Maria Carmela Tartaglia

White matter damage in primary progressive aphasias: a diffusion tensor tractography study.

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.

Syntactic processing depends on dorsal language tracts

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.

Neuroimaging in Dementia

SummaryDementia is a common illness with an incidence that is rising as the aged population increases. There are a number of neurodegenerative diseases that cause dementia, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, which is subdivided into the behavioral variant, the semantic variant, and nonfluent variant. Numerous other neurodegenerative illnesses have an associated dementia, including corticobasal degeneration, Creutzfeldt–Jakob disease, Huntington’s disease, progressive supranuclear palsy, multiple system atrophy, Parkinson’s disease dementia, and amyotrophic lateral sclerosis. Vascular dementia and AIDS dementia are secondary dementias. Diagnostic criteria have relied on a constellation of symptoms, but the definite diagnosis remains a pathologic one. As treatments become available and target specific molecular abnormalities, differentiating amongst the various primary dementias early on becomes essential. The role of imaging in dementia has traditionally been directed at ruling out treatable and reversible etiologies and not to use imaging to better understand the pathophysiology of the different dementias. Different brain imaging techniques allow the examination of the structure, biochemistry, metabolic state, and functional capacity of the brain. All of the major neurodegenerative disorders have relatively specific imaging findings that can be identified. New imaging techniques carry the hope of revolutionizing the diagnosis of neurodegenerative disease so as to obtain a complete molecular, structural, and metabolic characterization, which could be used to improve diagnosis and to stage each patient and follow disease progression and response to treatment. Structural and functional imaging modalities contribute to the diagnosis and understanding of the different dementias.

Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP-43 mutations

Transactive response DNA-binding protein 43 (TDP-43) is a major pathological protein in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). There are many disease-associated mutations in TDP-43, and several cellular and animal models with ectopic overexpression of mutant TDP-43 have been established. Here we sought to study altered molecular events in FTD and ALS by using induced pluripotent stem cell (iPSC) derived patient neurons. We generated multiple iPSC lines from an FTD/ALS patient with the TARDBP A90V mutation and from an unaffected family member who lacked the mutation. After extensive characterization, two to three iPSC lines from each subject were selected, differentiated into postmitotic neurons, and screened for relevant cell-autonomous phenotypes. Patient-derived neurons were more sensitive than control neurons to 100 nM straurosporine but not to other inducers of cellular stress. Three disease-relevant cellular phenotypes were revealed under staurosporine-induced stress. First, TDP-43 was localized in the cytoplasm of a higher percentage of patient neurons than control neurons. Second, the total TDP-43 level was lower in patient neurons with the A90V mutation. Third, the levels of microRNA-9 (miR-9) and its precursor pri-miR-9-2 decreased in patient neurons but not in control neurons. The latter is likely because of reduced TDP-43, as shRNA-mediated TDP-43 knockdown in rodent primary neurons also decreased the pri-miR-9-2 level. The reduction in miR-9 expression was confirmed in human neurons derived from iPSC lines containing the more pathogenic TARDBP M337V mutation, suggesting miR-9 downregulation might be a common pathogenic event in FTD/ALS. These results show that iPSC models of FTD/ALS are useful for revealing stress-dependent cellular defects of human patient neurons containing rare TDP-43 mutations in their native genetic contexts.

The neural basis of syntactic deficits in primary progressive aphasia

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.

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.

Executive dysfunction in frontotemporal dementia is related to abnormalities in frontal white matter tracts

Cognitive deficits in behavioral-variant frontotemporal dementia (bvFTD) and AD are linked to frontal and temporal lobe gray matter (GM) pathology. The aim of this study was to assess the relative contribution of white (WM) and GM abnormalities to cognitive dysfunction in bvFTD and AD. Fractional anisotropy (FA) for the corpus callosum, cingulum (Cg), and uncinate fasciculus (Unc) was determined in 17 bvFTD and 10 AD patients who underwent neuropsychological testing. Regressions were performed to assess the relative contribution of WM and GM abnormalities to cognitive deficits. Multiple regression analysis revealed that in bvFTD, the left anterior Cg FA was related to executive function, the right anterior Cg FA to visual-spatial attention and working memory, the right posterior Cg to visual-constructional abilities and the left Unc FA to Modified Trails Errors. After adding corresponding GM volumes, the left anterior Cg FA, the right anterior cingulate FA, the right posterior cingulate FA and the left uncinate FA remained significant predictors of the cognitive tasks. In the AD group, the left posterior Cg FA and right descending Cg FA were related to visual recall performance but did not remain significant predictors when GM volumes were added to the regression. These results suggest that reduced integrity of specific WM tracts contribute to cognitive deficits observed in bvFTD after accounting for GM atrophy. In AD, memory impairment was related to WM tract injury but this relationship was no longer observed when GM volumes were included.

Brain atrophy in primary lateral sclerosis

Background: Primary lateral sclerosis (PLS) is an idiopathic upper motor neuron degenerative disorder. The aim of this study was to compare brain volumes in patients with PLS and controls and determine whether differences were due to loss of gray matter (GM), white matter (WM), or both. Methods: T1-weighted images were acquired in patients with PLS and controls. Freesurfer was used for volumetric segmentation of whole brain, cortical GM, precentral and postcentral cortex, WM, corpus callosum, basal ganglia, thalamus, cerebellum, and CSF. Relationships were sought between disease severity, disease duration, age and brain volumes. Results: Eleven patients with PLS and 10 age-matched healthy controls were included in this study. Compared to control subjects, patients with PLS had significantly smaller whole brain (p = 0.043), frontal lobe (p = 0.036), precentral cortex (p = 0.016), and corpus callosum (p = 0.036) volumes. There was a trend toward a smaller thalamus (p = 0.051). Disease severity correlated with ventricular CSF volume (rho = −0.604, p = 0.025) and precentral cortex volume loss (rho = 0.599, p = 0.026). Disease duration tended to correlate with a loss of WM (rho = −0.636, p = 0.063). Conclusions: Our results suggest that there is focal atrophy in patients with primary lateral sclerosis compared with controls especially in the precentral cortex and the corpus callosum, specifically where there is transfer of motor fibers. ALS = amyotrophic lateral sclerosis; ALSFRS-R = ALS Functional Rating Scale; fSPGR = fast spoiled gradient echo sequence; GM = gray matter; PLS = primary lateral sclerosis; TE = echo time; TR = repetition time; WM = white matter.

Abhorring the vacuum: use of Alzheimer’s disease medications in frontotemporal dementia.

The spectrum of idiopathic inflammatory-demyelinating disorders of the CNS is classified based on clinical symptoms and signs, clinical severity, lesion distribution, neuroimaging features and cerebrospinal fluid characteristics. There is a wide variety of conditions in this broad spectrum. In some cases, the dissemination in the CNS is limited to the optic nerves and spinal cord. Neuromyelitis optica (NMO) and the NMO spectrum disorders have a predilection for the optic nerves and spinal cord. Clinical, MRI, cerebrospinal fluid and neuropathological features show that NMO could be considered as a distinct disease rather than as a variant of multiple sclerosis. Accurate and early diagnosis is critical to facilitate initiation of immunosuppressive and/or immunomodulatory therapy to prevent attacks and disability progression.There is no dedicated therapy for frontotemporal dementia (FTD). In order to treat the often devastating behavioral disturbances that interfere with both normal social functioning and the ability of caregivers to provide needed support, off-label medication usage is frequent. In addition to antidepressant and antipsychotic medications, which afford some benefits, US FDA-approved treatments for Alzheimer’s disease are often used, including both cholinesterase inhibitors and memantine. Here, we review the various clinical manifestations of FTD, a general approach to treatment and the goals of any potential therapies. We review all of the existing literature on the use of cholinesterase inhibitors and memantine in FTD. While cholinesterase inhibitors do not currently have a place in FTD treatment, memantine may be helpful, although the results of two placebo-controlled trials with this agent are not yet available. Finally, we discuss our view that such approaches will probably become supplanted by rational, molecularly-based therapies currently in development.

Sporadic corticobasal syndrome due to FTLD-TDP

Sporadic corticobasal syndrome (CBS) has been associated with diverse pathological substrates, but frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) has only been linked to CBS among progranulin mutation carriers. We report the clinical, neuropsychological, imaging, genetic, and neuropathological features of GS, a patient with sporadic corticobasal syndrome. Genetic testing revealed no mutations in the microtubule associated protein tau or progranulin (PGRN) genes, but GS proved homozygous for the T allele of the rs5848 PGRN variant. Autopsy showed ubiquitin and TDP-43 pathology most similar to a pattern previously associated with PGRN mutation carriers. These findings confirm that FTLD-TDP should be included in the pathological differential diagnosis for sporadic CBS.