BASIC AND TRANSLATIONAL RESEARCH ON THE COGNITIVE SEQUELAE OF PARKINSON"S 
DISEASE

PA NUMBER: PAS-02-107 (This PAS has been reissued, see PA-06-105, PA-06-106, 
                       and PA-06-107)

RELEASE DATE: May 8, 2002

EXPIRATION DATE: April 30, 2005, unless reissued

National Institute of Neurological Disorders and Stroke 
 (http://www.ninds.nih.gov)
National Institute on Aging
 (http://www.nia.nih.gov)
National Institute of Mental Health            
 (http://www.nimh.nih.gov)
National Institute on Deafness and Other Communication Disorders 
 (http://www.nidcd.nih.gov)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE
Under this PA, the National Institute of Neurological Disorders and 
Stroke (NINDS), the National Institute on Aging (NIA), the National 
Institute on Deafness and Other Communication Disorders, and the 
National Institute of Mental Health (NIMH) invites research grant 
applications (R01) that address the underlying neurobiological 
mechanisms associated with the cognitive and linguistic sequelae of 
Parkinson"s disease. A major goal of this PA is to begin a process 
where basic and clinical scientists from various disciplines can 
overcome barriers to cross-disciplinary research and examine all 
aspects of cognition in the context of the diagnosis and treatment of 
Parkinson"s disease. The purpose of this initiative is to: 1) focus the 
attention of neuroscientists on the detrimental neurodegenerative 
processes that affect cognition and language in Parkinson"s disease, 2) 
promote the interaction of cognitive neuroscientists and clinical 
scientists conducting research in Parkinson"s disease patients, and 3) 
develop integrative research programs that advance our understanding of 
the substrates of cognitive function in health and in Parkinson"s 
disease. Applications that demonstrate the establishment of 
collaborative research programs with researchers at existing Centers of 
Excellence for Parkinson"s disease research are particularly encouraged.

RESEARCH OBJECTIVES

Parkinson"s disease (PD) is commonly viewed as an extrapyramidal motor 
disorder. Hence, a substantial body of research has focused on 
understanding the neural mechanisms underlying the most apparent 
symptoms (tremors, slowness, initiation of movements) and on treatment 
of these debilitating clinical manifestations. However, PD is more than 
a motor disease, it also affects thinking, reasoning, learning and 
other cognitive abilities. Consequently, Parkinson"s patients 
exhibiting motor and cognitive symptoms present unique challenges for 
the assessment and treatment of psychopathology in their disease 
process. In such patients, both quality of life and treatment outcome 
are severely compromised. The cognitive deficits seen in PD patients 
are less understood and studied than parkinsonian motor symptoms.  In 
order to address this disparity, this PA encourages research on all 
aspects of cognition in the context of the diagnosis and treatment of 
PD, the progression of the disease, and its co-morbidity with dementia 
and neuropsychiatric disorders. Although most cognition research 
involves human populations, Parkinson"s disease animal models with 
induced cognitive impairments are also considered valuable for the 
investigation of particular aspects of cognition. We recognize that 
cognitive impairments are common features of other neurodegenerative 
disorders, however the focus of this PA is on PD and on the cognitive 
sequelae of this disorder.

SCOPE

PD is associated with subtle but widespread cognitive impairments. Many 
of these deficits are reminiscent of those observed in patients with 
lesions of the prefrontal cortex, namely failure in executive function. 
Executive processes involve skills required for anticipation, planning, 
and allocation of attentional resources, as well as for the initiation 
and monitoring of goal-directed behaviors. In addition to these changes 
in executive function, PD patients may also exhibit deficits in working 
memory, semantic knowledge, various forms of learning (i.e., 
associative learning, habit learning, procedural learning), and 
visuospatial orientation. The cognitive impairments in PD patients may 
differ in either qualitative or quantitative ways from normal cognitive 
processes. Moreover, cognitive function may impact the course of the 
disease process and the time course of the disorder. 

In recent years we have seen the rapid expansion of concepts and 
methods for studying various aspects of cognition, including imaging 
technologies, psychophysiological approaches (EEG, MEG, TMS, etc.), 
cellular, anatomical and molecular neuroscience methodologies, targeted 
neurobehavioral assessment, and computational approaches.  Outlined in 
this program announcement are current needs for research on the 
cognitive aspects of PD that stem from these advances. Areas of 
research provided for illustration are seen below, they are not 
intended to be exhaustive: 

Animal Studies

o Development of relevant animal models for studying cognitive deficits 
in PD.

o Pre-clinical studies of cognitive tests and paradigms in animal 
models of PD.

o Studies of neuroprotective agents in animal models of PD with induced 
cognitive deficits. 

o In non-human primates, investigations of parameters that can 
delineate the anatomy and physiology of basal ganglia-cortical-limbic 
loops relevant to cognition.

o Investigation of the extent to which older animals may be more 
vulnerable to PD-related cognitive deficits.

o Development of transgenic animals that would model the late-life 
onset of PD as seen in humans (e.g. conditional expression of genes).

Human Clinical studies

o Studies of neuroanatomical circuits and neurochemical processes 
mediating cognitive states and cognition-based individual differences 
in PD. 

o Development of pathological markers in the basal ganglia that better 
define PD with motoric changes alone as compared to PD with motoric and 
cognitive impairments or motoric changes and depression. 

o Studies that utilize novel imaging techniques for human neuroanatomy 
to examine the neural systems damaged in PD (MRI brain morphometry, MRI 
perfusion methods, MRI diffusion tensor analysis, MRI 
cytoarchitectonic). These studies should also investigate whether this 
information can be correlated with the cognitive or language 
impairments or depression seen in PD patients.

o Studies of specific clinical populations with anatomic lesions 
potentially analogous to those in PD that could provide insights into 
the damaged circuitry of PD patients (Examples: ischemic strokes, 
traumatic brain injury and patients with basal ganglia lesions from 
hypertensive related hemorrhages). These studies would investigate 
whether the cognitive or language deficits in these populations are 
similar to the deficits seen in PD patients. 

o Studies that examine the potential correlation between neuropathology 
in PD and development of cognitive or language impairments.

o Studies that examine the correlation between the precipitating causes 
of PD, the progression of the disease and its association with 
cognitive symptoms.

o Development and validation of specific assessment tools for PD 
patients with cognitive impairments or depression.

o Studies that characterize the language comprehension and production 
abilities and deficits in PD patients.

o Studies of best outcome measures in PD patients with cognitive 
impairments and in PD co-morbid with dementia or co-morbid with 
depression.

o Investigations of the relationship between age of onset of PD and PD-
related cognitive changes.

Human Clinical Interventions

o Studies that compare the effects of anti-Parkinsonian drugs, 
antidepressant drugs, antipsychotic drugs and cholinergic drugs on the 
cognitive impairments seen in PD patients. 

o Examination of the specific consequences of deep brain stimulation 
(DBS) on the cognitive, linguistic, or mood aspects of Parkinson"s 
disease. 

o Studies that assess the impact of surgical interventions other than 
DBS, and the effect of cell transplantation, on cognition in PD 
patients. 

SUMMARY
A systematic review of the literature indicates that a complete 
characterization of the cognitive impairments, including language in PD 
should be undertaken. There is a need to evaluate the processes of 
executive function, learning, memory, attention, and sensory perception 
as well as to understand the development of dementia in these patients. 
Since the purpose of this PA is to broaden the base inquiry in 
understudied areas of PD research, the focus will be on innovation in 
the development of novel concepts, new methodologies and/or new, cross-
disciplinary collaborations. The research plan must be soundly 
developed in the context of the current knowledge/research base, with 
well-defined and clear objectives. Applicants should elaborate on 
innovative aspects of the proposed research, novel collaborations, and 
special attributes of the resources and environment. In addition, 
applicants must identify how the proposed studies could provide new 
insights or capabilities for research into neurodegenerative processes 
associated with cognitive dysfunction.

MECHANISM OF SUPPORT
This PA will use the National Institutes of Health (NIH) R01 award 
mechanism. As an applicant, you will be solely responsible for the 
planning, directing, and executing the proposed project. The total 
project period for an application submitted in response to this PA may 
not exceed five years. This PA uses just-in-time concepts.  It also 
uses the modular as well as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise 
follow the standard instructions as described in the PHS 398 grant 
application form.  Relevant applications and amended applications are 
welcome throughout the duration of this PA (3 years).

FUNDS AVAILABLE
NINDS has set aside one million dollars total costs, in addition to 
funds available for applications sent in response to this program 
announcement that score within the NINDS payline (see NINDS Funding 
Strategy http://www.ninds.nih.gov/funding/ninds_funding_strategy.htm), 
depending on the overall scientific merit of the applications and the 
availability of funds throughout the duration of this solicitation (3 
years). NIA has set aside $250,000 direct costs contingent upon the 
availability of funds, and the receipt of a sufficient number of 
meritorious applications of outstanding scientific and technical merit, 
additional grants may be awarded from regular program funds. NIDCD and 
NIMH intend to commit $ 250,000 and $500,000 total costs in FY 2003, 
respectively

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics: 
	
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs

WHERE TO SEND INQUIRIES
We encourage your inquiries concerning this PA and welcome the 
opportunity answer questions from potential applicants.  Inquiries may 
fall into two areas:  scientific/research, and financial or grants 
management issues:

Direct your questions about scientific/research issues to:

Emmeline Edwards, Ph.D.
Systems and Cognitive Neuroscience 
National Institute of Neurological Disorders and Stroke 
6001 Executive Blvd., Room 2109 
Bethesda, MD 20892-9521 
Telephone: (301) 496-9964 
FAX: (30l) 402-2060 
Email: [email protected]

Eugene Oliver, Ph.D.
Neurodegeneration 
National Institute of Neurological Disorders and Stroke 
6001 Executive Blvd., Room 2203 
Bethesda, MD 20892-9521 
Telephone: (301) 496- 5680 FAX: (30l) 480-1080 
Email: [email protected]

Judith A. Finkelstein, Ph.D.
Neuroscience and Neuropsychology of Aging 
National Institute on Aging
Gateway Building, Suite 3C307
7201 Wisconsin Avenue
Bethesda MD 20892-9205 (Express Zip 20814)
Telephone: (301) 496-9350  FAX: (301) 496-1494
Email: [email protected]

Debra Babcock, Ph.D., M.D.
Clinical Neurosciences, DNBBS 
National Institute of Mental Health 
6001 Executive Blvd., Room 7178 
Bethesda, MD 20892-9639 
Telephone: (301) 443- 1692 FAX: (30l) 402-4740 
Email: [email protected]

Judith A. Cooper, Ph.D.
Chief, Scientific Programs Branch
Division of Extramural Research
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, Room 400-C, MSC-7180
Bethesda, MD 20892-7180
Telephone: (301) 496-5061 FAX: (301) 402-6251
Email: [email protected]

Direct your questions about financial or grants management matters to:

Kim Pendleton 
Grants Management Branch 
National Institute of Neurological Disorders and Stroke 
6001 Executive Blvd., Room 3290 
Bethesda, MD 20892 
Telephone: (301) 496-9231 
FAX: (301) 402-0219 
Email: [email protected]

Ms. Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  [email protected]

Diana Trunnell 
Grants Management Branch 
National Institute of Mental Health 
6001 Executive Blvd., Room 6115 
Bethesda, MD 20892-9605 
Telephone: (301) 443-2805 
FAX: (301) 443-6885 
Email: [email protected]

Sara Stone 
Grants Management Branch
Division of Extramural Research
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, Room 400B, MSC-7180
Bethesda, MD  20892-7180
Telephone:  301-402-0909
Fax:  301-402-1758
Email:  [email protected]

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: [email protected].

APPLICATION RECEIPT DATES: Applications submitted in response to this 
program announcement will be accepted at the standard application 
deadlines, which are available at http://grants.nih.gov/grants/dates.htm.  
Application deadlines are also indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 
requesting up to $250,000 per year in direct costs must be submitted in 
a modular grant format.  The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level 
of budgetary detail.  Applicants request direct costs in $25,000 
modules.  Section C of the research grant application instructions for 
the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER 
YEAR: Applications requesting $500,000 or more in direct costs for any 
year must include a cover letter identifying the NIH staff member 
within one of NIH institutes or centers who has agreed to accept 
assignment of the application.   

Applicants requesting more than $500,000 must carry out the following 
steps:
	
1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study, 
2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award, and,  
3) Identify, in a cover letter sent with the application, the staff 
member and IC who agreed to accept assignment of the application.  
This policy applies to all investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended 
or revised version of these grant application types. Additional 
information on this policy is available in the NIH Guide for Grants and 
Contracts, October 19, 2001 at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the checklist, and five signed 
photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: Applications must be received by or mailed on 
or before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR 
will not accept any application in response to this PA that is 
essentially the same as one currently pending initial review unless the 
applicant withdraws the pending application.  The CSR will not accept 
any application that is essentially the same as one already reviewed.  
This does not preclude the submission of a substantial revision of an 
application already reviewed, but such application must include an 
Introduction addressing the previous critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review 
group convened in accordance with the standard NIH peer review 
procedures (http://www.csr.nih.gov/refrev.htm) will evaluate 
applications for scientific and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed 
to have the highest scientific merit, generally the top half of 
applications under review, will be discussed and assigned a priority 
score
o Receive a second level review by the appropriate national advisory 
council or board

REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health. 
In the written comments, reviewers will be asked to discuss the 
following aspects of the application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals:
o Significance
o Approach
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these 
criteria in assigning your application"s overall score, weighting them 
as appropriate for each application. Your application does not need to 
be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score. For example, 
you may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

(1) SIGNIFICANCE: Does your study address an important problem? If the 
aims of your application are achieved, how do they advance scientific 
knowledge? What will be the effect of these studies on the concepts or 
methods that drive this field?

(2) APPROACH: Are the conceptual framework, design, methods, and 
analyses adequately developed, well integrated, and appropriate to the 
aims of the project? Do you acknowledge potential problem areas and 
consider alternative tactics?

(3) INNOVATION: Does your project employ novel concepts, approaches or 
method? Are the aims original and innovative? Does your project 
challenge existing paradigms or develop new methodologies or 
technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to 
carry out this work? Is the work proposed appropriate to your 
experience level as the principal investigator and other researchers 
(if any)?

(5) ENVIRONMENT: Does the scientific environment in which your work 
will be done contribute to the probability of success? Do the proposed 
experiments take advantage of unique features of the scientific 
environment or employ useful collaborative arrangements? Is there 
evidence of institutional support?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:
PROTECTIONS: The adequacy of the proposed protection for humans, 
animals or the environment, to the extent they may be adversely 
affected by the project proposed in the application.
INCLUSION: The adequacy of plans to include subjects from genders, all 
racial and ethnic groups (and subgroups), and children as appropriate 
for the scientific goals of the research. Plans for the recruitment and 
retention of subjects will also be evaluated. (See Inclusion Criteria 
included in the section on Federal Citations, below) 
BUDGET: The reasonableness of the proposed budget and duration in 
relation to the proposed research

AWARD CRITERIA
Applications submitted in response to this PA will only compete for 
available funds with all other recommended applications received in 
this solicitation. The following will be considered in making funding 
decisions: 
o Quality of the proposed project as determined by peer review
o Availability of funds
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH : It is the 
policy of the NIH that women and members of minority groups and their 
sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear 
and compelling rationale and justification are provided indicating that 
inclusion is inappropriate with respect to the health of the subjects 
or the purpose of the research. This policy results from the NIH 
Revitalization Act of 1993 (Section 492B of Public Law 103-43).
All investigators proposing research involving human subjects should 
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: 
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to provide a 
description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable, and b) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects. You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement, 
dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT
The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances. Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA. It is important for 
applicants to understand the basic scope of this amendment. NIH has 
provided guidance at:  
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm  
 
Applicants may wish to place data collected under this PAS in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time. If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES
All applications and proposals for NIH funding must be self-contained 
within specified page limitations. Unless otherwise specified in an NIH 
solicitation, Internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no 
obligation to view the Internet sites. Furthermore, we caution 
reviewers that their anonymity may be compromised when they directly 
access an Internet site.

HEALTHY PEOPLE 2010
The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a 
PHS led national activity for setting priority areas. This Program 
Announcement (PA), Basic and Translational Research on the Cognitive 
Sequelae of Parkinson"s Disease, is related to one or more of the 
priority areas. Potential applicants may obtain a copy of "Healthy 
People 2010" at http://www.health.gov/healthypeople/.

AUTHORITY AND REGULATIONS 
This program is described in the Catalog of Federal Domestic Assistance 
No. 93.853 (NINDS), No. 93.866 (NIA), No. 93.242 (NIMH), No. 93.173 
(NIDCD) and is not subject to the intergovernmental review requirements 
of Executive Order 12372 or Health Systems Agency review. Awards are 
made under authorization of sections 301 and 405 of the Public Health 
Service Act as amended (42 USC 241 and 284) and administered under NIH 
grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 
and 92. 
The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and promote the non-use of all tobacco products. In 
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits 
smoking in certain facilities (or in some cases, any portion of a 
facility) in which regular or routine education, library, day care, 
health care or early childhood development services are provided to 
children. This is consistent with the PHS mission to protect and 
advance the physical and mental health of the American people.

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