Neuropsychological and Neuroanatomical Features of Patients with Behavioral/Dysexecutive Variant Alzheimer's Disease (AD): A Comparison to Behavioral Variant Frontotemporal Dementia and Amnestic AD Groups.

BACKGROUND: An understudied variant of Alzheimer's disease (AD), the behavioral/dysexecutive variant of AD (bvAD), is associated with progressive personality, behavior, and/or executive dysfunction and frontal atrophy. OBJECTIVE: This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to behavioral variant frontotemporal dementia (bvFTD), amnestic AD (aAD), and subjects with normal cognition. METHODS: Subjects included 16 bvAD, 67 bvFTD, 18 aAD patients, and 26 healthy controls. Neuropsychological assessment and MRI data were compared between these groups. RESULTS: Compared to bvFTD, bvAD showed more significant visuospatial impairments (Rey Figure copy and recall), more irritability (Neuropsychological Inventory), and equivalent verbal memory (Philadelphia Verbal Learning Test). Compared to aAD, bvAD indicated more executive dysfunction (F-letter fluency) and better visuospatial performance. Neuroimaging analysis found that bvAD showed cortical thinning relative to bvFTD posteriorly in left temporal-occipital regions; bvFTD had cortical thinning relative to bvAD in left inferior frontal cortex. bvAD had cortical thinning relative to aAD in prefrontal and anterior temporal regions. All patient groups had lower volumes than controls in both anterior and posterior hippocampus. However, bvAD patients had higher average volume than aAD patients in posterior hippocampus and higher volume than bvFTD patients in anterior hippocampus after adjustment for age and intracranial volume. CONCLUSION: Findings demonstrated that underlying pathology mediates disease presentation in bvAD and bvFTD.

Survey on Acceptance of Passive Technology Monitoring for Early Detection of Cognitive Impairment.

INTRODUCTION: Digital biomarkers may act as a tool for early detection of changes in cognition. It is important to understand public perception of technologies focused on monitoring cognition to better guide the design of these tools and inform patients appropriately about the associated risks and benefits. Health care systems may also play a role in the clinical, legal, and financial implications of such technologies. OBJECTIVE: To evaluate public opinion on the use of passive technology for monitoring cognition. METHODS: This was a one-time, Internet-based survey conducted in English and Spanish. RESULTS: Within the English survey distributed in the USA (n = 173), 58.1% of respondents would be highly likely to agree to passive monitoring of cognition via a smartphone application. Thirty-eight percent of those with a higher degree of experience with technology were likely to agree to monitoring versus 20% of those with less experience with technology (p = 0.003). Sixty-two percent of non-health-care professionals were likely to agree to monitoring versus 45% of health-care workers (p = 0.012). There were significant concerns regarding privacy (p < 0.01). We compared the surveys answered in Spanish in Costa Rica via logistic regression (n = 43, total n = 216), adjusting for age, education level, health-care profession, owning a smartphone, experience with technology, and perception of cognitive decline. Costa Rican/Spanish-speaking respondents were 7 times more likely to select a high probability of agreeing to such a technology (p < 0.01). English-speaking respondents from the USA were 5 times more likely to be concerned about the impact on health insurance (p = 0.001) and life insurance (p = 0.01). CONCLUSIONS: Understanding public perception and ethical implications should guide the design of digital biomarkers for cognition. Privacy and the health-care system in which the participants take part are 2 major factors to be considered. It is the responsibility of researchers to convey the ethical and legal implications of cognition monitoring.

Clinical Correlates of Alzheimer's Disease Cerebrospinal Fluid Analytes in Primary Progressive Aphasia.

Background: While primary progressive aphasia (PPA) is associated with frontotemporal lobar degeneration (FTLD) pathology due to tau or TDP, clinical-pathological studies also demonstrate many cases have Alzheimer's disease (AD) pathology. The logopenic variant of PPA (lvPPA) is most often associated with AD pathology, but this has proven to be the least reliable PPA to diagnose using published clinical criteria. In this study, we used cerebrospinal fluid (CSF) analytes to identify patients with likely AD pathology, and relate phenotypic features of lvPPA to CSF. Methods: We studied 46 PPA patients who had available CSF analytes, including 26 with a clinical diagnosis of lvPPA, 9 with non-fluent/agrammatic variant (naPPA), and 11 with semantic variant (svPPA). We identified patients with likely AD pathology using amyloid-beta 1-42 (Aß1-42) < 192 pg/ml and assessed MRI gray matter atrophy in these patients. Results: We found that 23 (49%) of 46 PPA patients have a low CSF Aß1-42 level consistent with AD pathology. Twenty-one (91%) of 23 patients had a lvPPA phenotype, and 18 (79%) of 23 cases with an elevated CSF Aß1-42 level did not have a lvPPA phenotype. Patients with a lvPPA phenotype demonstrated GM atrophy in the left lateral temporal lobe, and this was also seen in those with a CSF Aß1-42 level < 192 pg/ml. Conclusion: The lvPPA clinical phenotype may be a useful screen for CSF analytes that are a surrogate for likely AD pathology, and may help establish eligibility of these patients for disease-modifying treatment trials.

Transcranial Direct Current Stimulation in Post-stroke Chronic Aphasia: The Impact of Baseline Severity and Task Specificity in a Pilot Sample.

Emerging evidence suggests that transcranial direct current stimulation (tDCS) can improve aspects of language production in persons with chronic non-fluent aphasia due to left hemisphere stroke. However, to date, studies exploring factors that predict response to tDCS in this or any patient population remain sparse, as are studies that investigate the specific aspects of language performance that are most responsive to stimulation. The current study explored factors that could predict recovery of language fluency and which aspects of language fluency could be expected to improve with the identified factor(s). We report nine patients who demonstrated deficits in fluency as assessed using the Cookie Theft picture description task of the Boston Diagnostic Aphasia Examination. In the treatment condition, subjects received a 2.0 mA current through 5 cm × 5 cm electrodes for 20 min at a site previously shown to elicit a patient-dependent optimal response to tDCS. They were then tested 2-weeks and 2-months after treatment. In the sham condition, a subset of these subjects were tested on the same protocol with sham instead of real tDCS. The current study assessed language fluency improvements in measures of production at the word-level and sentence level, grammatical accuracy, and lexical selection as a function of baseline aphasia severity. A more severe baseline language profile was associated with larger improvements in fluency at the word-level after real tDCS but not sham stimulation. These improvements were maintained at the 2-week follow-up. The results suggest that for at least some outcome measures, baseline severity may be an important factor in predicting the response to tDCS in patients with chronic non-fluent aphasia. Moving forward, the ability to identify patient factors that can predict response could help refine strategies for the administration of therapeutic tDCS, focusing attention on those patients most likely to benefit from stimulation.

Non-invasive Brain Stimulation in the Treatment of Post-stroke and Neurodegenerative Aphasia: Parallels, Differences, and Lessons Learned.

Numerous studies over the span of more than a decade have shown that non-invasive brain stimulation (NIBS) techniques, namely transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), can facilitate language recovery for patients who have suffered from aphasia due to stroke. While stroke is the most common etiology of aphasia, neurodegenerative causes of language impairment-collectively termed primary progressive aphasia (PPA)-are increasingly being recognized as important clinical phenotypes in dementia. Very limited data now suggest that (NIBS) may have some benefit in treating PPAs. However, before applying the same approaches to patients with PPA as have previously been pursued in patients with post-stroke aphasia, it will be important for investigators to consider key similarities and differences between these aphasia etiologies that is likely to inform successful approaches to stimulation. While both post-stroke aphasia and the PPAs have clear overlaps in their clinical phenomenology, the mechanisms of injury and theorized neuroplastic changes associated with the two etiologies are notably different. Importantly, theories of plasticity in post-stroke aphasia are largely predicated on the notion that regions of the brain that had previously been uninvolved in language processing may take on new compensatory roles. PPAs, however, are characterized by slow distributed degeneration of cellular units within the language system; compensatory recruitment of brain regions to subserve language is not currently understood to be an important aspect of the condition. This review will survey differences in the mechanisms of language representation between the two etiologies of aphasia and evaluate properties that may define and limit the success of different neuromodulation approaches for these two disorders.

Individualized treatment with transcranial direct current stimulation in patients with chronic non-fluent aphasia due to stroke.

While evidence suggests that transcranial direct current stimulation (tDCS) may facilitate language recovery in chronic post-stroke aphasia, individual variability in patient response to different patterns of stimulation remains largely unexplored. We sought to characterize this variability among chronic aphasic individuals, and to explore whether repeated stimulation with an individualized optimal montage could lead to persistent reduction of aphasia severity. In a two-phase study, we first stimulated patients with four active montages (left hemispheric anode or cathode; right hemispheric anode or cathode) and one sham montage (Phase 1). We examined changes in picture naming ability to address (1) variability in response to different montages among our patients, and (2) whether individual patients responded optimally to at least one montage. During Phase 2, subjects who responded in Phase 1 were randomized to receive either real-tDCS or to receive sham stimulation (10 days); patients who were randomized to receive sham stimulation first were then crossed over to receive real-tDCS (10 days). In both phases, 2 mA tDCS was administered for 20 min per real-tDCS sessions and patients performed a picture naming task during stimulation. Patients' language ability was re-tested after 2-weeks and 2-months following real and sham tDCS in Phase 2. In Phase 1, despite considerable individual variability, the greatest average improvement was observed after left-cathodal stimulation. Seven out of 12 subjects responded optimally to at least one montage as demonstrated by transient improvement in picture-naming. In Phase 2, aphasia severity improved at 2-weeks and 2-months following real-tDCS but not sham. Despite individual variability with respect to optimal tDCS approach, certain montages result in consistent transient improvement in persons with chronic post-stroke aphasia. This preliminary study supports the notion that individualized tDCS treatment may enhance aphasia recovery in a persistent manner.

Utilizing repetitive transcranial magnetic stimulation to improve language function in stroke patients with chronic non-fluent aphasia.

Transcranial magnetic stimulation (TMS) has been shown to significantly improve language function in patients with non-fluent aphasia(1). In this experiment, we demonstrate the administration of low-frequency repetitive TMS (rTMS) to an optimal stimulation site in the right hemisphere in patients with chronic non-fluent aphasia. A battery of standardized language measures is administered in order to assess baseline performance. Patients are subsequently randomized to either receive real rTMS or initial sham stimulation. Patients in the real stimulation undergo a site-finding phase, comprised of a series of six rTMS sessions administered over five days; stimulation is delivered to a different site in the right frontal lobe during each of these sessions. Each site-finding session consists of 600 pulses of 1 Hz rTMS, preceded and followed by a picture-naming task. By comparing the degree of transient change in naming ability elicited by stimulation of candidate sites, we are able to locate the area of optimal response for each individual patient. We then administer rTMS to this site during the treatment phase. During treatment, patients undergo a total of ten days of stimulation over the span of two weeks; each session is comprised of 20 min of 1 Hz rTMS delivered at 90% resting motor threshold. Stimulation is paired with an fMRI-naming task on the first and last days of treatment. After the treatment phase is complete, the language battery obtained at baseline is repeated two and six months following stimulation in order to identify rTMS-induced changes in performance. The fMRI-naming task is also repeated two and six months following treatment. Patients who are randomized to the sham arm of the study undergo sham site-finding, sham treatment, fMRI-naming studies, and repeat language testing two months after completing sham treatment. Sham patients then cross over into the real stimulation arm, completing real site-finding, real treatment, fMRI, and two- and six-month post-stimulation language testing.

Finding the Right Words: Transcranial Magnetic Stimulation Improves Discourse Productivity in Non-fluent Aphasia After Stroke.

BACKGROUND: Loss of fluency is a significant source of functional impairment in many individuals with aphasia. Repetitive transcranial magnetic stimulation (rTMS) administered to the right inferior frontal gyrus (IFG) has been shown to facilitate naming in persons with chronic left hemisphere stroke and non-fluent aphasia. However, changes in fluency in aphasic subjects receiving rTMS have not been adequately explored. AIMS: To determine whether rTMS improves fluency in individuals with chronic nonfluent aphasia, and to identify aspects of fluency that are modulated in persons who respond to rTMS. METHODS #ENTITYSTARTX00026; PROCEDURES: Ten individuals with left hemisphere MCA strokes and mild to moderate non-fluent aphasia participated in the study. Before treatment, subjects were asked to describe the Cookie Theft picture in three separate sessions. During treatment, all subjects received 1200 pulses of 1 Hz rTMS daily in 10 sessions over two weeks at a site that had previously been shown to improve naming. Subjects repeated the Cookie Theft description two months after treatment. Five subjects initially received sham stimulation instead of real TMS. Two months after sham treatment, these individuals received real rTMS. Performance both at baseline and after stimulation was coded using Quantitative Production Analysis (Saffran, Berndt & Schwartz, 1989) and Correct Information Unit (Nicholas & Brookshire, 1993) analysis. OUTCOMES #ENTITYSTARTX00026; RESULTS: Across all subjects (n=10), real rTMS treatment resulted in a significant increase in multiple measures of discourse productivity compared to baseline performance. There was no significant increase in measures of sentence productivity or grammatical accuracy. There was no significant increase from baseline in the sham condition (n=5) on any study measures. CONCLUSIONS: Stimulation of the right IFG in patients with chronic non-fluent aphasia facilitates discourse production. We posit that this effect may be attributable to improved lexical-semantic access.

The right hemisphere is not unitary in its role in aphasia recovery.

Neurologists and aphasiologists have debated for over a century whether right hemisphere recruitment facilitates or impedes recovery from aphasia. Here we present a well-characterized patient with sequential left and right hemisphere strokes whose case substantially informs this debate. A 72-year-old woman with chronic nonfluent aphasia was enrolled in a trial of transcranial magnetic stimulation (TMS). She underwent 10 daily sessions of inhibitory TMS to the right pars triangularis. Brain activity was measured during picture naming using functional magnetic resonance imaging (fMRI) prior to TMS exposure and before and after TMS on the first day of treatment. Language and cognition were tested behaviorally three times prior to treatment, and at 2 and 6 months afterward. Inhibitory TMS to the right pars triangularis induced immediate improvement in naming, which was sustained 2 months later. fMRI confirmed a local reduction in activity at the TMS target, without expected increased activity in corresponding left hemisphere areas. Three months after TMS, the patient suffered a right hemisphere ischemic stroke, resulting in worsening of aphasia without other clinical deficits. Behavioral testing 3 months later confirmed that language function was impacted more than other cognitive domains. The paradoxical effects of inhibitory TMS and the stroke to the right hemisphere demonstrate that even within a single patient, involvement of some right hemisphere areas may support recovery, while others interfere. The behavioral evidence confirms that compensatory reorganization occurred within the right hemisphere after the original stroke. No support is found for interhemispheric inhibition, the theoretical framework on which most therapeutic brain stimulation protocols for aphasia are based.

Are networks for residual language function and recovery consistent across aphasic patients?

OBJECTIVES: If neuroplastic changes in aphasia are consistent across studies, this would imply relatively stereotyped mechanisms of recovery which could guide the design of more efficient noninvasive brain stimulation treatments. To address this question, we performed a meta-analysis of functional neuroimaging studies of chronic aphasia after stroke. METHODS: Functional neuroimaging articles using language tasks in patients with chronic aphasia after stroke (n = 105) and control subjects (n = 129) were collected. Activation likelihood estimation meta-analysis determined areas of consistent activity in each group. Functional homology between areas recruited by aphasic patients and controls was assessed by determining whether they activated under the same experimental conditions. RESULTS: Controls consistently activated a network of left hemisphere language areas. Aphasic patients consistently activated some spared left hemisphere language nodes, new left hemisphere areas, and right hemisphere areas homotopic to the control subjects' language network. Patients with left inferior frontal lesions recruited right inferior frontal gyrus more reliably than those without. Some areas, including right dorsal pars opercularis, were functionally homologous with corresponding control areas, while others, including right pars triangularis, were not. CONCLUSIONS: The network of brain areas aphasic patients recruit for language functions is largely consistent across studies. Several recruitment mechanisms occur, including persistent function in spared nodes, compensatory recruitment of alternate nodes, and recruitment of areas that may hinder recovery. These findings may guide development of brain stimulation protocols that can be applied across populations of aphasic patients who share common attributes.

Stimulating conversation: enhancement of elicited propositional speech in a patient with chronic non-fluent aphasia following transcranial magnetic stimulation.

Although evidence suggests that patients with left hemisphere strokes and non-fluent aphasia who receive 1Hz repetitive transcranial magnetic stimulation (rTMS) over the intact right inferior frontal gyrus experience persistent benefits in naming, it remains unclear whether the effects of rTMS in these patients generalize to other language abilities. We report a subject with chronic non-fluent aphasia who showed stable deficits of elicited propositional speech over the course of 5 years, and received 1200 pulses of 1Hz rTMS daily for 10 days at a site identified as being optimally responsive to rTMS in this patient. Consistent with prior studies there was improvement in object naming, with a statistically significant improvement in action naming. Improvement was also demonstrated in picture description at 2, 6, and 10 months after rTMS with respect to the number of narrative words and nouns, sentence length, and use of closed class words. Compared to his baseline performance, the patient showed significant improvement on the Western Aphasia Battery (WAB) subscale for spontaneous speech. These findings suggest that manipulation of the intact contralesional cortex in patients with non-fluent aphasia may result in language benefits that generalize beyond naming to include other aspects of language production.