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Neurosciences I

Neurodegenerative and Neuropsychiatric Disorders

Objectives

•     Define biomarker, intermediate endpoint, and surrogate endpoint

•     Consider how to approach identification and validation of a biomarker or set of markers for complex diseases in which the pathophysiology is unknown (markers of disease state, progression, severity, diagnostic and epidemiological issues)

•     Evaluate how to identify and validate predictive treatment response biomarkers

•     Develop an understanding of:

      -     the advantages and disadvantages of including biomarkers in clinical trials

      -     the use of biomarkers to select patient subpopulations for clinical studies and clinical trials

      -     statistical and modeling issues for validating biomarkers and surrogate markers for use in clinical studies and clinical trials

 

Agenda

 

Moderators:   Linda S. Brady, Ph.D., National Institute of Mental Health

Ira Shoulson, M.D., University of Rochester

Introduction/Overview of Session Objectives

Linda S. Brady, Ph.D.

Overview of Statistical and Modeling Issues for Evaluating Biomarkers

Scott L. Zeger, Ph.D., Johns Hopkins University School of Hygiene and Public Health 

 

Session I.  Neuroimaging Markers

 

Magnetic Resonance Imaging in Multiple Sclerosis Revealing In Vivo Pathology

Donald W. Paty, M.D., Vancouver Hospital and Health Sciences Center

Novel Brain Imaging Techniques and Drug Development in Schizophrenia

Marc Laruelle, M.D., New York State Psychiatric Institute

Discussant:   Mony J. deLeon, Ed.D., New York University School of Medicine

Open Discussion 

Break

Session II.  Behavioral and Genetic Markers

Biomarkers for Cerebrovascular Diseases

Justin A. Zivin, M.D., Ph.D., University of California School of Medicine, San Diego

Cognitive Markers of Alzheimer's Disease and Schizophrenia

Richard C. Mohs, Ph.D., Mount Sinai School of Medicine

Biochemical and Neuroendocrine Markers in Psychiatric Disorders

Stanley J. Watson, Jr., M.D., Ph.D., University of Michigan School of Medicine

Linking Genetic Markers to Disease Patterns
Kathleen R. Merikangas, Ph.D., Yale University

Discussant:   Scott L. Zeger, Ph.D.

Open Discussion

Summary of Session Recommendations

 

ABSTRACTS

 

Magnetic Resonance Imaging in Multiple Sclerosis Revealing In Vivo Pathology

Donald W. Paty, M.D.

The technique of magnetic resonance imaging (MRI) has provided a window on the brain for the actual pathology of multiple sclerosis (MS) to be visualized as it evolves in the living patient.  Natural history studies of the activity of new and otherwise active lesions have shown that MRI‑detected pathological activity can be seen at a rate of 5 to 10 times the rate of clinical relapses.  Systematic MRI monitoring has now been used to supplement the clinical monitoring of clinical trials (Paty and McFarland 1998; Miller et al. 1996).  Beginning in the 1980s, it was clear that MRI could define MS lesions quite precisely in both the brain and spinal cord.  Diagnostically abnormal scans can be seen in more than 90 percent of patients with clinically definite MS (CDMS).  In spite of the advances related to MRI scanning, however, the final diagnosis of MS relies on clinical findings and clinical judgment.  The use of MRI after the age of 50 is more difficult because of the nonspecificity of white‑matter lesions at that age.  The correlation between clinical findings and MRI findings are statistically significant but without a high correlation coefficient.  This lack of specific correlation is probably due to the fact that most of the lesions are not located in eloquent tracts.  In addition, the major use of MRI is in diagnosis, precisely because MRI reveals many neurologically assymtomatic lesions.  Also, the analysis of data from groups of patients has shown that MRI techniques can measure the evolving pathology over time in both an accurate and objective way.  MRI findings correlate modestly with neurological findings.  The best correlations have been with neuropsychological function.  When natural history studies are done using frequent systematic MRI scans, new lesions can be seen to appear and old stable lesions enlarge.  In addition, most active lesions enhance with gadolinium.  The time scale of the evolution of active lesion changes is usually about 4 weeks waxing and 8 weeks waning.  Enhancement probably occurs as the first event in active lesions and lasts on average about 4 weeks (1 to 8 weeks).  Active lesions gradually reduce in size and degree of enhancement to then remain stable for an extended period.  This period of lesion stability probably reflects the stable residual chronically demyelinated plaque.  Some chronically active plaques gradually enlarge over time.  New MRI techniques such as magnetization transfer (MT) imaging (Dousset et al. 1994) and T2 relaxation (MacKay 1994) analysis may help identify the degree of demyelination that has occurred in these stable lesions.  In addition, MR spectroscopy (MRS) may also identify the elements of active demyelination by the detection of neutral fat as a degradation product of myelin.  The final irreversible damage in the MS lesion is axonal loss (Trapp et al. 1998).  Axonal integrity can be measured by MRS techniques such as the height of the N‑acetyl aspartate (NAA) peak (Arnold et al. 1992).  These new combinations of MRI investigative techniques are exciting for understanding the evolution of MS pathology.  A practical application of MRI monitoring in MS has been the adjudication of clinical trials (Paty and Li 1993).  Acute phase monitoring can be done by identifying active (new, enlarging, or enhancing) lesions.  One can then compare a placebo group with treated groups in a way similar to measuring the number of clinical relapses in both placebo and treated groups.  Repeated pretreatment scans prior to baseline can also give a reasonable idea of the untreated MRI activity rates.  Baseline activity also seems to predict on‑study activity.  Chronic phase monitoring is done by measuring the total extent of the MRI detected MS pathological involvement in the brain.  This measurement of the MRI burden of disease (BOD) or lesion load can be considered the MRI equivalent of the chronic neurological impairment measures such as the EDSS.  Over the past 10 years, several studies have shown that MRI activity and quantitative measures have predictable changes over time and are sensitive to treatment effects.  Four clinical trials with interferon beta show both a clinical effect on relapses or disability and an MRI effect on both activity measures and chronic impairment measures (IFNB Multiple Sclerosis Study Group 1995; Jacobs et al. 1996; PRISMS Study Group 1998; European Study Group 1998).  In the future, the application MR techniques to clinical trials will be enhanced by more specific measures of pathology such as MT, T2 relaxation analysis, and MRS.  It is the understanding of evolving pathology in vivo that is the most exciting aspect for MR in the future.

 

Key References

 

Arnold DL, Matthews PM, Francis GS, Antel J. Proton magnetic resonance spectroscopic imaging for metabolic characterization of demyelinating plaques. Neurol 1992;31(3):235‑241.

 

Dousset V, Brochet B, Gaillou A, Mieze S, Lafont P, Caille JM. Longitudinal magnetization transfer study of MS lesions. 10th Congress of the European Committee for Treatment and Research in Multiple Sclerosis. 1994;49.

 

European Study Group on Interferon alpha‑1b in Secondary Progressive MS. Placebo‑controlled multicentre randomised trial of interferon beta‑1b in treatment of secondary progressive multiple sclerosis. Lancet 1998;352:1491‑1497.

 

IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group: Interferon beta‑1b in the treatment of multiple sclerosis: Final outcome of the randomized controlled trial. Neurol 1995;45:1277‑1285.

 

Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Granger CV, Simon JH, Alam JJ, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munschauer FE 3rd, Priore RL, Pullicino PM, Scherokman BJ, Whitham RH, et al. Intramuscular interferon beta‑1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. Ann Neurol 1996;39:285‑294.

 

MacKay A, Whittall K, Adler J, Li D, Paty D, Graeb D. In vivo visualization of myelin water in brain by magnetic resonance. Magn Reson Med 1994;31:673‑677.

 

Miller DH, Albert PS, Barkhof F, Francis G, Frank JA, Hodgkinson S, Lublin FD, Paty DW, Reingold SC, Simon J. Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis. Ann Neurol 1996;39:6‑16.

 

Paty DW, Ebers GC. Contemporary Neurology Series: Vol. 50, Multiple Sclerosis. Philadelphia: F.A. Davis, 1997;ch.9.

 

Paty DW, Li DKB, UBC MS/MRI Study Group, and the IFNB Multiple Sclerosis Study Group. Interferon beta‑1b is effective in relapsing‑remitting multiple sclerosis. II. MRI analysis results of a multicenter randomized, double‑blind, placebo‑controlled trial. Neurol 1993;43:662‑667.

 

Paty DW, McFarland H. MR Techniques to monitor the long term evolution of MS pathology and to monitor definitive clinical trials. J Neurol Neurosurg Psychiatry, in press.

PRISMS (Prevention of Relapses and Disability by Interferon beta‑1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double‑blind placebo‑controlled study of interferon beta‑1a in relapsing/remitting multiple sclerosis. Lancet 1998;352:1498‑1504.

Trapp B, Peterson J, Ransohoff RM, Rudick R, Mork S, Lars B. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278‑85.

 

Novel Brain Imaging Techniques and Drug Development in Schizophrenia

Marc Laruelle, M.D.

Abnormalities of dopamine function in schizophrenia are suggested by the common antidopaminergic properties of antipsychotic medications.  However, direct evidence of a hyperdopaminergic state in schizophrenia has been difficult to demonstrate given the difficulty of measuring dopamine transmission in the living human brain.  Such evidence has recently emerged from new brain imaging techniques.  Three studies reported an increase in dopamine transmission following acute amphetamine challenge in patients with schizophrenia compared with matched healthy controls (Laruelle et al. 1996; Breier et al. 1997; Abi‑Dargham et al. 1998), thus demonstrating a dysregulation of dopamine in schizophrenia.  The dysregulation of dopamine function revealed by the amphetamine challenge is present at onset of illness and in patients never previously exposed to neuroleptic medications.  However, this dysregulation was observed in patients experiencing an episode of illness exacerbation but not in patients studied during a remission phase.  This finding has important consequences for the development of new treatment strategies for both the exacerbation and remission phases of schizophrenia.  To study modulation of this abnormal response by drugs such as 5HT2A antagonists or metabotropic receptor agonists might be useful as proof of concept in drug development.  In addition, the recent availability of high‑resolution positron emission tomography cameras might document the possible mesolimbic selectivity of these alterations, providing further guidance to drug development.

 

Key References

Abi‑Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck CH, Charney DS, Innis RB, Laruelle M. Increased striatal dopamine transmission in schizophrenia: Confirmation in a second cohort. Am J Psychiatry 1998;155:761‑767.

Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D. Schizophrenia is associated with elevated amphetamine‑induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 1997;94:2569‑2574.

Laruelle M, Abi‑Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB. Single photon emission computerized tomography imaging of amphetamine‑induced dopamine release in drug‑free schizophrenic subjects. Proc Natl Acad Sci U S A 1996;93:9235‑9240.

 

 

Brain Stages of Alzheimer's Disease as Determined by In Vivo Magnetic

Resonance Imaging

Mony de Leon, Ed.D.; A. Convit; M. Bobinski; S. DeSanti

We present the first evidence that structural in vivo magnetic resonance imaging (MRI) of the brain over the course of Alzheimer's disease (AD) supports a neuropathology/neuroanatomy staging model of sequential and progressive regional involvement of the entorhinal cortex (EC), hippocampus, and neocortex (Braak et al. 1993; Gomez‑Isla et al. 1996; West et al. 1994; Bobinski et al. 1995).  Currently, only reductions in the size of the hippocampus are sufficiently characterized in vivo to be considered as an early (preclinical) diagnostic marker for AD.  Hippocampal atrophy is nearly always found in patients with AD, and it is relatively uncommon in normal elderly persons (de Leon et al. 1997).  Hippocampal atrophy is associated with memory deficits in normal subjects (Golomb et al. 1994); in preclinical AD, it is anatomically specific (Convit et al. 1997) and predicts future AD (de Leon et al. 1989, 1993).  AD is marked by both hippocampal and neocortical atrophy (Convit et al. 1997).  Recent MRI data show that EC surface area measurements were superior to hippocampal volume in classifying very mild AD patients and controls (Bobinski et al. 1999).  In a 3‑year longitudinal study of normal elderly persons, the baseline EC uniquely predicted hippocampal volume reductions and was superior to hippocampal volume in predicting memory decline.  In summary, MRI data support a model where the EC is the first brain region affected in the course of AD.  Subsequent hippocampus atrophy is associated with significant memory impairments and predicts future neocortical atrophy and dementia.

 

Key References

Bobinski M, de Leon MJ, Convit A, De Santi S, Wegiel J, Tarshish CY, Saint‑Louis LA, Wisniewski HH. MRI of entorhinal cortex in mild Alzheimer's disease. Lancet 1999;353:38‑40.

Bobinski M, Wegiel J, Wisniewski HM, Tarnawski M, Reisberg B, Mlodzik B, de Leon MJ, Miller DC. Atrophy of hippocampal formation subdivisions correlates with stage and duration of Alzheimer's disease. Dementia 1995;6:205‑210.

Braak H, Braak E, Bohl J. Staging of Alzheimer‑related cortical destruction. Euro Neurol 1993;33:403‑408.

Convit A, de Leon MJ, Tarshish C, De Santi S, Tsui W, Rusinek H, George AE. Specific hippocampal volume reductions in individuals at risk for Alzheimer's disease. Neurobiol Aging 1997;18:131‑138.

de Leon MJ, George AE, Golomb J, Tarshish C, Convit A, Kluger A, De Santi S, McRae T, Ferris SH, Reisberg B, Ince C, Rusinek H, Bobinski M, Quinn B, Miller DC, Wisniewski HM. Frequency of hippocampus atrophy in normal elderly and Alzheimer's disease patients. Neurobiol Aging 1997;18:1‑11.

de Leon MJ, George AE, Stylopoulos LA, Smith G, Miller DC. Early marker for Alzheimer's disease: The atrophic hippocampus. Lancet 1989;2:672‑673.

de Leon MJ, Golomb J, George AE, Convit A, Tarshish CY, McRae T, De Santi S, Smith G, Ferris SH, Noz M, Rusinek H. The radiologic prediction of Alzheimer's disease: The atrophic hippocampal formation. Am J Neuroradiol 1993;14:897‑906.

Golomb J, Kluger A, de Leon MJ, Ferris SH, Convit A, Mittelman MS, Cohen J, Rusinek H, De Santi S, George A. Hippocampal formation size in normal human aging: A correlate of delayed secondary memory performance. Learn Mem 1994;1:45‑54.

Gomez‑Isla T, Price JL, McKeel DW Jr., Morris JC, Growdon JH, Hyman BT. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J Neurosci 1996;16:4491‑4500.

West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease. Lancet 1994;344:769‑772.

 

Biomarkers for Cerebrovascular Diseases

Justin A. Zivin, M.D., Ph.D.

The only proven acute stroke treatments act by improving blood flow to the ischemic brain region.  Numerous neuroprotective drugs are effective in animal models but have failed in clinical trials.  Many of these failures are because preclinical investigations optimize the conditions for treatment and often differ substantially from feasible patient studies.  Identification of critical treatment variables is essential, and the available clinical rating scales are rather inefficient.  Specifically, we would like to identify surrogate endpoints that can be used in phase II trials to facilitate protocol designs for phase III studies.  An important advantage of stroke investigations is that the cause of the disorder is simply a mechanical disruption of blood supply.  Therefore, it is possible to model the problem quite well in animals.  At present, no single abnormality has been identified that is responsible for irreversible ischemic nervous system damage.  Further understanding of the pathophysiology of ischemic injury is needed to develop valid biomarkers. Until then, clinical investigation will depend on empiric methods.  For this purpose, imaging methods may provide usable surrogate endpoints for identifying salvageable tissue, but no such methods have yet been proven useful.

 

Key References

Choi DW. Ischemia‑induced neuronal apoptosis. Curr Opin Neurobiol 1996;6(5):667‑672.

Fisher M. Characterizing the target of acute stroke therapy. Stroke 1997;28:866‑872.

Ginsberg MD. The validity of rodent brain‑ischemia models is self‑evident. Arch Neurol 1996;53:1065‑1067.

Powers WJ, Zivin J. Magnetic resonance imaging in acute stroke: Not ready for prime time.  Neurology 1998;50:842‑843.

Zivin JA, Choi D. Stroke therapy. Sci Am 1991;265:56‑63.

Zivin JA, Grotta JC. Animal stroke models: They are relevant to human disease. Stroke 1990;21:981‑983.

Cognitive Markers of Alzheimer's Disease and Schizophrenia

Richard C. Mohs, Ph.D.

Cognitive impairment is a defining feature of Alzheimer's disease (AD).  Proposed treatments for AD must be shown to improve cognitive function in a way that is clinically meaningful.  Nearly all current clinical trials of proposed treatments for AD use two outcome measures, a performance‑based assessment of cognitive function and a clinician's global evaluation of the patient's clinical condition.  The most widely used cognitive assessment is the Alzheimer's Disease Assessment Scale (ADAS).  Data supporting the usefulness of the ADAS as a surrogate marker include studies of its reliability, coverage of cognitive domains recognized as clinically important in AD, correlations with functional impairment, and the scale's ability to measure longitudinal cognitive decline.  Cognitive impairment is also present in many patients with schizophrenia.  Recent data indicate that cognitive impairment, more that the severity of psychosis, is the major determinant of poor functional outcome in schizophrenic patients.  Recent clinical trials in schizophrenia include assessments of cognition along with measures of the severity of positive and negative symptoms.  Data necessary for the selection and interpretation of cognitive test results in schizophrenia clinical trials are lacking or incomplete.  Data suggest that a variety of cognitive functions, particularly attention and verbal memory, are impaired in schizophrenic patients, that impairment may precede the onset of psychosis, that impairment is not closely related to the severity of psychosis, and that cognitive impairments gradually worsen throughout a patient's life.

 

Key References

Davidson M, Harvey PD, Welsh KA, Powchik P, Putnam KM, Mohs RC. Cognitive functioning in late‑life schizophrenia: A comparison of elderly schizophrenic patients and patients with Alzheimer's disease. Am J Psychiatry 1996;153:1274‑1279.

Harvey PD, Howanitz E, Parrella M, White L, Davidson M, Mohs RC, Hoblyn J, Davis KL. Symptoms, cognitive functioning, and adaptive skills in geriatric patients with lifelong schizophrenia: A comparison across treatment sites. Am J Psychiatry, 1998;155:1080‑1086.

Marin DB, Green CR, Schmeidler J, Harvey PD, Lawlor BA, Ryan T, Aryan M, Davis KL, Mohs RC. Noncognitive disturbances in Alzheimer's disease: Frequency, longitudinal course and relationship to cognitive symptoms. J Am Geriatr Soc 1997;45:1331‑1338.

Mohs RC. Assessing cognitive function in schizophrenics and patients with Alzheimer's disease. Schizophrenia Res 1995;17:115‑121.

Mohs RC. Neuropsychological assessment of patients with Alzheimer's disease. In: Psychopharmacology: The Fourth Generation of Progress. Bloom FE, Kupfer DJ (eds.) New York: Raven: 1995;1377-1388.

Rogers SL, Doody RS, Mohs RC, Friedhoff LT, Donepezil Study Group. Donepezil improves cognition and global function in Alzheimer's disease: A 15‑week, double‑blind, placebo‑controlled study. Arch Intern Med 1998;158:1021‑1031.

Biochemical and Neuroendocrine Markers in Psychiatric Disorders

Stanley J. Watson, Jr., Ph.D., M.D.

Biological markers for complex cognitive and affective behavioral states are difficult to envision.  There are relatively few biological indices of the subtleties of brain function.  Among the most actively studied are those found with sleep electroencephalograph, neuroendocrine, behavior, and genetics (neuroimaging is being presented separately). Each of these four areas has produced some information useful for tracking patient status, response or response potential, yet none is very powerful.  Each brings novel data to the question—sleep patterns, genetics of drug metabolism, basal and stress responses via responses to social stressors.  It is likely that integration of these several markers will provide the best index of treatment response.