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Photomicrographs showing severity of neuronal loss across temporal lobe regions, sections also showing occasional Pick cells (Case 15: haematoxylin and eosin). (A) Superior temporal gyrus is well preserved, cortical laminae and columns are clearly visible. (B) Middle temporal gyrus shows moderately severe cell loss. (C) Medial bank of the collateral sulcus shows extremely severe neuronal loss. (D) Moderate neuronal loss in CA1.
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Semantic dementia is a syndrome of progressive deterioration in semantic memory (knowledge of objects, people, concepts and words). It falls within the clinical spectrum of frontotemporal dementia but its pathology is yet to be studied systematically. This study included 18 consecutive post mortem cases meeting clinical criteria for semantic dement...
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Context 1
... the series, the distribution of the microscopic abnor- malities confirmed the involvement of the temporal lobe and, in particular, the anteroinferior-medial temporal gyri (Fig. 3). As predicted from recent volumetric MRI studies, the medial temporal cortices showed severe neuronal loss ( Davies et al., 2004) with median score of 3 for perirhinal, entorhinal, pos- terior parahippocampal and anterior CA1 (Fig. 4). The peri- rhinal cortex achieved the worst rating most consistently (all except Case 12). Across the ...
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Objective
Anti-leucine-rich glioma-inactivated 1 limbic encephalitis (LGI1-LE) is a rare autoimmune condition that affects the structural integrity and functioning of the brain’s limbic system. Little is known about its impact on long-term neuropsychological functioning and the structural integrity of the medial temporal lobe. Here we examined the...
Citations
... Overall, SD patients experience a progressive and severe loss of conceptual knowledge, with the main deficit involving word meaning (Gorno-Tempini et al., 2011;Mesulam et al., 2014). This results in anomia, impaired word comprehension and fluent but content-empty speech (Davies et al., 2005), and with preserved grammar and speech articulation (Mesulam et al., 2014). Furthermore, SD can affect face recognition (Snowden et al., 2004;Luzzi et al., 2017), object feature attribution (Garrard and Carroll, 2006), sound-picture matching (Bozeat et al., 2000), object-use matching (Corbett et al., 2009), and arithmetic knowledge (Luzzi et al., 2013). ...
The semantic variant of primary progressive aphasia (svPPA), known also as “semantic dementia (SD),” is a neurodegenerative disorder that pertains to the frontotemporal lobar degeneration clinical syndromes. There is currently no approved pharmacological therapy for all frontotemporal dementia variants. Transcranial direct current stimulation (tDCS) is a promising non-invasive brain stimulation technique capable of modulating cortical excitability through a sub-threshold shift in neuronal resting potential. This technique has previously been applied as adjunct treatment in Alzheimer’s disease, while data for frontotemporal dementia are controversial. In this scoped review, we summarize and critically appraise the currently available evidence regarding the use of tDCS for improving performance in naming and/or matching tasks in patients with svPPA. Clinical trials addressing this topic were identified through MEDLINE (accessed by PubMed) and Web of Science, as of November 2022, week 3. Clinical trials have been unable to show a significant benefit of tDCS in enhancing semantic performance in svPPA patients. The heterogeneity of the studies available in the literature might be a possible explanation. Nevertheless, the results of these studies are promising and may offer valuable insights into methodological differences and overlaps, raising interest among researchers in identifying new non-pharmacological strategies for treating svPPA patients. Further studies are therefore warranted to investigate the potential therapeutic role of tDCS in svPPA.
... Primary progressive aphasia (PPA) is a family of neurodegenerative syndromes characterized by a relatively isolated and progressive loss of speech and language abilities that occurs when either frontotemporal lobar degeneration (FTLD) or Alzheimer's disease (AD) pathology preferentially targets language-related brain networks. Within this family, three main variants have been described (Gorno-Tempini et al., 2011): (1) the non-fluent/agrammatic variant (nfvPPA), characterized by impaired motor speech and/or agrammatism, and most often associated with abnormal deposition of microtubule-associated protein tau (Josephs et al., 2006;Kertesz et al., 2005;Spinelli et al., 2017); (2) the semantic variant (svPPA), characterized by impaired naming and single word comprehension, and most often associated with abnormal deposition of transactive response DNA-binding protein of 43kD (TDP-43) (Davies et al., 2005;Marsel Mesulam et al., 2008;Snowden et al., 2007;Spinelli et al., 2017); and (3) the logopenic variant (lvPPA), characterized by impaired single-word retrieval in spontaneous speech and naming and impaired repetition of phrases and sentences, and most often caused by underlying AD pathology (Giannini et al., 2017;Grossman, 2010;Harris & Jones, 2014;Kirshner, 2012;Mesulam, 2008;Migliaccio et al., 2009;Rabinovici et al., 2008;Rohrer et al., 2012;Spinelli et al., 2017). ...
The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis.
... https://doi.org/10. /2023 associated with abnormal deposition of microtubule-associated protein tau (Josephs et al. 2006;Kertesz et al. 2005;Spinelli et al. 2017); 2) the semantic variant (svPPA), characterized by impaired naming and single word comprehension, and most often associated with abnormal deposition of transactive response DNA-binding protein of 43kD (TDP-43) (Davies et al. 2005;Snowden, Neary, and Mann 2007;Marsel Mesulam et al. 2008;Spinelli et al. 2017); and 3) the logopenic variant (lvPPA), characterized by impaired single-word retrieval in spontaneous speech and naming and impaired repetition of phrases and sentences, and most often caused by underlying AD pathology (Mesulam 2008;Rabinovici et al. 2008; ...
The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills, resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through pre-determined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically-fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporo-parietal junction regions, predominantly follows at least two partially non-overlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis.
... Recently, our group identified somatic mutations in the gene TARDBP, encoding for TAR DNA Binding Protein 43 , as cause of disease in two patients [8]. Post mortem examination shows typical TDP-43 positive neuronal inclusions in the dentate gyrus of the hippocampus and long dystrophic neurites in the temporal cortex [9,10]. This neuropathological entity, classified as frontotemporal lobar degeneration (FTLD) TDP type C, is consistently found in the majority of SD patients. ...
Abstract Semantic dementia (SD) is a clinical subtype of frontotemporal dementia consistent with the neuropathological diagnosis frontotemporal lobar degeneration (FTLD) TDP type C, with characteristic round TDP-43 protein inclusions in the dentate gyrus. Despite this striking clinicopathological concordance, the pathogenic mechanisms are largely unexplained forestalling the development of targeted therapeutics. To address this, we carried out laser capture microdissection of the dentate gyrus of 15 SD patients and 17 non-demented controls, and assessed relative protein abundance changes by label-free quantitative mass spectrometry. To identify SD specific proteins, we compared our results to eight other FTLD and Alzheimer’s disease (AD) proteomic datasets of cortical brain tissue, parallel with functional enrichment analyses and protein–protein interactions (PPI). Of the total 5,354 quantified proteins, 151 showed differential abundance in SD patients (adjusted P-value
... Planned comparisons revealed that patients with left TLE (t (47) = 3.701, P , 0.0001) and right TLE (t (48) = −3.023, P = 0.004) performed significantly worse than controls; there was no significant difference between left and right TLE (t (35) = −0.656, P = 0.514; Fig. 1A). ...
... 8 Semantic dementia is a clinical condition that reflects progressive degeneration of the anterior temporal lobes, typically lateralized to the left. The double hit (poor scene construction + future thinking) seen in our cohort of patients with left temporal lobe disease may speak to the greater involvement of the mesial temporal structures in left TLE, 34 compared with the typically more neocortical predilection of semantic dementia 35 pathology. The significance of the relationship between scene construction and future thinking in TLE is examined further below. ...
The ability to mentally travel forward through time allows humans to envisage a diverse array of possible events taking place in the future, helping us to choose which pathway to take in life. In epilepsy, we assume that patients use this cognitive ability when deciding between various treatment options but this assumption has not been robustly tested. The temporal lobes are key contributors to this ‘future thinking’ and its building blocks include cognitive functions commonly impaired in temporal lobe epilepsy such as memory and language, giving rise to a hypothesis that ‘future thinking’ is impaired in this patient cohort. Participants were 68 adults: 37 with neurosurgically-naïve, unilateral temporal lobe epilepsy (51% right lateralised) and 31 healthy controls of similar age, sex, and intellectual ability to the participants with epilepsy. Future thinking was measured using an imagined experiences task validated in other neurological populations. Tools well-established in temporal lobe epilepsy were used to measure potential cognitive correlates of future thinking. Analysis of variance revealed significantly impoverished future thinking in both left and right temporal lobe epilepsy relative to controls (P=.001, ηp2=.206), with no difference between temporal lobe epilepsy groups (P>.05). Future thinking deficits in left temporal lobe epilepsy were paralleled by deficits in scene construction, whereas impoverished future thinking in right temporal lobe epilepsy occurred in the setting of intact scene construction. Deficits in future thinking were associated with reductions in lexical access and episodic autobiographic memory in both epilepsy groups. In sum, future thinking is compromised in both left and right temporal lobe epilepsy. The deficit in left temporal lobe epilepsy is largely explainable by dysfunction in verbal cognitive processes including scene construction. While the basis of the deficits observed with right temporal foci shares features with that of left temporal lobe epilepsy, their intact scene construction raises questions about the role of the left and right temporal lobes in future thinking and scene construction, and the relationship between these two constructs, including whether right temporal lobe might play a specific role in future thinking in terms of creative processing. Clinicians should take impaired future thinking into account when counselling temporal lobe epilepsy patients about various treatment options, as they may struggle to vividly imagine what different outcomes might mean for their future selves.
... Frontotemporal lobar degeneration trans-activator regulatory DNA binding protein 43 (FTLD-TDP-43) is the CLINICAL AND NEUROIMAGING CHARACTERISTICS most common underlying neuropathology in svPPA (Hodges et al., 2010;Josephs et al., 2011;Rohrer et al., 2011;Mesulam et al., 2014b;Leyton et al., 2016). Less commonly, Alzheimer's disease (AD) pathology (Alladi et al., 2007;Mesulam et al., 2014b) and Pick bodies (Davies et al., 2005) are associated with svPPA. ...
The chapter covers the clinical syndrome of a primary progressive aphasia (PPA), the demographics of this rare neurodegenerative disease, defining clinical and neuroanatomic characteristics of each PPA variant, disease progression, and behavioral features. The chapter begins with a brief introduction that includes references to seminal papers that defined this clinical syndrome and its three variants. The classic PPA subtypes discussed in the chapter are semantic variant PPA (svPPA), nonfluent/agrammatic PPA (nfaPPA), and logopenic variant PPA (lvPPA). The key language and cognitive characteristics, and language tasks that can elicit these language impairments, are detailed. Overlap in the clinical profiles of the PPA variants, which make differential diagnosis challenging, are explained. Disease progression is described, revealing that the PPA variants become more similar over time. Although PPA is language-predominant dementia, there are behavioral manifestations, particularly in svPPA. Changes in behavior in this variant are addressed as well as behavioral changes in nfaPPA and lvPPA that are less well recognized. The patterns of atrophy in the left temporal, parietal, and/or frontal cortices unique to each PPA variant are described. The underlying neuropathologies of the PPA variants are discussed, specifically tauopathies and non-tauopathies associated with svPPA and nfaPPA and Alzheimer's disease pathology in lvPPA.
... Furthermore, the anterior portion of the fusiform gyrus and adjacent regions are also critical areas systematically affected in svPPA and appear to play a pivotal role in semantic degradation [10][11][12][13]. Between 75% and 100% of all svPPA cases are associated with underlying TDP-43-C pathology, with the remainder mostly involving FTD tau [8,[14][15][16] and a small proportion of cases showing concomitant Alzheimer's disease pathology [8,17]. ...
People with semantic variant primary progressive aphasia (svPPA) present with a characteristic 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.
... The following left-hemisphere regions were obtained: pars opercularis, pars orbitalis, pars triangularis of the inferior frontal gyrus (IFG), superior temporal gyrus (STG), middle temporal gyrus, inferior temporal gyrus, anterior temporal gyrus (ATG), posterior temporal gyrus, and dorsolateral prefrontal cortex (DLPFC). We selected these regions because they have been reported to be prominent areas of atrophy in individuals with nfvPPA and because they have also been implicated in language in studies of individuals with PPA and HC (Brambati et al, 2009;Davies et al, 2005;Ikeda et al, 1996;Lippa et al, 1991;Mesulam et al, 2009;Rogalski et al, 2011;Shim et al, 2012;Suppa et al, 2020;Wilson et al, 2010). ...
Background:
Primary progressive aphasia (PPA) is a clinical syndrome that is characterized by progressive deterioration of language while other cognitive domains remain relatively intact. The extent to which print exposure and cortical volume atrophy jointly influence picture naming and general language ability in individuals with PPA remains underexplored.
Objective:
To investigate the language performance of individuals with the nonfluent variant of primary progressive aphasia (nfvPPA) and to explore the impact of print exposure and cortical volume atrophy on their language ability.
Method:
We compared 14 Greek individuals with nfvPPA and similar age, education, disease duration, and cognitive ability with age-, gender- and education-matched Greek controls on picture naming and on language tasks of the Boston Diagnostic Aphasia Examination-Short Form, including oral word reading, word and sentence repetition, complex ideational material, and reading comprehension. The effects of print exposure and left-hemisphere cortical volume on the individuals' language performance were estimated through stepwise regression models.
Results:
The language performance of the individuals with nfvPPA was affected by print exposure and cortical volume atrophy. Picture naming and word reading were affected by print exposure. The highest contributions of cortical volume atrophy were found for the repetition, complex ideational material, and reading comprehension tasks.
Conclusion:
Print exposure and cortical volume atrophy may help explain variability in the language performance of nfvPPA individuals with similar age, education, disease duration, and cognitive ability.
... Although the clinicopathological correspondence of PPA is not absolute, the two most common neuropathological correlates of PPA are Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). The SV and NFV are most frequently associated with FTLD pathology and the LV with AD pathology, but other pathologies have been found as well (Davies et al., 2005;Kertesz et al., 2005;Amici et al., 2006;Grossman, 2010;Leyton and Ballard, 2016). ...
Aims: This study aimed to investigate phoneme perception in patients with primary progressive aphasia (PPA) by using the event-related potential (ERP) technique. These ERP components might contribute to the diagnostic process of PPA and its clinical variants (NFV: nonfluent variant, SV: semantic variant, LV: logopenic variant) and reveal insights about phoneme perception processes in these patients.
Method: Phoneme discrimination and categorization processes were investigated by the mismatch negativity (MMN) and P300 in eight persons with early- and late-stage PPA (3 NFV, 2 LV, 2 SV, and 1 PPA-NOS; not otherwise specified) and 30 age-matched healthy adults. The mean amplitude, the onset latency, and the topographic distribution of both components in each patient were compared to the results of the control group.
Results: The MMN was absent or the onset latency of the MMN was delayed in the patients with the NFV, LV, and PPA-NOS in comparison to the control group. In contrast, no differences in mean amplitudes and onset latencies of the MMN were found between the patients with the SV and the control group. Concerning the P300, variable results were found in the patients with the NFV, SV, and PPA-NOS, but the P300 of both patients with the LV was delayed and prolonged with increased mean amplitude in comparison to the control group.
Conclusion: In this preliminary study, phoneme discrimination deficits were found in the patients with the NFV and LV, and variable deficits in phoneme categorization processes were found in all patients with PPA. In clinical practice, the MMN might be valuable to differentiate the SV from the NFV and the LV and the P300 to differentiate the LV from the NFV and the SV. Further research in larger and independent patient groups is required to investigate the applicability of these components in the diagnostic process and to determine the nature of these speech perception deficits in the clinical variants of PPA.
... Conversely, individuals with the neurodegenerative disorder semantic dementia, whose degeneration (largely in left anterior temporal cortex) and lexical/semantic declines leave motor functions largely unaffected (R. R. Davies et al., 2005), appear to remain relatively spared at aspects of processing the names of tools versus the names of animals (Breedin, Saffran, & Coslett, 1994), action words as compared to object words (Bak & Hodges, 2003;Cotelli et al., 2006), and more broadly verbs versus nouns (Bird, Lambon Ralph, Patterson, & Hodges, 2000;Breedin et al., 1994). Indeed, the relative sparing of (action) verbs compared to (object) nouns appears to be explained by greater motorrelated knowledge in the former (Lin, Guo, Han, & Bi, 2011). ...
Lexical-processing declines are a hallmark of aging. However, the extent of these declines may vary as a function of different factors. Motivated by findings from neurodegenerative diseases and healthy aging, we tested whether ‘motor-relatedness’ (the degree to which words are associated with particular human body movements) might moderate such declines. We investigated this question by examining data from three experiments. The experiments were carried out in different languages (Dutch, German, English) using different tasks (lexical decision, picture naming), and probed verbs and nouns, in all cases controlling for potentially confounding variables (e.g., frequency, age-of-acquisition, imageability). Whereas ‘non-motor words’ (e.g., steak) showed age-related performance
decreases in all three experiments, ‘motor words’ (e.g., knife) yielded either smaller decreases (in one experiment) or no decreases (in two experiments). The findings suggest that motor-relatedness can attenuate or even prevent age-related lexical declines, perhaps due to the relative sparing of neural circuitry underlying such words.
