Targeting Language-specific and Executive-control Networks With Transcranial Direct Current Stimulation in Logopenic Variant PPA
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ClinicalTrials.gov Identifier: NCT03887481 |
Recruitment Status :
Recruiting
First Posted : March 25, 2019
Last Update Posted : June 22, 2022
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Language deficits are a common feature of neurodegenerative disorders, and are the primary deficit in primary progressive aphasia (PPA), a syndrome accounting for approximately 2/3 fronto-temporal lobar dementia (FTLD) variants, and at least one Alzheimer's disease (AD) variant. Language deficits dramatically impair communication and quality of life for both patients and caregivers. PPA usually has an early onset (50-65 years of age), detrimentally affecting work and family life. There are no disease-modifying pharmacological agents for PPA and the only treatment available is a few sessions of compensatory speech-language therapy. In the first cycle of this award the investigators asked the question of whether language therapy effects could be augmented by electrical stimulation. The investigators conducted the largest to-date randomized, double-blind, sham-controlled, crossover, clinical trial to determine the effects of transcranial direct current stimulation (tDCS) in PPA. The investigators found that tDCS over the left inferior frontal gyrus (L_IFG), one of the major language hubs in the brain, significantly augments the effects of a written naming and spelling intervention. However, the investigators found great heterogeneity in the effects of tDCS. Surprisingly, patients with the largest tDCS effects in the therapy task and the largest generalization effects to other tasks were the non-fluent variant (nfvPPA) group, with an epicenter of atrophy in the L_IFG. Although the investigators showed that those who improved naming the most, after stimulation of subjects' L_IFG, were those who have atrophy there, a key question remains. What is the explanation: (1) the great plasticity of the L_IFG (as recently shown in post-stroke aphasia) or (2) a general principle of neuromodulation, i.e., stimulation is most effective over atrophied and compromised areas. The latter hypothesis is strengthened by the absence of correlation between atrophy and functional connectivity (FC), which was shown to be one of the mechanisms of tDCS effects, the other being changes in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
Therefore, to address the above question, the investigators will stimulate another major area of atrophy in PPA, the parietal cortex. The anterior inferior parietal cortex, and in particular the left supramarginal gyrus (L_SMG), specialize in phonological processing, namely phonological verbal short-term memory (vSTM), i.e., the ability to temporarily store phonological (and graphemic) information in order. The domain of vSTM affects many language tasks (repetition, naming, syntax), which makes it an ideal treatment target and the L_SMG an ideal stimulation target, since generalization of tDCS effects to other language tasks is driven by the function (computation) of the stimulated area. The proposed research capitalizes on the investigators' extensive experience with tDCS in PPA (18 published and 7 under review papers from the previous clinical trial) and will experimentally address the fundamental question of whether stimulation over atrophied and compromised cortex is most effective. By testing a fundamental principle of neuromodulation in a devastating neurodegenerative disorder, the investigators will significantly advance the field of neurorehabilitation in early-onset dementias.
Aim 1: To determine whether vSTM treatment ('RAM', for 'Repeat After Me') combined with high definition (HD)-tDCS over the L_SMG will be more effective for patients with the local epicenter of atrophy there than for patients with frontal atrophy.
Aim 2: To understand the mechanism of tDCS by measuring tDCS-induced changes in network FC and GABA over the L_SMG. The investigators will carry out resting-state functional magnetic resonance imaging (rsfMRI), (MPRAGE), diffusion weighted imaging (DWI), perfusion imaging (pCASL), and magnetic resonance spectroscopy (MRS), before, after, and 3-months post-intervention.
Aim 3: To identify neural, cognitive, physiological, clinical and demographic characteristics (biomarkers) that predict sham, tDCS, and tDCS vs. sham effects on vSTM and related language tasks in PPA. The investigators will evaluate neural (functional and structural connectivity, cortical volume, neuropeptides, and perfusion), cognitive (memory, attention, executive) and language functions, clinical (severity), and demographic (age, gender) characteristics, and the investigators will analyze the effects on vSTM and other language/cognitive outcomes immediately after intervention and at 3 months post-intervention.
Condition or disease | Intervention/treatment | Phase |
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Primary Progressive Aphasia | Device: High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) Treatment Device: Sham + "Repeat After Me" (RAM) Treatment | Not Applicable |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 60 participants |
Allocation: | Randomized |
Intervention Model: | Crossover Assignment |
Intervention Model Description: | This is a crossover design of active HD-tDCS + Language/Cognitive Intervention that crossovers to Sham + Language/Cognitive Intervention in Arm 1 and Sham + Language/Cognitive Intervention that crossovers to active HD-tDCS + Language/Cognitive Intervention in Arm 2. |
Masking: | Triple (Participant, Care Provider, Outcomes Assessor) |
Primary Purpose: | Treatment |
Official Title: | Targeting Language-specific and Executive-control Networks With Transcranial Direct Current Stimulation in Aphasic AD (Logopenic Variant PPA) |
Actual Study Start Date : | August 28, 2019 |
Estimated Primary Completion Date : | October 2027 |
Estimated Study Completion Date : | October 2027 |

Arm | Intervention/treatment |
---|---|
Experimental: Active HD-tDCS + Language/Cognitive Intervention(s) first
Participants will receive active HD-tDCS + Language/Cognitive Intervention(s) first and then receive Sham + Language/Cognitive Intervention(s) after a three-month washout period.
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Device: High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) Treatment
Device: Active HD-tDCS & "Repeat After Me" (RAM) Treatment Stimulation will be delivered by a battery-driven constant current stimulator. Electrical current will be administered to left supramarginal gyrus (L_SMG). The stimulation will be delivered at an intensity of 2 milliamperes (mA) (estimated current density 0.04 mA/cm2; estimated total charge 0.048 Coulombs/cm2) in a ramp-like fashion for a maximum of 20 minutes. Participants will receive RAM consisting of word span repetition span (increasing length, with/without response delay). Span tasks will be manipulated in terms of list length (single words, pair, triplets) and response delay (1 sec, 5 sec). Each list will consist of 10 spans. During each trial, participants will be asked to repeat words in the span after a response delay. Device: Sham + "Repeat After Me" (RAM) Treatment Device: Sham Current will be administered in a ramp-like fashion but after the ramping phase the intensity will drop to 0 mA. Current under the Sham condition will last for a maximum of 30 seconds. Participants will receive RAM consisting of word span repetition span (increasing length, with/without response delay). Span tasks will be manipulated in terms of list length (single words, pair, triplets) and response delay (1 sec, 5 sec). Each list will consist of 10 spans. During each trial, participants will be asked to repeat words in the span after a response delay. |
Experimental: Sham + Language/Cognitive Intervention(s) first
Participants will receive Sham + Language/Cognitive Intervention(s) first and then receive active HD-tDCS + Language/Cognitive Intervention(s) after a three-month washout period.
|
Device: High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) Treatment
Device: Active HD-tDCS & "Repeat After Me" (RAM) Treatment Stimulation will be delivered by a battery-driven constant current stimulator. Electrical current will be administered to left supramarginal gyrus (L_SMG). The stimulation will be delivered at an intensity of 2 milliamperes (mA) (estimated current density 0.04 mA/cm2; estimated total charge 0.048 Coulombs/cm2) in a ramp-like fashion for a maximum of 20 minutes. Participants will receive RAM consisting of word span repetition span (increasing length, with/without response delay). Span tasks will be manipulated in terms of list length (single words, pair, triplets) and response delay (1 sec, 5 sec). Each list will consist of 10 spans. During each trial, participants will be asked to repeat words in the span after a response delay. Device: Sham + "Repeat After Me" (RAM) Treatment Device: Sham Current will be administered in a ramp-like fashion but after the ramping phase the intensity will drop to 0 mA. Current under the Sham condition will last for a maximum of 30 seconds. Participants will receive RAM consisting of word span repetition span (increasing length, with/without response delay). Span tasks will be manipulated in terms of list length (single words, pair, triplets) and response delay (1 sec, 5 sec). Each list will consist of 10 spans. During each trial, participants will be asked to repeat words in the span after a response delay. |
- Change in percent accuracy on word repetition (no delay) assessed by Temple Assessment of Language and Short-Term Memory in Aphasia (TALSA) Test 3 [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The investigators will assess any changes in performance from pre- to post-treatment and 1- and 3- month follow-up intervals in percent accuracy on word repetition with no delay. This will be measured using the Temple Assessment of Language and Short-Term Memory (TALSA) Test 3: Word and Non-Word Repetition Test. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference as well as other arithmetic differences between percentage scores before intervention and each time point after. Increase in scores is considered a benefit. This outcome measure corresponds to Aim 1.
- Change in percent accuracy on word repetition (with 5-sec delay) assessed by TALSA Test 3 [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The investigators will assess any changes in performance from pre- to post-treatment and 1- and 3- month follow-up intervals in percent accuracy on word repetition with delay (5-sec). This will be measured using the TALSA Test 3: Word and Non-Word Repetition Test. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference as well as other arithmetic differences between percentage scores before intervention and each time point after. Increase in scores is considered a benefit. This outcome measure corresponds to Aim 1.
- Change in percent accuracy on word span assessed by TALSA Test 14 [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The investigators will assess any changes in performance from pre- to post-treatment and 1- and 3- month follow-up intervals in percent accuracy on word span. This will be measured using the TALSA Test 14: Word and Non-Word Repetition Span Test. The investigators will use the span calculation outlined in the TALSA. Span calculations consist of two numbers: the number of the last list length (LL) passed (e.g., 2 for pairs), and the proportion of correct strings out of the required strings to pass (5) of the next list. The highest spans obtainable for this test is 5.00. Increase in scores is considered a benefit. This outcome measure corresponds to Aim 1.
- Change in TALSA sentence repetition (Test 7) score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]This sentence repetition task comes from the TALSA (Test 7) with scoring based on percent of words in sentences correctly repeated. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
- Change in National Alzheimer's Coordinating Center's (NACC) sentence repetition score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]This sentence repetition task comes from National Alzheimer's Coordinating Center's (NACC) FTLD Module with scoring based on percent of words in sentences correctly repeated. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
- Change in digit span forward score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The digit span forward is a well-established task that assesses rote immediate verbal memory. Participants are presented with a series of digits and are instructed to repeat the digits in the same order. The investigators will compute the raw score of items correctly repeated (up to 9) and compute change in outcome between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
- Change in visual rhyming score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The visual rhyming test assesses link between phonological and orthographic information. Participants are presented words orthographically only and must indicate whether two words rhyme (e.g., pair-spare). The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
- Change in Northwestern Anagram Test (NAT) score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The Northwestern Anagram Test (NAT) assesses accuracy of word order (syntax) in sentence production. Participants assemble individual words cards to create meaningful sentences. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
- Change in NAVS - Argument Structure Production Test (ASPT) score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The Northwestern Assessment of Verbs and Sentences (NAVS) Argument Structure Production Test (ASPT) assesses combination of verbs with arguments in a sentence production task. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
- Change in spelling of non-words to dictation score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]Accuracy in spelling non-words using the Johns Hopkins Dysgraphia battery will be assessed. The investigators will compute the raw score of graphemes correct using a spelling scoring system accounting for additions, substitutions, and deletions, and transform to percent correct (range: 0-100%), computing change in outcome in percent difference before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
- Change in Apraxia Battery of Adults-Second Edition (ABA-2) score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The presence and severity of apraxia of speech (AOS) is measured using the Apraxia Battery for Adults-Second Edition (ABA-2), specifically through repeating words of increasing length and complexity and describing pictures. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Decrease in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a near-transfer task (i.e., vSTM related, showing generalization to other vSTM tasks).
- Change in spelling of words to dictation score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]Accuracy in spelling words using the Johns Hopkins Dysgraphia battery will be assessed. The investigators will compute the raw score of graphemes correct using a spelling scoring system accounting for additions, substitutions, and deletions, and transform to percent correct (range: 0-100%), computing change in outcome in percent difference before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language & cognitive tasks).
- Change in NAVS - Sentence Comprehension Test score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The Northwestern Assessment of Verbs and Sentences (NAVS) Sentence Comprehension Test (SCT) assesses comprehension of sentences given multiple types of sentences (e.g., canonical vs. non-canonical). The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language & cognitive tasks).
- Change in Subject-Relative, Object-Relative, Active Passive (SOAP): Test of Syntactic Complexity score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The SOAP: Test of Syntactic Complexity assesses comprehension abilities given 4 syntactic construction types. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%). Subsequently, the investigators will compute change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language & cognitive tasks).
- Change in Boston Naming Test (Short-Version) score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The Boston Naming Test is a widely used picture naming test that detects lexical retrieval deficits in the oral modality. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language & cognitive tasks).
- Change in oral naming of action as assessed by Hopkins Assessment of Naming Actions (HANA) [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The Hopkins Assessment of Naming Actions (HANA) assesses picture naming (specifically verbs) in the oral modality. The investigators will compute the raw score of items correct and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language & cognitive tasks).
- Change in category fluency score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]Category fluency tasks involve generating as many words as possible in one minute for a given semantic category (fruits, animals, vegetables). Scoring will be based on number of words generated per minute. The investigators will compute the raw score of items correct and subsequently the percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language & cognitive tasks).
- Change in content & efficiency of connected speech [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]Using picture descriptions (e.g., Cookie Theft image from the Boston Diagnostic Aphasia Examination [BDAE]) and personal/procedural discourse tasks, investigators will obtain representative language samples. The investigators will compute the raw score of content (content information units [CIUs]) and efficiency (proportion of mazes: false starts, pauses) and transform to percent correct (range: 0-100%), computing change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language & cognitive tasks).
- Change in N-back (2-back) word score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The N-back task is a well-established task that assesses working memory and working memory capacity. Participants are presented with words in sequence and instructed to reply whether the current word matches the one presented 2 words ago. Scoring will be based on the total number of correct responses (hit rate) minus the number of incorrect responses (false alarm rate). The investigators will compute the change in outcome in percent difference between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language & cognitive tasks).
- Change in digit span backward score [ Time Frame: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention ]The digit span backward is a well-established task that assesses rote immediate verbal memory and working memory. Participants are presented with a series of digits and are instructed to repeat the digits in the reverse order. The investigators will compute the raw score of items correctly repeated and compute change in outcome between before intervention and each time point after. Increase in score is considered a benefit. This outcome measure corresponds to Aim 1 and is considered a far-transfer task (i.e., unrelated to vSTM, showing generalization to other language & cognitive tasks).
- Change in functional connectivity of select brain regions (z-correlations) [ Time Frame: Before intervention, immediately after intervention, 3 months post intervention ]Using resting stage functional MRI (rs-fMRI) investigators will detect activity of various brain regions under a resting/task-negative condition, which will help evaluate functional regional interactions as indicated by the z-correlations between the selected brain area. This outcome measure corresponds to Aim 2.
- Change in Gamma-Aminobutyric Acid (GABA) concentration at stimulated site [ Time Frame: Before intervention, immediately after intervention, 3 months post intervention ]Using Magnetic Resonance Spectroscopy (MRS) investigators will measure metabolite (GABA) concentrations from select brain regions in international units (IU).

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Ages Eligible for Study: | 45 Years to 75 Years (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
- Must be between 45-75 years of age.
- Must be right-handed.
- Must be proficient in English.
- Must have a minimum of high-school education.
- Must be diagnosed with Primary Progressive Aphasia (PPA) or with non-fluent variant PPA or logopenic variant PPA.
- Participants will be diagnosed with PPA or with any of the PPA variants in specialized or early dementias clinics at Johns Hopkins University or other specialized centers in the US based on the current consensus criteria.
- Healthy age- and education-matched controls: The investigators will include 30 healthy age- and education-matched controls, usually spouses, to maximize similarity in terms of other demographic or life-style factors that contribute to language and cognitive performance.
Exclusion Criteria:
- People with previous neurological disease including vascular dementia (e.g., stroke, developmental dyslexia, dysgraphia or attentional deficit).
- People with uncorrected hearing loss
- People with uncorrected visual acuity loss.
- People with advanced dementia or severe language impairments: Mini Mental State -Examination (MMSE)<18, or Montreal Cognitive Assessment (MOCA)<15, or language Frontotemporal Dementia specific - Clinical Dementia Rating (FTD-CDR)<=2.
- Left handed individuals.
- People with pre-existing psychiatric disorders such as behavioral disturbances, severe depression, or schizophrenia that do not allow these people to comply or follow the study schedule and requirements such as repeated evaluation and therapy.
Exclusion Criteria for MRI Participation:
- People with severe claustrophobia.
- People with cardiac pacemakers or ferromagnetic implants.
- Pregnant women.

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03887481
Contact: Kyrana Tsapkini, PhD | 410-736-2940 | tsapkini@jhmi.edu | |
Contact: Kelly Williamson, M.S. | kwill261@jh.edu |
United States, Maryland | |
Johns Hopkins Hospital | Recruiting |
Baltimore, Maryland, United States, 21287 | |
Contact: Kyrana Tsapkini, PhD 410-736-2940 tsapkini@jhmi.edu | |
Principal Investigator: Kyrana Tsapkini, PhD |
Principal Investigator: | Kyrana Tsapkini, PhD | Johns Hopkins University |
Responsible Party: | Johns Hopkins University |
ClinicalTrials.gov Identifier: | NCT03887481 |
Other Study ID Numbers: |
IRB00201027 |
First Posted: | March 25, 2019 Key Record Dates |
Last Update Posted: | June 22, 2022 |
Last Verified: | March 2022 |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | Yes |
Product Manufactured in and Exported from the U.S.: | No |
transcranial direct current stimulation (tDCS) neurodegeneration verbal short-term memory |
non-fluent variant logopenic variant primary progressive aphasia |
Aphasia Aphasia, Primary Progressive Pick Disease of the Brain Frontotemporal Dementia Speech Disorders Language Disorders Communication Disorders Neurobehavioral Manifestations Neurologic Manifestations Nervous System Diseases |
Dementia Brain Diseases Central Nervous System Diseases Neurocognitive Disorders Mental Disorders Frontotemporal Lobar Degeneration TDP-43 Proteinopathies Neurodegenerative Diseases Proteostasis Deficiencies Metabolic Diseases |