Cynthia K. Thompson

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.

Agrammatic and non-brain-damaged subjects' verb and verb argument structure production

This study examined verb and verb argument structure production in 10 agrammatic aphasic and 10 non-brain-damaged subjects. Production of six types of verbs was examined in two conditions-a confrontation and an elicited condition; and production of verb arguments was examined in a sentence condition in which each target verb was elicited with all possible argument structure arrangements. Results showed statistically significant differences between the aphasic and non-brain-damaged subjects in all conditions, but no significant differences were found between confrontation and elicited labelling conditions for either subject group. The aphasic subjects, however, produced obligatory one-place verbs correctly significantly more often than three-place or complement verbs in the elicited condition and a consistent hierarchy of verb difficulty was found in both the confrontation and elicited conditions, For both subject groups sentence production was influenced by the number of arguments or participant roles and by the type of arguments required by the verb. In addition, the complexity of the verb (i.e. the number of possible argument structure arrangements) influenced sentence production with simple verbs produced correctly with their arguments more often than complex ones. Finally, obligatory arguments were produced correctly more often than optional ones, even when production of the optional arguments was requested. These data indicate that the argument structure properties of verbs are important dimensions of lexical organization that influence both verb retrieval and sentence production in agrammatic aphasic subjects.

Primary progressive aphasia: PPA and the language network

Primary Progressive Aphasia (PPA) is a behaviorally focal dementia syndrome with deterioration of language functions but relative preservation of other cognitive domains for at least the first two years of disease. In this study, PPA patients with impaired word finding but intact comprehension of conversational speech and their matched control subjects were examined using voxel‐based morphometry (VBM) and functional magnetic resonance imaging (fMRI). fMRI compared signal changes during phonological and semantic language tasks with those during a control task (matching letters). PPA patients showed longer reaction times and reduced accuracy versus controls on the language tasks, but no performance differences on the control task. VBM demonstrated reduced gray matter in left superior temporal and inferior parietal regions in the PPA group. However, these patients showed a normal pattern of activation within the classical language regions. In addition, PPA patients showed activations, not seen in normals, in fusiform gyrus, precentral gyrus, and intra‐parietal sulcus. These activations were found to correlate negatively with measures of naming and task performance. The additional activations in PPA may therefore represent a compensatory spread of language‐related neural activity or a failure to suppress activity in areas normally inhibited during language tasks. Ann Neurol 2003;53:000–000

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.

Patterns of language decline in non-fluent primary progressive aphasia

Language samples collected yearly for up to 11 years post-onset of symptoms from four subjects presenting with non-fluent primary progressive aphasia (PPA) were analyzed and compared with samples collected from both non-brain-damaged subjects and those with agrammatic Brocas aphasia resulting from a single left-hemisphere stroke. Extensive analysis of lexical and morphosyntactic variables in these samples revealed two patterns of expressive language decline in the PPA subjects - one resembling that seen in our agrammatic aphasic subjects - i.e. impaired production of closed-class elements and loss of sentential structures governed by these elements-and the other characterized by advancing word-retrieval difficulties. These data are relevant for patient-management purposes and, in addition, they provide information relevant to language representation and organization.

Hemodynamic response function in patients with stroke-induced aphasia: implications for fMRI data analysis.

Functional MRI is based on changes in cerebral microvasculature triggered by increased neuronal oxidative metabolism. This change in blood flow follows a pattern known as the hemodynamic response function (HRF), which typically peaks 4-6 s following stimulus delivery. However, in the presence of cerebrovascular disease the HRF may not follow this normal pattern, due to either the temporal signal to noise (tSNR) ratio or delays in the HRF, which may result in misinterpretation or underestimation of fMRI signal. The present study examined the HRF and SNR in five individuals with aphasia resulting from stroke and four unimpaired participants using a lexical decision task and a long trial event-related design. T1-weighted images were acquired using an MP-RAGE sequence and BOLD T2*-weighted images were acquired using Echo Planar Imaging to measure time to peak (TTP) in the HRF. Data were analyzed using Brain Voyager in four anatomic regions known to be involved in language processing: Brocas area and the posterior perisylvian network (PPN) (including Wernickes area, the angular and supramarginal gyri) and right hemisphere homologues of these regions. The occipital area also was examined as a control region. Analyses showed that the TTP in three out of five patients in the left perisylvian area was increased significantly as compared to normal individuals and the left primary visual cortex in the same patients. In two other patients no significant delays were detected. We also found that the SNR for BOLD signal detection may by insufficient in damaged areas. These findings indicate that obtaining physiologic (TTP) and quality assurance (tSNR) information is essential for studying activation patterns in brain-damaged patients in order to avoid errors in interpretation of the data. An example of one such misinterpretation and the need for alternative data analysis strategies is discussed.

Neural correlates of verb argument structure processing

Neuroimaging and lesion studies suggest that processing of word classes, such as verbs and nouns, is associated with distinct neural mechanisms. Such studies also suggest that subcategories within these broad word class categories are differentially processed in the brain. Within the class of verbs, argument structure provides one linguistic dimension that distinguishes among verb exemplars, with some requiring more complex argument structure entries than others. This study examined the neural instantiation of verbs by argument structure complexity: one-, two-, and three-argument verbs. Stimuli of each type, along with nouns and pseudowords, were presented for lexical decision using an event-related functional magnetic resonance imaging design. Results for 14 young normal participants indicated largely overlapping activation maps for verbs and nouns, with no areas of significant activation for verbs compared to nouns, or vice versa. Pseudowords also engaged neural tissue overlapping with that for both word classes, with more widespread activation noted in visual, motor, and peri-sylvian regions. Examination of verbs by argument structure revealed activation of the supramarginal and angular gyri, limited to the left hemisphere only when verbs with two obligatory arguments were compared to verbs with a single argument. However, bilateral activation was noted when both two- and three-argument verbs were compared to one-argument verbs. These findings suggest that posterior peri-sylvian regions are engaged for processing argument structure information associated with verbs, with increasing neural tissue in the inferior parietal region associated with increasing argument structure complexity. These findings are consistent with processing accounts, which suggest that these regions are crucial for semantic integration.

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.