Cognitive Training and Neuroplasticity in Mild Cognitive Impairment

In this clinical trial, investigators will evaluate if systematic cognitive training can
improve cognitive performance in participants with memory loss. This study is for those who
have demonstrated difficulty with memory. It will evaluate the effects of Computerized
Cognitive Training (CCT) for improvement in everyday cognitive and function status, in
addition to long-term changes in brain networks over an 18-month period. In this study,
participants will be randomly assigned to Training Group 1 or 2; therefore, one will have a
50% chance of being assigned to CCT, and a 50% chance of being assigned to Crossword Puzzle
Training (CPT). During the 18- month period, participants will be asked to come to the Memory
Disorders Clinic at the New York State Psychiatric Institute (NYSPI) for a screening
evaluation, and if eligible, will return for five follow-up visits at Weeks 12, 32, 52, and
78.

Inclusion Criteria:

1. Males and females 55 to 95 years of age (inclusive) at the time of informed consent.

2. Subjective cognitive complaints, i.e., memory or other cognitive complaints, e.g.,
naming/language.

3. Meets criteria for cognitive impairment (CI) defined as scores > 1 below standardized
norms on memory function as identified by the Wechsler Memory Scale (WMS) III Logical
Memory immediate or delayed recall score.

4. Folstein Mini Mental State (MMSE) score ≥ 23 out of 30.

5. A family member or other individual who is in contact with the patient and consents to
serve as informant during the study; this can be a telephone informant in the case of
patients who do not have a live-in informant or close significant other.

6. Access to a home desktop or laptop computer at acceptable internet speed for the study
duration.

Exclusion Criteria:

1. Diagnosis of dementia of any type.

2. Current clinical evidence of schizophrenia, schizoaffective disorder, major
depression, psychosis, or bipolar I disorder (DSM-IV criteria).

3. Active suicidal ideation or plan.

4. Current or recent (past 6 months) alcohol or substance use disorder (DSM-5 criteria).

5. Clinical stroke with residual neurological deficits. While we will not exclude
patients with cerebrovascular disease, we will not include patients who have had a
stroke with residual clinical deficits because it is not clear that this type of
patient is similar to the MCI (Mild Cognitive Impairment) patient generally, and
clear-cut neurological impairment, e.g., hemiplegia/hemiparesis or speech impairment,
may compromise the patient's ability to do the CCT or active control procedures and to
complete the neuropsychological test battery.

6. Use of medications known to have a negative impact on cognition: benzodiazepines in
lorazepam equivalents greater than or equal to 1 mg daily, narcotics,
anticholinergics. Other patients receive medications that may be associated with
cognitive impairment but are rarely considered the likely etiology, e.g.,
theophylline, nifedipine, beta blockers; they will not be excluded. Patients receiving
other psychotropic medications not expected to have a material impact on cognition,
e.g., SSRIs (Selective Serotonin Reuptake Inhibitors) and SNRIs
(Serotonin-norepinephrine reuptake inhibitors) will be eligible.

7. Presence of any of the following disorders: a) Central Nervous System infection, with
cerebrospinal fluid evidence of meningitis, encephalitis, or other infectious process;
b) dementia of any type; c) Huntington's disease; d) Multiple sclerosis; e)
Parkinson's disease; f) Other neurologic disorders with focal signs, e.g., amyotrophic
lateral sclerosis; g) Mental retardation.

8. Acute, severe unstable medical illness. For cancer, acutely ill patients (including
those with metastases) will be excluded, but past history of successfully treated
cancer will not result in exclusion.

9. Contraindication to MRI scan: pacemaker, metal implants following surgery, any other
contraindication to MRI. Eligibility for the MRI scan is a requirement for the study.

10. UPSIT (University of Pennsylvania Smell Identification Test) exclusions: current
smoker > 1 pack daily, current upper respiratory infection (retested as soon as the
infection clears). UPSIT scores are reduced in schizophrenia, Parkinson's disease and
Parkinson's related conditions; these disorders are exclusion criteria for this study.
Patients with UPSIT exclusions, e.g., current heavy smoker (less than 3% of older
adults in our experience), will not receive the UPSIT but will continue to participate
in all other aspects of the study.

11. Patients lacking English-speaking ability as determined by self-report and clinical
evaluation.

12. Regular online brain training or regular crossword puzzle user, defined as doing these
procedures at a frequency of twice weekly or greater during the year prior to
screening. Eligible participants who join the trial are instructed not to do these
procedures on their own during the trial, i.e., independent of the study.

13. Participation in another intervention trial for cognitive impairment.