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1.  Frontal White Matter Tracts Sustaining Speech Production in Primary Progressive Aphasia 
The Journal of Neuroscience  2014;34(29):9754-9767.
In primary progressive aphasia (PPA), speech and language difficulties are caused by neurodegeneration of specific brain networks. In the nonfluent/agrammatic variant (nfvPPA), motor speech and grammatical deficits are associated with atrophy in a left fronto-insular-striatal network previously implicated in speech production. In vivo dissection of the crossing white matter (WM) tracts within this “speech production network” is complex and has rarely been performed in health or in PPA. We hypothesized that damage to these tracts would be specific to nfvPPA and would correlate with differential aspects of the patients' fluency abilities. We prospectively studied 25 PPA and 21 healthy individuals who underwent extensive cognitive testing and 3 T MRI. Using residual bootstrap Q-ball probabilistic tractography on high angular resolution diffusion-weighted imaging (HARDI), we reconstructed pathways connecting posterior inferior frontal, inferior premotor, insula, supplementary motor area (SMA) complex, striatum, and standard ventral and dorsal language pathways. We extracted tract-specific diffusion tensor imaging (DTI) metrics to assess changes across PPA variants and perform brain–behavioral correlations. Significant WM changes in the left intrafrontal and frontostriatal pathways were found in nfvPPA, but not in the semantic or logopenic variants. Correlations between tract-specific DTI metrics with cognitive scores confirmed the specific involvement of this anterior–dorsal network in fluency and suggested a preferential role of a posterior premotor-SMA pathway in motor speech. This study shows that left WM pathways connecting the speech production network are selectively damaged in nfvPPA and suggests that different tracts within this system are involved in subcomponents of fluency. These findings emphasize the emerging role of diffusion imaging in the differential diagnosis of neurodegenerative diseases.
PMCID: PMC4099550  PMID: 25031413
diffusion tensor imaging; frontal tracts; primary progressive aphasia; speech production; tractography; white matter
2.  What role does the anterior temporal lobe play in sentence-level processing? Neural correlates of syntactic processing in semantic PPA 
Journal of cognitive neuroscience  2013;26(5):970-985.
Neuroimaging and neuropsychological studies have implicated the anterior temporal lobe (ATL) in sentence-level processing, with syntactic structure-building and/or combinatorial semantic processing suggested as possible roles. A potential challenge to the view that the ATL is involved in syntactic aspects of sentence processing comes from the clinical syndrome of semantic variant primary progressive aphasia (semantic PPA, also known as semantic dementia). In semantic PPA, bilateral neurodegeneration of the anterior temporal lobes is associated with profound lexical semantic deficits, yet syntax is strikingly spared. The goal of this study was to investigate the neural correlates of syntactic processing in semantic PPA, in order to determine which regions normally involved in syntactic processing are damaged in semantic PPA, and whether spared syntactic processing depends on preserved functionality of intact regions, preserved functionality of atrophic regions, or compensatory functional reorganization. We scanned 20 individuals with semantic PPA and 24 age-matched controls using structural and functional MRI. Participants performed a sentence comprehension task that emphasized syntactic processing and minimized lexical semantic demands. We found that in controls, left inferior frontal and left posterior temporal regions were modulated by syntactic processing, while anterior temporal regions were not significantly modulated. In the semantic PPA group, atrophy was most severe in the anterior temporal lobes, but extended to the posterior temporal regions involved in syntactic processing. Functional activity for syntactic processing was broadly similar in patients and controls; in particular, whole-brain analyses revealed no significant differences between patients and controls in the regions modulated by syntactic processing. The atrophic left anterior temporal lobe did show abnormal functionality in semantic PPA patients, however this took the unexpected form of a failure to deactivate. Taken together, our findings indicate that spared syntactic processing in semantic PPA depends on preserved functionality of structurally intact left frontal regions and moderately atrophic left posterior temporal regions, but no functional reorganization was apparent as a consequence of anterior temporal atrophy and dysfunction. These results suggest that the role of the anterior temporal lobe in sentence processing is less likely to relate to syntactic structure-building, and more likely to relate to higher level processes such as combinatorial semantic processing.
PMCID: PMC4006153  PMID: 24345172
3.  Handedness and language learning disability differentially distribute in progressive aphasia variants 
Brain  2013;136(11):3461-3473.
Primary progressive aphasia is a neurodegenerative clinical syndrome that presents in adulthood with an isolated, progressive language disorder. Three main clinical/anatomical variants have been described, each associated with distinctive pathology. A high frequency of neurodevelopmental learning disability in primary progressive aphasia has been reported. Because the disorder is heterogeneous with different patterns of cognitive, anatomical and biological involvement, we sought to identify whether learning disability had a predilection for one or more of the primary progressive aphasia subtypes. We screened the University of California San Francisco Memory and Aging Center's primary progressive aphasia cohort (n = 198) for history of language-related learning disability as well as hand preference, which has associations with learning disability. The study included logopenic (n = 48), non-fluent (n = 54) and semantic (n = 96) variant primary progressive aphasias. We investigated whether the presence of learning disability or non-right-handedness was associated with differential effects on demographic, neuropsychological and neuroimaging features of primary progressive aphasia. We showed that a high frequency of learning disability was present only in the logopenic group (χ2 = 15.17, P < 0.001) and (χ2 = 11.51, P < 0.001) compared with semantic and non-fluent populations. In this group, learning disability was associated with earlier onset of disease, more isolated language symptoms, and more focal pattern of left posterior temporoparietal atrophy. Non-right-handedness was instead over-represented in the semantic group, at nearly twice the prevalence of the general population (χ2 = 6.34, P = 0.01). Within semantic variant primary progressive aphasia the right-handed and non-right-handed cohorts appeared homogeneous on imaging, cognitive profile, and structural analysis of brain symmetry. Lastly, the non-fluent group showed no increase in learning disability or non-right-handedness. Logopenic variant primary progressive aphasia and developmental dyslexia both manifest with phonological disturbances and posterior temporal involvement. Learning disability might confer vulnerability of this network to early-onset, focal Alzheimer’s pathology. Left-handedness has been described as a proxy for atypical brain hemispheric lateralization. As non-right-handedness was increased only in the semantic group, anomalous lateralization mechanisms might instead be related to frontotemporal lobar degeneration with abnormal TARDBP. Taken together, this study suggests that neurodevelopmental signatures impart differential trajectories towards neurodegenerative disease.
PMCID: PMC3808687  PMID: 24056533
Alzheimer’s disease; frontotemporal dementia; dementia aphasia; case control study; risk factors in epidemiology
4.  In vivo signatures of nonfluent/agrammatic primary progressive aphasia caused by FTLD pathology 
Neurology  2014;82(3):239-247.
To identify early cognitive and neuroimaging features of sporadic nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) caused by frontotemporal lobar degeneration (FTLD) subtypes.
We prospectively collected clinical, neuroimaging, and neuropathologic data in 11 patients with sporadic nfvPPA with FTLD-tau (nfvPPA-tau, n = 9) or FTLD–transactive response DNA binding protein pathology of 43 kD type A (nfvPPA-TDP, n = 2). We analyzed patterns of cognitive and gray matter (GM) and white matter (WM) atrophy at presentation in the whole group and in each pathologic subtype separately. We also considered longitudinal clinical data.
At first evaluation, regardless of pathologic FTLD subtype, apraxia of speech (AOS) was the most common cognitive feature and atrophy involved the left posterior frontal lobe. Each pathologic subtype showed few distinctive features. At presentation, patients with nfvPPA-tau presented with mild to moderate AOS, mixed dysarthria with prominent hypokinetic features, clear agrammatism, and atrophy in the GM of the left posterior frontal regions and in left frontal WM. While speech and language deficits were prominent early, within 3 years of symptom onset, all patients with nfvPPA-tau developed significant extrapyramidal motor signs. At presentation, patients with nfvPPA-TDP had severe AOS, dysarthria with spastic features, mild agrammatism, and atrophy in left posterior frontal GM only. Selective mutism occurred early, when general neurologic examination only showed mild decrease in finger dexterity in the right hand.
Clinical features in sporadic nfvPPA caused by FTLD subtypes relate to neurodegeneration of GM and WM in frontal motor speech and language networks. We propose that early WM atrophy in nfvPPA is suggestive of FTLD-tau pathology while early selective GM loss might be indicative of FTLD-TDP.
PMCID: PMC3902758  PMID: 24353332
5.  Distinct Neural Substrates for Semantic Knowledge and Naming in the Temporoparietal Network 
Cerebral Cortex (New York, NY)  2011;22(10):2217-2226.
Patients with anterior temporal lobe (ATL) lesions show semantic and lexical retrieval deficits, and the differential role of this area in the 2 processes is debated. Functional neuroimaging in healthy individuals has not clarified the matter because semantic and lexical processes usually occur simultaneously and automatically. Furthermore, the ATL is a region challenging for functional magnetic resonance imaging (fMRI) due to susceptibility artifacts, especially at high fields. In this study, we established an optimized ATL-sensitive fMRI acquisition protocol at 4 T and applied an event-related paradigm to study the identification (i.e., association of semantic biographical information) of celebrities, with and without the ability to retrieve their proper names. While semantic processing reliably activated the ATL, only more posterior areas in the left temporal and temporal–parietal junction were significantly modulated by covert lexical retrieval. These results suggest that within a temporoparietal network, the ATL is relatively more important for semantic processing, and posterior language regions are relatively more important for lexical retrieval.
PMCID: PMC3895951  PMID: 22047967
EPI optimization; famous faces; lexical retrieval; MRI; susceptibility artifacts
6.  White Matter atrophy in Alzheimer Disease variants 
In comparison to late-onset Alzheimer’s disease (LO-AD, onset > 65), early age-of-onset Alzheimer’s disease (EO-AD, onset<65 years) more often presents with language, visuospatial and/or executive impairment, often occurring earlier than a progressive memory deficit. The logopenic variant of primary progressive aphasia (lv-PPA) and the posterior cortical atrophy (PCA) have recently been described as possible atypical variants of EO-AD. Lv-PPA is characterized by isolated language deficit, while PCA is characterized by predominant visuospatial deficits. Severe hemispheric grey matter (GM) atrophy associated with EO-AD, lv-PPA and PCA has been described, but regional patterns of white matter (WM) damage are still poorly understood.
Using structural MRI and voxel-based morphometry, we investigated WM damage in 16 EO-AD, 13 PCA, 10 lv-PPA, and 14 LO-AD patients at presentation, and 72 age-matched controls.
In EO-AD, PCA and lv-PPA patients, WM atrophy was centered on lateral temporal and parietal regions, including cingulum and posterior corpus callosum. Compared to controls, lv-PPA patients showed a more severe left parietal damage, and PCA showed a more severe occipital atrophy. Moreover, EO-AD had greater cingulum atrophy compared with LO-AD. LO-AD showed WM damage in medial temporal regions and less extensive hemispheric involvement.
Patterns of WM damage in EO-AD, lv-PPA and PCA are consistent with the clinical syndromes and GM atrophy patterns. WM injury in AD atypical variants may contribute to symptoms and disease pathogenesis.
PMCID: PMC3717610  PMID: 23021625
Alzheimer’s disease; white matter damage; cerebral network; age of onset; VBM
7.  White matter damage in primary progressive aphasias: a diffusion tensor tractography study 
Brain  2011;134(10):3011-3029.
Primary progressive aphasia is a clinical syndrome that encompasses three major phenotypes: non-fluent/agrammatic, semantic and logopenic. These clinical entities have been associated with characteristic patterns of focal grey matter atrophy in left posterior frontoinsular, anterior temporal and left temporoparietal regions, respectively. Recently, network-level dysfunction has been hypothesized but research to date has focused largely on studying grey matter damage. The aim of this study was to assess the integrity of white matter tracts in the different primary progressive aphasia subtypes. We used diffusion tensor imaging in 48 individuals: nine non-fluent, nine semantic, nine logopenic and 21 age-matched controls. Probabilistic tractography was used to identify bilateral inferior longitudinal (anterior, middle, posterior) and uncinate fasciculi (referred to as the ventral pathway); and the superior longitudinal fasciculus segmented into its frontosupramarginal, frontoangular, frontotemporal and temporoparietal components, (referred to as the dorsal pathway). We compared the tracts’ mean fractional anisotropy, axial, radial and mean diffusivities for each tract in the different diagnostic categories. The most prominent white matter changes were found in the dorsal pathways in non-fluent patients, in the two ventral pathways and the temporal components of the dorsal pathways in semantic variant, and in the temporoparietal component of the dorsal bundles in logopenic patients. Each of the primary progressive aphasia variants showed different patterns of diffusion tensor metrics alterations: non-fluent patients showed the greatest changes in fractional anisotropy and radial and mean diffusivities; semantic variant patients had severe changes in all metrics; and logopenic patients had the least white matter damage, mainly involving diffusivity, with fractional anisotropy altered only in the temporoparietal component of the dorsal pathway. This study demonstrates that both careful dissection of the main language tracts and consideration of all diffusion tensor metrics are necessary to characterize the white matter changes that occur in the variants of primary progressive aphasia. These results highlight the potential value of diffusion tensor imaging as a new tool in the multimodal diagnostic evaluation of primary progressive aphasia.
PMCID: PMC3187537  PMID: 21666264
primary progressive aphasia; progressive non-fluent aphasia; semantic dementia; logopenic progressive aphasia; diffusion tensor imaging
8.  Language networks in semantic dementia 
Brain  2009;133(1):286-299.
Cognitive deficits in semantic dementia have been attributed to anterior temporal lobe grey matter damage; however, key aspects of the syndrome could be due to altered anatomical connectivity between language pathways involving the temporal lobe. The aim of this study was to investigate the left language-related cerebral pathways in semantic dementia using diffusion tensor imaging-based tractography and to combine the findings with cortical anatomical and functional magnetic resonance imaging data obtained during a reading activation task. The left inferior longitudinal fasciculus, arcuate fasciculus and fronto-parietal superior longitudinal fasciculus were tracked in five semantic dementia patients and eight healthy controls. The left uncinate fasciculus and the genu and splenium of the corpus callosum were also obtained for comparison with previous studies. From each tract, mean diffusivity, fractional anisotropy, as well as parallel and transverse diffusivities were obtained. Diffusion tensor imaging results were related to grey and white matter atrophy volume assessed by voxel-based morphometry and functional magnetic resonance imaging activations during a reading task. Semantic dementia patients had significantly higher mean diffusivity, parallel and transverse in the inferior longitudinal fasciculus. The arcuate and uncinate fasciculi demonstrated significantly higher mean diffusivity, parallel and transverse and significantly lower fractional anisotropy. The fronto-parietal superior longitudinal fasciculus was relatively spared, with a significant difference observed for transverse diffusivity and fractional anisotropy, only. In the corpus callosum, the genu showed lower fractional anisotropy compared with controls, while no difference was found in the splenium. The left parietal cortex did not show significant volume changes on voxel-based morphometry and demonstrated normal functional magnetic resonance imaging activation in response to reading items that stress sublexical phonological processing. This study shows that semantic dementia is associated with anatomical damage to the major superior and inferior temporal white matter connections of the left hemisphere likely involved in semantic and lexical processes, with relative sparing of the fronto-parietal superior longitudinal fasciculus. Fronto-parietal regions connected by this tract were activated normally in the same patients during sublexical reading. These findings contribute to our understanding of the anatomical changes that occur in semantic dementia, and may further help to explain the dissociation between marked single-word and object knowledge deficits, but sparing of phonology and fluency in semantic dementia.
PMCID: PMC2801321  PMID: 19759202
semantic dementia; semantic knowledge; diffusion tensor-based tractography; functional MRI; voxel-based morphometry
9.  The neural basis of surface dyslexia in semantic dementia 
Brain  2008;132(1):71-86.
Semantic dementia (SD) is a neurodegenerative disease characterized by atrophy of anterior temporal regions and progressive loss of semantic memory. SD patients often present with surface dyslexia, a relatively selective impairment in reading low-frequency words with exceptional or atypical spelling-to-sound correspondences. Exception words are typically ‘over-regularized’ in SD and pronounced as they are spelled (e.g. ‘sew’ is pronounced as ‘sue’). This suggests that in the absence of sufficient item-specific knowledge, exception words are read by relying mainly on subword processes for regular mapping of orthography to phonology. In this study, we investigated the functional anatomy of surface dyslexia in SD using functional magnetic resonance imaging (fMRI) and studied its relationship to structural damage with voxel-based morphometry (VBM). Five SD patients and nine healthy age-matched controls were scanned while they read regular words, exception words and pseudowords in an event-related design. Vocal responses were recorded and revealed that all patients were impaired in reading low-frequency exception words, and made frequent over-regularization errors. Consistent with prior studies, fMRI data revealed that both groups activated a similar basic network of bilateral occipital, motor and premotor regions for reading single words. VBM showed that these regions were not significantly atrophied in SD. In control subjects, a region in the left intraparietal sulcus was activated for reading pseudowords and low-frequency regular words but not exception words, suggesting a role for this area in subword mapping from orthographic to phonological representations. In SD patients only, this inferior parietal region, which was not atrophied, was also activated by reading low-frequency exception words, especially on trials where over-regularization errors occurred. These results suggest that the left intraparietal sulcus is involved in subword reading processes that are differentially recruited in SD when word-specific information is lost. This loss is likely related to degeneration of the anterior temporal lobe, which was severely atrophied in SD. Consistent with this, left mid-fusiform and superior temporal regions that showed reading-related activations in controls were not activated in SD. Taken together, these results suggest that the left inferior parietal region subserves subword orthographic-to-phonological processes that are recruited for exception word reading when retrieval of exceptional, item-specific word forms is impaired by degeneration of the anterior temporal lobe.
PMCID: PMC2638692  PMID: 19022856
semantic dementia; dyslexia; parietal lobe; voxel-based morphometry; functional MRI
10.  Clinical, Cognitive and Anatomical Evolution from Nonfluent Progressive Aphasia to Corticobasal Syndrome: A Case Report 
Neurocase  2004;10(6):426-436.
Recent clinical and pathological studies have suggested that frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS) show clinical and pathological overlap. We present four years of longitudinal clinical, cognitive and anatomical data in the case of a 56-year-old woman, AS, whose clinical picture evolved from FTLD to CBS. For the first three years, AS showed a progressive speech and language disorder compatible with a diagnosis of the nonfluent aphasia variant of FTLD. At year four, 10 years after her first symptom, AS developed the classical clinical signs of CBS, including alien limb phenomenon and dystonia. Voxel-based morphometry (VBM) applied to AS’s four annual scans showed progression of atrophy from the inferior posterior frontal gyrus, to the left insula and finally to the medial frontal lobe. This case demonstrates the clinical overlap between FTLD and CBS and shows that the two can appear in the same patient at different stages of the disease in relation to the progression of anatomical damage.
PMCID: PMC2365737  PMID: 15788282
11.  Sporadic Jakob-Creutzfeldt Disease Presenting as Primary Progressive Aphasia 
JAMA neurology  2013;70(2):254-257.
To report the clinical, neuropsychological, linguistic, imaging, and neuropathological features of a unique case of sporadic Jakob-Creutzfeldt disease in which the patient presented with a logopenic variant of primary progressive aphasia.
Case report.
Large referral center for atypical memory and aging disorders, particularly Jakob-Creutzfeldt disease.
Patient presenting with logopenic variant primary progressive aphasia initially thought to be due to Alzheimer disease.
Despite the long, slow 3.5-year course, the patient was shown to have pathology-proven sporadic Jakob-Creutzfeldt disease.
These findings expand the differential of primary progressive aphasia to include prion disease.
PMCID: PMC4365870  PMID: 23400721
12.  Longitudinal gray matter contraction in three variants of primary progressive aphasia: A tenser-based morphometry study 
NeuroImage : Clinical  2015;8:345-355.
The present study investigated the pattern of longitudinal changes in cognition and anatomy in three variants of primary progressive aphasia (PPA). Eight patients with the non-fluent variant of PPA (nfvPPA), 13 patients with the semantic variant (svPPA), seven patients with the logopenic variant (lvPPA), and 29 age-matched, neurologically healthy controls were included in the study. All participants underwent longitudinal MRI, neuropsychological and language testing at baseline and at a 1-year follow-up. Tenser-based morphometry (TBM) was applied to T1-weighted MRI images in order to map the progression of gray and white matter atrophy over a 1-year period. Results showed that each patient group was characterized by a specific pattern of cognitive and anatomical changes. Specifically, nfvPPA patients showed gray matter atrophy progression in the left frontal and subcortical areas as well as a decline in motor speech and executive functions; svPPA patients presented atrophy progression in the medial and lateral temporal lobe and decline in semantic memory abilities; and lvPPA patients showed atrophy progression in lateral/posterior temporal and medial parietal regions with a decline in memory, sentence repetition and calculations. In addition, in all three variants, the white matter fibers underlying the abovementioned cortical areas underwent significant volume contraction over a 1-year period.
Overall, these results indicate that the three PPA variants present distinct patterns of neuroanatomical contraction, which reflect their clinical and cognitive progression.
•PPA variants present distinct patterns of neuroanatomical contraction.•Non-fluent variant of PPA shows GM contraction in left frontal and subcortical areas.•Semantic variant of PPA shows GM contraction in medial and lateral temporal lobe.•Logopenic variant of PPA shows GM contraction in lateral/posterior temporal and medial parietal regions.
PMCID: PMC4473099  PMID: 26106560
13.  Neurodegenerative disease phenotypes in carriers of MAPT p.A152T, a risk factor for frontotemporal dementia spectrum disorders and Alzheimer's disease 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e31828cc357.
Recently, Coppola and colleagues demonstrated that a rare MAPT sequence variant, c.454G>A (p.A152T), significantly increases the risk of frontotemporal dementia (FTD) spectrum disorders and Alzheimer's disease (AD) in a screen of 15,369 subjects1. We describe clinical features of 9 patients with neurodegenerative disease (4 women) harboring p.A152T, aged 51 to 79 years at symptom onset. Seven developed FTD spectrum clinical syndromes, including progressive supranuclear palsy syndrome (PSP, n=2), behavioral variant FTD (bvFTD, n=1), nonfluent variant primary progressive aphasia (nfvPPA, n=2), and corticobasal syndrome (CBS, n=2); two patients were diagnosed with clinical AD. Thus, MAPT p.A152T is associated with a variety of FTD spectrum clinical presentations, although patients with clinical AD are also identified. These data warrant larger studies with clinicopathological correlation to elucidate the influence of this genetic variant on neurodegenerative disease.
PMCID: PMC3796183  PMID: 23518664
All Cognitive Disorders/Dementia; Alzheimer's disease; Frontotemporal Dementia; Corticobasal degeneration; Progressive Supranuclear Palsy
14.  Anterior temporal lobe degeneration produces widespread network-driven dysfunction 
Brain  2013;136(10):2979-2991.
The neural organization of semantic memory remains much debated. A ‘distributed-only’ view contends that semantic knowledge is represented within spatially distant, modality-selective primary and association cortices. Observations in semantic variant primary progressive aphasia have inspired an alternative model featuring the anterior temporal lobe as an amodal hub that supports semantic knowledge by linking distributed modality-selective regions. Direct evidence has been lacking, however, to support intrinsic functional interactions between an anterior temporal lobe hub and upstream sensory regions in humans. Here, we examined the neural networks supporting semantic knowledge by performing a multimodal brain imaging study in healthy subjects and patients with semantic variant primary progressive aphasia. In healthy subjects, the anterior temporal lobe showed intrinsic connectivity to an array of modality-selective primary and association cortices. Patients showed focal anterior temporal lobe degeneration but also reduced physiological integrity throughout distributed modality-selective regions connected with the anterior temporal lobe in healthy controls. Physiological deficits outside the anterior temporal lobe correlated with scores on semantic tasks and with anterior temporal subregion atrophy, following domain-specific and connectivity-based predictions. The findings provide a neurophysiological basis for the theory that semantic processing is orchestrated through interactions between a critical anterior temporal lobe hub and modality-selective processing nodes.
PMCID: PMC3857932  PMID: 24072486
anterior temporal lobe; semantic dementia; cognition; semantics; functional neuroimaging
15.  TDP-43 Frontotemporal Lobar Degeneration and Autoimmune Disease 
Journal of neurology, neurosurgery, and psychiatry  2013;84(9):10.1136/jnnp-2012-304644.
The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored.
To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared to neurologically healthy normal controls (NC) and Alzheimer’s disease (AD) as dementia controls.
Case control.
Academic medical centres.
129 svPPA, 39 PGRN, 186 NC, and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN, and NC cohorts underwent serum analysis for tumor necrosis factor α (TNF-α) levels.
Outcome Measures
Chi-square comparison of autoimmune prevalence and follow up logistic regression.
There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders, and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared to NC.
svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared to NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 (TDP-43) aggregation.
PMCID: PMC3840954  PMID: 23543794
16.  Machine learning approaches to diagnosis and laterality effects in semantic dementia discourse 
Advances in automatic text classification have been necessitated by the rapid increase in the availability of digital documents. Machine learning (ML) algorithms can ‘learn’ from data: for instance a ML system can be trained on a set of features derived from written texts belonging to known categories, and learn to distinguish between them. Such a trained system can then be used to classify unseen texts. In this paper, we explore the potential of the technique to classify transcribed speech samples along clinical dimensions, using vocabulary data alone. We report the accuracy with which two related ML algorithms [naive Bayes Gaussian (NBG) and naive Bayes multinomial (NBM)] categorized picture descriptions produced by: 32 semantic dementia (SD) patients versus 10 healthy, age-matched controls; and SD patients with left- (n = 21) versus right-predominant (n = 11) patterns of temporal lobe atrophy. We used information gain (IG) to identify the vocabulary features that were most informative to each of these two distinctions.
In the SD versus control classification task, both algorithms achieved accuracies of greater than 90%. In the right- versus left-temporal lobe predominant classification, NBM achieved a high level of accuracy (88%), but this was achieved by both NBM and NBG when the features used in the training set were restricted to those with high values of IG. The most informative features for the patient versus control task were low frequency content words, generic terms and components of metanarrative statements. For the right versus left task the number of informative lexical features was too small to support any specific inferences. An enriched feature set, including values derived from Quantitative Production Analysis (QPA) may shed further light on this little understood distinction.
PMCID: PMC4072460  PMID: 23876449
Semantic dementia; Discourse; Laterality; Machine learning; Information gain
17.  Elicitation of specific syntactic structures in primary progressive aphasia 
Brain and language  2012;123(3):183-190.
Many patients with primary progressive aphasia (PPA) are impaired in syntactic production. Because most previous studies of expressive syntax in PPA have relied on quantitative analysis of connected speech samples, which is a relatively unconstrained task, it is not well understood which specific syntactic structures are most challenging for these patients. We used an elicited syntactic production task to identify which syntactic structures pose difficulties for 31 patients with three variants of PPA: non-fluent/agrammatic, semantic and logopenic. Neurodegenerative and healthy age-matched participants were included as controls. As expected, non-fluent/agrammatic patients made the most syntactic errors. The structures that resulted in the most errors were constructions involving third person singular present agreement, and constructions involving embedded clauses. Deficits on this elicited production task were associated with atrophy of the left posterior inferior frontal gyrus.
PMCID: PMC3502680  PMID: 23046707
syntax; production; primary progressive aphasia; voxel-based morphometry
18.  Patterns of longitudinal brain atrophy in the logopenic variant of primary progressive aphasia 
Brain and Language  2013;127(2):121-126.
► Patterns of cell loss in lvPPA remain asymmetrical over time. ► More anterior left hemisphere areas become involved over time. ► Right hemisphere regions become affected that mirror early left hemisphere change. ► Left hemisphere atrophy rates are greater than right hemisphere. ► Over time patients with lvPPA develop single word level processing deficits.
The logopenic variant of primary progressive aphasia (PPA) is characterised by impaired sentence repetition and word retrieval difficulties. Post mortem studies, amyloid imaging and CSF tau/Aβ measurements suggest Alzheimer’s disease (AD) pathology as the underlying cause. Relatively little is known about patterns of progression in patients with the logopenic variant of PPA. 21 patients (3 with post mortem confirmation of AD and 5 with positive amyloid PIB-PET scans) were studied with longitudinal T1-weighted MR imaging (mean interscan interval 1.2 years) using volumetric analysis and voxel-based morphometry (VBM). Baseline imaging showed asymmetrical (left greater than right) involvement of the posterior superior temporal and inferior parietal lobes as well as posterior cingulate and medial temporal lobes. The whole brain rate of volume loss was 2.0% per year with a greater rate of left hemisphere atrophy (2.3%/year) than right hemisphere (1.6%/year). Longitudinal VBM analysis showed increasing involvement of other areas in the left hemisphere (temporal, parietal, frontal and caudate) and atrophy of areas in the right hemisphere that had been involved earlier in the disease in the left hemisphere, particularly posterior cingulate/precuneus. With disease progression there was worsening of anomia, sentence repetition and sentence comprehension but consistent with the spread of imaging changes also deficits in single word comprehension, single word repetition and verbal memory. This study shows that the logopenic variant of PPA remains an asymmetrical disease, with spread through the left hemisphere language network but also involvement to a lesser degree of regions in the right hemisphere that mirror the earlier left hemisphere changes.
PMCID: PMC3880853  PMID: 23395096
Primary progressive aphasia; Logopenic aphasia
19.  The neural basis of syntactic deficits in primary progressive aphasia 
Brain and language  2012;122(3):190-198.
Patients with primary progressive aphasia (PPA) vary considerably in terms of which brain regions are impacted, as well as in the extent to which syntactic processing is impaired. Here we review the literature on the neural basis of syntactic deficits in PPA. Structural and functional imaging studies have most consistently associated syntactic deficits with damage to left inferior frontal cortex. Posterior perisylvian regions have been implicated in some studies. Damage to the superior longitudinal fasciculus, including its arcuate component, has been linked with syntactic deficits, even after gray matter atrophy is taken into account. These findings suggest that syntactic processing depends on left frontal and posterior perisylvian regions, as well as intact connectivity between them. In contrast, anterior temporal regions, and the ventral tracts that link frontal and temporal language regions, appear to be less important for syntax, since they are damaged in many PPA patients with spared syntactic processing.
PMCID: PMC3418470  PMID: 22546214
syntax; primary progressive aphasia; voxel-based morphometry; functional MRI; diffusion tensor imaging
20.  MRI Signatures of Brain Macrostructural Atrophy and Microstructural Degradation in Frontotemporal Lobar Degeneration Subtypes 
Brain magnetic resonance imaging (MRI) studies have demonstrated regional patterns of brain macrostructural atrophy and white matter microstructural alterations separately in the three major subtypes of frontotemporal lobar degeneration (FTLD), which includes behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). This study was to investigate to what extent the pattern of white matter microstructural alterations in FTLD subtypes mirrors the pattern of brain atrophy, and to compare the ability of various diffusion tensor imaging (DTI) indices in characterizing FTLD patients, as well as to determine whether DTI measures provide greater classification power for FTLD than measuring brain atrophy. Twenty-five patients with FTLD (13 with bvFTD, 6 with SD, and 6 with PNFA) and 19 healthy age-matched control subjects underwent both structural MRI and DTI scans. Measurements of regional brain atrophy were based on T1-weighted MRI data and voxel-based morphometry. Measurements of regional white matter degradation were based on voxelwise as well as regions-of-interest tests of DTI variations, expressed as fractional anisotropy, axial diffusivity, and radial diffusivity. Compared to controls, bvFTD, SD, and PNFA patients each exhibited characteristic regional patterns of brain atrophy and white matter damage. DTI overall provided significantly greater accuracy for FTLD classification than brain atrophy. Moreover, radial diffusivity was more sensitive in assessing white matter damage in FTLD than other DTI indices. The findings suggest that DTI in general and radial diffusivity in particular are more powerful measures for the classification of FTLD patients from controls than brain atrophy.
PMCID: PMC3738303  PMID: 22976075
Behavioral variant frontotemporal dementia; diffusion tensor imaging; frontotemporal lobar degeneration; multimodality MRI; progressive nonfluent aphasia; semantic dementia
21.  Music Recognition in Frontotemporal Lobar Degeneration and Alzheimer Disease 
To compare music recognition in patients with frontotemporal dementia, semantic dementia, Alzheimer disease, and controls and to evaluate the relationship between music recognition and brain volume.
Recognition of familiar music depends on several levels of processing. There are few studies about how patients with dementia recognize familiar music.
Subjects were administered tasks that assess pitch and melody discrimination, detection of pitch errors in familiar melodies, and naming of familiar melodies.
There were no group differences on pitch and melody discrimination tasks. However, patients with semantic dementia had considerable difficulty naming familiar melodies and also scored the lowest when asked to identify pitch errors in the same melodies. Naming familiar melodies, but not other music tasks, was strongly related to measures of semantic memory. Voxel-based morphometry analysis of brain MRI showed that difficulty in naming songs was associated with the bilateral temporal lobes and inferior frontal gyrus, whereas difficulty in identifying pitch errors in familiar melodies correlated with primarily the right temporal lobe.
The results support a view that the anterior temporal lobes play a role in familiar melody recognition, and that musical functions are affected differentially across forms of dementia.
PMCID: PMC3691095  PMID: 21617528
Pitch; Melody; temporal lobe; auditory perception
22.  Nonfluent/agrammatic PPA with in-vivo cortical amyloidosis and Pick’s disease pathology 
Behavioural neurology  2013;26(1):95-106.
The role of biomarkers in predicting pathological findings in the frontotemporal dementia (FTD) clinical spectrum disorders is still being explored. We present comprehensive, prospective longitudinal data for a 66 year old, right-handed female who met current criteria for the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA). She first presented with a 3-year history of progressive speech and language impairment mainly characterized by severe apraxia of speech. Neuropsychological and general motor functions remained relatively spared throughout the clinical course. Voxel-based morphometry (VBM) showed selective cortical atrophy of the left posterior inferior frontal gyrus (IFG) and underlying insula that worsened over time, extending along the left premotor strip. Five years after her first evaluation, she developed mild memory impairment and underwent PET-FDG and PiB scans that showed left frontal hypometabolism and cortical amyloidosis. Three years later (11 years from first symptom), post-mortem histopathological evaluation revealed Pick’s disease, with severe degeneration of left IFG, mid-insula, and precentral gyrus. Alzheimer’s disease (AD) (CERAD frequent / Braak Stage V) was also detected. This patient demonstrates that biomarkers indicating brain amyloidosis should not be considered conclusive evidence that AD pathology accounts for a typical FTD clinical/anatomical syndrome.
PMCID: PMC3526142  PMID: 22713404
Nonfluent primary progressive aphasia; PPA; apraxia of speech; Voxel-based morphometry; PiB-PET; Pick’s disease; Alzheimer disease; Frontotemporal dementia
23.  Behavioral-variant frontotemporal dementia with corticobasal degeneration pathology: Phenotypic comparison to bvFTD with Pick’s disease 
Patients with corticobasal degeneration (CBD) pathology present with diverse clinical syndromes also associated with other neuropathologies, including corticobasal syndrome, progressive nonfluent aphasia, and an Alzheimer’s-type dementia. Some present with behavioral variant frontotemporal dementia (bvFTD), though this subtype still requires more detailed phenotypic characterization. All patients with CBD pathology and clinical assessment were reviewed (N=17) and selected if they initially met criteria for bvFTD [bvFTD(CBD): N=5]. Available bvFTD patients with Pick’s [bvFTD(Pick’s): N=5] were selected as controls. Patients were also compared to healthy older controls [N=53] on neuropsychological and neuroimaging measures. At initial presentation, bvFTD(CBD) showed few neuropsychological or motor differences from bvFTD(Pick’s). Neuropsychiatrically, they were predominantly apathetic with less florid social disinhibition and eating disturbances, and were more anxious than bvFTD(Pick’s) patients. Voxel-based morphometry revealed similar patterns of predominantly frontal atrophy between bvFTD groups, though overall degree of atrophy was less severe in bvFTD(CBD), who also showed comparative preservation of the frontoinsular rim, with dorsal > ventral frontal atrophy, and sparing of temporal and parietal structures relative to bvFTD(Pick’s) patients. Despite remarkable overlap between the two patient types, bvFTD patients with underlying CBD pathology show subtle clinical features that may distinguish them from patients with Pick’s disease neuropathology.
PMCID: PMC3208125  PMID: 21881831
Corticobasal degeneration; frontotemporal dementia; behavior; neuropsychiatry; neuropsychology; neuropathology
24.  Syntactic processing depends on dorsal language tracts 
Neuron  2011;72(2):397-403.
Frontal and temporal language areas involved in syntactic processing are connected by several dorsal and ventral tracts, but the functional roles of the different tracts are not well understood. To identify which white matter tract(s) are important for syntactic processing, we examined the relationship between white matter damage and syntactic deficits in patients with primary progressive aphasia, using multimodal neuroimaging and neurolinguistic assessment. Diffusion tensor imaging showed that microstructural damage to left hemisphere dorsal tracts—the superior longitudinal fasciculus including its arcuate component—was strongly associated with deficits in comprehension and production of syntax. Damage to these dorsal tracts predicted syntactic deficits after gray matter atrophy was taken into account, and fMRI confirmed that these tracts connect regions modulated by syntactic processing. In contrast, damage to ventral tracts—the extreme capsule fiber system or the uncinate fasciculus—was not associated with syntactic deficits. Our findings show that syntactic processing depends primarily on dorsal language tracts.
PMCID: PMC3201770  PMID: 22017996
25.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia 
Brain  2011;134(9):2456-2477.
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
PMCID: PMC3170532  PMID: 21810890
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology

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