Edmond Teng - Academia.edu (original) (raw)
Papers by Edmond Teng
JAMA Neurology
IMPORTANCE Neurofibrillary tangles composed of aggregated tau protein are one of the neuropatholo... more IMPORTANCE Neurofibrillary tangles composed of aggregated tau protein are one of the neuropathological hallmarks of Alzheimer disease (AD) and correlate with clinical disease severity. Monoclonal antibodies targeting tau may have the potential to ameliorate AD progression by slowing or stopping the spread and/or accumulation of pathological tau. OBJECTIVE To evaluate the safety and efficacy of the monoclonal anti-tau antibody semorinemab in prodromal to mild AD. DESIGN, SETTING, AND PARTICIPANTS This phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted between October 18, 2017, and July 16, 2020, at 97 sites in North America, Europe, and Australia. Individuals aged 50 to 80 years (inclusive) with prodromal to mild AD, Mini-Mental State Examination scores between 20 and 30 (inclusive), and confirmed β-amyloid pathology (by positron emission tomography or cerebrospinal fluid) were included. INTERVENTIONS During the 73-week blinded study period, participants received intravenous infusions of placebo or semorinemab (1500 mg, 4500 mg, or 8100 mg) every 2 weeks for the first 3 infusions and every 4 weeks thereafter. MAIN OUTCOMES AND MEASURES The primary outcomes were change from baseline on the Clinical Dementia Rating-Sum of Boxes score from baseline to week 73 and assessments of the safety and tolerability for semorinemab compared with placebo. RESULTS In the modified intent-to-treat cohort (n = 422; mean [SD] age, 69.6 [7.0] years; 235 women [55.7%]), similar increases were seen on the Clinical Dementia Rating-Sum of Boxes score in the placebo (n = 126; Δ = 2.19 [95% CI, 1.74-2.63]) and semorinemab (1500 mg: n = 86; Δ = 2.36 [95% CI, 1.83-2.89]; 4500 mg: n = 126; Δ = 2.36 [95% CI, 1.92-2.79]; 8100 mg: n = 84; Δ = 2.41 [95% CI, 1.88-2.94]) arms. In the safety-evaluable cohort (n = 441), similar proportions of participants experienced adverse events in the placebo (130 [93.1%]) and semorinemab (1500 mg: 89 [88.8%]; 4500 mg: 132 [94.7%]; 8100 mg: 90 [92.2%]) arms. CONCLUSIONS AND RELEVANCE In participants with prodromal to mild AD in this randomized clinical trial, semorinemab did not slow clinical AD progression compared with placebo throughout the 73-week study period but did demonstrate an acceptable and well-tolerated safety profile. Additional studies of anti-tau antibodies may be needed to determine the clinical utility of this therapeutic approach.
Marjorie Seybold, and Arnold Starr for their assistance in gathering historical material. Disclos... more Marjorie Seybold, and Arnold Starr for their assistance in gathering historical material. Disclosures: Drs. Teng and Mishra have nothing to disclose.
Neurology, 2013
OBJECTIVE: To determine the prevalence of hippocampal sclerosis (HS) and medial temporal lobe scl... more OBJECTIVE: To determine the prevalence of hippocampal sclerosis (HS) and medial temporal lobe sclerosis (MTS) and their relationship to tau neuropathology in a large, multi-center cohort of clinically diagnosed behavioral variant frontotemporal dementia (bvFTD) cases. BACKGROUND: Both HS and MTS are characterized by selective neuronal loss and astrocytic gliosis of the hippocampus and/or neighboring cortex and are associated with memory impairment. HS/MTS frequently coexist with dementia, and previous single-center neuropathological studies have demonstrated an association between HS/MTS and bvFTD, particularly in tau-negative cases with TDP-43 proteinopathies. DESIGN/METHODS: We identified patients with a clinical diagnosis of bvFTD (n=107) who were included in both the Neuropathology and Uniform Datasets maintained by the National Alzheimer9s Coordinating Committee (NACC). We excluded 12 patients with ambiguous pathologies and 21 patients with predominant Alzheimer9s disease patho...
![Research paper thumbnail of Cognitive indices correlate with [ 18 F]GTP1 tau PET signal and white matter hyperintensities in prodromal‐to‐mild Alzheimer's disease: Baseline data from the Tauriel Study](https://attachments.academia-assets.com/96997059/thumbnails/1.jpg)
](Alzheimer's & Dementia, 2020
Background: In prior cross-sectional studies using [ 18 F]GTP1 or other tau PET tracers across a ... more Background: In prior cross-sectional studies using [ 18 F]GTP1 or other tau PET tracers across a spectrum of Alzheimer's disease (AD) severity, tau PET signal has independently correlated with cognition, even after adjustments for β-amyloid (Aβ) load and atrophy. However, it remains uncertain how robust these correlations are in more homogeneous patient populations (e.g., clinical trial participants) and after adjustment for MRI white-matter hyperintensities (WMH). We sought to address this question by examining baseline data from the Phase 2 Tauriel study (NCT03289143), which is investigating the safety and efficacy of semorinemab (an anti-tau antibody) in prodromal-to-mild AD. Method: We analyzed data from a subset of Tauriel participants who underwent baseline [ 18 F]GTP1 tau PET imaging and met criteria for probable AD dementia (n=244) or mild cognitive impairment (MCI; n=137), with MMSE of 20-30, global Clinical Dementia Rating (CDR) of 0.5 or 1, significant Aβ pathology (PET or CSF), and significant episodic memory impairment on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Other screening/baseline assessments included the 13-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) and MRI (WMH scored with Fazekas scale). Relationships between cognitive indices, whole cortical gray (WCG) [ 18 F]GTP1 SUVR, WMH, and age were assessed using Pearson correlations and multiple linear regression. Result: Univariate analyses revealed significant correlations between all cognitive indices [MMSE, CDR Sum of Boxes, ADAS-Cog13, and RBANS] and [ 18 F]GTP1 SUVR across the whole cortical gray (WCG; p's<0.001). Significant univariate correlations were also seen between WMH and ADAS-Cog13 scores (p=0.035) and between age and RBANS scores (p<0.001). Multivariate linear regression analyses that included all three factors consistently identified both WCG [ 18 F]GTP1 SUVR and WMH as inde
Alzheimer's & Dementia, 2016
Clinical Diagnosis and Management of Alzheimer's Disease, 2006
Neurology, 2016
Objective: To determine the effect of extended Alzheimer9s Disease Assessment Scale-Cognitive Sub... more Objective: To determine the effect of extended Alzheimer9s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and amyloid imaging standardized uptake value ratio (SUVR) thresholds on clinical trial effect size. Background: Recent clinical trials of anti-beta amyloid interventions have used extended versions of the ADAS-Cog as outcome measures and positive positron emission tomography (PET) imaging with a ligand specific for beta amyloid as inclusion criteria, in part, in an effort to increase the sensitivity to detect treatment effects in mild AD. The implications on trial statistical power, however, remain uncertain. Methods: We used data from mild AD participants (Mini-Mental Status Exam 20-26) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to model trial effect sizes (Δμ/σ) for 12- and 24-month trials using the ADAS-Cog11, 12 and 13 as the primary outcome. The ADAS-Cog11 incorporates tests of memory and language in addition to other cognitive abilities. ADAS-Cog12 ...
NEJM Journal Watch, 2008
Results of research in cellular and animal models of Alzheimer disease (AD) suggest that statins ... more Results of research in cellular and animal models of Alzheimer disease (AD) suggest that statins can reduce the production of neurotoxic amyloid-beta peptides by reducing cholesterol levels and, thus, might help prevent or delay AD-related cognitive impairment or dementia. Statins also exhibit anti-inflammatory, antioxidant, and antithrombotic properties, which may help minimize cognitive decline caused by vascular brain injury. Retrospective studies in humans …
American Journal of Alzheimer's Disease & Other Dementiasr, 2011
Background: Posterior cortical atrophy (PCA) may represent a discrete syndrome of Alzheimer’s dis... more Background: Posterior cortical atrophy (PCA) may represent a discrete syndrome of Alzheimer’s disease (AD) rather than amnestic AD with visual deficits. Methods: We separated 30 patients with PCA based on ventral and dorsal visual symptoms using cluster analysis and analyzed the demographic, cognitive, and functional imaging features. Results: This analysis revealed subgroups of 26 dorsal and 4 ventral patients. The ventral subgroup had greater confrontational naming impairment, and the dorsal subgroup had greater hypofunction in the parietal regions. The PCA cohort had memory retrieval rather than encoding deficits, and clinical follow-up showed relative isolation of dorsal and ventral visual manifestations. Conclusion: These results support 2, mostly nonoverlapping syndromes in patients with PCA, with the commonest affecting the dorsal visual pathway; moreover, the memory retrieval difficulty in the patients with PCA was dissimilar to the amnestic pattern in typical AD. These resu...
Alzheimer disease and associated disorders, Jan 18, 2016
Recent clinical trials in mild Alzheimer disease (AD) have enriched for amyloid-specific positron... more Recent clinical trials in mild Alzheimer disease (AD) have enriched for amyloid-specific positron emission tomography (PET) imaging and used extended versions of the AD Assessment Scale-Cognitive Subscale (ADAS-Cog) in an effort to increase the sensitivity to detect treatment effects. We used data from mild AD participants in the AD Neuroimaging Initiative to model trial effect sizes for 12- and 24-month trials using 3 versions of the ADAS-Cog and increased standardized uptake value ratio (SUVR) cutoffs for amyloid imaging inclusion criteria. For 12-month trials, extended ADAS-Cog versions improved effect sizes. The ADAS-Cog11 elicited larger effect sizes when enriching for SUVR 1.1 only, whereas the ADAS-Cog12 and ADAS-Cog13 were associated with larger effect sizes with higher SUVR thresholds. For 24-month trials, extended ADAS-Cog versions increased effect sizes for trials not enriched for amyloid and trials enriched for SUVR 1.1. Only enriching for higher SUVR thresholds (1.3 and...
![Research paper thumbnail of Baseline [18F]GTP1 tau PET imaging is associated with subsequent cognitive decline in Alzheimer’s disease](https://attachments.academia-assets.com/79752772/thumbnails/1.jpg)
](Alzheimer's Research & Therapy
Background The role and implementation of tau PET imaging for predicting subsequent cognitive dec... more Background The role and implementation of tau PET imaging for predicting subsequent cognitive decline in Alzheimer’s disease (AD) remains uncertain. This study was designed to evaluate the relationship between baseline [18F]GTP1 tau PET and subsequent longitudinal change across multiple cognitive measures over 18 months. Methods Our analyses incorporated data from 67 participants, including cognitively normal controls (n = 10) and β-amyloid (Aβ)-positive individuals ([18F] florbetapir Aβ PET) with prodromal (n = 26), mild (n = 16), or moderate (n = 15) AD. Baseline measurements included cortical volume (MRI), tau burden ([18F]GTP1 tau PET), and cognitive assessments [Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), 13-item version of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)]. Cognitive assessments were repeated at 6-month intervals over an 18-month per...
Dr. Finucane dismisses the utility of etiological diagnoses for dementia, claiming: “most dementi... more Dr. Finucane dismisses the utility of etiological diagnoses for dementia, claiming: “most dementia syndromes have no known cause, no clear diagnostic definition, and no good treatment.” Not only do we fundamentally disagree with these assertions, but we also observe that his own commentary provides compelling reasons to pursue more accurate etiological diagnoses in dementia, including those supported by biomarker evidence. His primary argument is that this diagnostic enterprise is not worth pursuing because different etiologies of dementia may have overlapping symptoms and are difficult to distinguish clinically. However, difficulty in precise clinical diagnosis does not justify imprecise diagnosis. Moreover, judicious application of biomarker data can assist in distinguishing clinically ambiguous dementias. Although we agree that biomarker assessments in every person with dementia would be expensive and ineffective, the wholesale rejection of such technologies as “gizmo idolatry” i...
The rat amyloid-beta (Abeta) intracerebroventricular infusion can model aspects of Alzheimer'... more The rat amyloid-beta (Abeta) intracerebroventricular infusion can model aspects of Alzheimer's disease (AD) and has predicted efficacy of therapies such as ibuprofen and curcumin in transgenic mouse models. High density lipoprotein (HDL), a normal plasma carrier of Abeta, is used to attenuate Abeta aggregation within the pump, causing Abeta-dependent toxicity and cognitive deficits within 3 months. Our goal was to identify factors that might accelerate onset of Abeta-dependent deficits to improve efficiency and cost-effectiveness of model. We focused on: 1) optimizing HDL-Abeta preparation for maximal toxicity; 2) evaluating the role of copper, a factor typically in water that can impact oligomer stability; and 3) determining impact of insulin resistance (type II diabetes), a risk factor for AD. In vitro studies were performed to determine doses of copper and methods of Abeta-HDL preparation that maximized toxicity. These preparations when infused resulted in earlier onset of co...
Single moderate-to-severe traumatic brain injuries (TBIs) may increase subsequent risk for neurod... more Single moderate-to-severe traumatic brain injuries (TBIs) may increase subsequent risk for neurodegenerative disease by facilitating β-amyloid (Aβ) deposition. However, the chronic effects on Aβ pathogenesis of repetitive mild TBIs (rTBI), which are common in adolescents and young adults, remain uncertain. We examined the effects of rTBI sustained during adolescence on subsequent deposition of Aβ pathology in a transgenic APP/PS1 rat model. Transgenic rats received sham or four individual mild TBIs (rTBIs) separated by either 24- or 72-h intervals at post-natal day 35 (before Aβ plaque deposition). Animals were euthanized at 12 months of age and underwent immunohistochemical analyses of Aβ plaque deposition. Significantly greater hippocampal Aβ plaque deposition was observed after rTBI separated by 24 h relative to rTBI separated by 72 h or sham injuries. These increases in hippocampal Aβ plaque load were driven by increases in both plaque number and size. Similar, though less-prono...
Brain‐derived neurotrophic factor (BDNF) plays an important role in Alzheimer's disease (AD) ... more Brain‐derived neurotrophic factor (BDNF) plays an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. BDNF function is adversely affected by amyloid beta in AD. BDNF levels in brain and peripheral tissues are lower in patients with AD and mild cognitive impairment (MCI) than in controls. Here we examined the association between plasma levels of BDNF and amyloid deposition in the brain measured with Pittsburgh Compound B (PiB).
OBJECTIVE: To examine the frequency and severity of extrapyramidal symptoms (EPS) for subtypes of... more OBJECTIVE: To examine the frequency and severity of extrapyramidal symptoms (EPS) for subtypes of primary progressive aphasia (PPA) in a large multi-center cohort. BACKGROUND: Previous studies reported higher frequencies of EPS in non-fluent PPA relative to semantic or logopenic PPA. However, interpretation of these reports has been limited by their reliance on retrospective clinical data and/or small sample sizes. DESIGN/METHODS: We analyzed the prevalence and severity of EPS in a cohort of 362 PPA subjects enrolled in the National Alzheimer9s Coordinating Center (NACC) Uniform Data Set (UDS) between 2005-2010. Subjects were diagnosed with progressive non-fluent aphasia (PNFA; n=148), semantic dementia (SD; n=118), or other PPA (PPA-other; n=96) per NACC UDS criteria. EPS were assessed with the Unified Parkinson9s Disease Rating Scale (UPDRS). Subgroup comparisons were performed using total UPDRS and mean UPDRS item scores as well as two UPDRS-derived factor analyses (Louis et al.,...
Background: Previous cross-sectional studies suggest that assessments of instrumental activities ... more Background: Previous cross-sectional studies suggest that assessments of instrumental activities of daily living (IADLs) may be useful for operationalizing the differences in functional deficits seen in mild cognitive impairment (MCI) and dementia. However, their utility for longitudinal changes in IADLs in the transition between MCI and dementia remains unclear. Methods: We analyzed longitudinal IADL data with the Functional Activities Questionnaire (FAQ) in stable (MCI-S; n = 1,318) or progressive (MCI-P; n = 1,108) MCI patients. Results: Larger increases in FAQ scores were seen in the MCI-P group across a 14.5-month interval, but overlapping distributions in the two groups yielded poorer discriminatory power than prior cross-sectional reports. Conclusion: Our findings emphasize the difficulties in operationalizing the criterion of ‘essentially intact' IADLs in MCI, which may complicate the interpretation of disease progression in MCI treatment trials. © 2014 S. Karger AG, Basel
Journal of Alzheimer's Disease
Background: Understanding patterns of association between CSF phosphorylated tau (p-tau) species ... more Background: Understanding patterns of association between CSF phosphorylated tau (p-tau) species and clinical disease severity will aid Alzheimer’s disease (AD) diagnosis and treatment. Objective: To evaluate changes in tau phosphorylation ratios to brain imaging (amyloid PET, [18F]GTP1 PET, and MRI) and cognition across clinical stages of AD in two different cohorts. Methods: A mass spectrometry (MS)-based method was used to evaluate the relationship between p-tau/tau phosphorylation ratios on 11 sites in CSF and AD pathology measured by tau PET ([18F]GTP1) and amyloid PET ([18F]florbetapir or [18F]florbetaben). Cohort A included cognitively normal-amyloid negative (n = 6) and positive (n = 5) individuals, and amyloid positive prodromal (n = 13), mild (n = 12), and moderate AD patients (n = 10); and Cohort B included amyloid positive prodromal (n = 24) and mild (n = 40) AD patients. Results: In this cross-sectional analysis, we identified clusters of phosphosites with different pro...
Translational Stroke Research
Behavioral Sleep Medicine
ABSTRACT Objective/Background: Sleep problems are common in women and caregiving for an adult is ... more ABSTRACT Objective/Background: Sleep problems are common in women and caregiving for an adult is a common role among women. However, the effects of caregiving on sleep and related daytime impairment are poorly understood among women veterans. This study compared stress-related sleep disturbances, insomnia symptoms, and sleep-related daytime impairment between women veterans who were caregivers and those who did not have a caregiving role. Participants: Of 12,225 women veterans who received care in one Veterans Administration Healthcare System, 1,457 completed data on a postal survey (mean age = 51.7 ± 15.9 years). Two hundred forty three (17%) respondents (mean age 53.8 ± 12.7 years) were caregivers for an adult, predominantly for a parent, providing transportation. Methods: The survey included items that addressed insomnia symptoms, total sleep time, sleep-related daytime impairments, caregiving characteristics, self-rated health, pain, stress, body mass index, and demographic information. Results: In adjusted analyses, caregiver status did not directly predict sleep complaints alone. However, in multiple regression analyses, being a caregiver (odds ratio 1.7, p = .001) significantly predicted stress-related sleep disturbance, even after adjusting for age, pain, self-rated health, and other characteristics. Furthermore, being a caregiver (β = 3.9, p = .031) significantly predicted more symptoms of sleep-related daytime impairment after adjusting for age, pain, self-rated health, and other factors. Conclusions: Compared to noncaregivers, women veterans who were caregivers for an adult were more likely to report stress causing poor sleep, and more daytime impairment due to poor sleep. These findings suggest the need to target stress and other factors when addressing sleep disturbance among women veterans who are caregivers.
JAMA Neurology
IMPORTANCE Neurofibrillary tangles composed of aggregated tau protein are one of the neuropatholo... more IMPORTANCE Neurofibrillary tangles composed of aggregated tau protein are one of the neuropathological hallmarks of Alzheimer disease (AD) and correlate with clinical disease severity. Monoclonal antibodies targeting tau may have the potential to ameliorate AD progression by slowing or stopping the spread and/or accumulation of pathological tau. OBJECTIVE To evaluate the safety and efficacy of the monoclonal anti-tau antibody semorinemab in prodromal to mild AD. DESIGN, SETTING, AND PARTICIPANTS This phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted between October 18, 2017, and July 16, 2020, at 97 sites in North America, Europe, and Australia. Individuals aged 50 to 80 years (inclusive) with prodromal to mild AD, Mini-Mental State Examination scores between 20 and 30 (inclusive), and confirmed β-amyloid pathology (by positron emission tomography or cerebrospinal fluid) were included. INTERVENTIONS During the 73-week blinded study period, participants received intravenous infusions of placebo or semorinemab (1500 mg, 4500 mg, or 8100 mg) every 2 weeks for the first 3 infusions and every 4 weeks thereafter. MAIN OUTCOMES AND MEASURES The primary outcomes were change from baseline on the Clinical Dementia Rating-Sum of Boxes score from baseline to week 73 and assessments of the safety and tolerability for semorinemab compared with placebo. RESULTS In the modified intent-to-treat cohort (n = 422; mean [SD] age, 69.6 [7.0] years; 235 women [55.7%]), similar increases were seen on the Clinical Dementia Rating-Sum of Boxes score in the placebo (n = 126; Δ = 2.19 [95% CI, 1.74-2.63]) and semorinemab (1500 mg: n = 86; Δ = 2.36 [95% CI, 1.83-2.89]; 4500 mg: n = 126; Δ = 2.36 [95% CI, 1.92-2.79]; 8100 mg: n = 84; Δ = 2.41 [95% CI, 1.88-2.94]) arms. In the safety-evaluable cohort (n = 441), similar proportions of participants experienced adverse events in the placebo (130 [93.1%]) and semorinemab (1500 mg: 89 [88.8%]; 4500 mg: 132 [94.7%]; 8100 mg: 90 [92.2%]) arms. CONCLUSIONS AND RELEVANCE In participants with prodromal to mild AD in this randomized clinical trial, semorinemab did not slow clinical AD progression compared with placebo throughout the 73-week study period but did demonstrate an acceptable and well-tolerated safety profile. Additional studies of anti-tau antibodies may be needed to determine the clinical utility of this therapeutic approach.
Marjorie Seybold, and Arnold Starr for their assistance in gathering historical material. Disclos... more Marjorie Seybold, and Arnold Starr for their assistance in gathering historical material. Disclosures: Drs. Teng and Mishra have nothing to disclose.
Neurology, 2013
OBJECTIVE: To determine the prevalence of hippocampal sclerosis (HS) and medial temporal lobe scl... more OBJECTIVE: To determine the prevalence of hippocampal sclerosis (HS) and medial temporal lobe sclerosis (MTS) and their relationship to tau neuropathology in a large, multi-center cohort of clinically diagnosed behavioral variant frontotemporal dementia (bvFTD) cases. BACKGROUND: Both HS and MTS are characterized by selective neuronal loss and astrocytic gliosis of the hippocampus and/or neighboring cortex and are associated with memory impairment. HS/MTS frequently coexist with dementia, and previous single-center neuropathological studies have demonstrated an association between HS/MTS and bvFTD, particularly in tau-negative cases with TDP-43 proteinopathies. DESIGN/METHODS: We identified patients with a clinical diagnosis of bvFTD (n=107) who were included in both the Neuropathology and Uniform Datasets maintained by the National Alzheimer9s Coordinating Committee (NACC). We excluded 12 patients with ambiguous pathologies and 21 patients with predominant Alzheimer9s disease patho...
Alzheimer's & Dementia, 2020
Background: In prior cross-sectional studies using [ 18 F]GTP1 or other tau PET tracers across a ... more Background: In prior cross-sectional studies using [ 18 F]GTP1 or other tau PET tracers across a spectrum of Alzheimer's disease (AD) severity, tau PET signal has independently correlated with cognition, even after adjustments for β-amyloid (Aβ) load and atrophy. However, it remains uncertain how robust these correlations are in more homogeneous patient populations (e.g., clinical trial participants) and after adjustment for MRI white-matter hyperintensities (WMH). We sought to address this question by examining baseline data from the Phase 2 Tauriel study (NCT03289143), which is investigating the safety and efficacy of semorinemab (an anti-tau antibody) in prodromal-to-mild AD. Method: We analyzed data from a subset of Tauriel participants who underwent baseline [ 18 F]GTP1 tau PET imaging and met criteria for probable AD dementia (n=244) or mild cognitive impairment (MCI; n=137), with MMSE of 20-30, global Clinical Dementia Rating (CDR) of 0.5 or 1, significant Aβ pathology (PET or CSF), and significant episodic memory impairment on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Other screening/baseline assessments included the 13-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) and MRI (WMH scored with Fazekas scale). Relationships between cognitive indices, whole cortical gray (WCG) [ 18 F]GTP1 SUVR, WMH, and age were assessed using Pearson correlations and multiple linear regression. Result: Univariate analyses revealed significant correlations between all cognitive indices [MMSE, CDR Sum of Boxes, ADAS-Cog13, and RBANS] and [ 18 F]GTP1 SUVR across the whole cortical gray (WCG; p's<0.001). Significant univariate correlations were also seen between WMH and ADAS-Cog13 scores (p=0.035) and between age and RBANS scores (p<0.001). Multivariate linear regression analyses that included all three factors consistently identified both WCG [ 18 F]GTP1 SUVR and WMH as inde
Alzheimer's & Dementia, 2016
Clinical Diagnosis and Management of Alzheimer's Disease, 2006
Neurology, 2016
Objective: To determine the effect of extended Alzheimer9s Disease Assessment Scale-Cognitive Sub... more Objective: To determine the effect of extended Alzheimer9s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and amyloid imaging standardized uptake value ratio (SUVR) thresholds on clinical trial effect size. Background: Recent clinical trials of anti-beta amyloid interventions have used extended versions of the ADAS-Cog as outcome measures and positive positron emission tomography (PET) imaging with a ligand specific for beta amyloid as inclusion criteria, in part, in an effort to increase the sensitivity to detect treatment effects in mild AD. The implications on trial statistical power, however, remain uncertain. Methods: We used data from mild AD participants (Mini-Mental Status Exam 20-26) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to model trial effect sizes (Δμ/σ) for 12- and 24-month trials using the ADAS-Cog11, 12 and 13 as the primary outcome. The ADAS-Cog11 incorporates tests of memory and language in addition to other cognitive abilities. ADAS-Cog12 ...
NEJM Journal Watch, 2008
Results of research in cellular and animal models of Alzheimer disease (AD) suggest that statins ... more Results of research in cellular and animal models of Alzheimer disease (AD) suggest that statins can reduce the production of neurotoxic amyloid-beta peptides by reducing cholesterol levels and, thus, might help prevent or delay AD-related cognitive impairment or dementia. Statins also exhibit anti-inflammatory, antioxidant, and antithrombotic properties, which may help minimize cognitive decline caused by vascular brain injury. Retrospective studies in humans …
American Journal of Alzheimer's Disease & Other Dementiasr, 2011
Background: Posterior cortical atrophy (PCA) may represent a discrete syndrome of Alzheimer’s dis... more Background: Posterior cortical atrophy (PCA) may represent a discrete syndrome of Alzheimer’s disease (AD) rather than amnestic AD with visual deficits. Methods: We separated 30 patients with PCA based on ventral and dorsal visual symptoms using cluster analysis and analyzed the demographic, cognitive, and functional imaging features. Results: This analysis revealed subgroups of 26 dorsal and 4 ventral patients. The ventral subgroup had greater confrontational naming impairment, and the dorsal subgroup had greater hypofunction in the parietal regions. The PCA cohort had memory retrieval rather than encoding deficits, and clinical follow-up showed relative isolation of dorsal and ventral visual manifestations. Conclusion: These results support 2, mostly nonoverlapping syndromes in patients with PCA, with the commonest affecting the dorsal visual pathway; moreover, the memory retrieval difficulty in the patients with PCA was dissimilar to the amnestic pattern in typical AD. These resu...
Alzheimer disease and associated disorders, Jan 18, 2016
Recent clinical trials in mild Alzheimer disease (AD) have enriched for amyloid-specific positron... more Recent clinical trials in mild Alzheimer disease (AD) have enriched for amyloid-specific positron emission tomography (PET) imaging and used extended versions of the AD Assessment Scale-Cognitive Subscale (ADAS-Cog) in an effort to increase the sensitivity to detect treatment effects. We used data from mild AD participants in the AD Neuroimaging Initiative to model trial effect sizes for 12- and 24-month trials using 3 versions of the ADAS-Cog and increased standardized uptake value ratio (SUVR) cutoffs for amyloid imaging inclusion criteria. For 12-month trials, extended ADAS-Cog versions improved effect sizes. The ADAS-Cog11 elicited larger effect sizes when enriching for SUVR 1.1 only, whereas the ADAS-Cog12 and ADAS-Cog13 were associated with larger effect sizes with higher SUVR thresholds. For 24-month trials, extended ADAS-Cog versions increased effect sizes for trials not enriched for amyloid and trials enriched for SUVR 1.1. Only enriching for higher SUVR thresholds (1.3 and...
Alzheimer's Research & Therapy
Background The role and implementation of tau PET imaging for predicting subsequent cognitive dec... more Background The role and implementation of tau PET imaging for predicting subsequent cognitive decline in Alzheimer’s disease (AD) remains uncertain. This study was designed to evaluate the relationship between baseline [18F]GTP1 tau PET and subsequent longitudinal change across multiple cognitive measures over 18 months. Methods Our analyses incorporated data from 67 participants, including cognitively normal controls (n = 10) and β-amyloid (Aβ)-positive individuals ([18F] florbetapir Aβ PET) with prodromal (n = 26), mild (n = 16), or moderate (n = 15) AD. Baseline measurements included cortical volume (MRI), tau burden ([18F]GTP1 tau PET), and cognitive assessments [Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), 13-item version of the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)]. Cognitive assessments were repeated at 6-month intervals over an 18-month per...
Dr. Finucane dismisses the utility of etiological diagnoses for dementia, claiming: “most dementi... more Dr. Finucane dismisses the utility of etiological diagnoses for dementia, claiming: “most dementia syndromes have no known cause, no clear diagnostic definition, and no good treatment.” Not only do we fundamentally disagree with these assertions, but we also observe that his own commentary provides compelling reasons to pursue more accurate etiological diagnoses in dementia, including those supported by biomarker evidence. His primary argument is that this diagnostic enterprise is not worth pursuing because different etiologies of dementia may have overlapping symptoms and are difficult to distinguish clinically. However, difficulty in precise clinical diagnosis does not justify imprecise diagnosis. Moreover, judicious application of biomarker data can assist in distinguishing clinically ambiguous dementias. Although we agree that biomarker assessments in every person with dementia would be expensive and ineffective, the wholesale rejection of such technologies as “gizmo idolatry” i...
The rat amyloid-beta (Abeta) intracerebroventricular infusion can model aspects of Alzheimer'... more The rat amyloid-beta (Abeta) intracerebroventricular infusion can model aspects of Alzheimer's disease (AD) and has predicted efficacy of therapies such as ibuprofen and curcumin in transgenic mouse models. High density lipoprotein (HDL), a normal plasma carrier of Abeta, is used to attenuate Abeta aggregation within the pump, causing Abeta-dependent toxicity and cognitive deficits within 3 months. Our goal was to identify factors that might accelerate onset of Abeta-dependent deficits to improve efficiency and cost-effectiveness of model. We focused on: 1) optimizing HDL-Abeta preparation for maximal toxicity; 2) evaluating the role of copper, a factor typically in water that can impact oligomer stability; and 3) determining impact of insulin resistance (type II diabetes), a risk factor for AD. In vitro studies were performed to determine doses of copper and methods of Abeta-HDL preparation that maximized toxicity. These preparations when infused resulted in earlier onset of co...
Single moderate-to-severe traumatic brain injuries (TBIs) may increase subsequent risk for neurod... more Single moderate-to-severe traumatic brain injuries (TBIs) may increase subsequent risk for neurodegenerative disease by facilitating β-amyloid (Aβ) deposition. However, the chronic effects on Aβ pathogenesis of repetitive mild TBIs (rTBI), which are common in adolescents and young adults, remain uncertain. We examined the effects of rTBI sustained during adolescence on subsequent deposition of Aβ pathology in a transgenic APP/PS1 rat model. Transgenic rats received sham or four individual mild TBIs (rTBIs) separated by either 24- or 72-h intervals at post-natal day 35 (before Aβ plaque deposition). Animals were euthanized at 12 months of age and underwent immunohistochemical analyses of Aβ plaque deposition. Significantly greater hippocampal Aβ plaque deposition was observed after rTBI separated by 24 h relative to rTBI separated by 72 h or sham injuries. These increases in hippocampal Aβ plaque load were driven by increases in both plaque number and size. Similar, though less-prono...
Brain‐derived neurotrophic factor (BDNF) plays an important role in Alzheimer's disease (AD) ... more Brain‐derived neurotrophic factor (BDNF) plays an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. BDNF function is adversely affected by amyloid beta in AD. BDNF levels in brain and peripheral tissues are lower in patients with AD and mild cognitive impairment (MCI) than in controls. Here we examined the association between plasma levels of BDNF and amyloid deposition in the brain measured with Pittsburgh Compound B (PiB).
OBJECTIVE: To examine the frequency and severity of extrapyramidal symptoms (EPS) for subtypes of... more OBJECTIVE: To examine the frequency and severity of extrapyramidal symptoms (EPS) for subtypes of primary progressive aphasia (PPA) in a large multi-center cohort. BACKGROUND: Previous studies reported higher frequencies of EPS in non-fluent PPA relative to semantic or logopenic PPA. However, interpretation of these reports has been limited by their reliance on retrospective clinical data and/or small sample sizes. DESIGN/METHODS: We analyzed the prevalence and severity of EPS in a cohort of 362 PPA subjects enrolled in the National Alzheimer9s Coordinating Center (NACC) Uniform Data Set (UDS) between 2005-2010. Subjects were diagnosed with progressive non-fluent aphasia (PNFA; n=148), semantic dementia (SD; n=118), or other PPA (PPA-other; n=96) per NACC UDS criteria. EPS were assessed with the Unified Parkinson9s Disease Rating Scale (UPDRS). Subgroup comparisons were performed using total UPDRS and mean UPDRS item scores as well as two UPDRS-derived factor analyses (Louis et al.,...
Background: Previous cross-sectional studies suggest that assessments of instrumental activities ... more Background: Previous cross-sectional studies suggest that assessments of instrumental activities of daily living (IADLs) may be useful for operationalizing the differences in functional deficits seen in mild cognitive impairment (MCI) and dementia. However, their utility for longitudinal changes in IADLs in the transition between MCI and dementia remains unclear. Methods: We analyzed longitudinal IADL data with the Functional Activities Questionnaire (FAQ) in stable (MCI-S; n = 1,318) or progressive (MCI-P; n = 1,108) MCI patients. Results: Larger increases in FAQ scores were seen in the MCI-P group across a 14.5-month interval, but overlapping distributions in the two groups yielded poorer discriminatory power than prior cross-sectional reports. Conclusion: Our findings emphasize the difficulties in operationalizing the criterion of ‘essentially intact' IADLs in MCI, which may complicate the interpretation of disease progression in MCI treatment trials. © 2014 S. Karger AG, Basel
Journal of Alzheimer's Disease
Background: Understanding patterns of association between CSF phosphorylated tau (p-tau) species ... more Background: Understanding patterns of association between CSF phosphorylated tau (p-tau) species and clinical disease severity will aid Alzheimer’s disease (AD) diagnosis and treatment. Objective: To evaluate changes in tau phosphorylation ratios to brain imaging (amyloid PET, [18F]GTP1 PET, and MRI) and cognition across clinical stages of AD in two different cohorts. Methods: A mass spectrometry (MS)-based method was used to evaluate the relationship between p-tau/tau phosphorylation ratios on 11 sites in CSF and AD pathology measured by tau PET ([18F]GTP1) and amyloid PET ([18F]florbetapir or [18F]florbetaben). Cohort A included cognitively normal-amyloid negative (n = 6) and positive (n = 5) individuals, and amyloid positive prodromal (n = 13), mild (n = 12), and moderate AD patients (n = 10); and Cohort B included amyloid positive prodromal (n = 24) and mild (n = 40) AD patients. Results: In this cross-sectional analysis, we identified clusters of phosphosites with different pro...
Translational Stroke Research
Behavioral Sleep Medicine
ABSTRACT Objective/Background: Sleep problems are common in women and caregiving for an adult is ... more ABSTRACT Objective/Background: Sleep problems are common in women and caregiving for an adult is a common role among women. However, the effects of caregiving on sleep and related daytime impairment are poorly understood among women veterans. This study compared stress-related sleep disturbances, insomnia symptoms, and sleep-related daytime impairment between women veterans who were caregivers and those who did not have a caregiving role. Participants: Of 12,225 women veterans who received care in one Veterans Administration Healthcare System, 1,457 completed data on a postal survey (mean age = 51.7 ± 15.9 years). Two hundred forty three (17%) respondents (mean age 53.8 ± 12.7 years) were caregivers for an adult, predominantly for a parent, providing transportation. Methods: The survey included items that addressed insomnia symptoms, total sleep time, sleep-related daytime impairments, caregiving characteristics, self-rated health, pain, stress, body mass index, and demographic information. Results: In adjusted analyses, caregiver status did not directly predict sleep complaints alone. However, in multiple regression analyses, being a caregiver (odds ratio 1.7, p = .001) significantly predicted stress-related sleep disturbance, even after adjusting for age, pain, self-rated health, and other characteristics. Furthermore, being a caregiver (β = 3.9, p = .031) significantly predicted more symptoms of sleep-related daytime impairment after adjusting for age, pain, self-rated health, and other factors. Conclusions: Compared to noncaregivers, women veterans who were caregivers for an adult were more likely to report stress causing poor sleep, and more daytime impairment due to poor sleep. These findings suggest the need to target stress and other factors when addressing sleep disturbance among women veterans who are caregivers.