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Publications (556)
Recently approved anti-amyloid immunotherapies for Alzheimer’s disease (AD) require evidence of amyloid-β pathology from positron emission tomography (PET) or cerebrospinal fluid (CSF) before initiating treatment. Blood-based biomarkers promise to reduce the need for PET or CSF testing; however, their interpretation at the individual level and the...
Importance
Since 2018, a movement has emerged to define Alzheimer disease (AD) as a purely biological entity based on biomarker findings. The recent revision of the Alzheimer Association (AA) criteria for AD furthers this direction. However, concerns about a purely biological definition of AD being applied clinically, the understanding of AD by soc...
Background: Varoglutamstat is a first-in-class, small molecule being investigated as a treatment for early Alzheimer’s disease (AD). It is an inhibitor of glutaminyl cyclase (QC), the enzyme that post-translationally modifies amyloid-β (Aβ) peptides into a toxic form of pyroglutamate Aβ (pGlu-Aβ) and iso-QC which post-translationally modifies cytok...
The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA, and SPARK studies, we developed and...
Background and objectives:
TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare t...
INTRODUCTION
Subjective cognitive decline (SCD) may be an early marker of Alzheimer's disease (AD) pathology. Until recently, it was impossible to measure biomarkers specific for α‐synuclein pathology; therefore, its association with subjective reports of cognitive decline is unknown.
METHODS
Alzheimer's Disease Neuroimaging Initiative participant...
There is a critical need to increase Latino participation in research on Alzheimer's disease and related disorders (ADRD). Applying principles of community-based participatory research, we convened a community advisory board (CAB) to identify barriers and recommend strategies to increase participation of older Latinos in a longitudinal observationa...
Background
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger m...
Background and objectives:
The clinical diagnosis of dementia with Lewy bodies (DLB) depends on identifying significant cognitive decline accompanied by core features of parkinsonism, visual hallucinations, cognitive fluctuations, and REM sleep behavior disorder (RBD). Hyposmia is one of the several supportive features. α-Synuclein seeding amplifi...
Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF...
Importance
Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD).
Objective
To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and ne...
Background
Diagnosing Dementia with Lewy Bodies (DLB) remains a challenge in clinical practice. The use of ¹²³I-ioflupane (DaTscan™) SPECT imaging, which detects reduced dopamine transporter (DAT) uptake—a key biomarker in DLB diagnosis—could improve diagnostic accuracy. However, DAT imaging is underutilized despite its potential, contributing to d...
Importance
Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated fo...
The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mut...
Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer’s disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoas...
Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, β, and γ duplications, have been identified. However,...
Subjective cognitive decline (SCD) is common in older adults and may be an early marker of future cognitive decline. Research suggest that SCD is more closely related to concurrent symptoms of depression than to objective cognitive performance in non-Hispanic Whites, but it is unknown whether the associations of SCD, cognition, and depression manif...
Background and Objectives: In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically
relevant. However, the longitudinal progression of AD CSF biomarkers—β-amyloid 1-42 (Aβ42), phosphorylated tau 181 (p-tau 181 ), and total tau (t-tau)—in PD is poorly understood and may be distinct from clinical AD. Moreover, it is uncl...
Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public‐health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public‐domain information...
Alzheimer’s disease (AD), due to its multifactorial nature and complex etiology, poses challenges for research, diagnosis, and treatment, and impacts millions worldwide. To address the need for minimally invasive, repeatable measures that aid in AD diagnosis and progression monitoring, studies leveraging RNAs associated with extracellular vesicles...
Background
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger m...
Subjective cognitive concerns (SCC) are often associated with Alzheimer’s disease (AD)-related cognitive declines in cognitively unimpaired (CU) individuals. However, it is unknown whether the same is true for CU individuals with Parkinson’s disease (PD). Therefore, this study examined relationships between SCC and 5-year neuropsychological traject...
Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer’s disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoas...
Introduction:
Many people with cognitive complaints or impairment never receive an accurate diagnosis of the underlying condition, potentially impacting their access to appropriate treatment. To address this unmet need, plasma biomarker tests are being developed for use in Alzheimer's disease (AD). Plasma biomarker tests span various stages of dev...
INTRODUCTION
Evidence on the onset of naming deficits in Alzheimer's disease (AD) is mixed. Some studies showed an early decline, but others did not. The present study introduces evidence from a novel naming test.
METHODS
Cognitively normal (n = 138), mild cognitive impairment (MCI; n = 21), and Alzheimer's disease (AD; n = 31) groups completed an...
Background:
Identifying a meaningful progression metric for Parkinson's disease (PD) that reflects heterogeneity remains a challenge.
Objective:
To assess the frequency and baseline predictors of progression to clinically relevant motor and non-motor PD milestones.
Methods:
Using data from the Parkinson's Progression Markers Initiative (PPMI)...
We determined the prevalence of Alzheimer's disease (AD) pathological hallmarks, amyloid-β and phosphorylated-Tau, in autopsied brains of 49 people with HIV (PWH) (ages: 50-68; mean age = 57.0) from the National NeuroAIDS Tissue Consortium and in a comparative cohort of 55 people without HIV (PWoH) from the UC San Diego Alzheimer's Disease Research...
Background: Identifying a meaningful progression metric for Parkinson's disease (PD) that reflects heterogeneity remains a challenge.
Objective: To assess the frequency and baseline predictors of progression to clinically relevant motor and non-motor PD milestones.
Methods: Using data from the Parkinson's Progression Markers Initiative (PPMI) de no...
Tau neurofibrillary tangles are a hallmark of Alzheimer’s disease neuropathological change. However, it remains largely unclear how distinctive Alzheimer’s disease tau seeds (i.e. 3R/4R) correlate with histological indicators of tau accumulation. Furthermore, AD tau co-pathology is thought to influence features and progression of other neurodegener...
Background:
Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson's disease from healthy controls. We used the well characterised, multicentre Parkinson's Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and...
Purpose
Pittsburgh Compound-B (¹¹C-PiB) and ¹⁸F-florbetapir are amyloid-β (Aβ) positron emission tomography (PET) radiotracers that have been used as endpoints in Alzheimer’s disease (AD) clinical trials to evaluate the efficacy of anti-Aβ monoclonal antibodies. However, comparing drug effects between and within trials may become complicated if dif...
Introduction:
Remote screening for cognitive impairment associated with Alzheimer's disease (AD) has grown in importance with the expected rise in prevalence of AD in an aging population and with new potential treatment options.
Methods:
The Telephone Interview for Cognitive Status (TICS) and new telephone adaptation of the Montreal Cognitive As...
Background
Recent research demonstrates that α-synuclein seed amplification assays (αSyn-SAA) accurately differentiate Parkinson’s disease (PD) patients from healthy controls (HC). We used the well-characterized, multicenter Parkinson’s Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of αSyn-SAA and to exam...
Unlabelled:
The regulatory path for drug approval is increasingly well defined. Drugs for the treatment of Alzheimer disease (AD) need to show statistically significant benefit over placebo with respect to cognitive and functional measures, with the Clinical Dementia Rating scale and Alzheimer's Disease Assessment Scale-Cognitive Subscale being am...
The pathogenesis and clinical heterogeneity of Parkinson’s disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profilin...
Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies and agreements with their corresponding CSF and neuroimaging biomarkers in the amyloid/tau/neurodegeneration [A/T/(N)] framework for Alzheimer’s disease. However, the blood-based neurodegeneration marker neurofilament light is not specific to Alzheimer’s...
Background: Genome-wide Association Studies (GWAS) have reshaped our understanding of the genetic bases of complex diseases in general and neurodegenerative diseases in particular. Despite being a common disorder, dementia with Lewy bodies (DLB), which, together with Parkinson's disease dementia (PDD), comprise the umbrella term Lewy body dementias...
We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive m...
3R/4R-tau species are found in Alzheimer disease (AD) and ∼50% of Lewy body dementias at autopsy (LBD+tau); 4R-tau accumulations are found in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Digital image analysis techniques can elucidate patterns of tau pathology more precisely than traditional methods but repeatability ac...
Background and Objective
Patients with dementia with Lewy bodies (DLB) perform worse than those with Alzheimer’s disease (AD) on tests of visual perception but the clinical utility of these tests remains unknown because studies often had clinically-diagnosed groups that may inadvertently cross-contaminate Lewy body disease (LBD) with pure AD pathol...
Objective: The present study investigated cognitive mechanisms underlying the ability to stop “autocorrect” errors elicited by unexpected words in a read-aloud task, and the utility of autocorrection for predicting Alzheimer’s disease (AD) biomarkers. Method: Cognitively normal participants (total n = 85; n = 64 with cerebrospinal fluid [CSF] bioma...
We report on the initial 17 (11 male:6 female) brain autopsies from across Europe and the United States in the Parkinson's Progression Markers Initiative (PPMI). Clinical diagnoses were Parkinson's disease (n = 15), multiple system atrophy (n = 1), and Dementia with Lewy bodies (n = 1); average age of death = 72 ± 8 yr. Cognitive assessment at last...
Introduction:
Objective and accessible markers for Alzheimer's disease (AD) and other dementias are critically needed.
Methods:
We identified NMDAR2A, a protein related to synaptic function, as a novel marker of central nervous system (CNS)-derived plasma extracellular vesicles (EVs) and developed a flow cytometry-based technology for detecting...
Studies have shown that women on the Alzheimer’s disease (AD) continuum have more pathological tau in the brain and cerebrospinal fluid (CSF), than men. Some studies have found that higher levels of tau biomarkers are more strongly associated with clinical AD, cognitive decline and neurodegeneration in women than in men. Despite major developments...
The pathogenesis and clinical heterogeneity of Parkinson’s disease have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of CSF has opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in Parkinson’s...
Currently, there is a need for diagnostic markers in Lewy body disorders (LBD). α-synuclein (αSyn) RT-QuIC has emerged as a promising assay to detect misfolded αSyn in clinically or neuropathologically established patients with various synucleinopathies. In this study, αSyn RT-QuIC was used to analyze lumbar CSF in a clinical cohort from the Swedis...
Objective:
Primary Age-Related Tauopathy (PART) refers to tau neurofibrillary tangles restricted largely to the medial temporal lobe in the absence of significant beta-amyloid plaques. PART has been associated with cognitive impairment, but contributions from concomitant Limbic Age-Related TDP-43 Encephalopathy neuropathologic change (LATE-NC) are...
Currently, there is a need for diagnostic markers in Lewy body disorders (LBD). αSyn RT-QuIC has emerged as a promising assay to detect misfolded α-synuclein in clinically or neuropathologically established patients with various synucleinopathies. In this study, αSyn RT-QuIC was used to analyze lumbar CSF in a clinical cohort from the Swedish BioFI...
Plasma biomarkers related to amyloid, tau, and neurodegeneration (ATN) show great promise for identifying these pathological features of Alzheimer’s Disease (AD) as shown by recent clinical studies and selected autopsy studies. We have evaluated ATN plasma biomarkers in a series of 312 well-characterized longitudinally followed research subjects wi...
Pathogenesis and clinical heterogeneity in Parkinson’s disease (PD) have been evaluated from genetic, pathological, and clinical perspective. Technology allowing for high-throughput proteomic analyses in cerebrospinal fluid (CSF) has opened new opportunities to scrutinize this heterogeneity. This is to date the most comprehensive proteomics profili...
This study investigates the diagnostic and prognostic potential of different forms of tau in
biofluids from patients with Creutzfeldt-Jakob disease (CJD). Extracellular tau, which is molecularly
heterogeneous, was measured using ultra-sensitive custom-made Simoa assays for N-terminal (NT1),
mid-region, and full-length tau. We assessed cross-section...
Multiple system atrophy (MSA) is a sporadic neurodegenerative disease clinically marked by autonomic failure and variable degrees of parkinsonism and cerebellar ataxias. The average age of onset is in the sixth decade of life with a five-year survival, although fulminant and more benign courses have been described (1). The pathologic hallmark of MS...
Background and Objective
Patients with earlier age at onset of sporadic Alzheimer’s Disease (AD) are more likely than those with later onset to present with atypical clinical and cognitive features. We sought to determine if this age-related clinical and cognitive heterogeneity is mediated by different topographical distributions of tau-aggregate n...
Aim
Several pathophysiological processes are involved in Parkinson’s disease (PD) and could inform in vivo biomarkers. We assessed an established biomarker panel, validated in Alzheimer’s Disease, in a PD cohort.
Methods
Longitudinal cerebrospinal fluid (CSF) samples from PPMI (252 PD, 115 healthy controls, HC) were analyzed at six timepoints (bas...
Background
Arterial stiffening has emerged as an important risk factor for Alzheimer’s disease (AD) and related dementias. Carotid-femoral pulse wave velocity has been proposed as a non-invasive and reproducible method to assess arterial stiffness. However, the association of pulse wave velocity with performance across multiple cognitive domains as...
Background:
Cerebrospinal fluid (CSF) levels of monoamine metabolites may represent biomarkers of Parkinson's disease (PD).
Objective:
The aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis.
Methods:
Absolute levels of multiple monoamine metabolites...
In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitivel...
Objective
To characterize age-related clinical heterogeneity in Alzheimer’s disease (AD) and determine if it is modified by APOE genotype or concomitant non-AD pathology, we analyzed data from 1750 patients with sporadic, pathologically-confirmed severe AD.
Methods
In this retrospective cohort study, regression and mixed effects models assessed ef...
A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with γ-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer’s disease (EOFAD). Unlike GSIs, GSMs do not inhibit γ-secretase activity but rather allosterically modulate γ-secretase, reducing the net p...
The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identifi...
Noncoding RNAs have diagnostic and prognostic importance in Parkinson’s disease (PD). We studied circulating small noncoding RNAs (sncRNAs) in two large-scale longitudinal PD cohorts (Parkinson’s Progression Markers Initiative (PPMI) and Luxembourg Parkinson’s Study (NCER-PD)) and modeled their impact on the transcriptome. Sequencing of sncRNAs in...