Semantic variant primary progressive aphasia: Practical recommendations for treatment from 20 years of behavioural research

People with semantic variant primary progressive aphasia (svPPA) present with a char-acteristic progressive breakdown of semantic knowledge. There are currently no pharmacological interventions to cure or slow svPPA, but promising behavioural approaches are increasingly reported. This article offers an overview of the last two decades of research into interventions to support language in people with svPPA including recommendations for clinical practice and future research based on the best available evidence. We offer a lay summary in English, Spanish and French for education and dissemination purposes. This paper discusses the implications of right-versus left-predominant atrophy in svPPA, which naming therapies offer the best outcomes and how to capitalise on preserved long-term memory systems. Current knowledge regarding the maintenance and generalisation of language therapy gains is described in detail along with the development of compensatory approaches and educational and support group programmes. It is concluded that there is evidence to support an integrative framework of treatment and care as best practice for svPPA. Such an approach should combine rehabilitation interventions addressing the language impairment, compensatory approaches to support activities of daily living and provision of education and support within the context of dementia

Principles and philosophies for speech and language therapists working with people with primary progressive aphasia: An international expert consensus

Purpose: Primary progressive aphasia (PPA) is a language-led dementia associated with Alzheimer’s pathology and fronto-temporal lobar degeneration. Multiple tailored speech and language interventions have been developed for people with PPA. Speech and language therapists/speech-language pathologists (SLT/Ps) report lacking confidence in identifying the most pertinent interventions options relevant to their clients living with PPA during their illness trajectory. Materials and methods: The aim of this study was to establish a consensus amongst 15 clinical-academic SLT/Ps on best practice in selection and delivery of speech and language therapy interventions for people with PPA. An online nominal group technique (NGT) and consequent focus group session were held. NGT rankings were aggregated and focus groups video recorded, transcribed, and reflexive thematic analysis undertaken. Results: The results of the NGT identified 17 items. Two main themes and seven further subthemes were identified in the focus groups. The main themes comprised (1) philosophy of person-centredness and (2) complexity. The seven subthemes were knowing people deeply, preventing disasters, practical issues, professional development, connectedness, barriers and limitations, and peer support and mentoring towards a shared understanding. Conclusions: This study describes the philosophy of expert practice and outlines a set of best practice principles when working with people with PPA.Implications for rehabilitation Primary progressive aphasia (PPA) describes a group of language led dementias which deteriorate inexorably over time. Providing speech and language therapy for people with PPA is complex and must be person centred and bespoke. This study describes the philosophy of expert practice and outlines a set of best practice principles for speech and language therapists/pathologists working with people with people with PPA

Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington\u27s disease

Neurons in Huntington\u27s disease exhibit selective morphological and subcellular alterations in the striatum and cortex. The link between these neuronal changes and behavioral abnormalities is unclear. We investigated relationships between essential neuronal changes that predict motor impairment and possible involvement of the corticostriatal pathway in developing behavioral phenotypes. We therefore generated heterozygote mice expressing the N-terminal one-third of huntingtin with normal (CT18) or expanded (HD46, HD100) glutamine repeats. The HD mice exhibited motor deficits between 3 and 10 months. The age of onset depended on an expanded polyglutamine length; phenotype severity correlated with increasing age. Neuronal changes in the striatum (nuclear inclusions) preceded the onset of phenotype, whereas cortical changes, especially the accumulation of huntingtin in the nucleus and cytoplasm and the appearance of dysmorphic dendrites, predicted the onset and severity of behavioral deficits. Striatal neurons in the HD mice displayed altered responses to cortical stimulation and to activation by the excitotoxic agent NMDA. Application of NMDA increased intracellular Ca(2+) levels in HD100 neurons compared with wild-type neurons. Results suggest that motor deficits in Huntington\u27s disease arise from cumulative morphological and physiological changes in neurons that impair corticostriatal circuitry

Primary progressive aphasia: a clinical approach

This work was supported by the Alzheimer’s Society (AS-PG-16-007), the National Institute for Health Research University College London Hospitals Biomedical Research Centre and the UCL Leonard Wolfson Experimental Neurology Centre (PR/ylr/18575). Individual authors were supported by the Leonard Wolfson Foundation (Clinical Research Fellowship to CRM), the National Institute for Health Research (NIHR Doctoral Training Fellowship to AV), the National Brain Appeal–Frontotemporal Dementia Research Fund (CNC) and the Medical Research Council (PhD Studentships to CJDH and RLB, MRC Research Training Fellowship to PDF, MRC Clinician Scientist to JDR). MNR and NCF are NIHR Senior Investigators. SJC is supported by Grants from ESRC-NIHR (ES/L001810/1), EPSRC (EP/M006093/1) and Wellcome Trust (200783). JDW was supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (091673/Z/10/Z)

Abnormal language-related oscillatory responses in primary progressive aphasia

Patients with Primary Progressive Aphasia (PPA) may react to linguistic stimuli differently than healthy controls, reflecting degeneration of language networks and engagement of compensatory mechanisms. We used magnetoencephalography (MEG) to evaluate oscillatory neural responses in sentence comprehension, in patients with PPA and age-matched controls. Participants viewed sentences containing semantically and syntactically anomalous words that evoke distinct oscillatory responses. For age-matched controls, semantic anomalies elicited left-lateralized 8-30 Hz power decreases distributed along ventral brain regions, whereas syntactic anomalies elicited bilateral power decreases in both ventral and dorsal regions. In comparison to controls, patients with PPA showed altered patterns of induced oscillations, characterized by delayed latencies and attenuated amplitude, which were correlated with linguistic impairment measured offline. The recruitment of right hemisphere temporo-parietal areas (also found in controls) was correlated with preserved semantic processing abilities, indicating that preserved neural activity in these regions was able to support successful semantic processing. In contrast, syntactic processing was more consistently impaired in PPA, regardless of neural activity patterns, suggesting that this domain of language is particularly vulnerable to the neuronal loss. In addition, we found that delayed peak latencies of oscillatory responses were associated with lower accuracy for detecting semantic anomalies, suggesting that language deficits observed in PPA may be linked to delayed or slowed information processing.Ontario Brain Institute Ontario Neurodegenerative Disease Research Initiative (ONDRI); Alzheimer's Association New Investigator Research Grant; Ontario Research CoalitionOpen Access Journal.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Electrophysiological connectivity markers of preserved language functions in post-stroke aphasia

Post-stroke aphasia is a consequence of localized stroke-related damage as well as global disturbances in a highly interactive and bilaterally-distributed language network. Aphasia is increasingly accepted as a network disorder and it should be treated as such when examining the reorganization and recovery mechanisms after stroke. In the current study, we sought to investigate reorganized patterns of electrophysiological connectivity, derived from resting-state magnetoencephalography (rsMEG), in post-stroke chronic (>6 months after onset) aphasia. We implemented amplitude envelope correlations (AEC), a metric of connectivity commonly used to describe slower aspects of interregional communication in resting-state electrophysiological data. The main focus was on identifying the oscillatory frequency bands and frequency-specific spatial topology of connections associated with preserved language abilities after stroke. RsMEG was recorded for 5 min in 21 chronic stroke survivors with aphasia and in 20 matched healthy controls. Source-level MEG activity was reconstructed and summarized within 72 atlas-defined brain regions (or nodes). A 72 × 72 leakage-corrected connectivity (of AEC) matrix was obtained for frequencies from theta to low-gamma (4–50 Hz). Connectivity was compared between groups, and, the correlations between connectivity and subscale scores from the Western Aphasia Battery (WAB) were evaluated in the stroke group, using partial least squares analyses. Posthoc multiple regression analyses were also conducted on a graph theory measure of node strengths, derived from significant connectivity results, to control for node-wise properties (local spectral power and lesion sizes) and demographic and stroke-related variables. Connectivity among the left hemisphere regions, i.e. those ipsilateral to the stroke lesion, was greatly reduced in stroke survivors with aphasia compared to matched healthy controls in the alpha (8–13 Hz; p = 0.011) and beta (15–30 Hz; p = 0.001) bands. The spatial topology of hypoconnectivity in the alpha vs. beta bands was distinct, revealing a greater involvement of ventral frontal, temporal and parietal areas in alpha, and dorsal frontal and parietal areas in beta. The node strengths from alpha and beta group differences remained significant after controlling for nodal spectral power. AEC correlations with WAB subscales of object naming and fluency were significant. Greater alpha connectivity was associated with better naming performance (p = 0.045), and greater connectivity in both the alpha (p = 0.033) and beta (p = 0.007) bands was associated with better speech fluency performance. The spatial topology was distinct between these frequency bands. The node strengths remained significant after controlling for age, time post stroke onset, nodal spectral power and nodal lesion sizes. Our findings provide important insights into the electrophysiological connectivity profiles (frequency and spatial topology) potentially underpinning preserved language abilities in stroke survivors with aphasia. © 2022Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Facilitated Glutamatergic Transmission in the Striatum of D 2 Dopamine Receptor-Deficient Mice

Dopamine (DA) receptors play an important role in the modulation of excitability and the responsiveness of neurons to activation of excitatory amino acid receptors in the striatum. In the present study, we utilized mice with genetic deletion of D2 or D4 DA receptors and their wild-type (WT) controls to examine if the absence of either receptor subtype affects striatal excitatory synaptic activity. Immunocytochemical analysis verified the absence of D2 or D4 protein expression in the striatum of receptor-deficient mutant animals. Sharp electrode current- and whole cell patch voltage-clamp recordings were obtained from slices of receptor-deficient and WT mice. Basic membrane properties were similar in D2 and D4 receptor-deficient mutants and their respective WT controls. In current-clamp recordings in WT animals, very little low-amplitude spontaneous synaptic activity was observed. The frequency of these spontaneous events was increased slightly in D2 receptor-deficient mice. In addition, large-amplitude depolarizations were observed in a subset of neurons from only the D2 receptor-deficient mutants. Bath application of the K+ channel blocker 4-aminopyridine (100 μM) and bicuculline methiodide (10 μM, to block synaptic activity due to activation of GABAA receptors) markedly increased spontaneous synaptic activity in receptor-deficient mutants and WTs. Under these conditions, D2 receptor-deficient mice displayed significantly more excitatory synaptic activity than their WT controls, while there was no difference between D4receptor-deficient mice and their controls. In voltage-clamp recordings, there was an increase in frequency of spontaneous glutamate receptor-mediated inward currents without a change in mean amplitude in D2 receptor-deficient mutants. In WT mice, activation of D2 family receptors with quinpirole decreased spontaneous excitatory events and conversely sulpiride, a D2 receptor antagonist, increased activity. In D2 receptor-deficient mice, sulpiride had very little net effect. Morphologically, a subpopulation of medium-sized spiny neurons from D2 receptor-deficient mice displayed decreased dendritic spines compared with cells from WT mice. These results provide evidence that D2 receptors play an important role in the regulation of glutamate receptor-mediated activity in the corticostriatal or thalamostriatal pathway. These receptors may function as gatekeepers of glutamate release or of its subsequent effects and thus may protect striatal neurons from excessive excitation.Fil: Cepeda, C.. University of California at Los Angeles; Estados UnidosFil: Hurst, R. S.. University of California at Los Angeles; Estados UnidosFil: Altemus, K. L.. University of California at Los Angeles; Estados UnidosFil: Flores Hernández, J.. University of California at Los Angeles; Estados UnidosFil: Calvert, C. R.. University of California at Los Angeles; Estados UnidosFil: Jokel, E. S.. University of California at Los Angeles; Estados UnidosFil: Grandy, David K.. Oregon Health Sciences University; Estados UnidosFil: Low, Malcolm J.. Oregon Health Sciences University; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Ariano, M. A.. The Chicago Medical School; Estados UnidosFil: Levine, M. S.. University of California at Los Angeles; Estados Unido