Christina Wieneke

A novel frontal pathway underlies verbal fluency in primary progressive aphasia

The frontal aslant tract is a direct pathway connecting Brocas region with the anterior cingulate and pre-supplementary motor area. This tract is left lateralized in right-handed subjects, suggesting a possible role in language. However, there are no previous studies that have reported an involvement of this tract in language disorders. In this study we used diffusion tractography to define the anatomy of the frontal aslant tract in relation to verbal fluency and grammar impairment in primary progressive aphasia. Thirty-five patients with primary progressive aphasia and 29 control subjects were recruited. Tractography was used to obtain indirect indices of microstructural organization of the frontal aslant tract. In addition, tractography analysis of the uncinate fasciculus, a tract associated with semantic processing deficits, was performed. Damage to the frontal aslant tract correlated with performance in verbal fluency as assessed by the Cinderella story test. Conversely, damage to the uncinate fasciculus correlated with deficits in semantic processing as assessed by the Peabody Picture Vocabulary Test. Neither tract correlated with grammatical or repetition deficits. Significant group differences were found in the frontal aslant tract of patients with the non-fluent/agrammatic variant and in the uncinate fasciculus of patients with the semantic variant. These findings indicate that degeneration of the frontal aslant tract underlies verbal fluency deficits in primary progressive aphasia and further confirm the role of the uncinate fasciculus in semantic processing. The lack of correlation between damage to the frontal aslant tract and grammar deficits suggests that verbal fluency and grammar processing rely on distinct anatomical networks.

Quantitative Template for Subtyping Primary Progressive Aphasia

BACKGROUND The syndrome of primary progressive aphasia (PPA) is diagnosed when a gradual failure of word usage or comprehension emerges as the principal feature of a neurodegenerative disease. OBJECTIVE To provide a quantitative algorithm for classifying PPA into agrammatic (PPA-G), semantic (PPA-S), and logopenic (PPA-L) variants, each of which is known to have a different probability of association with Alzheimer disease vs frontotemporal lobar degeneration. DESIGN Prospective study. SETTING University medical center. PATIENTS Sixteen consecutively enrolled patients with PPA who underwent neuropsychological testing and magnetic resonance imaging recruited nationally in the United States as part of a longitudinal study. RESULTS A 2-dimensional template that reflects performance on tests of syntax (Northwestern Anagram Test) and lexical semantics (Peabody Picture Vocabulary Test-Fourth Edition) classified all 16 patients in concordance with a clinical diagnosis that had been made before the administration of quantitative tests. All 3 PPA subtypes had distinctly asymmetrical atrophy of the left perisylvian language network. Each subtype also had distinctive peak atrophy sites: PPA-G in the inferior frontal gyrus (Broca area), PPA-S in the anterior temporal lobe, and PPA-L in Brodmann area 37. CONCLUSIONS Once an accurate root diagnosis of PPA is made, subtyping can be quantitatively guided using a 2-dimensional template based on orthogonal tasks of grammatical competence and word comprehension. Although the choice of tasks and the precise cutoff levels may need to be adjusted to fit linguistic and educational backgrounds, these 16 patients demonstrate the feasibility of using a simple algorithm for clinicoanatomical classification in PPA. Prospective studies will show whether this subtyping can improve clinical prediction of the underlying neuropathologic condition.

Neural Integration of Top-Down Spatial and Feature-Based Information in Visual Search

Visual search is aided by previous knowledge regarding distinguishing features and probable locations of a sought-after target. However, how the human brain represents and integrates concurrent feature-based and spatial expectancies to guide visual search is currently not well understood. Specifically, it is not clear whether spatial and feature-based search information is initially represented in anatomically segregated regions, nor at which level of processing expectancies regarding target features and locations may be integrated. To address these questions, we independently and parametrically varied the degree of spatial and feature-based (color) cue information concerning the identity of an upcoming visual search target while recording blood oxygenation level-dependent (BOLD) responses in human subjects. Search performance improved with the amount of spatial and feature-based cue information, and cue-related BOLD responses showed that, during preparation for visual search, spatial and feature cue information were represented additively in shared frontal, parietal, and cingulate regions. These data show that representations of spatial and feature-based search information are integrated in source regions of top-down biasing and oculomotor planning before search onset. The purpose of this anticipatory integration could lie with the generation of a “top-down salience map,” a search template of primed target locations and features. Our results show that this role may be served by the intraparietal sulcus, which additively integrated a spatially specific activation gain in relation to spatial cue information with a spatially global activation gain in relation to feature cue information.

Asymmetry and heterogeneity of Alzheimer’s and frontotemporal pathology in primary progressive aphasia

Fifty-eight autopsies of patients with primary progressive aphasia are reported. Twenty-three of these were previously described (Mesulam et al., 2008) but had their neuropathological diagnoses updated to fit current criteria. Thirty-five of the cases are new. Their clinical classification was guided as closely as possible by the 2011 consensus guidelines (Gorno-Tempini et al., 2011). Tissue diagnoses included Alzheimers disease in 45% and frontotemporal lobar degeneration (FTLD) in the others, with an approximately equal split between TAR DNA binding protein 43 proteinopathies and tauopathies. The most common and distinctive feature for all pathologies associated with primary progressive aphasia was the asymmetric prominence of atrophy, neuronal loss, and disease-specific proteinopathy in the language-dominant (mostly left) hemisphere. The Alzheimers disease pathology in primary progressive aphasia displayed multiple atypical features. Males tended to predominate, the neurofibrillary pathology was more intense in the language-dominant hemisphere, the Braak pattern of hippocampo-entorhinal prominence was tilted in favour of the neocortex, and the APOE e4 allele was not a risk factor. Mean onset age was under 65 in the FTLD as well as Alzheimers disease groups. The FTLD-TAR DNA binding protein 43 group had the youngest onset and fastest progression whereas the Alzheimers disease and FTLD-tau groups did not differ from each other in either onset age or progression rate. Each cellular pathology type had a preferred but not invariant clinical presentation. The most common aphasic manifestation was of the logopenic type for Alzheimer pathology and of the agrammatic type for FTLD-tau. The progressive supranuclear palsy subtype of FTLD-tau consistently caused prominent speech abnormality together with agrammatism whereas FTLD-TAR DNA binding protein 43 of type C consistently led to semantic primary progressive aphasia. The presence of agrammatism made Alzheimers disease pathology very unlikely whereas the presence of a logopenic aphasia or word comprehension impairment made FTLD-tau unlikely. The association of logopenic primary progressive aphasia with Alzheimers disease pathology was much more modest than has been implied by results of in vivo amyloid imaging studies. Individual features of the aphasia, such as agrammatism and comprehension impairment, were as informative of underlying pathology as more laborious subtype diagnoses. At the single patient level, no clinical pattern was pathognomonic of a specific neuropathology type, highlighting the critical role of biomarkers for diagnosing the underlying disease. During clinical subtyping, some patients were unclassifiable by the 2011 guidelines whereas others simultaneously fit two subtypes. Revisions of criteria for logopenic primary progressive aphasia are proposed to address these challenges.

Anatomy of Language Impairments in Primary Progressive Aphasia

Primary progressive aphasia (PPA) is a clinical dementia syndrome characterized by progressive decline in language function but relative sparing of other cognitive domains. There are three recognized PPA variants: agrammatic, semantic, and logopenic. Although each PPA subtype is characterized by the nature of the principal deficit, individual patients frequently display subtle impairments in additional language domains. The present study investigated the distribution of atrophy related to performance in specific language domains (i.e., grammatical processing, semantic processing, fluency, and sentence repetition) across PPA variants to better understand the anatomical substrates of language. Results showed regionally specific relationships, primarily in the left hemisphere, between atrophy and impairments in language performance. Most notable was the neuroanatomical distinction between fluency and grammatical processing. Poor fluency was associated with regions dorsal to the traditional boundaries of Brocas area in the inferior frontal sulcus and the posterior middle frontal gyrus, whereas grammatical processing was associated with more widespread atrophy, including the inferior frontal gyrus and supramarginal gyrus. Repetition performance was correlated with atrophy in the posterior superior temporal gyrus. The correlation of atrophy with semantic processing impairment was localized to the anterior temporal poles. Atrophy patterns were more closely correlated with domain-specific performance than with subtype. These results show that PPA reflects a selective disruption of the language network as a whole, with no rigid boundaries between subtypes. Further, these atrophy patterns reveal anatomical correlates of language that could not have been surmised in patients with aphasia resulting from cerebrovascular lesions.

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.

Words and objects at the tip of the left temporal lobe in primary progressive aphasia

Eleven of 69 prospectively enrolled primary progressive aphasics were selected for this study because of peak atrophy sites located predominantly or exclusively within the anterior left temporal lobe. Cortical volumes in these areas were reduced to less than half of control values, whereas average volume elsewhere in the left hemisphere deviated from control values by only 8%. Failure to name objects emerged as the most consistent and severe deficit. Naming errors were attributed to pure retrieval failure if the object could not be named even when the denoting word was understood, the object recognized and the two accurately matched. Surprisingly many of the naming errors reflected pure retrieval failures, without discernible semantic or associative component. The remaining set of errors had associative components. These errors reflected the inability to define the word denoting the object more often than the inability to define the nature of the pictured object. In a separate task where the same object had to be linked to verbal or non-verbal associations, performance was abnormal only in the verbal format. Excessive taxonomic interference was observed for picture-word, but not picture-picture, matching tasks. This excessive interference reflected a blurring of intra- rather than inter-category distinctions as if the acuity of word-object associations had been diminished so that correspondences were easier to recognize at generic than specific levels. These dissociations between verbal and non-verbal markers of object knowledge indicate that the reduced neural mass at peak atrophy sites of the left temporal tip, accounting for half or more of the presumed premorbid volume, was unlikely to have contained domain-independent semantic representations of the type that would be expected in a strictly amodal hub. A more likely arrangement entails two highly interactive routes--a strongly left lateralized temporosylvian language network for verbal concepts, and a presumably more bilateral or right-sided inferotemporal/fusiform object recognition network, which remained relatively spared because peak atrophy sites were concentrated on the left. The current results also suggest that the left anterior temporal neocortex should be inserted into the language network where it is likely to play a major role in selecting verbal labels for objects and mediating the progression of word comprehension from generic to specific levels of precision.

The Northwestern Anagram Test: Measuring Sentence Production in Primary Progressive Aphasia

Primary progressive aphasia (PPA) is a clinical dementia syndrome with early symptoms of language dysfunction. Postmortem findings are varied and include Alzheimer disease and frontotemporal lobar degeneration (FTLD), both tauopathies and TAR DNA binding protein (TDP-43) proteinopathies. Clinical-pathological correlations in PPA are complex but the presence in the clinical profile of agrammatism has a high association with tauopathy. Grammatical competence is difficult to assess in the clinical setting with available methods. This article describes the Northwestern Anagram Test (NAT), a new clinical measure of sentence production. A total of 16 patients with PPA and their controls assembled single printed words to create sentences describing pictures. Northwestern Anagram Test performance was significantly correlated with a measure of sentence production and with aphasia severity but not with measures of naming, single word comprehension, object recognition, or motor speech. The NAT can be used to assess syntax competence when patients cannot be tested with measures that require intact speech production.

Clinically concordant variations of Alzheimer pathology in aphasic versus amnestic dementia

Primary progressive aphasia is a neurodegenerative syndrome characterized by gradual dissolution of language but relative sparing of other cognitive domains, especially memory. It is associated with asymmetric atrophy in the language-dominant hemisphere (usually left), and differs from typical Alzheimer-type dementia where amnesia is the primary deficit. Various pathologies have been reported, including the tangles and plaques of Alzheimers disease. Identification of Alzheimer pathology in these aphasic patients is puzzling since tangles and related neuronal loss in Alzheimers disease typically emerge in memory-related structures such as entorhinal cortex and spread to language-related neocortex later in the disease. Furthermore, Alzheimer pathology is typically symmetric. How can a predominantly limbic and symmetric pathology cause the primary progressive aphasia phenotype, characterized by relative preservation of memory and asymmetric predilection for the language-dominant hemisphere? Initial investigations into the possibility that Alzheimer pathology displays an atypical distribution in primary progressive aphasia yielded inconclusive results. The current study was based on larger groups of patients with either primary progressive aphasia or a typical amnestic dementia. Alzheimer pathology was the principal diagnosis in all cases. The goal was to determine whether Alzheimer pathology had clinically-concordant, and hence different distributions in these two phenotypes. Stereological counts of tangles and plaques revealed greater leftward asymmetry for tangles in primary progressive aphasia but not in the amnestic Alzheimer-type dementia (P < 0.05). Five of seven aphasics had more leftward tangle asymmetry in all four neocortical regions analysed, whereas this pattern was not seen in any of the predominantly amnestic cases. One aphasic case displayed higher right-hemisphere tangle density despite greater left-hemisphere hypoperfusion and atrophy during life. Although there were more tangles in the memory-related entorhinal cortex than in language-related neocortical areas in both phenotypes (P < 0.0001), the ratio of neocortical-to-entorhinal tangles was significantly higher in the aphasic cases (P = 0.034). Additionally, overall numbers of tangles and plaques were greater in the aphasic than amnestic cases (P < 0.05), especially in neocortical areas. No significant hemispheric asymmetry was found in plaque distribution, reinforcing the conclusion that tangles have greater clinical concordance than plaques in the spectrum of Alzheimer pathologies. The presence of left-sided tangle predominance and higher neocortical-to-entorhinal tangle ratio in primary progressive aphasia establishes clinical concordance of Alzheimer pathology with the aphasic phenotype. The one case with reversed asymmetry, however, suggests that these concordant clinicopathological relationships are not universal and that individual primary progressive aphasia cases with Alzheimer pathology exist where distributions of plaques and tangles do not account for the observed phenotype.

Dissociations between fluency and agrammatism in primary progressive aphasia

Background: Classical aphasiology, based on the study of stroke sequelae, fuses speech fluency and grammatical ability. Nonfluent (Brocas) aphasia often is accompanied by agrammatism; whereas in the fluent aphasias grammatical deficits are not typical. The assumption that a similar relationship exists in primary progressive aphasia (PPA) has led to the dichotomisation of this syndrome into fluent and nonfluent subtypes. Aims: This study compared elements of fluency and grammatical production in the narrative speech of individuals with PPA to determine if they can be dissociated from one another. Methods & Procedures: Speech samples from 37 individuals with PPA, clinically assigned to agrammatic (N = 11), logopaenic (N = 20), and semantic (N = 6) subtypes, and 13 cognitively healthy control participants telling the “Cinderella Story” were analysed for fluency—i.e., words per minute (WPM) and mean length of utterance in words (MLU-W)—and grammaticality, i.e., the proportion of grammatically correct sentences, open-to-closed-class word ratio, noun-to-verb ratio, and correct production of verb inflection, noun morphology, and verb argument structure. Between-group differences were analysed for each variable. Correlational analyses examined the relation between WPM and each grammatical variable, and an off-line measure of sentence production. Outcomes & Results: Agrammatic and logopaenic groups both had lower scores on the fluency measures and produced significantly fewer grammatical sentences than did semantic and control groups. However, only the agrammatic group evinced significantly impaired production of verb inflection and verb argument structure. In addition some semantic participants showed abnormal open-to-closed and noun-to-verb ratios in narrative speech. When the sample was divided on the basis of fluency, all the agrammatic participants fell in the nonfluent category. The logopaenic participants varied in fluency but those with low fluency showed variable performance on measures of grammaticality. Correlational analyses and scatter plots comparing fluency and each grammatical variable revealed dissociations within PPA participants, with some nonfluent participants showing normal grammatical skill. Conclusions: Grammatical production is a complex construct comprising correct usage of several language components, each of which can be selectively affected by disease. This study demonstrates that individuals with PPA show dissociations between fluency and grammatical production in narrative speech. Grammatical ability, and its relationship to fluency, varies from individual to individual, and from one variant of PPA to another, and can even be found in individuals with semantic PPA in whom a fluent aphasia is usually thought to accompany preserved ability to produce grammatical utterances.