The volume and the distribution of premorbid white matter hyperintensities: Impact on post-stroke aphasia.

White matter hyperintensities (WMH) are a radiological manifestation of progressive white matter integrity loss. The total volume and distribution of WMH within the corpus callosum have been associated with pathological cognitive ageing processes but have not been considered in relation to post-stroke aphasia outcomes. We investigated the contribution of both the total volume of WMH, and the extent of WMH lesion load in the corpus callosum to the recovery of language after first-ever stroke. Behavioural and neuroimaging data from individuals (N = 37) with a left-hemisphere stroke were included at the early subacute stage of recovery. Spoken language comprehension and production abilities were assessed using word and sentence-level tasks. Neuroimaging data was used to derive stroke lesion variables (volume and lesion load to language critical regions) and WMH variables (WMH volume and lesion load to three callosal segments). WMH volume did not predict variance in language measures, when considered together with stroke lesion and demographic variables. However, WMH lesion load in the forceps minor segment of the corpus callosum explained variance in early subacute comprehension abilities (t = -2.59, p = .01) together with corrected stroke lesion volume and socio-demographic variables. Premorbid WMH lesions in the forceps minor were negatively associated with early subacute language comprehension after aphasic stroke. This negative impact of callosal WMH on language is consistent with converging evidence from pathological ageing suggesting that callosal WMH disrupt the neural networks supporting a range of cognitive functions.

Return to work for stroke survivors with aphasia: A quantitative scoping review.

The international incidence of stroke in people of working age is rising. As such, meaningful work return is a major rehabilitation goal for many individuals, including those with aphasia. This scoping review aimed to outline the post-stroke aphasia evidence related to work outcomes, factors influencing employment along with contemporary vocational-language and communication rehabilitation practice. The review employed terms related to aphasia, stroke, rehabilitation, and return to work in publications preceding 25.6.2023. Data were descriptively analysed, and vocational outcomes were summarized at defined timepoints. Of the 908 articles reviewed, 31 papers were included. Individuals with post-stroke aphasia consistently have lower rates of return to work than those post-stroke without aphasia. Employment at one year was 34.29% for those with aphasia compared to 58.46% for people without aphasia. No literature reported vocational-language assessment practices and there were minimal work-focused aphasia interventions identified. There was insufficient evidence to clearly identify person-related, rehabilitation, workplace or other factors influencing work return. This scoping review has identified that there are gaps in knowledge about the factors that influence work return and targeted vocational rehabilitation for this group. Future research to optimize return to work for individuals with aphasia is recommended.

Tumour necrosis factor-mediated macrophage activation in the target organ is critical for clinical manifestation of uveitis.

Clinically available anti-tumour necrosis factor (TNF) biologics, which inhibit both soluble (sTNF) and transmembrane forms (tmTNF) of TNF, eliminating all TNF signalling, have successfully treated autoimmune diseases including uveitis. These have potentially serious side effects such as reactivation of latent Mycobacterium tuberculosis and, therefore, more specific inhibition of TNF signalling pathways may maintain clinical efficacy while reducing adverse effects. To determine the effects of specific pharmacological inhibition of sTNF on macrophage activation and migration, we used a mouse model of uveitis (experimental autoimmune uveoretinitis; EAU). We show that selective inhibition of sTNF is sufficient to suppress EAU by limiting inflammatory CD11b(+) macrophages and CD4(+) T cell migration into the eye. However, inhibition of both sTNF and tmTNF is required to inhibit interferon-γ-induced chemokine receptor 2, CD40, major histocompatibility complex class II and nitric oxide (NO) up-regulation, and signalling via tmTNF is sufficient to mediate tissue damage. In confirmation, intravitreal inhibition of sTNF alone did not suppress disease, and inflammatory cells that migrated into the eye were activated, generating NO, thus causing structural damage to the retina. In contrast, intravitreal inhibition of both sTNF and tmTNF suppressed macrophage activation and therefore disease. We conclude that sTNF is required for inflammatory cell infiltration into target tissue, but at the tissue site inhibition of both sTNF and tmTNF is required to inhibit macrophage activation and to protect from tissue damage.

Systemic and local anti-C5 therapy reduces the disease severity in experimental autoimmune uveoretinitis.

Activation of complement occurs during autoimmune retinal and intraocular inflammatory disease as well as neuroretinal degenerative disorders. The cleavage of C5 into fragments C5a and C5b is a critical event during the complement cascade. C5a is a potent proinflammatory anaphylatoxin capable of inducing cell migration, adhesion and cytokine release, while membrane attack complex C5b-9 causes cell lysis. Therapeutic approaches to prevent complement-induced inflammation include the use of blocking monoclonal antibodies (mAb) to prevent C5 cleavage. In these current experiments, the rat anti-mouse C5 mAb (BB5.1) was utilized to investigate the effects of inhibition of C5 cleavage on disease progression and severity in experimental autoimmune uveoretinitis (EAU), a model of organ-specific autoimmunity in the eye characterized by structural retinal damage mediated by infiltrating macrophages. Systemic treatment with BB5.1 results in significantly reduced disease scores compared with control groups, while local administration results in an earlier resolution of disease. In vitro, contemporaneous C5a and interferon-gamma signalling enhanced nitric oxide production, accompanied by down-regulation of the inhibitory myeloid CD200 receptor, contributing to cell activation. These experiments demonstrate that C5 cleavage contributes to the full expression of EAU, and that selective C5 blockade via systemic and local routes of administration can suppress disease. This presents great therapeutic potential to protect against tissue damage during autoimmune responses in the retina or inflammation-induced degenerative disease.

Effects of subthalamic deep brain stimulation on noun/verb generation and selection from competing alternatives in Parkinson's disease.

BACKGROUND AND AIMS: Impaired generation of verbs relative to nouns has been reported in Parkinson's disease (PD) and has been associated with the frontal pathophysiology of PD. The aim of the present study was to measure noun/verb generation abilities in PD and to determine whether noun/verb generation is affected by stimulation of the subthalamic nucleus (STN). PATIENTS AND METHODS: 8 participants who had been diagnosed with PD and had received surgery for deep brain stimulation (DBS) of the STN as well as 15 control participants completed a noun/verb generation task with four probe-response conditions-namely, noun-noun, verb-noun, noun-verb and verb-verb conditions. Patients with PD were assessed while receiving STN stimulation and without stimulation. RESULTS: During the off stimulation condition, patients with PD presented with a selective deficit in verb generation compared with control participants. However, when receiving STN stimulation, patients with PD produced significantly more errors than controls during the noun-noun and verb-verb conditions, supporting evidence from previous studies that STN stimulation modulates a frontotemporal network associated with word generation. Finally, errors during verb generation were significantly correlated with item selection constraint (ie, the degree to which a response competes with other response alternatives) in the on stimulation condition, but not the off stimulation condition. CONCLUSION: Our results suggest that STN stimulation affects the ability to select from many competing lexical alternatives during verb generation.

The role of lipoprotein-associated phospholipase A2 in a murine model of experimental autoimmune uveoretinitis.

Macrophage activation is, in part, regulated via hydrolysis of oxidised low density lipoproteins by Lipoprotein-Associated phospholipase A2 (Lp-PLA2), resulting in increased macrophage migration, pro-inflammatory cytokine release and chemokine expression. In uveitis, tissue damage is mediated as a result of macrophage activation; hence inhibition of Lp-PLA2 may limit macrophage activation and protect the tissue. Utilising Lp-PLA2 gene-deficient (KO) mice and a pharmacological inhibitor of Lp-PLA2 (SB-435495) we aimed to determine the effect of Lp-PLA2 suppression in mediating retinal protection in a model of autoimmune retinal inflammation, experimental autoimmune uveoretinitis (EAU). Following immunisation with RBP-3 (IRBP) 1-20 or 161-180 peptides, clinical disease was monitored and severity assessed, infiltrating leukocytes were enumerated by flow cytometry and tissue destruction quantified by histology. Despite ablation of Lp-PLA2 enzyme activity in Lp-PLA2 KO mice or wild-type mice treated with SB-435495, the number of infiltrating CD45+ cells in the retina was equivalent to control EAU animals, and there was no reduction in disease severity. Thus, despite the reported beneficial effects of therapeutic Lp-PLA2 depletion in a variety of vascular inflammatory conditions, we were unable to attenuate disease, show delayed disease onset or prevent progression of EAU in Lp-PLA2 KO mice. Although EAU exhibits inflammatory vasculopathy there is no overt defect in lipid metabolism and given the lack of effect following Lp-PLA2 suppression, these data support the hypothesis that sub-acute autoimmune inflammatory disease progresses independently of Lp-PLA2 activity.

Processing lexical ambiguities in word triplets: evidence of lexical-semantic deficits following dominant nonthalamic subcortical lesions.

Lexical-semantic function was investigated in 10 participants with lesions of the dominant nonthalamic subcortical (NS) region and a matched normal control group. Participants performed speeded lexical decisions on the 3rd member of auditorily presented word triplets. The 4 critical triplet conditions were concordant (coin-bank-money), discordant (river-bank-money), neutral (day-bank-money), and unrelated (river-day-money). When the interstimulus interval (ISI) between the words in the triplets was 100 ms, patients with NS lesions obtained priming that indicated nonselective lexical access; at 1,250-ms ISI, however, there was no significant priming effect. This pattern of results is consistent with the view that patients with NS lesions can automatically access lexical-semantic information but may be unable to sustain lexical activation through controlled or attentional forms of processing.

Understanding ambiguous words in biased sentences: evidence of transient contextual effects in individuals with nonthalamic subcortical lesions and Parkinson's disease.

A cross-modal priming experiment was used to investigate lexical ambiguity resolution during sentence processing in individuals with nonthalamic subcortical lesions (NSL) (n = 10), compared to matched normal controls (n = 10), and individuals with cortical lesions (CL) (n = 10) and Parkinson's disease (PD) (n = 10). Critical sentences biased towards the dominant or subordinate meaning of a sentence-final lexical ambiguity were presented auditorily, followed after a short interstimulus-interval (ISI) (0 msec) or a long ISI (1000 msec), by the presentation of a visual target which was related to the dominant or subordinate meaning, or was an unrelated control word. Subjects made speeded lexical decisions on the targets. At the short ISI, lexical activation for the neurological patient groups appeared influenced by contextual information to a greater extent than in normal controls, which may indicate delayed lexical decision making or disturbed automatic lexical activation. At the long ISI, only the PD and NSL individuals failed to selectively activate the contextually appropriate meaning, suggesting a breakdown in the attention-based control of semantic activation through contextual integration. This finding may implicate disruptions to proposed frontal-striatal mechanisms which mediate attentional allocation and strategy formation.

Discourse priming of homophones in individuals with dominant nonthalamic subcortical lesions, cortical lesions and Parkinson's disease.

An on-line priming experiment was used to investigate discourse-level processing in four matched groups of subjects: individuals with nonthalamic subcortical lesions (NSL) (n = 10), normal control subjects (n = 10), subjects with Parkinson's disease (PD) (n = 10), and subjects with cortical lesions (n = 10). Subjects listened to paragraphs that ended in lexical ambiguities, and then made speeded lexical decisions on visual letter strings that were: nonwords, matched control words, contextually appropriate associates of the lexical ambiguity, contextually inappropriate associates of the ambiguity, and inferences (representing information which could be drawn from the paragraphs but was not explicitly stated). Targets were presented at an interstimulus interval (ISI) of 0 or 1000 ms. NSL and PD subjects demonstrated priming for appropriate and inappropriate associates at the short ISI, similar to control subjects and cortical lesion subjects, but were unable to demonstrate selective priming of the appropriate associate and inference words at the long ISI. These results imply intact automatic lexical processing and a breakdown in discourse-based meaning selection and inference development via attentional/strategic mechanisms.