William Z Potter

• National Institute of Mental Health, National Institutes of Health

Importance Understanding the characteristics of discordance between plasma biomarkers and positron emission tomography (PET) results in Alzheimer disease (AD) is crucial for accurate interpretation of the findings. Objective To compare (1) medical comorbidities affecting plasma biomarker concentrations, (2) imaging and clinical features, and (3) c...

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear. Cross-sectional and longitudinal resting-state fu...

Background Blood tests that accurately determine the presence of amyloid pathology are critically needed. Compared to amyloid PET and CSF tests, blood tests are less expensive, less invasive, more accessible, and highly scalable. The Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium evaluated the accuracies of leading AD...

Plasma biomarkers for Alzheimer's disease (AD) are increasingly being used to assist in making an etiological diagnosis for cognitively impaired (CI) individuals or to identify cognitively unimpaired (CU) individuals with AD pathology who may be eligible for prevention trials. However, a better understanding of the timing of plasma biomarker change...

INTRODUCTION Blood tests have the potential to improve the accuracy of Alzheimer's disease (AD) clinical diagnosis, which will enable greater access to AD‐specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD‐related outcomes. METHODS Plasma samples from the Alzheimer's Disease Neuroimaging Init...

Importance The lack of an in vivo measure for α-synuclein (α-syn) pathology until recently has limited thorough characterization of its brain atrophy pattern, especially during early disease stages. Objective To assess the association of state-of-the-art cerebrospinal fluid (CSF) seed amplification assays (SAA) α-syn positivity (SAA α-syn+) with m...

Introduction: Blood tests have the potential to improve the accuracy of Alzheimer disease (AD) clinical diagnosis, which will enable greater access to AD-specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD-related outcomes. Methods: Plasma samples from the Alzheimers Disease Neuroimaging Initia...

We introduce a novel framework for the classification of functional data supported on nonlinear, and possibly random, manifold domains. The motivating application is the identification of subjects with Alzheimer’s disease from their cortical surface geometry and associated cortical thickness map. The proposed model is based upon a reformulation of...

Background Functional connectivity (FC) biomarkers play a crucial role in the early diagnosis and mechanistic study of Alzheimer’s disease (AD). However, the identification of effective FC biomarkers remains challenging. In this study, we introduce a novel approach, the spatiotemporal graph convolutional network (ST-GCN) combined with the gradient-...

Various plasma biomarkers for amyloid-β (Aβ) have shown high predictability of amyloid PET positivity. However, the characteristics of discordance between amyloid PET and plasma Aβ42/40 positivity are poorly understood. Thorough interpretation of discordant cases is vital as Aβ plasma biomarker is imminent to integrate into clinical guidelines. We...

Background A previous comparative analysis of plasma Aβ42/40 immunoassays and mass spectrometry‐based assays conducted in 2021 found that several assays had strong performance in predicting amyloid PET status (Zicha et al., 2022). In the spirit of enabling the National Institute on Aging and the Alzheimer’s Association framework for classifying Alz...

Background Deep learning has shown potential in various scientific domains but faces challenges when applied to complex, high-dimensional multi-omics data. Alzheimer's Disease (AD) is a neurodegenerative disorder that lacks targeted therapeutic options. This study introduces the Circular-Sliding Window Association Test (c-SWAT) to improve the class...

Importance Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

We propose a new approach, called as functional deep neural network (FDNN), for classifying multidimensional functional data. Specifically, a deep neural network is trained based on the principal components of the training data which shall be used to predict the class label of a future data function. Unlike the popular functional discriminant analy...

Introduction: This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (Aβ) peptides in plasma and the extent to which they improve the prediction of amyloid positivity. Methods: Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding...

Purpose/background: Drug trials of the central nervous system(CNS) have been plagued with uninformative failures, often because of the difficulties of knowing definitively whether dosing achieved was sufficient to modulate the intended CNS target at adequate concentrations to produce pharmacodynamic or dose-related changes in readouts of brain fun...

Background The National Institute on Aging and the Alzheimer’s Association framework for classifying Alzheimer’s disease (AD) utilizes measures of pathology for amyloid, tau, and neurodegeneration (ATN), that can identify participants for clinical trials. Currently, amyloid pathology is determined by costly PET or invasive CSF measurements. When ap...

A biological research framework to define Alzheimer’ disease with dichotomized biomarker measurement was proposed by National Institute on Aging–Alzheimer’s Association (NIA–AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic...

Alzheimer’s disease (AD) is a complex and heterogeneous disease that can be affected by various genetic factors. Although the cause of AD is not yet known and there is no treatment to cure this disease, its progression can be delayed. AD has recently been recognized as a brain-specific type of diabetes called type 3 diabetes. Several studies have s...

Neuroinflammation is associated with Alzheimer’s disease, but the application of cerebrospinal fluid measures of inflammatory proteins may be limited by overlapping pathways and relationships between them. In this work, we measure 15 cerebrospinal proteins related to microglial and T-cell functions, and show them to reproducibly form functionally-r...

Introduction: Biomarkers that reflect pathologic processes affecting neuronal function during preclinical and early stages of Alzheimer's disease (AD) are needed to aid drug development. Methods: A targeted, stable isotope, quantitative mass spectrometry-based investigation of longitudinal changes in concentrations of previously identified candi...

Background Many biomarkers have been identified which are relevant to studies of Alzheimer’s disease (AD), especially pertaining to the evolution of amyloid plaque, tau tangle pathology and loss of brain tissue. There remains, however, the need for additional biomarkers that reflect pathologic processes affecting neuronal function during pre‐clinic...

In 2012, the US National Institute of Mental Health launched three clinical trial contracts under a new FAST initiative. The overall goal for these contracts (Fast-Fail Trials) was to focus early-stage trials, testing novel pharmacologic agents that target the central nervous system, on pharmacologic-based designs to objectively identify doses that...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined i...

We tested two metabotropic glutamate receptor 2/3 (mGluR2/3) agonist prodrugs: pomaglumetad (POMA) and TS-134 including a high-dose of POMA that was four times the dose tested in the failed phase schizophrenia III trials in two proof of mechanism, Phase Ib studies using identical pharmacoBOLD target-engagement methodology. The POMA study was a doub...

Causal Structure Discovery (CSD) is the problem of identifying causal relationships from large quantities of data through computational methods. With the limited ability of traditional association-based computational methods to discover causal relationships, CSD methodologies are gaining popularity. The goal of the study was to systematically exami...

Dementia severity can be quantitatively described by the latent dementia phenotype “δ” and its various composite “homologs”. We have explored δ’s blood-based protein biomarkers in the Texas Alzheimer’s Research and Care Consortium. However, it would be convenient to replicate them in the Alzheimer’s Disease Neuroimaging Initiative. To that end, we...

Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and...

Ketamine is an uncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. It induces effects in healthy individuals that mimic symptoms associated with schizophrenia. We sought to root these experiences in altered brain function, specifically aberrant resting state functional connectivity (rsfMRI). In the present study, we acquired rs...

Objectives: Prescription stimulants are vulnerable to oral and parenteral abuse. Intravenous forms of abuse may be most detrimental due to an enhanced risk of dependence, overdose, and infectious diseases. Our objective was to discover an orally active prodrug of a stimulant that would not be easily converted to its parent when injected, thus hind...

Background: Amyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively. Methods: Amyloid depositi...

Importance Despite strong theoretical rationale and preclinical evidence, several glutamate-targeted treatments for schizophrenia have failed in recent pivotal trials, prompting questions as to target validity, compound inadequacy, or lack of target engagement. A key limitation for glutamate-based treatment development is the lack of functional tar...

Brain genetics is an active research area. The degree to which genetic variants impact variations in brain structure and function remains largely unknown. We examined the heritability of regional brain volumes (p ~ 100) captured by single-nucleotide polymorphisms (SNPs) in UK Biobank (n ~ 9000). We found that regional brain volumes are highly herit...

Mild cognitive impairment (MCI) is a precursor phase of Alzheimer’s disease (AD). As current treatments may be effective only at the early stages of AD, it is important to track MCI patients who will convert to AD. The aim of this study is to develop a high performance semi-mechanism based approach to predict the conversion from MCI to AD and impro...

Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes, and mul...

The Alzheimer's Association's Research Roundtable met in May 2014 to explore recent progress in developing biomarkers to improve understanding of disease pathogenesis and expedite drug development. Although existing biomarkers have proved extremely useful for enrichment of subjects in clinical trials, there is a clear need to develop novel biomarke...

Given the high risk of developing drugs for neurodegenerative diseases if post-phase I decisions to go into efficacy studies were made with quantitative knowledge of an agent's action in brain, the risks should be diminished. Furthermore, if biomarkers were compelling, they could be utilized during a lengthy trial as an early measure of futility. W...

Disease modifying treatments for Alzheimer's disease (AD) constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifi-able by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remain...

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partner Scientific Board (PPSB) is comprised of representatives of private, for-profit entities (including pharmaceutical, biotechnology, diagnostics, imaging companies, and imaging contract research organizations), and nonprofit organizations that provide financial and scientific suppo...

site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays an important role in the development of Alzheimer’s disease (AD), freeing the amyloid-β (Aβ) N-terminus from the amyloid-β protein precursor (AβPP), the first step in Aβ formation. Increased BACE1 activity in AD brain or cerebrospinal fluid (CSF) has been reported. Other studies, howeve...

For decades, there has been a distinct disconnect translating a compound's effects from basic neuroscience into clinical efficacy. This disconnect has not only been in terms of generating approved compounds, but also in rejecting targets. During the drug discovery process there are key points to be adhered to that would strengthen the likelihood of...

We describe the outcome of the Biomarkers Consortium CSF Proteomics Project, a public-private partnership of government, academia, non-profit, and industry. The goal of this study was to evaluate a multiplexed mass spectrometry-based approach for the qualification of candidate Alzheimer's Disease (AD) biomarkers using CSF samples from the AD Neuroi...

Cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau have been studied as markers of Alzheimer's disease (AD). Combined Aβ42 and t-tau distinguishes AD from healthy controls with a sensitivity and specificity (sens/spec) near 89% across studies. This study examined these markers in the homogeneous OPTIMA cohort, using extensive longitudinal follow up a...

Go/No Go decisions concerning development of any single compound determine investment in increasingly costly studies from Phases I-III. Such decisions are problematic for CNS drug development where the variety of molecular targets in the brain have stimulated decades of studies without major therapeutic advances. Many costly studies do not even yie...

Several large pharmaceutical companies have selectively downsized their neuroscience research divisions, reflecting a growing view that developing drugs to treat brain diseases is more difficult and often more time-consuming and expensive than developing drugs for other therapeutic areas, and thus represents a weak area for investment. These withdr...

With increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the U...

This review provides perspectives on the utility of magnetic resonance imaging (MRI) as a neuroimaging approach in the development of novel treatments for Alzheimer's disease. These considerations were generated in a roundtable at a recent Wellcome Trust meeting that included experts from academia and industry. It was agreed that MRI, either struct...

Placebo response impacts the development of treatments for central nervous system disorders. Despite significant attention in scientific literature, the magnitude of placebo response continues to increase. The present work reviews empirical and theoretical literature on associations of trial design features, patient selection, and investigative sit...

Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology, publishing the highest quality original research and advancing our understanding of the brain and behavior.

Introduction: Precompetitive public-private partnerships (PPPs) have the potential to improve psychiatric drug discovery by addressing gaps in the research and development pipeline such as the identification and validation of new targets, models, biomarkers and disease phenotyping. PPPs are a model to strategically bring together expertise, in-kin...

Our ability to track the progression of neurological disorders like Parkinson's disease (PD) is hampered by a lack of biomarkers, rendering the neuronal changes that underlie clinical symptoms largely a mystery. In this issue of the JCI, Fanara et al. report the development of an innovative approach to biomarker development. They describe a method...

Our ability to track the progression of neurological disorders like Parkinson's disease (PD) is hampered by a lack of biomarkers, rendering the neuronal changes that underlie clinical symptoms largely a mystery. In this issue of the JCI, Fanara et al. report the development of an innovative approach to biomarker development. They describe a method...

Background A blood-based test that could be used as a screen for Alzheimer disease (AD) may enable early intervention and better access to treatment. Objective To apply a multiplex immunoassay panel to identify plasma biomarkers of AD using plasma samples from the Alzheimer's Disease Neuroimaging Initiative cohort. Design Cohort study. Setting The...

This report outlines a goal-directed scientific agenda for a national initiative to overcome the Alzheimer's disease (AD) crisis. The statement, which reflects the collective views and recommendations of leaders in AD research, is intended to aid the implementation of the National Alzheimer's Project Act (NAPA)'s National Plan to defeat AD. The pri...

Converging lines of evidence suggest that the glutamatergic system may play an increasingly important role in the development of novel therapeutics for major depressive disorder (MDD), particularly agents associated with rapid antidepressant effects. Diverse glutamatergic modulators targeting N-methyl-D-aspartate receptors have shown efficacy in MD...

Because this piece does not have an abstract, we have provided for your benefit the first 3 sentences of the full text. When the Early Clinical Drug Evaluation Unit meeting was first held over a half century ago, psychopharmacology and indeed modern-day psychiatry were in their infancy, yet there was enormous excitement surrounding the introduction...

Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology, publishing the highest quality original research and advancing our understanding of the brain and behavior.

The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders-including schizophrenia, drug abuse and addiction, autis...

Stimulation of 5-HTIA receptors appears to be the most plausible basis for the anxiolytic effects of buspirone and has been hypothesized to explain effects of SSRIs in depression and panic disorder [1]. A surprising number of relatively selective agonists have been developed since the introduction of buspirone (Mead Johnson) in 1986 for anxiety. De...

Supplementary methods. A document outlining additional diagnostic considerations.

The close correlation between abnormally low pre-mortem cerebrospinal fluid (CSF) concentrations of amyloid-β1-42 (Aβ(1-42)) and plaque burden measured by amyloid imaging as well as between pathologically increased levels of CSF tau and the extent of neurodegeneration measured by MRI has led to growing interest in using these biomarkers to predict...

Levels of cerebrospinal fluid (CSF) β-amyloid (Aβ) and Tau proteins change in Alzheimer's disease (AD). We tested if the relationships of these biomarkers with cognitive impairment are linear or non-linear. We assessed cognitive function and assayed CSF Aβ and Tau biomarkers in 95 non-demented volunteers and 97 AD patients. We then tested non-linea...

A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to in...

Supplemental Tables

Novel biomarkers are important for identifying as well as differentiating subcortical vascular dementia (SVD) and Alzheimer's disease (AD) at an early stage in the disease process. In two independent cohorts, a multiplex immunoassay was utilized to analyze 90 proteins in cerebrospinal fluid (CSF) samples from dementia patients and patients at risk...

Unipolar major depressive disorder is a common condition that has both emotional (mood and anxiety) and physical aspects (1). The physical manifestations are common features of depression present in up to 80% of depressed patients (2). These physical symptoms occur in nearly all body systems and are often the presenting features in the nonpsychiatr...

The ε4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for Alzheimer’s disease (AD), but limited work has suggested that APOE genotype may modulate disease phenotype. Carriers of the ε4 allele have been reported to have greater medial temporal lobe (MTL) pathology and poorer memory than noncarriers. Less attention has fo...

The Alzheimer's Disease Neuroimaging Initiative (ADNI) beginning in October 2004, is a 6-year research project that studies changes of cognition, function, brain structure and function, and biomarkers in elderly controls, subjects with mild cognitive impairment, and subjects with Alzheimer's disease (AD). A major goal is to determine and validate M...

Here, we review progress by the Penn Biomarker Core in the Alzheimer's Disease Neuroimaging Initiative (ADNI) toward developing a pathological cerebrospinal fluid (CSF) and plasma biomarker signature for mild Alzheimer's disease (AD) as well as a biomarker profile that predicts conversion of mild cognitive impairment (MCI) and/or normal control sub...

The Industry Scientific Advisory Board (ISAB) consists of representatives from the private companies and nonprofit foundations participating as sponsors of Alzheimer's Disease Neuroimaging Initiative (ADNI). Currently 21 companies are represented including pharmaceutical, imaging, and biotech concerns, and two foundations including the Alzheimer's...

To test the hypothesis that excess amyloid deposition is an essential step in the pathophysiology of Alzheimer's disease appropriate biomarkers are essential in selecting agents that modify amyloid formation or clearance. Cerebrospinal fluid concentrations of relevant analytes and PET measures of total brain load have been developed. These are dire...

The Pharmacogenomics Journal is dedicated to the rapid publication of original research on basic pharmacogenomics research and its clinical applications.

Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. Amyloid-beta 1 to 42 peptide (A beta(1-42)), total tau (t-tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of...

This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a...

The development of new antidepressant drugs has reached a plateau. There is an unmet need for faster, better, and safer medications, but as placebo-response rates rise, effect sizes shrink, and more studies fail or are negative, pharmaceutical companies are increasingly reluctant to invest in new drug development because of the risk of failure. In...

BACKGROUND: The development of new antidepressant drugs has reached a plateau. There is an unmet need for faster, better, and safer medications, but as placebo-response rates rise, effect sizes shrink, and more studies fail or are negative, pharmaceutical companies are increasingly reluctant to invest in new drug development because of the risk of...

Previous research has demonstrated neurophysiologic effects of antidepressants in depressed subjects. We evaluated neurophysiologic effects of venlafaxine in normal subjects. Healthy adults (n=32) received a 1-week placebo lead-in followed by 4 weeks randomized double-blind treatment with venlafaxine IR 150 mg. (n = 17) or placebo (n = 15). Brain f...

[Correction Notice: An erratum for this article was reported in Vol 69(12) of Journal of Clinical Psychiatry (see record 2009-02760-023).] Background: The development of new antidepressant drugs has reached a plateau. There is an unmet need for faster, better, and safer medications, but as placebo-response rates rise, effect sizes shrink, and mor...

There are significant unmet needs in the treatment of schizophrenia, especially for the treatment of cognitive impairment, negative syndrome, and cognitive function. Preclinical data suggest that agonists with selective affinity for acetylcholine muscarinic receptors provide a potentially new mechanism to treat schizophrenia. The authors studied xa...

A key assumption underlying the principle that power increases with sample size is that the standardized effect size is fixed over time. In therapeutic areas where it may be difficult to continually recruit from a homogeneous population, this assumption may not be valid; patients randomized toward the end of enrollment may derive from a more hetero...

A recent clinical trial in patients with Mild Cognitive Impairment (MCI) found an increased rate of possible or probable Alzheimer's disease (AD) diagnoses in patients assigned to rofecoxib compared to placebo. This unexpected finding was difficult to interpret due to methodological issues and a lack of confirmation on secondary endpoints, as well...

Recognizing specific protein changes in response to drug administration in humans has the potential for significant utility in clinical research. In spite of this, many methodological and practical questions related to assessing such changes are unanswered. We conducted a series of clinical studies to assess the feasibility of measuring changes in...