Everyday Memory Impairment in PD-related Cognitive Decline

The investigators will aim enroll participants into our study within 3-6 months after their parent study visit so the investigators can utilize some key data points (e.g. PD-MCI diagnosis, rs-fcMRI data) from that study. PD participants will participate in a single-blind RCT with two treatment arms: process training and strategy training (Fig 4). They will complete pre-training assessment (Pre), be randomized to treatment arm (1:1 ratio stratified by sex), and then complete 8 training sessions over an 8-week period. They will return within 1 week for post-training assessment (Post) and then will complete Follow-up (FU) assessments via web or mailed survey 3 and 6 months after training ends. They will complete a 12mo FU assessment in person in conjunction with their annual parent study visit. HC participants will complete prospective memory assessment at one time point coinciding with (or within 3-6 months of) their parent study visit to determine whether any relationships observed between rs-fcMRI data and prospective memory are specific to PD.

Parkinson disease (PD) causes cognitive deficits that can impair instrumental activities of daily living function and quality of life (QOL) even in the absence of dementia. Currently, there are no treatments to address this pressing burden and, even worse, some medical treatments for PD can exacerbate cognitive deficits. For these reasons, behavioral interventions that attenuate the negative functional consequences of cognitive decline in PD and thus potentially delay the onset of dementia are in high demand. An intervention that enables people with PD to remember to perform necessary and meaningful daily activities could improve or maintain their independence, disease self-management, participation in society, and reduce caregiver burden. The primary goal of this study is to determine the efficacy of such an intervention. Importantly, in doing so, the investigators will directly address a critical point of contention in cognitive intervention research: Which approach (process or strategy training) is the best option for producing functionally-relevant benefits for people with PD? Additionally, the study team will investigate behavioral and neurobiological correlates of prospective memory in PD, including individual characteristics that may predict treatment response. This work will lead to a targeted and tailored biobehavioral intervention that optimizes function, promotes QOL, and improves the long-term management of a common chronic neurological condition. It will move the field of rehabilitation forward by providing valuable theoretical and practical information related to the type of cognitive intervention approach that is most appropriate for people with PD. This then will stimulate and justify the channeling of future research efforts and funding toward further development, testing, dissemination, and implementation of said approach.

Primary Outcomes:

Aim 1. Laboratory prospective memory performance - The Virtual Week test will be administered to PD participants at Pre and Post to assess near transfer of training objectively (primary endpoint). It will also be administered to PD participants at 12mo FU to explore long term training effects (secondary endpoint) and to HC participants at Pre to investigate neural mechanisms of prospective memory performance (Aim 3). It is a computerized board game that simulates daily life and real-world prospective memory challenges. Each circuit represents one day in which the participant completes time-appropriate activities and makes choices about them. Embedded in each day are 8 prospective memory tasks (4 event, 4 time). Participants complete a practice day and then 4 test days; equivalent versions are counterbalanced across testing sessions. The main outcome variable is prospective memory accuracy, defined as the proportion of correct prospective memory responses (32 total: 16 event, 16 time). To further explore the effects of time-based training, the investigators will record strategic clock-checking behavior by requiring participants to click a button to reveal the virtual time of day.

Aim 2. Reported everyday prospective memory: (2a) General everyday prospective memory function - The Prospective and Retrospective Memory Questionnaire (PRMQ)will be administered via web-based or mailed survey to PD participants and informants at Pre, Post and 3mo FU to assess far transfer of training (primary endpoint), to PD participants and informants at 6mo and 12mo FU to explore long term training effects (secondary endpoint), and to HC participants at Pre to determine neural mechanisms of everyday prospective memory (Aim 3). The PRMQ is the most widely used questionnaire for everyday prospective memory. Participants rate the frequency of 8 everyday prospective memory failures (1=Never, 5=Very Often), item scores are summed, and higher scores indicate worse everyday prospective memory. The PRMQ includes environment- and self-cued subscales (4 items each) that parallel the event- and time-based task distinction, respectively. (2b) Personalized real-life prospective memory tasks - The Bangor Goal-Setting Interview (BGSI)offers a standardized means of eliciting individual goals and rating goal attainment over time and has been successfully used in cognitive rehabilitation RCTs with older adults, including those with mild to moderate dementia. During the first two training sessions, after an explanation of the prospective memory task types (session 1: event, session 2: time), participants will complete the BGSI with the trainer to identify and set goals for 3-6 real-life prospective memory tasks they anticipate having to complete over the training period. They and their informants will rate their Pre and Post attainment of these goals on a 10-point scale (1=never remember to do; 10=always remember to do). Goal attainment ratings are averaged to yield mean attainment scores.

Additional measures:

Aims 3 \& 4. Neural correlates of prospective memory and treatment response - Rs-fcMRI data will be collected and managed under the auspices of the parent study at Pre. Briefly, MRIs will be completed OFF PD medications on a 3T Siemens Prisma scanner with a 20 channel head coil and include up to 6 BOLD rs-fcMRI scans (416 volumes/run, TE=26.6ms, TR=800ms, FOV= 213mm, flip angle=61°, 3mm3 voxels; multiband factor=4; 5:39min) during fixation (eyes open). More details, including rigorous quality control methods, are in references. The investigators will use a network-level analysis approach using standard nodes from canonical networks. Our primary variables of interest will be intranetwork integrity scores, calculated based on the cross-correlations of each node within the network, for the following cognitive networks: DMN, CON, FPN, PMN, and MTL. Alternate approaches may include seed-based analyses (e.g. DLPFC) and Object Oriented Data Analysis followed by post-hoc identification of significant networks.

Aim 4. Behavioral predictors of treatment response - Based on our pilot RCT (Prelim Data 2)1, The investigators will administer the Credibility and Expectancy Questionnaire (CEQ) and Beck Depression Inventory-II (BDI-II) at Pre as potential motivational predictors of treatment response. The CEQ will be administered at the end of training session 2, so participants have some knowledge of the intervention on which to base their perceptions of credibility and expectancy. The investigators will utilize the extensive neuropsychological data collected at Pre in the parent study to assess potential cognitive predictors of treatment response. Our primary cognitive variables will be the domain z-scores for Memory and Executive Function, computed as the average of standardized scores from measures assessing that domain. Other - PD (and normal cognition for HCs) will be determined via MDS Level II diagnostic criteria in the parent study based on a comprehensive neuropsychological assessment battery and in-depth clinical interviews (CDR). In addition to the main measures of interest described above, the investigators will collect other data to characterize participants, as covariates, or as secondary outcomes (Table 3). This will permit exploration of the influence of sex or other relevant biological variables (e.g. co-morbidities, medication) and broader functional outcomes. The investigators will obtain much of this data from the parent study.

Eligibility Criteria:
Inclusion Criteria:

* Males and females over age 50 who meet criteria for typical idiopathic PD
* Hoehn \& Yahr stage I-III,
* Treated with levodopa/carbidopa
* Have subjective memory complaints (as identified in phone screen),
* Have an informant to complete relevant ratings,
* Medications should be stable for 4 weeks prior with no changes planned during the treatment portion of the study (Pre to Post); changes over the follow-up period will be tracked and accounted for as appropriate.

Exclusion Criteria:

* Dementia according to MDS criteria or MoCA score \<21.
* Other neurological disorders (e.g. stroke, seizures), brain surgery, severe systemic diseases, major psychiatric disorder or history of psychotic symptoms (e.g. schizophrenia, bipolar disorder, delusions, hallucinations), or drug abuse.
* Treatment with medications that interfere with cognition (e.g. anticholinergics).
* Any other condition that would interfere with participation (e.g., non-English speaking, significant current depression).
* Psychiatric conditions/ symptoms that are common in PD (e.g. anxiety, depression) are allowed if they are deemed insufficient to interfere with participation.