The eyes speak when the mouth cannot: Using eye movements to interpret omissions in primary progressive aphasia.

Though it may seem simple, object naming is a complex multistage process that can be impaired by lesions at various sites of the language network. Individuals with neurodegenerative disorders of language, known as primary progressive aphasias (PPA), have difficulty with naming objects, and instead frequently say "I don't know" or fail to give a vocal response at all, known as an omission. Whereas other types of naming errors (paraphasias) give clues as to which aspects of the language network have been compromised, the mechanisms underlying omissions remain largely unknown. In this study, we used a novel eye tracking approach to probe the cognitive mechanisms of omissions in the logopenic and semantic variants of PPA (PPA-L and PPA-S). For each participant, we identified pictures of common objects (e.g., animals, tools) that they could name aloud correctly, as well as pictures that elicited an omission. In a separate word-to-picture matching task, those pictures appeared as targets embedded among an array with 15 foils. Participants were given a verbal cue and tasked with pointing to the target, while eye movements were monitored. On trials with correctly-named targets, controls and both PPA groups ceased visual search soon after foveating the target. On omission trials, however, the PPA-S group failed to stop searching, and went on to view many foils "post-target". As further indication of impaired word knowledge, gaze of the PPA-S group was subject to excessive "taxonomic capture", such that they spent less time viewing the target and more time viewing related foils on omission trials. In contrast, viewing behavior of the PPA-L group was similar to controls on both correctly-named and omission trials. These results indicate that the mechanisms of omission in PPA differ by variant. In PPA-S, anterior temporal lobe degeneration causes taxonomic blurring, such that words from the same category can no longer be reliably distinguished. In PPA-L, word knowledge remains relatively intact, and omissions instead appear to be caused by downstream factors (e.g., lexical access, phonological encoding). These findings demonstrate that when words fail, eye movements can be particularly informative.

Taxonomic Interference Associated with Phonemic Paraphasias in Agrammatic Primary Progressive Aphasia.

Phonemic paraphasias are thought to reflect phonological (post-semantic) deficits in language production. Here we present evidence that phonemic paraphasias in non-semantic primary progressive aphasia (PPA) may be associated with taxonomic interference. Agrammatic and logopenic PPA patients and control participants performed a word-to-picture visual search task where they matched a stimulus noun to 1 of 16 object pictures as their eye movements were recorded. Participants were subsequently asked to name the same items. We measured taxonomic interference (ratio of time spent viewing related vs. unrelated foils) during the search task for each item. Target items that elicited a phonemic paraphasia during object naming elicited increased taxonomic interference during the search task in agrammatic but not logopenic PPA patients. These results could reflect either very subtle sub-clinical semantic distortions of word representations or partial degradation of specific phonological word forms in agrammatic PPA during both word-to-picture matching (input stage) and picture naming (output stage). The mechanism for phonemic paraphasias in logopenic patients seems to be different and to be operative at the pre-articulatory stage of phonological retrieval. Glucose metabolic imaging suggests that degeneration in the left posterior frontal lobe and left temporo-parietal junction, respectively, might underlie these different patterns of phonemic paraphasia.

Revisiting the Cholinergic Hypothesis in Alzheimer's Disease: Emerging Evidence from Translational and Clinical Research.

Scientific evidence collected over the past 4 decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer's disease is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the "Cholinergic Hypothesis of AD" and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the cholinergic system and suggesting that cholinergic therapy may slow brain atrophy. Other pathways that contribute to cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the cholinergic system as one of several interacting systems failures that contribute to AD pathogenesis.

Prominent microglial activation in cortical white matter is selectively associated with cortical atrophy in primary progressive aphasia.

AIMS: Primary progressive aphasia (PPA) is a clinical syndrome characterized by selective language impairments associated with focal cortical atrophy favouring the language dominant hemisphere. PPA is associated with Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and significant accumulation of activated microglia. Activated microglia can initiate an inflammatory cascade that may contribute to neurodegeneration, but their quantitative distribution in cortical white matter and their relationship with cortical atrophy remain unknown. We investigated white matter activated microglia and their association with grey matter atrophy in 10 PPA cases with either AD or FTLD-TDP pathology. METHODS: Activated microglia were quantified with optical density measures of HLA-DR immunoreactivity in two regions with peak cortical atrophy, and one nonatrophied region within the language dominant hemisphere of each PPA case. Nonatrophied contralateral homologues of the language dominant regions were examined for hemispheric asymmetry. RESULTS: Qualitatively, greater densities of activated microglia were observed in cortical white matter when compared to grey matter. Quantitative analyses revealed significantly greater densities of activated microglia in the white matter of atrophied regions compared to nonatrophied regions in the language dominant hemisphere (P < 0.05). Atrophied regions of the language dominant hemisphere also showed significantly more activated microglia compared to contralateral homologues (P < 0.05). CONCLUSIONS: White matter activated microglia accumulate more in atrophied regions in the language dominant hemisphere of PPA. While microglial activation may constitute a response to neurodegenerative processes in white matter, the resultant inflammatory processes may also exacerbate disease progression and contribute to cortical atrophy.

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.

Linking human brain local activity fluctuations to structural and functional network architectures.

Activity of cortical local neuronal populations fluctuates continuously, and a large proportion of these fluctuations are shared across populations of neurons. Here we seek organizational rules that link these two phenomena. Using neuronal activity, as identified by functional MRI (fMRI) and for a given voxel or brain region, we derive a single measure of full bandwidth brain-oxygenation-level-dependent (BOLD) fluctuations by calculating the slope, α, for the log-linear power spectrum. For the same voxel or region, we also measure the temporal coherence of its fluctuations to other voxels or regions, based on exceeding a given threshold, Θ, for zero lag correlation, establishing functional connectivity between pairs of neuronal populations. From resting state fMRI, we calculated whole-brain group-averaged maps for α and for functional connectivity. Both maps showed similar spatial organization, with a correlation coefficient of 0.75 between the two parameters across all brain voxels, as well as variability with hodology. A computational model replicated the main results, suggesting that synaptic low-pass filtering can account for these interrelationships. We also investigated the relationship between α and structural connectivity, as determined by diffusion tensor imaging-based tractography. We observe that the correlation between α and connectivity depends on attentional state; specifically, α correlated more highly to structural connectivity during rest than while attending to a task. Overall, these results provide global rules for the dynamics between frequency characteristics of local brain activity and the architecture of underlying brain networks.

Progression of language decline and cortical atrophy in subtypes of primary progressive aphasia.

OBJECTIVES: To examine the longitudinal course of primary progressive aphasia (PPA) over a 2-year period and to offer quantitative ranges of expected change that could be used to guide the design and evaluation of therapeutic intervention trials. METHODS: Regional changes of cortical thickness and whole-brain cortical volume loss as well as neuropsychological language performance were assessed at baseline and 2 years later in 13 rigorously characterized patients who fulfilled research criteria for logopenic, agrammatic, and semantic PPA subtypes (6 PPA-L, 3 PPA-G, and 4 PPA-S). RESULTS: There was substantial progression of clinical deficits and cortical atrophy over 2 years. Neuropsychological language performance patterns lost the sharp distinctions that differentiated one PPA variant from another. Nonetheless, the subtype-specific differential impairment of word comprehension vs grammatical processing was largely maintained. Peak atrophy sites spread beyond the initial distinctive locations that characterized each of the 3 subtypes and displayed a more convergent distribution encompassing all 3 major components of the language network: the inferior frontal gyrus, the temporoparietal junction, and lateral temporal cortex. Despite the progression, overall peak atrophy remained lateralized to the left hemisphere. CONCLUSIONS: The results suggest that the unique features, which sharply differentiate the PPA variants at the early to middle stages, may lose their distinctiveness as the degeneration becomes more severe. Given the substantial atrophy over 2 years, PPA clinical trials may require fewer patients and shorter study durations than Alzheimer disease trials to detect significant therapeutic effects.

Classification of primary progressive aphasia and its variants.

This article provides a classification of primary progressive aphasia (PPA) and its 3 main variants to improve the uniformity of case reporting and the reliability of research results. Criteria for the 3 variants of PPA--nonfluent/agrammatic, semantic, and logopenic--were developed by an international group of PPA investigators who convened on 3 occasions to operationalize earlier published clinical descriptions for PPA subtypes. Patients are first diagnosed with PPA and are then divided into clinical variants based on specific speech and language features characteristic of each subtype. Classification can then be further specified as "imaging-supported" if the expected pattern of atrophy is found and "with definite pathology" if pathologic or genetic data are available. The working recommendations are presented in lists of features, and suggested assessment tasks are also provided. These recommendations have been widely agreed upon by a large group of experts and should be used to ensure consistency of PPA classification in future studies. Future collaborations will collect prospective data to identify relationships between each of these syndromes and specific biomarkers for a more detailed understanding of clinicopathologic correlations.

Cortical neuroanatomic correlates of symptom severity in primary progressive aphasia.

OBJECTIVE: To test the validity and reliability of a new measure of clinical impairment in primary progressive aphasia (PPA), the Progressive Aphasia Severity Scale (PASS), and to investigate relationships with MRI-based cortical thickness biomarkers for localizing and quantifying the severity of anatomic abnormalities. METHODS: Patients with PPA were rated using the PASS and underwent performance-based language testing and MRI scans that were processed for cortical thickness measures. RESULTS: The level of impairment in PASS fluency, syntax/grammar, and word comprehension showed strong specific correlations with performance-based measures of these domains of language, and demonstrated high interrater reliability. Left inferior frontal thinning correlated with impairment in fluency and grammar/syntax, while left temporopolar thinning correlated with impairment in word comprehension. Discriminant function analysis demonstrated that a combination of left inferior frontal, left temporopolar, and left superior temporal sulcal thickness separated the 3 PPA subtypes from each other with 100% accuracy (87% accuracy in a leave-one-out analysis). CONCLUSIONS: The PASS, a novel measure of the severity of clinical impairment within domains of language typically affected in PPA, demonstrates reliable and valid clinical-behavioral properties. Furthermore, the presence of impairment in individual PASS domains demonstrates specific relationships with focal abnormalities in particular brain regions and the severity of impairment is strongly related to the severity of anatomic abnormality within the relevant brain region. These anatomic imaging biomarkers perform well in classifying PPA subtypes. These data provide robust support for the value of this novel clinical measure and the new imaging measure as markers for potential use in clinical research and trials in PPA.

Asymmetric TDP-43 distribution in primary progressive aphasia with progranulin mutation.

OBJECTIVE: Primary progressive aphasia (PPA) results from an asymmetric degeneration of the language dominant (usually left) hemisphere and can be associated with the pathology of Alzheimer disease (AD) or frontotemporal lobar degeneration (FTLD). This study aimed to investigate whether the anatomic distribution of TDP-43 inclusions displayed a corresponding leftward asymmetry in a patient with PPA with a mutation in the progranulin gene and FTLD pathology. METHODS: Brain tissue from a 65-year-old patient with PPA and progranulin mutation was analyzed using immunohistochemical methods for TDP-43. Analysis was performed in the superior temporal gyrus, inferior temporal gyrus, inferior parietal lobule, orbitofrontal cortex, entorhinal cortex, and dentate gyrus. Neuronal intranuclear inclusions, neuronal cytoplasmic inclusions, and dystrophic neurites were quantified using modified stereologic analysis. Analysis of variance was used to determine significant effects. RESULTS: All 3 types of inclusions predominated on the left side of analyzed cortical regions. They were also more frequent in language areas than in memory-related areas. CONCLUSION: These results demonstrate a phenotypically concordant distribution of abnormal TDP-43 inclusions in primary progressive aphasia (PPA). This contrasts with PPA cases with Alzheimer pathology where no consistent leftward asymmetry of neurofibrillary degeneration or amyloid deposition has been demonstrated despite the leftward asymmetry of the atrophy, and where neurofibrillary tangles show a greater density in memory than language areas despite the predominantly aphasic phenotype. This case suggests that the TDP-43 inclusions in PPA-frontotemporal lobar degeneration are more tightly linked to neuronal death and dysfunction than neurofibrillary and amyloid deposits in PPA-Alzheimer disease.

Clinical trajectories and biological features of primary progressive aphasia (PPA).

Primary Progressive Aphasia (PPA) is a neurodegenerative syndrome characterized by a gradual dissolution of language, but relative sparing of other cognitive domains during the initial stages of the disease. Research has led to substantial progress in understanding the clinical characteristics, genetics, and neuropathology of this syndrome. This article reviews the clinical criteria for diagnosing PPA, discusses the utility of defining the mild cognitive impairment (MCI) stage of PPA, and highlights some of the more recent research advances particularly in the area of pathology and genetics.

Clinicopathologic correlation in PGRN mutations.

BACKGROUND: Frontotemporal dementia (FTD) has been linked to the microtubule associated protein tau (MAPT) gene region of chromosome 17. However, many chromosome-17 linked FTLDs do not have MAPT mutations or tau protein deposits, but have ubiquitin positive, tau and alpha-synuclein negative inclusions. Mutations in the progranulin (PGRN) gene, located 1.7 Mb from MAPT at 17q21.31, were recently discovered in some of these individuals. The pathologic phenotype in all cases has thus far included ubiquitinated neuronal intranuclear inclusions (NIIs) and neuronal cytoplasmic inclusions (NCIs). METHODS: PGRN mutation analysis was performed in 12 individuals. Informed consent was obtained from next of kin under an IRB-approved protocol. We compared clinical and pathologic findings in those cases with and without PGRN mutations. RESULTS: PGRN mutations were found in four patients, two with clinical FTD and a positive family history, and two with clinical primary progressive aphasia (PPA), one with and one without a family history. All four cases with, and five of eight cases without, PGRN mutations had ubiquitinated NCIs and NIIs. Brains of individuals with PGRN mutations are associated with more frequent frontal NCIs and dystrophic neurites, less frequent dentate gyrus NCIs, and more frequent striatal NIIs than FTLD-U cases without PGRN mutations. CONCLUSION: PGRN mutations at 17q21 may occur in apparently sporadic frontotemporal lobar dementia with ubiquitinated inclusions cases and in cases presenting with either primary progressive aphasia or the behavioral variant of frontotemporal dementia. Some cases without PGRN mutations also have ubiquitinated neuronal intranuclear inclusions. Clinicopathologic differences are observed among individuals with and without PGRN mutations.

Neural correlates of rule-based and information-integration visual category learning.

An emerging theory of the neurobiology of category learning postulates that there are separate neural systems supporting the learning of categories based on verbalizeable rules (RB) or through implicit information integration (II). The medial temporal lobe (MTL) is thought to play a crucial role in successful RB categorization, whereas the posterior regions of the caudate are hypothesized to support II categorization. Functional neuroimaging was used to assess activity in these systems during category-learning tasks with category structures designed to afford either RB or II learning. Successful RB categorization was associated with relatively increased activity in the anterior MTL. Successful II categorization was associated with increased activity in the caudate body. The dissociation observed with neuroimaging is consistent with the roles of these systems in memory and dissociations reported in patient populations. Convergent evidence from these approaches consistently reinforces the idea of multiple neural systems supporting category learning.

Subfield-specific increase in brain growth protein in postmortem hippocampus of Alzheimer's patients.

The neuropathology of Alzheimer's disease (AD) reflects a precarious balance between neurodegenerative phenomena and reactive events of neuroplasticity. This latter aspect of AD neuropathology has received less attention than it deserves and its contribution to memory loss is therefore not well understood. To monitor neuroplastic-related events we studied the distribution of the plasticity-associated, brain growth protein GAP-43 in AD subjects and age-matched controls. In tissue from AD patients, we observed a consistent elevation of GAP-43 in a subfield of the hippocampus, stratum lacunosum moleculare. This subfield contains inputs from multiple brain regions and is known to regulate declarative memory function. Levels of potentially aberrant sprouting, as marked by elevated growth protein, were positively correlated with the severity of AD suggesting that increased expression of GAP-43 leads to a miswiring of circuits critical for memory function. Our findings suggest a mechanism, aberrant neuroplasticity, that in concert with neurodegeneration may importantly contribute to the memory loss in AD.

Orienting attention to locations in perceptual versus mental representations.

Extensive clinical and imaging research has characterized the neural networks mediating the adaptive distribution of spatial attention. In everyday behavior, the distribution of attention is guided not only by extrapersonal targets but also by mental representations of their spatial layout. We used event-related functional magnetic resonance imaging to identify the neural system involved in directing attention to locations in arrays held as mental representations, and to compare it with the system for directing spatial attention to locations in the external world. We found that these two crucial aspects of spatial cognition are subserved by extensively overlapping networks. However, we also found that a region of right parietal cortex selectively participated in orienting attention to the extrapersonal space, whereas several frontal lobe regions selectively participated in orienting attention within on-line mental representations.

The posterior cingulate and medial prefrontal cortex mediate the anticipatory allocation of spatial attention.

The purpose of this study was to identify brain regions underlying internally generated anticipatory biases toward locations where significant events are expected to occur. Subjects fixated centrally and responded to peripheral targets preceded by a spatially valid (predictive), invalid (misleading), or neutral central cue while undergoing fMRI scanning. In some validly cued trials, reaction time was significantly shorter than in trials with neutral cues, indicating that the cue had successfully induced a spatial redistribution of motivational valence, manifested as expectancy. The largest cue benefits led to selectively greater activations within the posterior cingulate and medial prefrontal cortex. These two areas thus appear to establish a neural interface between attention and motivation. An inverse relationship to cue benefit was seen in the parietal cortex, suggesting that spatial expectancy may entail the inhibition of attention-related areas to reduce distractibility by events at irrelevant locations.

Possible association of the tau H1/H1 genotype with primary progressive aphasia.

The authors screened for tau gene mutations and polymorphisms to determine whether genetic variation at or near the tau locus contributes to the development of primary progressive aphasia (PPA). No mutations were detected in 25 patients with PPA. However, a significant overrepresentation of the tau H1/H1 genotype, also found in progressive supranuclear palsy and corticobasal degeneration, was found in the PPA group. Whether tau haplotypes have a primary causal role or whether they affect the topology of neurodegeneration remains to be determined.

Neural correlates of artificial grammar learning.

Artificial grammar learning (AGL) is a form of nondeclarative memory that involves the nonconscious acquisition of abstract rules. While data from amnesic patients indicate that AGL does not depend on the medial temporal lobe, the neural basis of this type of memory is unknown and was therefore examined using event-related fMRI. Prior to scanning, participants studied letter strings constructed according to an artificial grammar. Participants then made grammaticality judgments about novel grammatical and nongrammatical strings while fMRI data were collected. The participants successfully acquired knowledge of the grammar, as evidenced by correct identification of the grammatical letter strings (57.4% correct; SE 1.9). During grammaticality judgments, widespread increases in activity were observed throughout the occipital, posterior temporal, parietal, and prefrontal cortical areas, reflecting the cognitive demands of the task. More specific analyses contrasting grammatical and nongrammatical strings identified greater activity in left superior occipital cortex and the right fusiform gyrus for grammatical stimuli. Increased activity was also observed in the left superior occipital and left angular gyrus for correct responses compared to incorrect. Comparing activity during grammaticality judgments versus a matched recognition control task again identified greater activation in the left angular gyrus. The network of areas exhibiting increased activity for grammatical stimuli appears to have more in common with studies examining word-form processing or mental calculation than the fluency effects previously reported for nondeclarative memory tasks such as priming and visual categorization. These results suggest that a novel nondeclarative memory mechanism supporting AGL exists in the left superior occipital and inferior parietal cortex.

Electromyography as a recording system for eyeblink conditioning with functional magnetic resonance imaging.

This study was designed to develop a suitable method of recording eyeblink responses while conducting functional magnetic resonance imaging (fMRI). Given the complexity of this behavioral setup outside of the magnet, this study sought to adapt and further optimize an approach to eyeblink conditioning that would be suitable for conducting event-related fMRI experiments. This method involved the acquisition of electromyographic (EMG) signals from the orbicularis oculi of the right eye, which were subsequently amplified and converted into an optical signal outside of the head coil. This optical signal was converted back into an electrical signal once outside the magnet room. Electromyography (EMG)-detected eyeblinks were used to measure responses in a delay eyeblink conditioning paradigm. Our results indicate that: (1) electromyography is a sensitive method for the detection of eyeblinks during fMRI; (2) minimal interactions or artifacts of the EMG signal were created from the magnetic resonance pulse sequence; and (3) no electromyography-related artifacts were detected in the magnetic resonance images. Furthermore, an analysis of the functional data showed areas of activation that have previously been shown in positron emission tomography studies of human eyeblink conditioning. Our results support the strength of this behavioral setup as a suitable method to be used in association with fMRI.

Filtering of distractors during visual search studied by positron emission tomography.

We investigated the sensitivity of brain areas to the presence of filtering operations during overt visual search in crowded displays. Task conditions involved either visual search or predetermined simple eye movements for the detection of target digits. Furthermore, visual displays either contained letter foils that required filtering or contained only target digits. Brain imaging using positron emission tomography showed extensive overlap between areas involved in overt visual search and eye movements. Selective filtering of foils affected visual processing in ventral areas associated with object recognition and in primary visual cortex.