Hemispheric asymmetries in hippocampal volume related to memory in left and right temporal variants of frontotemporal degeneration.

In addition to Alzheimer's disease (AD), the hippocampus is now known to be affected in variants of frontotemporal degeneration (FTD). In semantic variant primary progressive aphasia (svPPA), characterized by language impairments, hippocampal atrophy is greater in the left hemisphere. Nonverbal impairments (e.g., visual object recognition) are prominent in the right temporal variant of FTD (rtvFTD), and hippocampal atrophy may be greater in the right hemisphere. In this study we examined the hypothesis that leftward hippocampal asymmetry (predicted in svPPA) would be associated with selective verbal memory impairments (with relative preservation of visual memory), while rightward asymmetry (predicted in rtvFTD) would be associated with the opposite pattern (greater visual memory impairment). In contrast, we predicted that controls and individuals in the amnestic mild cognitive impairment stage of AD (aMCI), both of whom were expected to show symmetrical hippocampal volumes, would show roughly equivalent scores in verbal and visual memory. Participants completed delayed recall tests with words and geometric shapes, and hippocampal volumes were assessed with MRI. The aMCI sample showed symmetrical hippocampal atrophy, and similar degree of verbal and visual memory impairment. The svPPA sample showed greater left hippocampal atrophy and verbal memory impairment, while rtvFTD showed greater right hippocampal atrophy and visual memory impairment. Greater asymmetry in hippocampal volumes was associated with larger differences between verbal and visual memory in the FTD samples. Unlike AD, asymmetry is a core feature of brain-memory relationships in temporal variants of FTD.

The Media Coverage of Bruce Willis Reveals Unfamiliarity With Frontotemporal Degeneration.

In 2022, Bruce Willis' family released a statement saying that he had been diagnosed with aphasia (an acquired language impairment) and would no longer be acting. Ten months later, the Willis family released another statement indicating that he received a more specific diagnosis of frontotemporal degeneration (FTD). This resulted in an explosion of media coverage, as prominent news outlets scrambled to produce stories describing FTD to a public largely unfamiliar with the disease. The quality of these stories varied widely, and in many cases the relationship between aphasia and FTD was misrepresented, as were basic descriptions and facts about FTD. FTD refers to a class of protein-misfolding diseases that are a common cause of aphasias due to neurodegeneration, or primary progressive aphasias (PPA). Rather than describing how FTD was discovered to be the underlying source of Mr. Willis' aphasia, many reports described his aphasia as "progressing into" FTD, implying they are two different disorders. Furthermore, these reports used the terminology of frontotemporal "dementia" rather than "degeneration", a term that invokes many stereotypes in the public imagination and may have contributed to misrepresentations in coverage. Instead of focusing on the language symptoms of PPA, reports often emphasized the personality and behavioral changes more closely associated with other variants of FTD. The substance of various facts, such as how common FTD is and how it can be treated, varied widely across reports. In sum, the media coverage of Mr. Willis' diagnosis reveals the extent to which the media and general public are uninformed about FTD and PPA. The remedy for this problem is to promote greater awareness of FTD, in both the public and the medical provider class. The Willis family's disclosure was a courageous act that helped bring much-needed attention to this disease.

Perturbations of language network connectivity in primary progressive aphasia.

Aphasias are caused by disruption in structural integrity and interconnectivity within a large-scale distributed language network. We investigated the distribution and behavioral consequences of altered functional connectivity in three variants of primary progressive aphasia (PPA). The goal was to clarify relationships among atrophy, resting connectivity, and the resulting behavioral changes in 73 PPA and 33 control participants. Three core regions of the left perisylvian language network: the inferior frontal gyrus (IFG), middle temporal gyrus (MTG), and anterior temporal lobe (ATL) were evaluated in agrammatic (PPA-G), logopenic (PPA-L), and semantic (PPA-S) PPA variants. All PPA groups showed decreased connectivity between IFG and MTG. The PPA-S group also showed additional loss of connectivity strength between ATL and the other language regions. Decreased connectivity between the IFG and MTG nodes in PPA-G remained significant even when controlled for the effect of atrophy. In the PPA group as a whole, IFG-MTG connectivity strength correlated with repetition and grammar scores, whereas MTG-ATL connectivity correlated with picture naming and single-word comprehension. There was no significant change in the connectivity of homologous regions in the right hemisphere. These results show that language impairments in PPA are associated with perturbations of functional connectivity within behaviorally concordant components of the language network. Altered connectivity in PPA may reflect not only the irreversible loss of cortical components indexed by atrophy, but also the dysfunction of remaining neurons.

Preferential Disruption of Auditory Word Representations in Primary Progressive Aphasia With the Neuropathology of FTLD-TDP Type A.

Four patients with primary progressive aphasia displayed a greater deficit in understanding words they heard than words they read, and a further deficiency in naming objects orally rather than in writing. All four had frontotemporal lobar degeneration-transactive response DNA binding protein Type A neuropathology, three determined postmortem and one surmised on the basis of granulin gene (GRN) mutation. These features of language impairment are not characteristic of any currently recognized primary progressive aphasia variant. They can be operationalized as manifestations of dysfunction centered on a putative auditory word-form area located in the superior temporal gyrus of the left hemisphere. The small size of our sample makes the conclusions related to underlying pathology and auditory word-form area dysfunction tentative. Nonetheless, a deeper assessment of such patients may clarify the nature of pathways that link modality-specific word-form information to the associations that mediate their recognition as concepts. From a practical point of view, the identification of these features in patients with primary progressive aphasia should help in the design of therapeutic interventions where written communication modalities are promoted to circumvent some of the oral communication deficits.

A nonverbal route to conceptual knowledge involving the right anterior temporal lobe.

The semantic variant of primary progressive aphasia (PPA-S) is diagnosed based on impaired single-word comprehension, but nonverbal impairments in face and object recognition can also be present, particularly in later disease stages. PPA-S is associated with focal atrophy in the left anterior temporal lobe (ATL), often accompanied by a lesser degree of atrophy in the right ATL. According to a dual-route account, the left ATL is critical for verbal access to conceptual knowledge while nonverbal access to conceptual knowledge depends upon the integrity of right ATL. Consistent with this view, single-word comprehension deficits in PPA-S have consistently been linked to the degree of atrophy in left ATL. In the current study we examined object processing and cortical thickness in 19 patients diagnosed with PPA-S, to evaluate the hypothesis that nonverbal object impairments would instead be determined by the amount of atrophy in the right ATL. All patients demonstrated inability to access conceptual knowledge on standardized tests with word stimuli: they were unable to match spoken words with their corresponding pictures on the Peabody Picture Vocabulary Test. Only a minority of patients, however, performed abnormally on an experimental thematic verification task, which requires judgments as to whether pairs of object pictures are thematically-associated, and does not rely on auditory or visual word input. The entire PPA-S group showed cortical thinning in left ATL, but atrophy in right ATL was more prominent in the subgroup with low verification scores. Thematic verification scores were correlated with cortical thickness in the right rather than left ATL, an asymmetric mapping which persisted when controlling for the degree of atrophy in the contralateral hemisphere. These results are consistent with a dual-route account of conceptual knowledge: breakdown of the verbal left hemispheric route produces an aphasic syndrome, which is only accompanied by visual object processing impairments when the nonverbal right hemispheric route is also compromised.

Functional Connectivity is Reduced in Early-stage Primary Progressive Aphasia When Atrophy is not Prominent.

Primary progressive aphasia (PPA) is a clinical syndrome of language decline caused by neurodegenerative pathology. Although language impairments in PPA are typically localized via the morphometric assessment of atrophy, functional changes may accompany or even precede detectable structural alterations, in which case resting state functional connectivity (RSFC) could provide an alternative approach. The goal of this study was to determine whether language network RSFC is reduced in early-stage PPA when atrophy is not prominent. We identified 10 individuals with early-stage agrammatic variant of PPA with no prominent cortical thinning compared with nonaphasic controls. RSFC between 2 nodes of the language network and 2 nodes of the default mode network were compared between agrammatic variant of PPA and healthy control participants. Language network connectivity was comparable with controls among patients with milder agrammatism, but was significantly reduced in patients with more pronounced agrammatism. No group differences were observed in default mode network connectivity, demonstrating specificity of findings. In early stages of PPA when cortical atrophy is not prominent, RSFC provides an alternative method for probing the neuroanatomic substrates of language impairment. RSFC may be of particular utility in studies on early interventions for neurodegenerative disease, either to identify anatomic targets for intervention or as an outcome measure of therapeutic efficacy.

Am I looking at a cat or a dog? Gaze in the semantic variant of primary progressive aphasia is subject to excessive taxonomic capture.

Object naming impairments or anomias are the most frequent symptom in aphasia, and can be caused by a variety of underlying neurocognitive mechanisms. Anomia in neurodegenerative or primary progressive aphasias (PPA) often appears to be based on taxonomic blurring of word meaning: words such as "dog" and "cat" are still recognized generically as referring to animals, but are no longer conceptually differentiated from each other, leading to coordinate errors in word-object matching. This blurring is the hallmark symptom of the "semantic variant" of PPA, who invariably show focal atrophy in the left anterior temporal lobe. In this study we used eye tracking to characterize information processing online (in real time) as non-aphasic controls, semantic and non-semantic PPA participants completed a word-to-object matching task. All participants (including controls) showed taxonomic capture of gaze, spending more time viewing foils that were from the same category as the target compared to unrelated foils, but capture was more extreme in the semantic PPA group. The semantic group showed heightened capture even on trials where they ultimately pointed to the correct target, demonstrating the superiority of eye movements over traditional testing methods in detecting subtle processing impairments. Heightened capture was primarily driven by a tendency to direct gaze back and forth, repeatedly, between a set of related foils on each trial, a behavior almost never shown by controls or non-semantic participants. This suggests semantic PPA participants were accumulating and weighing evidence for a probabilistic rather than definitive mapping between the noun and several candidate objects. Neurodegeneration in PPA thus appears to distort lexical concepts prior to extinguishing them altogether, causing uncertainty in recognition and word-object matching.

Eye movements as probes of lexico-semantic processing in a patient with primary progressive aphasia.

Eye movement trajectories during a verbally cued object search task were used as probes of lexico-semantic associations in an anomic patient with primary progressive aphasia. Visual search was normal on trials where the target object could be named but became lengthy and inefficient on trials where the object failed to be named. The abnormality was most profound if the noun denoting the object could not be recognized. Even trials where the name of the target object was recognized but not retrieved triggered abnormal eye movements, demonstrating that retrieval failures can have underlying associative components despite intact comprehension of the corresponding noun.

Asymmetric connectivity between the anterior temporal lobe and the language network.

The anterior temporal lobe (ATL) sits at the confluence of auditory, visual, olfactory, transmodal, and limbic processing hierarchies. In keeping with this anatomical heterogeneity, the ATL has been implicated in numerous functional domains, including language, semantic memory, social cognition, and facial identification. One question that has attracted considerable discussion is whether the ATL contains a mosaic of differentially specialized areas or whether it provides a domain-independent amodal hub. In the current study, based on task-free fMRI in right-handed neurologically intact participants, we found that the left lateral ATL is interconnected with hubs of the temporosylvian language network, including the inferior frontal gyrus and middle temporal gyrus of the ipsilateral hemisphere and, to a lesser extent, with homotopic areas of the contralateral hemisphere. In contrast, the right lateral ATL had much weaker functional connectivity with these regions in either hemisphere. Together with evidence that has been gathered in lesion-mapping and event-related neuroimaging studies, this asymmetry of functional connectivity supports the inclusion of the left ATL within the language network, a relationship that had been overlooked by classic aphasiology. The asymmetric domain selectivity for language of the left ATL, together with the absence of such an affiliation in the right ATL, is inconsistent with a strict definition of domain-independent amodal functionality in this region of the brain.

A designated odor-language integration system in the human brain.

Odors are surprisingly difficult to name, but the mechanism underlying this phenomenon is poorly understood. In experiments using event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI), we investigated the physiological basis of odor naming with a paradigm where olfactory and visual object cues were followed by target words that either matched or mismatched the cue. We hypothesized that word processing would not only be affected by its semantic congruency with the preceding cue, but would also depend on the cue modality (olfactory or visual). Performance was slower and less precise when linking a word to its corresponding odor than to its picture. The ERP index of semantic incongruity (N400), reflected in the comparison of nonmatching versus matching target words, was more constrained to posterior electrode sites and lasted longer on odor-cue (vs picture-cue) trials. In parallel, fMRI cross-adaptation in the right orbitofrontal cortex (OFC) and the left anterior temporal lobe (ATL) was observed in response to words when preceded by matching olfactory cues, but not by matching visual cues. Time-series plots demonstrated increased fMRI activity in OFC and ATL at the onset of the odor cue itself, followed by response habituation after processing of a matching (vs nonmatching) target word, suggesting that predictive perceptual representations in these regions are already established before delivery and deliberation of the target word. Together, our findings underscore the modality-specific anatomy and physiology of object identification in the human brain.

Primary progressive aphasia and the evolving neurology of the language network.

Primary progressive aphasia (PPA) is caused by selective neurodegeneration of the language-dominant cerebral hemisphere; a language deficit initially arises as the only consequential impairment and remains predominant throughout most of the course of the disease. Agrammatic, logopenic and semantic subtypes, each reflecting a characteristic pattern of language impairment and corresponding anatomical distribution of cortical atrophy, represent the most frequent presentations of PPA. Such associations between clinical features and the sites of atrophy have provided new insights into the neurology of fluency, grammar, word retrieval, and word comprehension, and have necessitated modification of concepts related to the functions of the anterior temporal lobe and Wernicke's area. The underlying neuropathology of PPA is, most commonly, frontotemporal lobar degeneration in the agrammatic and semantic forms, and Alzheimer disease (AD) pathology in the logopenic form; the AD pathology often displays atypical and asymmetrical anatomical features consistent with the aphasic phenotype. The PPA syndrome reflects complex interactions between disease-specific neuropathological features and patient-specific vulnerability. A better understanding of these interactions might help us to elucidate the biology of the language network and the principles of selective vulnerability in neurodegenerative diseases. We review these aspects of PPA, focusing on advances in our understanding of the clinical features and neuropathology of PPA and what they have taught us about the neural substrates of the language network.

Anatomic, clinical, and neuropsychological correlates of spelling errors in primary progressive aphasia.

This study evaluates spelling errors in the three subtypes of primary progressive aphasia (PPA): agrammatic (PPA-G), logopenic (PPA-L), and semantic (PPA-S). Forty-one PPA patients and 36 age-matched healthy controls were administered a test of spelling. The total number of errors and types of errors in spelling to dictation of regular words, exception words and nonwords, were recorded. Error types were classified based on phonetic plausibility. In the first analysis, scores were evaluated by clinical diagnosis. Errors in spelling exception words and phonetically plausible errors were seen in PPA-S. Conversely, PPA-G was associated with errors in nonword spelling and phonetically implausible errors. In the next analysis, spelling scores were correlated to other neuropsychological language test scores. Significant correlations were found between exception word spelling and measures of naming and single word comprehension. Nonword spelling correlated with tests of grammar and repetition. Global language measures did not correlate significantly with spelling scores, however. Cortical thickness analysis based on MRI showed that atrophy in several language regions of interest were correlated with spelling errors. Atrophy in the left supramarginal gyrus and inferior frontal gyrus (IFG) pars orbitalis correlated with errors in nonword spelling, while thinning in the left temporal pole and fusiform gyrus correlated with errors in exception word spelling. Additionally, phonetically implausible errors in regular word spelling correlated with thinning in the left IFG pars triangularis and pars opercularis. Together, these findings suggest two independent systems for spelling to dictation, one phonetic (phoneme to grapheme conversion), and one lexical (whole word retrieval).

Neural mechanisms of object naming and word comprehension in primary progressive aphasia.

Primary progressive aphasia (PPA) is a neurodegenerative syndrome that causes a gradual atrophy of the left hemisphere language network, leading to impairments of object naming (anomia) and word comprehension. In 33 human subjects with PPA, object naming and word comprehension were explored with N400 potentials elicited by picture-word or picture-picture matching tasks. Two mechanisms of impairment were identified. In one group of patients, where the object name could be recognized but not retrieved during verbal naming, N400s in picture-word trials were also abnormal, revealing an associative basis for retrieval anomia. In these patients, a putative prephonological signal (i.e., lemma) evoked by the object picture appears to have become too weak to elicit retrieval, but not necessarily too weak to support the informationally less taxing process of recognition. A second group of PPA patients showed more severe naming deficits-the object name was neither verbalized nor recognized. Furthermore, nouns of the same category (but not those of other object categories) could not be identified as mismatches. This blurring of intracategory but not intercategory differentiation of word meaning was correlated with anterior temporal atrophy, predominantly in the left hemisphere, especially along the superior temporal gyrus. Although not part of the classic language network, this area appears critical for proceeding from generic to specific levels of word comprehension and object naming. N400 abnormalities emerged for lexical (picture-word) but not nonverbal (picture-picture) associations, supporting a dual-route rather than amodal organization of object concepts.

Electrophysiology of object naming in primary progressive aphasia.

Primary progressive aphasia (PPA), a selective neurodegeneration of the language network, frequently causes object naming impairments. We examined the N400 event-related potential (ERP) to explore interactions between object recognition and word processing in 20 PPA patients and 15 controls. Participants viewed photographs of objects, each followed by a word that was either a match to the object, a semantically related mismatch, or an unrelated mismatch. Patients judged whether word-object pairs matched with high accuracy (94% PPA group; 98% control group), but they failed to exhibit the normal N400 category effect (N400c), defined as a larger N400 to unrelated versus related mismatch words. In contrast, the N400 mismatch effect (N400m), defined as a larger N400 to mismatch than match words, was observed in both groups. N400m magnitude was positively correlated with neuropsychological measures of word comprehension but not fluency or grammatical competence, and therefore reflected the semantic component of naming. After ERP testing, patients were asked to name the same set of objects aloud. Trials with objects that could not be named were found to lack an N400m, although the name had been correctly recognized at the matching stage. Even accurate overt naming did not necessarily imply normal semantic processing, as shown by the absent N400c. The N400m was preserved in one patient with postsemantic anomia, who could write the names of objects she could not verbalize. N400 analyses can thus help dissect the multiple cognitive mechanisms that contribute to object naming failures in PPA.

Anatomical physiology of spatial extinction.

Neurologically intact volunteers participated in a functional magnetic resonance imaging experiment that simulated the unilateral (focal) and bilateral (global) stimulations used to elicit extinction in patients with hemispatial neglect. In peristriate areas, attentional modulations were selectively sensitive to contralaterally directed attention. A higher level of mapping was observed in the intraparietal sulcus (IPS), inferior parietal lobule (IPL), and inferior frontal gyrus (IFG). In these areas, there was no distinction between contralateral and ipsilateral focal attention, and the need to distribute attention globally led to greater activity than either focal condition. These physiological characteristics were symmetrically distributed in the IPS and IFG, suggesting that the effects of unilateral lesions in these 2 areas can be compensated by the contralateral hemisphere. In the IPL, the greater activation by the bilateral attentional mode was seen only in the right hemisphere. Its contralateral counterpart displayed equivalent activations when attention was distributed to the right, to the left, or bilaterally. Within the context of this experiment, the IPL of the right hemisphere emerged as the one area where unilateral lesions can cause the most uncompensated and selective impairment of global attention (without interfering with unilateral attention to either side), giving rise to the phenomenon of extinction.

Analysis of face gaze in autism using "Bubbles".

One of the components of abnormal social functioning in autism is an impaired ability to direct eye gaze onto other people's faces in social situations. Here, we investigated the relationship between gaze onto the eye and mouth regions of faces, and the visual information that was present within those regions. We used the "Bubbles" method to vary the facial information available on any given trial by revealing only small parts of the face, and measured the eye movements made as participants viewed these stimuli. Compared to ten IQ- and age-matched healthy controls, eight participants with autism showed less fixation specificity to the eyes and mouth, a greater tendency to saccade away from the eyes when information was present in those regions, and abnormal directionality of saccades. The findings provide novel detail to the abnormal way in which people with autism look at faces, an impairment that likely influences all subsequent face processing.

Abnormal use of facial information in high-functioning autism.

Altered visual exploration of faces likely contributes to social cognition deficits seen in autism. To investigate the relationship between face gaze and social cognition in autism, we measured both face gaze and how facial regions were actually used during emotion judgments from faces. Compared to IQ-matched healthy controls, nine high-functioning adults with autism failed to make use of information from the eye region of faces, instead relying primarily on information from the mouth. Face gaze accounted for the increased reliance on the mouth, and partially accounted for the deficit in using information from the eyes. These findings provide a novel quantitative assessment of how people with autism utilize information in faces when making social judgments.

The broad autism phenotype questionnaire.

The broad autism phenotype (BAP) is a set of personality and language characteristics that reflect the phenotypic expression of the genetic liability to autism, in non-autistic relatives of autistic individuals. These characteristics are milder but qualitatively similar to the defining features of autism. A new instrument designed to measure the BAP in adults, the Broad Autism Phenotype Questionnaire (BAPQ), was administered to 86 parents of autistic individuals and 64 community control parents. Sensitivity and specificity of the BAPQ for detecting the BAP were high (>70%). Parents of children with autism had significantly higher scores on all three subscales: aloof personality, rigid personality, and pragmatic language. This instrument provides a valid and efficient measure for characterizing the BAP.