817449. The analyses were adjusted for sex, age, APOE genotype and average body mass index (BMI) over the follow-up interval. Results: There were 72 individuals in the risk group and 48 in the nonrisk group. The minor allele frequency was 0.41. There were no differences between the two groups in APOE ε 4 carrier status and average BMI. We did not observe any differences in global, lobar or regional brain volumes at baseline. Risk allele carriers showed significantly greater rates of decline in volume in the cuneus (one-tailed p¼0.001; Bonferroni corrected p¼0.038) relative to the non-risk group. Conclusions: Non-demented older individuals carrying one or more copies of the obesity-related SNP rs17817449 in the FTO gene show greater rates of brain atrophy within the cuneus of the occipital lobe. Together with previous cross-sectional findings of reduced occipital lobe volume in risk allele carriers, these results suggest that the FTO gene influences regional vulnerability to rates of brain atrophy during aging.1.
Alzheimer's & Dementia, 2011
Alzheimer's & Dementia, 2011
Peripheral blood RNA was extracted using Paxgene tubes, amplified, labeled, and hybridized onto I... more Peripheral blood RNA was extracted using Paxgene tubes, amplified, labeled, and hybridized onto Illumina Human RefSeq-8 BeadChip arrays, querying the expression of w24,000 RefSeq curated transcripts followed by quality control, quantile normalization with R and Bioconductor packages. The imaging data were analyzed with the cortical pattern matching and cortical thickness mapping techniques. Linear regression was used to examine the relationship between log2-transformed absolute gene expression levels and cortical thickness while adjusting for age and gender. For multiple comparison correction we used permutation tests with a threshold of p< 0.01. Results: Higher expression of Sialic acid binding lg-like lectin 10 (SIGLEC10), a gene associated with tissue damage-induced immune responses, showed associations with bilateral temporo-occipital, precuneal, posterior cingulate and inferior temporal cortical thinning (left hemisphere p corrected1⁄4 0.032; right hemisphere p corrected1⁄4 0.043). Higher expression of Myosin IIIA(MYO3A), a gene encoding the subtype of myosin that interacts with the GRINLIA glutamatergic receptor, while showing regionally similar associations with cortical thinning, also showed an association with the left lateral parietal cortex (left hemisphere p corrected 1⁄4 0.049, right hemisphere p 1⁄4 0.12). Higher expression of growth hormone 1 (GH1), a regulator of neuronal survival via insulin-like growth factor, showed a pattern of association similar to that of MYO3Awith trend-level significance on the left (p corrected 1⁄4 0.059). Finally higher expression of Amyotrophic lateral sclerosis (ALS) 2 chromosome region 11(ALS2CR11), a gene encoding a protein with calcium binding properties that has been implicated in the pathogenesis of ALS, correlated with bilateral cortical thinning of the sensorimotor strip, supplementary motor area and precuneus/ posterior cingulate cortex as well as left inferior frontal and anterior cingulate cortex (left hemisphere p corrected1⁄4 0.044, right hemisphere p1⁄4 0.3). Conclusions: Altered peripheral blood gene expression is associated with cortical atrophy in the pre-dementia cognitive spectrum.
Alzheimer's & Dementia, 2011
quences using Fazekas’ subcortical and periventricular scores, the Age-Related White Matter Chang... more quences using Fazekas’ subcortical and periventricular scores, the Age-Related White Matter Changes Rating Scale (ARWMC) and the Cholinergic Pathways Hyperintensities scale (CHIPS). A CHIPS analogy for CMBs was also provided (the Cholinergic Pathways Microbleeds scale-CHMBS). Lacuna infarctions are counted on FLAIR images. Normalized inter-caudate (ICD) and inter-uncal distance (IUD) were calculated on T1. Besides MiniMental State Examination and geriatric depression scale, detailed neuropsychological tests were administered to assess various cognitive domains including attention (digit span forward and backwards, trial making A), executive functions (Trial making B, verbal fluency), language (Boston naming test, verbal fluency), visuospatial abilities (clock drawing test, line orientation test, Benton’s face recognition), and memory (Rey’s auditory verbal learning test, enhanced cued recall, category fluency, Weshler memory scalevisual memory test). Results: CMBs burden was not related to cognitive function or dysfunction (p>0.05). Irrespective to the severity of cerebral atrophy, WMHs load along with lacunae had more significant effects on cognitive functions in comparison with CMBs burden. Conclusions: Distinct topographical distribution of CMBs and WMHs in relation to cholinergic pathways seems to be important in affecting cognition.
Alzheimer's & Dementia, 2010
Among the major impediments to the design of clinical trials for the prevention of Alzheimer'... more Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Symposium 2009 (LTS'09), on October 27–28, 2009 in Las Vegas, Nevada, was convened to explore strategies to surmount the barriers in designing a multisite, comparative study to evaluate and validate various approaches for detecting and selecting asymptomatic people at risk for cognitive disorders/dementia. The deliberations of LTS'09 included presentations and reviews of different approaches (algorithms, biomarkers, or measures) for identifying asymptomatic individuals at elevated risk for AD who would be candidates for longitudinal or prevention studies. The key nested recommendations of LTS'09 included: (1) establishment of a ...
Alzheimer's & Dementia, 2011
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 2019
IntroductionConventional Z‐scores are generated by subtracting the mean and dividing by the stand... more IntroductionConventional Z‐scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these “adjusted” Z‐scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z‐scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency.MethodsIn this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance).ResultsCorrected Z‐scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted‐R2.DiscussionNonlinearly corrected Z‐scores with respect to age, sex, and education with age‐va...
Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2019
1Over the last few years, as more and more sequencing studies have been performed, it has become ... more 1Over the last few years, as more and more sequencing studies have been performed, it has become apparent that the identification of pathogenic mutations is, more often than not, a complex issue. Here, with a focus on neurodegenerative diseases, we have performed a survey of coding genetic variability that is unlikely to be pathogenic.We have performed whole-exome sequencing in 478 samples derived from several brain banks in the United Kingdom and the United States of America. Samples were included when subjects were, at death, over 60 years of age, had no signs of neurological disease and were subjected to a neuropathological examination, which revealed no evidence of neurodegeneration. This information will be valuable to studies of genetic variability as a causal factor for neurodegenerative syndromes. We envisage it will be particularly relevant for diagnostic laboratories as a filter step to the results being produced by either genome-wide or gene-panel sequencing. We have made...
The Lancet Neurology, 2018
Annals of clinical and translational neurology, 2017
Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variabl... more Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression. We screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein (SNCA) expression in the GTEx (Genotype-Tissue Expression project) consortium database. Genotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) an...
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2004
The +16 exon 10 splice mutation of the tau gene (microtubule‐associated protein tau, MAPT) has be... more The +16 exon 10 splice mutation of the tau gene (microtubule‐associated protein tau, MAPT) has been reported in numerous families with frontotemporal dementia (FTD). To date, the majority of these families are from England and Wales in the UK, although families with this mutation have been reported from Australia and the USA. Our own analysis has identified eight families with the +16 MAPT splice mutation from around the Manchester and North Wales areas of the UK. Given the proximity of the UK families to one another it is likely that they are related and represent a single extended pedigree. In order to investigate this possibility, and the possibility that the families with this mutation from London, the USA, and Australia are related, we genotyped 11 microsatellite markers around the tau locus. In most cases (20/25, 80%), a common haplotype, approximately 3 cM in size, was identified. In the remaining cases, this haplotype appears to have been varyingly reduced in size by recombi...
Alzheimer's & Dementia, 2012
Alzheimer's & Dementia, 2012
Alzheimer's & Dementia, 2012
Background: A new ultra performance 2D-LC method with tandem mass spectrometric detection was dev... more Background: A new ultra performance 2D-LC method with tandem mass spectrometric detection was developed for accurate, reliable and efficient quantification of three amyloid beta peptides, 1-38, 1-40 and 1-42 in human CSF following an initial extraction step using 5M guanidine HCL (GUCL). Methods: An API 5000 triple quadrupole instrument (ABSciex) with an ESI ion source, interfaced with an ACQUITY UPLC (Waters), was used. Artificial CSF containing 4mg/mL bovine serum albumin was used as a matrix for standards and quality control samples. The analytes were isolated from CSF using Oasis MCX m Elution 96-well plates (Waters) after an initial extraction/denaturation step using 5M GUCL. During the first step of chromatography 50 m L of sample extracts undergo on-line dilution/cleaning, using an Xbridge BEH C18 column (Waters). After desalting with a highly aqueous solvent the valve was switched and analytes were transferred to the analytical column (BEH-300, C18, 2.1x150mm, 1.7 mm; Waters). An isocratic gradient of 0.1% ammonia in water and a mixture of organic solvents was used for efficient separation of the three peptides and their internal standards (isotopically labeled). The mass spectrometer was operated in the positive ion mode and MRM scanning. The quadrupoles were set to detect the 4+ molecular ions and their fragments: m/z 1033.9/1001.0 (A b 1-38), m/z 1083.5/1054.3 (A b 1-40) and m/z 1129.5/1079.1 (A b 1-42), m/z 1046.0/1012.5 (15 N-A b 1-38), m/z 1096.0/1066.5 (15 N-A b 1-40) and m/z 1142.5/1091.5 (15 N-A b 1-42). Results: The lower limit of quantification was 100pg/mL for all three peptides (Table 1). The upper limit of quantification was 7500pg/mL for A b 1-38 and 1-40, and 3000pg/mL for A b 1-42. For 4 quality control samples between-day precision varied from 11.1-12.8% (A b 1-38), 7.3-13.2% (A b 1-40) and 10-14.9% (A b 1-42) (Table 2). Mean analytical recovery of the abeta peptides for QC samples was 101.8% (A b 1-38), 100.2% (A b 1-40) and 97.3% (A b 142). Between-day precision for all calibrators not including LLOQ ranged from 4.6% to 16.3% and accuracy ranged from 92 to 109%. Under these conditions no ion suppression of the detection of any ion was found and no carry over effects were observed. Conclusions:We believe this newly developed and validated assay confirms its potential utility for the direct measurement of Abeta peptides in CSF samples and further analyses are underway to demonstrate this. Acknowledgments: We thank Rand Jenkins 1 from PPD Inc. for sharing his extensive experience in development and optimization of the 2-D liquid chromatography tandem mass spectrometry method and Erin Chambers from Waters for Table 2 Precision and accuracy of Ab38, Ab40, Ab42, pTau181 and Total Tau measurements
Alzheimer's & Dementia, 2012
SUBJECTS WITH ALZHEIMER’S DISEASE Alexey Nefedov, Juan Toledo, Yuk Yee Leung, Nandini Raghavan, S... more SUBJECTS WITH ALZHEIMER’S DISEASE Alexey Nefedov, Juan Toledo, Yuk Yee Leung, Nandini Raghavan, Sharon Xie, Robi Polikar, Michael Farnum, Tim Schultz, Young Baek, Victor Lobanov, Allitia DiBernardo, Vaibhav Narayan, Virginia Lee, Steven Arnold, John Trojanowski, Li-San Wang, Gayle Wittenberg, 1 University of Pennsylvania, Philadelphia, Pennsylvania, United States; 2 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; University of Pennsylvania, Philadelphia, Pennsylvania, United States; Janssen Pharmaceuticals, Raritan, New Jersey, United States; 5 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 6 Rowan University, Glassboro, New Jersey, United States; Janssen Pharmaceuticals, Spring House, Pennsylvania, United States; Janssen Pharmaceuticals, Spring House, Pennsylvania, United States; 9 Janssen Pharmaceuticals, Titusville, New Jersey, United States; Janssen Pharmaceuticals, Titusville, Pennsylvania, United States.
Alzheimer's & Dementia, 2012
Different inflammatory and metabolic pathways have been associated with Alzheimers disease (AD). ... more Different inflammatory and metabolic pathways have been associated with Alzheimers disease (AD). However, only recently multi-analyte panels to study a large number of molecules in well characterized cohorts have been made available. These panels could help identify molecules that point to the affected pathways. We studied the relationship between a panel of plasma biomarkers (Human DiscoveryMAPH) and presence of AD-like brain atrophy patterns defined by a previously published index (SPARE-AD) at baseline in subjects of the ADNI cohort. 818 subjects had MRI-derived SPARE-AD scores, of these subjects 69% had plasma biomarkers and 51% had CSF tau and Ab measurements. Significant analyte-SPARE-AD and analytes correlations were studied in adjusted models. Plasma cortisol and chromogranin A showed a significant association that did not remain significant in the CSF signature adjusted model. Plasma macrophage inhibitory protein-1a and insulinlike growth factor binding protein 2 showed a significant association with brain atrophy in the adjusted model. Cortisol levels showed an inverse association with tests measuring processing speed. Our results indicate that stress and insulin responses and cytokines associated with recruitment of inflammatory cells in MCI-AD are associated with its characteristic AD-like brain atrophy pattern and correlate with clinical changes or CSF biomarkers.
Alzheimer's & Dementia, 2012
Alzheimer's & Dementia, 2013
Alzheimer's & Dementia, 2013
Alzheimer's & Dementia, 2013
lower brain volumes in the frontal and occipital lobes 2. We examined the influence of the obesit... more lower brain volumes in the frontal and occipital lobes 2. We examined the influence of the obesity associated SNP rs17817449 in FTO on longitudinal changes in brain volume in non-demented older individuals within the Baltimore Longitudinal Study of Aging (BLSA). We hypothesized that obesityassociated risk allele carriers of the FTO gene would show faster rates of brain atrophy relative to non-carriers. Methods: Non-demented individuals (N¼120; mean baseline age 70.5 years) received annual volumetric MRI (826 MRI scans in total) over a mean six-year interval and underwent genome-wide genotyping. Linear mixed effects models were used in a region of interest approach to examine differences in longitudinal rates of change in brain volumes between obesity-associated risk allele carriers and non-carriers of rs17817449. The analyses were adjusted for sex, age, APOE genotype and average body mass index (BMI) over the follow-up interval. Results: There were 72 individuals in the risk group and 48 in the nonrisk group. The minor allele frequency was 0.41. There were no differences between the two groups in APOE ε 4 carrier status and average BMI. We did not observe any differences in global, lobar or regional brain volumes at baseline. Risk allele carriers showed significantly greater rates of decline in volume in the cuneus (one-tailed p¼0.001; Bonferroni corrected p¼0.038) relative to the non-risk group. Conclusions: Non-demented older individuals carrying one or more copies of the obesity-related SNP rs17817449 in the FTO gene show greater rates of brain atrophy within the cuneus of the occipital lobe. Together with previous cross-sectional findings of reduced occipital lobe volume in risk allele carriers, these results suggest that the FTO gene influences regional vulnerability to rates of brain atrophy during aging.1.
Alzheimer's & Dementia, 2011
Alzheimer's & Dementia, 2011
Peripheral blood RNA was extracted using Paxgene tubes, amplified, labeled, and hybridized onto I... more Peripheral blood RNA was extracted using Paxgene tubes, amplified, labeled, and hybridized onto Illumina Human RefSeq-8 BeadChip arrays, querying the expression of w24,000 RefSeq curated transcripts followed by quality control, quantile normalization with R and Bioconductor packages. The imaging data were analyzed with the cortical pattern matching and cortical thickness mapping techniques. Linear regression was used to examine the relationship between log2-transformed absolute gene expression levels and cortical thickness while adjusting for age and gender. For multiple comparison correction we used permutation tests with a threshold of p< 0.01. Results: Higher expression of Sialic acid binding lg-like lectin 10 (SIGLEC10), a gene associated with tissue damage-induced immune responses, showed associations with bilateral temporo-occipital, precuneal, posterior cingulate and inferior temporal cortical thinning (left hemisphere p corrected1⁄4 0.032; right hemisphere p corrected1⁄4 0.043). Higher expression of Myosin IIIA(MYO3A), a gene encoding the subtype of myosin that interacts with the GRINLIA glutamatergic receptor, while showing regionally similar associations with cortical thinning, also showed an association with the left lateral parietal cortex (left hemisphere p corrected 1⁄4 0.049, right hemisphere p 1⁄4 0.12). Higher expression of growth hormone 1 (GH1), a regulator of neuronal survival via insulin-like growth factor, showed a pattern of association similar to that of MYO3Awith trend-level significance on the left (p corrected 1⁄4 0.059). Finally higher expression of Amyotrophic lateral sclerosis (ALS) 2 chromosome region 11(ALS2CR11), a gene encoding a protein with calcium binding properties that has been implicated in the pathogenesis of ALS, correlated with bilateral cortical thinning of the sensorimotor strip, supplementary motor area and precuneus/ posterior cingulate cortex as well as left inferior frontal and anterior cingulate cortex (left hemisphere p corrected1⁄4 0.044, right hemisphere p1⁄4 0.3). Conclusions: Altered peripheral blood gene expression is associated with cortical atrophy in the pre-dementia cognitive spectrum.
Alzheimer's & Dementia, 2011
quences using Fazekas’ subcortical and periventricular scores, the Age-Related White Matter Chang... more quences using Fazekas’ subcortical and periventricular scores, the Age-Related White Matter Changes Rating Scale (ARWMC) and the Cholinergic Pathways Hyperintensities scale (CHIPS). A CHIPS analogy for CMBs was also provided (the Cholinergic Pathways Microbleeds scale-CHMBS). Lacuna infarctions are counted on FLAIR images. Normalized inter-caudate (ICD) and inter-uncal distance (IUD) were calculated on T1. Besides MiniMental State Examination and geriatric depression scale, detailed neuropsychological tests were administered to assess various cognitive domains including attention (digit span forward and backwards, trial making A), executive functions (Trial making B, verbal fluency), language (Boston naming test, verbal fluency), visuospatial abilities (clock drawing test, line orientation test, Benton’s face recognition), and memory (Rey’s auditory verbal learning test, enhanced cued recall, category fluency, Weshler memory scalevisual memory test). Results: CMBs burden was not related to cognitive function or dysfunction (p>0.05). Irrespective to the severity of cerebral atrophy, WMHs load along with lacunae had more significant effects on cognitive functions in comparison with CMBs burden. Conclusions: Distinct topographical distribution of CMBs and WMHs in relation to cholinergic pathways seems to be important in affecting cognition.
Alzheimer's & Dementia, 2010
Among the major impediments to the design of clinical trials for the prevention of Alzheimer'... more Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Symposium 2009 (LTS'09), on October 27–28, 2009 in Las Vegas, Nevada, was convened to explore strategies to surmount the barriers in designing a multisite, comparative study to evaluate and validate various approaches for detecting and selecting asymptomatic people at risk for cognitive disorders/dementia. The deliberations of LTS'09 included presentations and reviews of different approaches (algorithms, biomarkers, or measures) for identifying asymptomatic individuals at elevated risk for AD who would be candidates for longitudinal or prevention studies. The key nested recommendations of LTS'09 included: (1) establishment of a ...
Alzheimer's & Dementia, 2011