Primary progressive aphasia (PPA) is a neurodegenerative disease that affects first and foremost language abilities. Mild cognitive impairment (MCI) is slowly progressive decline in a single domain of cognition (e.g. language) not attributable to motor or sensory loss, without impediment of social or occupational function. MCI can be an early sign of neurodegenerative disease, or can be due to normal aging. When language is the prominent affected domain in MCI, the person may later meet criteria for PPA or may progress to the clinical syndrome of Alzheimer's dementia. Spelling, naming, and working memory (e.g. repetition) are among the language abilities affected early in the course of PPA or language-centered MCI, and different variants have distinct deficits in these domains. This research project investigates the behavioral and neuromodulatory effects of high definition transcranial direct current stimulation (HD-tDCS) during language therapy in PPA participants over time. Anodal HD-tDCS targeting the left inferior frontal gyrus (IFG) administered in combination with language therapy is expected to be more beneficial when compared to language therapy alone. It will 1) improve language performance or decrease rate of decline, 2) have better-sustained effects at 2 weeks and 2 months post-treatment, and 3) produce generalization to untrained language items and some other cognitive functions. Resting-state fMRI, diffusion tensor imaging (DTI), and volumetric data are also collected to investigate changes in functional brain connectivity associated with HD-tDCS in individuals with PPA. A better understanding of the therapeutic and neuromodulatory mechanisms of HD-tDCS as an adjunct to language therapy in PPA may have a significant impact on the development of effective therapies for PPA and MCI, and may offer insight into ways of impeding neurodegeneration that may improve patients' quality of life, as well as extend their ability to work and manage their affairs.

A. Evaluation Tasks

Language Tasks:

Participants will be administered baseline language and cognitive tasks, including 1 or more of the following, depending on their residual language and cognitive skills:

a) writing to dictation b) oral spelling c) oral and written naming of pictures d) word-picture matching f) written and oral picture description g) digit span h) spatial span i) verbal learning j) grammatical sentence production k) oral word repetition l) sentence comprehension

Quality of Life questionnaires:

Participants will be administered standardized and non-standardized quality-of-life questionnaires before, after, and at follow-up intervals of each experimental period. The purpose of these questionnaires is to assess whether the proposed interventions have affected participants' well-being and the general quality of their life.

B. Spoken and Written Word Production Therapy Interventions

Individuals with PPA will receive spoken and written word production intervention tailored to their degree of deficit. Two interventions (basic and advanced) will be implemented, treating the main lexical retrieval deficits in PPA, in oral and written modalities. The goal of the combined interventions is to promote interaction between phonological and orthographic representations and processes in the remediation of lexical retrieval deficits that are prominent in all PPA subtypes.

C. Assessment of Language Therapy Tasks:

Follow-up assessment will probe all sets of trained phoneme-grapheme correspondences, words, or other stimuli (e.g. sentences) to identify whether or not the patient has retained knowledge of the trained items. Differences in baseline measures in pre- and post-therapy accuracy for phoneme-grapheme correspondences for each patient will be evaluated using the following: percentages of total number of points correct, arithmetic differences between percentage scores, and permutation tests (Pearson's chi-square test; Fisher's exact test).

C. HD-tDCS Methods:

Participants will take part in 10-15 consecutive training sessions (3-5 per week), separated by 2 months. Anodal HD-tDCS has typically been shown to up-regulate neuronal excitability and produce enhancement of behavioral performance. A Soterix-CT device will be delivering current at an intensity of 1-2 milliamps(mA) (estimated current density 0.04 mA/cm2; estimated total charge 0.048C/cm2) for a maximum of 20 minutes in the HD-tDCS groups and for a maximum of 30 seconds in the Sham group. For both interventions (HD-tDCS and Sham) the electrical current will be increased in a ramp-like fashion at the onset of the stimulation eliciting a transient tingling sensation on the scalp that usually disappears over seconds.

D. Imaging Methods:

Imaging will be performed at the beginning of enrollment, before and after each 12-to-15-day HD-tDCS treatment, and at follow-up intervals for up to 8 time points per individual on a 3T Philips system, and will consist of resting-state fMRI (rsfMRI), MPRAGE, and diffusion tensor imaging (DTI). Each scanning session will last approximately 1 hour.

E. Statistical Analyses:

In the within-subject crossover protocol, each participant will be administered three experimental conditions: Control (natural progression), IFG HD-tDCS+language (henceforth abbr. HD-tDCS treatment (word production) and sham HD-tDCS+language (henceforth abbr. sham treatment). To achieve an accurate estimate of degeneration and rate of decline in each participant at their particular stage of the disease progression, each participant will first be enrolled in the control condition (natural progression), such that for the first 12 weeks they will not receive any therapy. Then the participant will receive either the HD-tDCS treatment followed by sham, or vice versa. All analyses, behavioral and imaging, will be under the oversight of the study statisticians.

F. Study duration and number of study visits required of research participants.

Before any intervention, participants will be enrolled in a control condition for 12 weeks during which no therapy will be provided to enable us to assess their personal decline rate. After this period they will be randomly assigned to either sham or HD-tDCS experimental conditions. After 1-3 weeks of HD-tDCS application (3-5 sessions in a week, 10-15 sessions per stimulation site) there will be an interval of approximately 2 months and then we will implement the other two HD-tDCS conditions in a within-subject cross-over design. Participants will be followed up at 2-week and 2-month follow-up intervals.

G. Blinding, including justification for blinding or not blinding the trial, if applicable.

Participants will be blinded to the application of anodal or sham HD-tDCS. To achieve blinding, all participants will be fitted with the HD-tDCS electrodes placed over the left inferior frontal gyrus. The Soterix-CT device will be used for double-blinding purposes.

H. Justification of why participants will not receive routine care or will have current therapy stopped

Participation in this study will not disrupt any current care or therapy.

I. Justification for inclusion of a placebo or non-treatment group

All participants will undergo active and sham conditions, thus serving as their own control.

J. Definition of treatment failure or participant removal criteria

Participants will be removed from the study if they are unable to comply with task instructions or tolerate the HD-tDCS procedure.

K. Description of what happens to participants receiving therapy when the study ends or if a participant's participation in the study ends prematurely

When the study ends participants will continue to receive management with their neurologist as usual. If a patient's participation in the study ends prematurely s/he will still receive care as before. In sum, termination of the study or termination of participation in it will not affect the regular therapy he or she may be receiving.

L. Qualification of investigators:

The PI and co-investigators have extensive research and clinical experience with all study tasks: behavioral language therapy (including spelling, naming, and repetition therapy. The investigators have already published a tDCS study on the behavioral results for the improvement of spelling abilities.

Inclusion Criteria:

• Must be clinically diagnosed with semantic variant PPA (svPPA), non-fluent variant PPA (nfvPPA), or logopenic variant PPA (lvPPA), unclassifiable PPA, or MCI. Diagnosis will be based on neuropsychological testing, language testing (most commonly the Western Aphasia Battery), MRI and clinical assessment.
• Must be right-handed.
• Must be speakers of English.
• Must have at least 9th grade education.

Exclusion Criteria:

• Uncorrected visual or hearing impairment by self report.
• Stroke/other premorbid neurological disorder affecting the brain.
• Any other language-based learning disorder other than PPA.
• Inability to follow directions for baseline tasks.
• Western Aphasia Battery Aphasia Quotient (AQ) <30 (indicating severe language impairment).

Exclusion Criteria for MRI Participation:

• Severe claustrophobia.
• Cardiac pacemakers or ferromagnetic implants.
• Pregnant women.

Adverse events were not assessed during the 12-week control condition (natural progression period) preceding treatment. Adverse events were assessed from randomization to up to 2 months post treatment for each intervention.