Clinical trial NCT04122001: Effects of Electrical Stimulation on Verbal Learning in Typical and Atypical Alzheimer's Disease
Official title: Transcranial Direct Current Stimulation in Typical and Atypical Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Alzheimer Disease, Early Onset
Atypical Alzheimer's Disease
Logopenic Progressive Aphasia
Keywords: transcranial direct current stimulation (tDCS)
Alzheimer's Disease (AD)
verbal learning treatment
word list learning
logopenic Progressive Aphasia
episodic memory
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2019-10-10
Enrollment: 90
Sex: ALL
Minimum age (years): 45
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a crossover design of active High-Definition tDCS (HD-tDCS) + Word List Learning Intervention (WordLLI) that crossovers to sham + WordLLI in Arm 1, and sham +WordLLI that crossovers to active HD-tDCS + WordLLI in Arm 2.
Primary purpose: TREATMENT

Brief summary: Alzheimer's disease (AD) is the leading neurodegenerative disease of aging characterized by multiple cognitive impairments. Given the recent failures of disease-modifying drugs, the current focus is on preventing or mitigating synaptic damage that correlates with cognitive decline in AD patients. Transcranial Direct Current Stimulation (tDCS) is a safe, non-invasive, non-painful electrical stimulation of the brain that is shown to act as a primer at the synaptic level when administered along with behavioral therapy, mostly involving language, learning and memory. Previous studies have shown that tDCS over the left angular gyrus (AG) improves language associative learning in the elderly through changes in functional connectivity between the AG and the hippocampus. The investigators' previous clinical trial on the effects of tDCS in neurodegenerative disorders has also shown augmented effects of lexical retrieval for tDCS. In the present study the investigators will compare the effects of active vs. sham tDCS over the AG-an area that is part of the default mode network but also a language area, particularly important for semantic integration and event processing-in two predominant AD variants: probable AD with amnesic phenotype (amnesic/typical AD) and probable AD with non-amnesic (language deficit) phenotype also described as logopenic variant PPA with AD pathology (aphasic/atypical AD). The investigators aim to: (1) determine whether active high-definition tDCS (HD-tDCS) targeting the left AG combined with a Word-List Learning Intervention (WordLLI) will improve verbal learning; (2) identify the changes in functional connectivity between the stimulated area (AG) and other structurally and functionally connected areas using resting-state functional magnetic resonance imaging; (3) identify changes in the inhibitory neurotransmitter GABA at the stimulation site using magnetic resonance spectroscopy. Furthermore, the investigators need to determine the characteristics of the people that may benefit from the new neuromodulatory approaches. For this reason, the investigators will evaluate neural and cognitive functions as well as physiological characteristics such as sleep, and will analyze the moderating effects on verbal learning outcomes. Study results can help provide treatment alternatives as well as a better understanding of the therapeutic and neuromodulatory effects of tDCS in AD, thus improving patients' and caregivers' quality of life.

Detailed description: The investigation implements a double-blind, sham-controlled, within-subject, cross-over design that allows for the evaluation of the cognitive and neural effects of word-list learning as modulated by tDCS compared to sham stimulation. Participants in all groups will receive word-list learning intervention (WordLLI)+ High-Definition tDCS (HD-tDCS) or WordLLI+ sham in Period 1 or 2, randomized for the Period 1 stimulation condition. Each learning Period will last 2 weeks, with 5 learning sessions per week (for a total of 10 learning sessions per Period) with a 3-month (stimulation-free) wash-out period between the two Periods. The intensity, total number of learning sessions and number of learning items is consistent with most other tDCS studies in neurodegenerative disorders and the investigators have used this design successfully over the past 7 years in neurodegenerative disorders (PPA, mild AD). Stimulation is implemented every weekday to take advantage of the long-term potentiation induced by tDCS as found in early multi-session studies. A tDCS-only condition (without any intervention) is not implemented in this design because no study to date has shown improvement on motor, cognitive, or language performance after anodal tDCS-only for 2 or even more weeks. After each period the investigators will perform 1-month and 3-month follow-up sessions for evaluation purposes. For those participants who are long-distance, at the 1-month time point only the investigators may use a video conferencing tool such as GoToMeeting to administer the assessments. This is to mitigate the costs of travel for a short appointment.

Eligibility criteria: Inclusion Criteria:

For the aphasic/atypical AD participants:

* Must be between 45-85 years of age.
* Must be right-handed.
* Must be proficient in English.
* Must have a minimum of high-school education.
* Must be diagnosed as logopenic variant Primary Progressive Aphasia (PPA) with Alzheimer's Disease (AD) biomarkers. Other possible diagnosis for the 'aphasic AD' variant would be Mild Cognitive Impairment (MCI) or 'possible AD' according to 2011 guidelines with AD biomarkers (CSF or positron emission tomography (PET) amyloid-beta or fluorodeoxyglucose (FDG)-positron emission tomography (PET) with unihemispheric atrophy).
* Participants will be diagnosed from PPA and early dementias clinics at Johns Hopkins University or other specialized centers in US using current consensus criteria. Diagnosis will be based on neuropsychological testing, language testing (most commonly the Western Aphasia Battery), MRI and clinical assessment. The investigators will also use two new variant classification tests the investigators have developed at the lab which discriminate PPA variants with great accuracy (above 80%): a spelling test and a speech production test (i.e.,Cookie Theft picture description task).

For the amnesic/typical AD participants:

* Must be between 45-85 years of age.
* Must be right-handed.
* Must be proficient in English.
* Must have a minimum of high-school education.
* Must be diagnosed with 'probable AD' in specialized diagnostic centers with neuropsychological (e.g., RAVLT) and AD biomarkers according to 2011 guidelines.
* The investigators will also perform extensive testing in the investigators' test battery including the Mnemonic Similarity Test (MST) that discriminates and measures the most salient hippocampal deficit-pattern separation (PS).

Exclusion Criteria:

* People with previous neurological disease including vascular dementia (e.g., stroke, developmental dyslexia, dysgraphia or attentional deficit).
* People with hearing loss (\> 25 decibel, using audiometric hearing screen).
* People with uncorrected visual acuity loss.
* People with advanced dementia or severe language impairments (MMSE \< 15, or Montreal Cognitive Assessment \<10, or language Frontotemporal Dementia-specific Clinical Dementia Rating (FTD-CDR) = 3).
* 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.

Primary outcomes:
measure: Change in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically related - trained word-lists
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in auditory delayed recall accuracy of semantically related - trained word-lists
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically unrelated - trained word-lists
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in auditory delayed recall accuracy of semantically unrelated - trained word-lists
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in auditory recall accuracy based the sum of words recalled in Trials 1-5 of semantically related - untrained word-lists
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in auditory delayed recall accuracy of semantically related - untrained word-lists
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in auditory recall accuracy based on the sum of words recalled in Trials 1-5 of semantically unrelated - untrained word-lists
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in auditory delayed recall accuracy of semantically unrelated - untrained word-lists
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
Secondary outcomes:
measure: Change in Rey Auditory-Verbal Learning Test (RAVLT) score
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in Mini Mental State Examination (MMSE)
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in Mnemonic Similarity Task (MST) score
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in word repetition score
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in non-word repetition score
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in sentence repetition score
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in oral naming Boston Naming Test score
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in oral naming Philadelphia Naming Test score
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in written naming as assessed by Boston Naming Test
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in written naming as assessed by Philadelphia Naming Test
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in oral naming of action as assessed by Hopkins Assessment of Naming Actions (HANA)
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in syntactic comprehension as assessed by Subject-relative, Object-relative, Active, Passive (S.O.A.P.) Syntactic Battery
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in verbal fluency task score
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in spelling as assessed by the Johns Hopkins Dysgraphia battery
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in digit span forward score
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in digit span backward score
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in spatial span forward score
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in spatial span backward score
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in semantic content of connected speech
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in attention and manipulation of information scores
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in volumetric measurements of select brain regions
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in functional connectivity of select brain regions (z-correlations)
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in Gamma-Aminobutyric Acid (GABA) concentration
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in location of white matter tracts of select brain regions
timeFrame: Before intervention, immediately after intervention, 1 month and 3 months post intervention, up to 31 weeks
measure: Change in anisotropy of white matter tracts of select brain regions
timeFrame: Before intervention, immediately after intervention and 3 months post intervention, up to 31 weeks
Other outcomes:
measure: Correlation of primary and secondary outcomes with sleep efficiency
timeFrame: One week before intervention and one week post intervention, up to 8 weeks
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Kyrana Tsapkini, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tsapkini K, Frangakis C, Gomez Y, Davis C, Hillis AE. Augmentation of spelling therapy with transcranial direct current stimulation in primary progressive aphasia: Preliminary results and challenges. Aphasiology. 2014;28(8-9):1112-1130. doi: 10.1080/02687038.2014.930410.
citation: Tsapkini K, Webster KT, Ficek BN, Desmond JE, Onyike CU, Rapp B, Frangakis CE, Hillis AE. Electrical brain stimulation in different variants of primary progressive aphasia: A randomized clinical trial. Alzheimers Dement (N Y). 2018 Sep 5;4:461-472. doi: 10.1016/j.trci.2018.08.002. eCollection 2018.
citation: Ficek BN, Wang Z, Zhao Y, Webster KT, Desmond JE, Hillis AE, Frangakis C, Vasconcellos Faria A, Caffo B, Tsapkini K. The effect of tDCS on functional connectivity in primary progressive aphasia. Neuroimage Clin. 2018 May 21;19:703-715. doi: 10.1016/j.nicl.2018.05.023. eCollection 2018.
citation: Reis J, Schambra HM, Cohen LG, Buch ER, Fritsch B, Zarahn E, Celnik PA, Krakauer JW. Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation. Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1590-5. doi: 10.1073/pnas.0805413106. Epub 2009 Jan 21.
citation: Huey ED, Probasco JC, Moll J, Stocking J, Ko MH, Grafman J, Wassermann EM. No effect of DC brain polarization on verbal fluency in patients with advanced frontotemporal dementia. Clin Neurophysiol. 2007 Jun;118(6):1417-8. doi: 10.1016/j.clinph.2007.02.026. Epub 2007 Apr 23. No abstract available.
citation: Antal A, Terney D, Poreisz C, Paulus W. Towards unravelling task-related modulations of neuroplastic changes induced in the human motor cortex. Eur J Neurosci. 2007 Nov;26(9):2687-91. doi: 10.1111/j.1460-9568.2007.05896.x. Epub 2007 Oct 26.
citation: Segrave RA, Arnold S, Hoy K, Fitzgerald PB. Concurrent cognitive control training augments the antidepressant efficacy of tDCS: a pilot study. Brain Stimul. 2014 Mar-Apr;7(2):325-31. doi: 10.1016/j.brs.2013.12.008. Epub 2013 Dec 19.
citation: McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):263-9. doi: 10.1016/j.jalz.2011.03.005. Epub 2011 Apr 21.
citation: Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, Ogar JM, Rohrer JD, Black S, Boeve BF, Manes F, Dronkers NF, Vandenberghe R, Rascovsky K, Patterson K, Miller BL, Knopman DS, Hodges JR, Mesulam MM, Grossman M. Classification of primary progressive aphasia and its variants. Neurology. 2011 Mar 15;76(11):1006-14. doi: 10.1212/WNL.0b013e31821103e6. Epub 2011 Feb 16.
citation: Neophytou K, Wiley RW, Rapp B, Tsapkini K. The use of spelling for variant classification in primary progressive aphasia: Theoretical and practical implications. Neuropsychologia. 2019 Oct;133:107157. doi: 10.1016/j.neuropsychologia.2019.107157. Epub 2019 Aug 8.
citation: Riello M, Faria AV, Ficek B, Webster K, Onyike CU, Desmond J, Frangakis C, Tsapkini K. The Role of Language Severity and Education in Explaining Performance on Object and Action Naming in Primary Progressive Aphasia. Front Aging Neurosci. 2018 Oct 30;10:346. doi: 10.3389/fnagi.2018.00346. eCollection 2018.