Nina F. Dronkers

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.

Cognition and anatomy in three variants of primary progressive aphasia

We performed a comprehensive cognitive, neuroimaging, and genetic study of 31 patients with primary progressive aphasia (PPA), a decline in language functions that remains isolated for at least 2 years. Detailed speech and language evaluation was used to identify three different clinical variants: nonfluent progressive aphasia (NFPA; n = 11), semantic dementia (SD; n = 10), and a third variant termed logopenic progressive aphasia (LPA; n = 10). Voxel‐based morphometry (VBM) on MRIs showed that, when all 31 PPA patients were analyzed together, the left perisylvian region and the anterior temporal lobes were atrophied. However, when each clinical variant was considered separately, distinctive patterns emerged: (1) NFPA, characterized by apraxia of speech and deficits in processing complex syntax, was associated with left inferior frontal and insular atrophy; (2) SD, characterized by fluent speech and semantic memory deficits, was associated with anterior temporal damage; and (3) LPA, characterized by slow speech and impaired syntactic comprehension and naming, showed atrophy in the left posterior temporal cortex and inferior parietal lobule. Apolipoprotein E ε4 haplotype frequency was 20% in NFPA, 0% in SD, and 67% in LPA. Cognitive, genetic, and anatomical features indicate that different PPA clinical variants may correspond to different underlying pathological processes.

Voxel-based lesion–symptom mapping

For more than a century, lesion–symptom mapping studies have yielded valuable insights into the relationships between brain and behavior, but newer imaging techniques have surpassed lesion analysis in examining functional networks. Here we used a new method—voxel-based lesion–symptom mapping (VLSM)—to analyze the relationship between tissue damage and behavior on a voxel-by-voxel basis, as in functional neuroimaging. We applied VLSM to measures of speech fluency and language comprehension in 101 left-hemisphere-damaged aphasic patients: the VLSM maps for these measures confirm the anticipated contrast between anterior and posterior areas, and they also indicate that interacting regions facilitate fluency and auditory comprehension, in agreement with findings from modern brain imaging.

The Neural Architecture of the Language Comprehension Network: Converging Evidence from Lesion and Connectivity Analyses

While traditional models of language comprehension have focused on the left posterior temporal cortex as the neurological basis for language comprehension, lesion and functional imaging studies indicate the involvement of an extensive network of cortical regions. However, the full extent of this network and the white matter pathways that contribute to it remain to be characterized. In an earlier voxel-based lesion-symptom mapping analysis of data from aphasic patients (Dronkers et al., 2004), several brain regions in the left hemisphere were found to be critical for language comprehension: the left posterior middle temporal gyrus, the anterior part of Brodmanns area 22 in the superior temporal gyrus (anterior STG/BA22), the posterior superior temporal sulcus (STS) extending into Brodmanns area 39 (STS/BA39), the orbital part of the inferior frontal gyrus (BA47), and the middle frontal gyrus (BA46). Here, we investigated the white matter pathways associated with these regions using diffusion tensor imaging from healthy subjects. We also used resting-state functional magnetic resonance imaging data to assess the functional connectivity profiles of these regions. Fiber tractography and functional connectivity analyses indicated that the left MTG, anterior STG/BA22, STS/BA39, and BA47 are part of a richly interconnected network that extends to additional frontal, parietal, and temporal regions in the two hemispheres. The inferior occipito-frontal fasciculus, the arcuate fasciculus, and the middle and inferior longitudinal fasciculi, as well as transcallosal projections via the tapetum were found to be the most prominent white matter pathways bridging the regions important for language comprehension. The left MTG showed a particularly extensive structural and functional connectivity pattern which is consistent with the severity of the impairments associated with MTG lesions and which suggests a central role for this region in language comprehension.

The logopenic/phonological variant of primary progressive aphasia

Objective: Primary progressive aphasia (PPA) is characterized by isolated decline in language functions. Semantic dementia and progressive nonfluent aphasia are accepted PPA variants. A “logopenic” variant (LPA) has also been proposed, but its cognitive and anatomic profile is less defined. The aim of this study was to establish the cognitive and anatomic features of LPA. Methods: Six previously unreported LPA cases underwent extensive neuropsychological evaluation and an experimental study of phonological loop functions, including auditory and visual span tasks with digits, letters, and words. For each patient, a voxel-wise, automated analysis of MRI or SPECT data were conducted using SPM2. Results: In LPA, speech rate was slow, with long word-finding pauses. Grammar and articulation were preserved, although phonological paraphasias could be present. Repetition and comprehension were impaired for sentences but preserved for single words, and naming was moderately affected. Investigation of phonological loop functions showed that patients were severely impaired in digit, letter, and word span tasks. Performance did not improve with pointing, was influenced by word length, and did not show the normal phonological similarity effect. Atrophy or decreased blood flow was consistently found in the posterior portion of the left superior and middle temporal gyri and inferior parietal lobule. Conclusions: Logopenic progressive aphasia (LPA) is a distinctive variant of primary progressive aphasia. Cognitive and neuroimaging data indicate that a deficit in phonological loop functions may be the core mechanism underlying the LPA clinical syndrome. Recent studies suggest that Alzheimer disease may be the most common pathology underlying the LPA clinical syndrome. GLOSSARY: AD = Alzheimer disease; BA = Brodmann area; CDR = Clinical Dementia Rating; CVLT-MS = California Verbal Learning Test–Mental Status Edition; ECD = ethyl cysteinate dimer; FWHM = full-width at half-maximum; GM = gray matter; LPA = logopenic progressive aphasia; MMSE = Mini-Mental State Examination; PNFA = progressive nonfluent aphasia; PPA = primary progressive aphasia; Rey-O = Rey–Osterrieth; SemD = semantic dementia; VBM = voxel-based morphometry; WAB = Western Aphasia Battery; WAIS-III = Wechsler Adult Intelligence Scale, Third Edition.

Aβ Amyloid and Glucose Metabolism in Three Variants of Primary Progressive Aphasia

Alzheimers disease (AD) is found at autopsy in up to one third of patients with primary progressive aphasia (PPA), but clinical features that predict AD pathology in PPA are not well defined. We studied the relationships between language presentation, Aβ amyloidosis, and glucose metabolism in three PPA variants using [11C]‐Pittsburgh compound B ([11C]PIB) and [18F]‐labeled fluorodeoxyglucose positron emission tomography ([18F]FDG‐PET).

COGNITIVE PROCESSING SPEED AND THE STRUCTURE OF WHITE MATTER PATHWAYS: CONVERGENT EVIDENCE FROM NORMAL VARIATION AND LESION STUDIES

We investigated the relation between cognitive processing speed and structural properties of white matter pathways via convergent imaging studies in healthy and brain-injured groups. Voxel-based morphometry (VBM) was applied to diffusion tensor imaging data from thirty-nine young healthy subjects in order to investigate the relation between processing speed, as assessed with the Digit-Symbol subtest from WAIS-III, and fractional anisotropy, an index of microstructural organization of white matter. Digit-Symbol performance was positively correlated with fractional anisotropy of white matter in the parietal and temporal lobes bilaterally and in the left middle frontal gyrus. Fiber tractography indicated that these regions are consistent with the trajectories of the superior and inferior longitudinal fasciculi. In a second investigation, we assessed the effect of white matter damage on processing speed using voxel-based lesion-symptom mapping (VLSM) analysis of data from seventy-two patients with left-hemisphere strokes. Lesions in left parietal white matter, together with cortical lesions in supramarginal and angular gyri were associated with impaired performance. These findings suggest that cognitive processing speed, as assessed by the Digit-Symbol test, is closely related to the structural integrity of white matter tracts associated with parietal and temporal cortices and left middle frontal gyrus. Further, fiber tractography applied to VBM results and the patient findings suggest that the superior longitudinal fasciculus, a major tract subserving fronto-parietal integration, makes a prominent contribution to processing speed.

Role of frontal versus temporal cortex in verbal fluency as revealed by voxel-based lesion symptom mapping

Category and letter fluency tasks have been used to demonstrate psychological and neurological dissociations between semantic and phonological aspects of word retrieval. Some previous neuroimaging and lesion studies have suggested that category fluency (semantic-based word retrieval) is mediated primarily by temporal cortex, while letter fluency (letter-based word retrieval) is mediated primarily by frontal cortex. Other studies have suggested that both letter and category fluency are mediated by frontal cortex. We tested these hypotheses using voxel-based lesion symptom mapping (VLSM) in a group of 48 left-hemisphere stroke patients. VLSM maps revealed that category and letter fluency deficits correlate with lesions in temporal and frontal cortices, respectively. Other regions, including parietal cortex, were significantly implicated in both tasks. Our findings are therefore consistent with the hypothesis that temporal cortex subserves word retrieval constrained by semantics, whereas frontal regions are more critical for strategic word retrieval constrained by phonology.

Retrieval from semantic memory in Alzheimer-type dementia

Retrieval from semantic memory, measured by tasks requiring subjects to name items from a given category, was studied in mild Alzheimer-type dementia (Mild-ATD) subjects, moderate-to-severe Alzheimer-type dementia (MS-ATD) subjects, and normal controls. Semantic retrieval performance was shown to be highly sensitive to both the presence and the severity of ATD. Retrieval from both semantic categories and letter categories showed differences in the rate of production of correct responses between subject groups. These rate differences were not due to differences in accessibility of low-dominance semantic category members or low-frequency letter category members. An increase in errors as well as a decrease in correct responses contributed to the performance deficits of the ATD subjects. Furthermore, the pattern of errors changed from Mild- to MS-ATD. Qualitative as well as quantitative differences were also observed in the performance of Mild- versus MS-ATD groups on a third type of semantic retrieval task--the supermarket task. As performance of the ATD subjects declined on these semantic retrieval tasks, so did their performance on other tasks assessing primarily attention, language, and memory. The findings are discussed in terms of the progressive breakdown in both attentional and semantic memory functions which are associated with ATD.

Conduction aphasia, sensory-motor integration, and phonological short-term memory - An aggregate analysis of lesion and fMRI data

Conduction aphasia is a language disorder characterized by frequent speech errors, impaired verbatim repetition, a deficit in phonological short-term memory, and naming difficulties in the presence of otherwise fluent and grammatical speech output. While traditional models of conduction aphasia have typically implicated white matter pathways, recent advances in lesions reconstruction methodology applied to groups of patients have implicated left temporoparietal zones. Parallel work using functional magnetic resonance imaging (fMRI) has pinpointed a region in the posterior most portion of the left planum temporale, area Spt, which is critical for phonological working memory. Here we show that the region of maximal lesion overlap in a sample of 14 patients with conduction aphasia perfectly circumscribes area Spt, as defined in an aggregate fMRI analysis of 105 subjects performing a phonological working memory task. We provide a review of the evidence supporting the idea that Spt is an interface site for the integration of sensory and vocal tract-related motor representations of complex sound sequences, such as speech and music and show how the symptoms of conduction aphasia can be explained by damage to this system.