Assessing network degeneration and phenotypic heterogeneity in genetic frontotemporal lobar degeneration by decoding FDG-PET.

Genetic mutations causative of frontotemporal lobar degeneration (FTLD) are highly predictive of a specific proteinopathy, but there exists substantial inter-individual variability in their patterns of network degeneration and clinical manifestations. We collected clinical and 18Fluorodeoxyglucose-positron emission tomography (FDG-PET) data from 39 patients with genetic FTLD, including 11 carrying the C9orf72 hexanucleotide expansion, 16 carrying a MAPT mutation and 12 carrying a GRN mutation. We performed a spectral covariance decomposition analysis between FDG-PET images to yield unbiased latent patterns reflective of whole brain patterns of metabolism ("eigenbrains" or EBs). We then conducted linear discriminant analyses (LDAs) to perform EB-based predictions of genetic mutation and predominant clinical phenotype (i.e., behavior/personality, language, asymptomatic). Five EBs were significant and explained 58.52 % of the covariance between FDG-PET images. EBs indicative of hypometabolism in left frontotemporal and temporo-parietal areas distinguished GRN mutation carriers from other genetic mutations and were associated with predominant language phenotypes. EBs indicative of hypometabolism in prefrontal and temporopolar areas with a right hemispheric predominance were mostly associated with predominant behavioral phenotypes and distinguished MAPT mutation carriers from other genetic mutations. The LDAs yielded accuracies of 79.5 % and 76.9 % in predicting genetic status and predominant clinical phenotype, respectively. A small number of EBs explained a high proportion of covariance in patterns of network degeneration across FTLD-related genetic mutations. These EBs contained biological information relevant to the variability in the pathophysiological and clinical aspects of genetic FTLD, and for offering valuable guidance in complex clinical decision-making, such as decisions related to genetic testing.

Synaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration.

There is extensive synaptic loss from frontotemporal lobar degeneration, in preclinical models and human in vivo and post mortem studies. Understanding the consequences of synaptic loss for network function is important to support translational models and guide future therapeutic strategies. To examine this relationship, we recruited 55 participants with syndromes associated with frontotemporal lobar degeneration and 24 healthy controls. We measured synaptic density with positron emission tomography using the radioligand [11C]UCB-J, which binds to the presynaptic vesicle glycoprotein SV2A, neurite dispersion with diffusion magnetic resonance imaging, and network function with task-free magnetic resonance imaging functional connectivity. Synaptic density and neurite dispersion in patients was associated with reduced connectivity beyond atrophy. Functional connectivity moderated the relationship between synaptic density and clinical severity. Our findings confirm the importance of synaptic loss in frontotemporal lobar degeneration syndromes, and the resulting effect on behaviour as a function of abnormal connectivity.

Retinal photoreceptor layer thickness has disease specificity and distinguishes predicted FTLD-Tau from biomarker-determined Alzheimer's disease.

While Alzheimer's disease (AD) is associated with inner retina thinning (retinal nerve fiber layer and ganglion cell layer), we have observed photoreceptor outer nuclear layer (ONL) thinning in patients with frontotemporal lobar degeneration tauopathy (FTLD-Tau) compared to normal controls. We hypothesized that ONL thinning may distinguish FTLD-Tau from patients with biomarker evidence of AD neuropathologic change (ADNC) and will correlate with FTLD-Tau disease severity. Predicted FTLD-Tau (pFTLD-Tau; n = 21; 33 eyes) and predicted ADNC (pADNC; n = 24; 46 eyes) patients were consecutively enrolled, underwent optical coherence tomography macula imaging, and disease was categorized (pFTLD-Tau vs. pADNC) with cerebrospinal fluid biomarkers, genetic testing, and autopsy data when available. Adjusting for age, sex, and race, pFTLD-Tau patients had a thinner ONL compared to pADNC, while retinal nerve fiber layer and ganglion cell layer were not significantly different. Reduced ONL thickness correlated with worse performance on Folstein Mini-Mental State Examination and clinical dementia rating plus frontotemporal dementia sum of boxes for pFTLD-Tau but not pADNC. Photoreceptor ONL thickness may serve as an important noninvasive diagnostic marker that distinguishes FTLD-Tau from AD neuropathologic change.

Association of cortical and subcortical microstructure with disease severity: impact on cognitive decline and language impairments in frontotemporal lobar degeneration.

BACKGROUND: Cortical and subcortical microstructural modifications are critical to understanding the pathogenic changes in frontotemporal lobar degeneration (FTLD) subtypes. In this study, we investigated cortical and subcortical microstructure underlying cognitive and language impairments across behavioral variant of frontotemporal dementia (bvFTD), semantic variant of primary progressive aphasia (svPPA), and nonfluent variant of primary progressive aphasia (nfvPPA) subtypes. METHODS: The current study characterized 170 individuals with 3 T MRI structural and diffusion-weighted imaging sequences as portion of the Frontotemporal Lobar Degeneration Neuroimaging Initiative study: 41 bvFTD, 35 nfvPPA, 34 svPPA, and 60 age-matched cognitively unimpaired controls. To determine the severity of the disease, clinical dementia rating plus national Alzheimer's coordinating center behavior and language domains sum of boxes scores were used; other clinical measures, including the Boston naming test and verbal fluency test, were also evaluated. We computed surface-based cortical thickness and cortical and subcortical microstructural metrics using tract-based spatial statistics and explored their relationships with clinical and cognitive assessments. RESULTS: Compared with controls, those with FTLD showed substantial cortical mean diffusivity alterations extending outside the regions with cortical thinning. Tract-based spatial statistics revealed that anomalies in subcortical white matter diffusion were widely distributed across the frontotemporal and parietal areas. Patients with bvFTD, nfvPPA, and svPPA exhibited distinct patterns of cortical and subcortical microstructural abnormalities, which appeared to correlate with disease severity, and separate dimensions of language functions. CONCLUSIONS: Our findings imply that cortical and subcortical microstructures may serve as sensitive biomarkers for the investigation of neurodegeneration-associated microstructural alterations in FTLD subtypes. Flowchart of the study design (see materials and methods for detailed description).

Awareness impairment in Alzheimer's disease and frontotemporal dementia: a systematic MRI review.

This review aims to define awareness impairment and related disturbances in neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) spectrum of disorders. An update of the available scientific literature on the use of magnetic resonance imaging (MRI) in the study of awareness in these disorders is also offered. MRI plays an important role in the characterization of neurodegenerative signatures and can increase our knowledge on brain structural and functional correlates of awareness. In the reviewing process, we established a-priori criteria and we searched the scientific literature for relevant articles on this topic. In summary, we selected 36 articles out of 1340 publications retrieved from PubMed. Based on this selection, this review discusses the multiple terms used to define different or overlapping aspects of awareness impairment, and specifically summarizes recent application of MRI for investigating anosognosia, social cognition, including theory of mind and emotional processing, free will, and autonoetic awareness alterations in different neurodegenerative disorders, with most of these studies focused on AD and FTLD. This systematic review highlights the importance of awareness impairment and related domains in neurodegenerative disorders, especially in AD and FTLD, and it outlines MRI structural and functional correlates in these populations.

Event-based modeling of T1-weighted MRI is related to pathology in frontotemporal lobar degeneration due to tau and TDP.

BACKGROUND: In previous studies of patients with frontotemporal lobar degeneration due to tau (FTLD-tau) and FTLD due to TDP (FTLD-TDP), cortical volumes derived from T1-weighted MRI have been used to identify a sequence of volume loss according to arbitrary volumetric criteria. Event-based modeling (EBM) is a probabilistic, generative machine learning model that determines the characteristic sequence of changes, or "events", occurring during disease progression. EBM also estimates an individual patient's disease "stage" by identifying which events have already occurred. In the present study, we use an EBM analysis to derive stages of regional anatomic atrophy in FTLD-tau and FTLD-TDP, and validated these stages against pathologic burden. METHODS: Sporadic autopsy-confirmed patients with FTLD-tau (N = 42) and FTLD-TDP (N = 21), and 167 healthy controls with available T1-weighted images were identified. A subset of patients had quantitative digital histopathology of cortex performed at autopsy (FTLD-tau = 30, FTLD-TDP = 17). MRI images were processed, producing regional measures of cortical volumes. K-means clustering was used to find cortical regions with similar amounts of GM volume changes (n = 5 clusters). EBM was used to determine the characteristic sequence of cortical atrophy of identified clusters in autopsy-confirmed FTLD-tau and FTLD-TDP, and estimate each patient's disease stage by cortical volume biomarkers. Linear regressions related pathologic burden to EBM-estimated disease stages. RESULTS: EBM for cortical volume biomarkers generated statistically robust characteristic sequences of cortical atrophy in each group of patients. Cortical volume-based EBM-estimated disease stage was associated with pathologic burden in FTLD-tau (R2 = 0.16, p = 0.017) and FTLD-TDP (R2 = 0.51, p = 0.0008). CONCLUSIONS: We provide evidence that EBM can identify sequences of pathologically-confirmed cortical atrophy in sporadic FTLD-tau and FTLD-TDP.

Clinical, radiologic, and pathologic features of the globular glial tauopathy subtype of frontotemporal lobar degeneration in right temporal variant frontotemporal dementia with salient features of Geschwind syndrome.

Globular Glial Tauopathy (GGT) is a rare form of Frontotemporal Lobar Degeneration (FTLD) consisting of 4-repeat tau globular inclusions in astrocytes and oligodendrocytes. We present the pathological findings of GGT in a previously published case of a 73-year-old woman with behavioral symptoms concerning for right temporal variant frontotemporal dementia with initial and salient features of Geschwind syndrome. Clinically, she lacked motor abnormalities otherwise common in previously published GGT cases. Brain MRI showed focal right anterior temporal atrophy (indistinguishable from five FTLD-TDP cases) and subtle ipsilateral white matter signal abnormalities. Brain autopsy showed GGT type III and Alzheimer's neuropathologic changes. .

Optimum Differentiation of Frontotemporal Lobar Degeneration from Alzheimer Disease Achieved with Cross-Sectional Tau Positron Emission Tomography.

OBJECTIVE: This study was undertaken to assess cross-sectional and longitudinal [18 F]-flortaucipir positron emission tomography (PET) uptake in pathologically confirmed frontotemporal lobar degeneration (FTLD) and to compare FTLD to cases with high and low levels of Alzheimer disease (AD) neuropathologic changes (ADNC). METHODS: One hundred forty-three participants who had completed at least one flortaucipir PET and had autopsy-confirmed FTLD (n = 52) or high (n = 58) or low ADNC (n = 33) based on Braak neurofibrillary tangle stages 0-IV versus V-VI were included. Flortaucipir standard uptake value ratios (SUVRs) were calculated for 9 regions of interest (ROIs): an FTLD meta-ROI, midbrain, globus pallidum, an AD meta-ROI, entorhinal, inferior temporal, orbitofrontal, precentral, and medial parietal. Linear mixed effects models were used to compare mean baseline SUVRs and annual rate of change in SUVR by group. Sensitivity and specificity to distinguish FTLD from high and low ADNC were calculated. RESULTS: Baseline uptake in the FTLD meta-ROI, midbrain, and globus pallidus was greater in FTLD than high and low ADNC. No region showed a greater rate of flortaucipir accumulation in FTLD. Baseline uptake in the AD-related regions and orbitofrontal and precentral cortices was greater in high ADNC, and all showed greater rates of accumulation compared to FTLD. Baseline differences were superior to longitudinal rates in differentiating FTLD from high and low ADNC. A simple baseline metric of midbrain/inferior temporal ratio of flortaucipir uptake provided good to excellent differentiation between FTLD and high and low ADNC (sensitivities/specificities = 94%/95% and 71%/70%). INTERPRETATION: There are cross-sectional and longitudinal differences in flortaucipir uptake between FTLD and high and low ADNC. However, optimum differentiation between FTLD and ADNC was achieved with baseline uptake rather than longitudinal rates. ANN NEUROL 2022;92:1016-1029.

Relationship between CSF tau biomarkers and structural brain MRI measures in frontotemporal lobar degeneration.

BACKGROUND: Recently in the field neurodegenerative diseases increasing attention has been pointed to CSF biomarkers and their integration with neuroimaging (1). Frontotemporal lobar degeneration (FTLD) refers to a heterogeneous group of clinical syndromes with different underlying proteinopathies including tau pathology. CSF biomarkers have been proposed as diagnostic and prognostic factors. Aim of our study was to evaluate the relationship between CSF tau biomarkers and structural MRI brain measures in FTLD. METHODS: We included early FTLD patient. All included patients underwent lumbar puncture to evaluate amyloid, total-tau (t-tau), phospho-tau 181 (p-tau); p-tau/t-tau ratio was also calculated; brain MRI was performed to estimate whole brain volume, volume of principal deep grey matter structures and regional cortical thickness. RESULTS: Demographic characteristics of the 28 included patients were as follows: female/male: 9/19; mean ± SD age: 68.1 ± 7.8 years. The p-tau/t-tau ratio was significantly correlated with whole brain volume (r = 0.69; p: 0.001), left putamen volume (r = 0.55 p: 0.009), left pallidum volume (r = 0.41; p: 0.01), right accumbens area (r = 0.47; p: 0.02). P-tau/t tau ratio showed also a significant correlation with cortical thickness of left temporal lobe (r = 0.74; p: 0.001) and right lateral orbital frontal cortex (r = 0.45; p: 0.03). Linear regression showed a significant relationship between p-tau/t-tau ratio and left temporal pole (p = 0.01; r2: 0.60) and brain volume (p:0.002; r2: 0.56) after controlling for age and gender. CONCLUSIONS: Our data suggest that CSF biomarkers, especially p-tau/t-tau ratio, could play a role as prognostic factor in FTLD. Further longitudinal investigations are needed to confirm these findings.

Right temporal degeneration and socioemotional semantics: semantic behavioural variant frontotemporal dementia.

Focal anterior temporal lobe degeneration often preferentially affects the left or right hemisphere. While patients with left-predominant anterior temporal lobe atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia and semantic dementia, patients with early right anterior temporal lobe atrophy are more difficult to diagnose as their symptoms are less well understood. Focal right anterior temporal lobe atrophy is associated with prominent emotional and behavioural changes, and patients often meet, or go on to meet, criteria for behavioural variant frontotemporal dementia. Uncertainty around early symptoms and absence of an overarching clinico-anatomical framework continue to hinder proper diagnosis and care of patients with right anterior temporal lobe disease. Here, we examine a large, well-characterized, longitudinal cohort of patients with right anterior temporal lobe-predominant degeneration and propose new criteria and nosology. We identified individuals from our database with a clinical diagnosis of behavioural variant frontotemporal dementia or semantic variant primary progressive aphasia and a structural MRI (n = 478). On the basis of neuroimaging criteria, we defined three patient groups: right anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 46), frontal-predominant atrophy with relative sparing of the right anterior temporal lobe (n = 79) and left-predominant anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 75). We compared the clinical, neuropsychological, genetic and pathological profiles of these groups. In the right anterior temporal lobe-predominant group, the earliest symptoms were loss of empathy (27%), person-specific semantic impairment (23%) and complex compulsions and rigid thought process (18%). On testing, this group exhibited greater impairments in Emotional Theory of Mind, recognition of famous people (from names and faces) and facial affect naming (despite preserved face perception) than the frontal- and left-predominant anterior temporal lobe-predominant groups. The clinical symptoms in the first 3 years of the disease alone were highly sensitive (81%) and specific (84%) differentiating right anterior temporal lobe-predominant from frontal-predominant groups. Frontotemporal lobar degeneration-transactive response DNA binding protein (84%) was the most common pathology of the right anterior temporal lobe-predominant group. Right anterior temporal lobe-predominant degeneration is characterized by early loss of empathy and person-specific knowledge, deficits that are caused by progressive decline in semantic memory for concepts of socioemotional relevance. Guided by our results, we outline new diagnostic criteria and propose the name, 'semantic behavioural variant frontotemporal dementia', which highlights the underlying cognitive mechanism and the predominant symptomatology. These diagnostic criteria will facilitate early identification and care of patients with early, focal right anterior temporal lobe degeneration as well as in vivo prediction of frontotemporal lobar degeneration-transactive response DNA binding protein pathology.

Phases of volume loss in patients with known frontotemporal lobar degeneration spectrum pathology.

Frontotemporal lobar degeneration (FTLD) includes clinically similar FTLD-tau or FTLD-TDP proteinopathies which lack in vivo markers for accurate antemortem diagnosis. To identify early distinguishing sites of cortical atrophy between groups, we retrospectively analyzed in vivo volumetric MRI from 42 FTLD-Tau and 21 FTLD-TDP patients and validated these findings with postmortem measures of pathological burden. Our frequency-based staging model revealed distinct loci of maximal early cortical atrophy in each group, including dorsolateral and medial frontal regions in FTLD-Tau and ventral frontal and anterior temporal regions in FTLD-TDP. Sørenson-Dice calculations between proteinopathy groups showed little overlap of phases. Conversely, within-group subtypes showed good overlap between 3R- and 4R-tauopathies, and between TDP-43 Types A and C for early regions with subtle divergence between subtypes in subsequent phases of atrophy. Postmortem validation found an association of imaging phases with pathologic burden within FTLD-tau (F(4, 238) = 17.44, p < 0.001) and FTLD-TDP (F(4,245) = 42.32, p < 0.001). These results suggest that relatively early, distinct markers of atrophy may distinguish FTLD proteinopathies during life.

The changing landscape of neuroimaging in frontotemporal lobar degeneration: from group-level observations to single-subject data interpretation.

INTRODUCTION: While the imaging signatures of frontotemporal lobar degeneration (FTLD) phenotypes and genotypes are well-characterized based on group-level descriptive analyses, the meaningful interpretation of single MRI scans remains challenging. Single-subject MRI classification frameworks rely on complex computational models and large training datasets to categorize individual patients into diagnostic subgroups based on distinguishing imaging features. Reliable individual subject data interpretation is hugely important in the clinical setting to expedite the diagnosis and classify individuals into relevant prognostic categories. AREAS COVERED: This article reviews (1) single-subject MRI classification strategies in symptomatic and pre-symptomatic FTLD, (2) practical clinical implications, and (3) the limitations of current single-subject data interpretation models. EXPERT OPINION: Classification studies in FTLD have demonstrated the feasibility of categorizing individual subjects into diagnostic groups based on multiparametric imaging data. Preliminary data indicate that pre-symptomatic FTLD mutation carriers may also be reliably distinguished from controls. Despite momentous advances in the field, significant further improvements are needed before these models can be developed into viable clinical applications.

TDP-43-associated atrophy in brains with and without frontotemporal lobar degeneration.

Transactive response DNA-binding protein of ∼43 kDa (TDP-43), a primary pathologic substrate in tau-negative frontotemporal lobar degeneration (FTLD), is also often found in the brains of elderly individuals without FTLD and is a key player in the process of neurodegeneration in brains with and without FTLD. It is unknown how rates and trajectories of TDP-43-associated brain atrophy compare between these two groups. Additionally, non-FTLD TDP-43 inclusions are not homogeneous and can be divided into two morphologic types: type-α and neurofibrillary tangle-associated type-ß. Therefore, we explored whether neurodegeneration also varies due to the morphologic type. In this longitudinal retrospective study of 293 patients with 843 MRI scans spanning over ∼10 years, we used a Bayesian hierarchical linear model to quantify similarities and differences between the non-FTLD TDP-43 (type-α/type-ß) and FTLD-TDP (n = 68) in both regional volume at various timepoints before death and annualized rate of atrophy. Since Alzheimer's disease (AD) is a frequent co-pathology in non-FTLD TDP-43, we further divided types α/ß based on presence/absence of intermediate-high likelihood AD: AD-TDP type-ß (n = 90), AD-TDP type-α (n = 104), and Pure-TDP (n = 31, all type-α). FTLD-TDP was associated with faster atrophy rates in the inferior temporal lobe and temporal pole compared to all non-FTLD TDP-43 groups. The atrophy rate in the frontal lobe was modulated by age with younger FTLD-TDP having the fastest rates. Older FTLD-TDP showed a limbic predominant pattern of neurodegeneration. AD-TDP type-α showed faster rates of hippocampal atrophy and smaller volumes of amygdala, temporal pole, and inferior temporal lobe compared to AD-TDP type-ß. Pure-TDP was associated with slowest rates and less atrophy in all brain regions. The results suggest that there are differences and similarities in longitudinal brain volume loss between FTLD-TDP and non-FTLD TDP-43. Within FTLD-TDP age plays a role in which brain regions are the most affected. Additionally, brain atrophy regional rates also vary by non-FTLD TDP-43 type.

Ex vivo MRI and histopathology detect novel iron-rich cortical inflammation in frontotemporal lobar degeneration with tau versus TDP-43 pathology.

Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging therapeutic trials tailored to disease-specific mechanisms. Moreover, MRI-derived measures have had limited success to date discriminating between FTLD-Tau or FTLD-TDP. T2*-weighted (T2*w) ex vivo MRI has previously been shown to be sensitive to non-heme iron in healthy intracortical lamination and myelin, and to pathological iron deposits in amyloid-beta plaques and activated microglia in Alzheimer's disease neuropathologic change (ADNC). However, an integrated, ex vivo MRI and histopathology approach is understudied in FTLD. We apply joint, whole-hemisphere ex vivo MRI at 7 T and histopathology to the study autopsy-confirmed FTLD-Tau (n = 4) and FTLD-TDP (n = 3), relative to ADNC disease-control brains with antemortem clinical symptoms of frontotemporal dementia (n = 2), and an age-matched healthy control. We detect distinct laminar patterns of novel iron-laden glial pathology in both FTLD-Tau and FTLD-TDP brains. We find iron-positive ameboid and hypertrophic microglia and astrocytes largely in deeper GM and adjacent WM in FTLD-Tau. In contrast, FTLD-TDP presents prominent superficial cortical layer iron reactivity in astrocytic processes enveloping small blood vessels with limited involvement of adjacent WM, as well as more diffuse distribution of punctate iron-rich dystrophic microglial processes across all GM lamina. This integrated MRI/histopathology approach reveals ex vivo MRI features that are consistent with these pathological observations distinguishing FTLD-Tau and FTLD-TDP subtypes, including prominent irregular hypointense signal in deeper cortex in FTLD-Tau whereas FTLD-TDP showed upper cortical layer hypointense bands and diffuse cortical speckling. Moreover, differences in adjacent WM degeneration and iron-rich gliosis on histology between FTLD-Tau and FTLD-TDP were also readily apparent on MRI as hyperintense signal and irregular areas of hypointensity, respectively that were more prominent in FTLD-Tau compared to FTLD-TDP. These unique histopathological and radiographic features were distinct from healthy control and ADNC brains, suggesting that iron-sensitive T2*w MRI, adapted to in vivo application at sufficient resolution, may eventually offer an opportunity to improve antemortem diagnosis of FTLD proteinopathies using tissue-validated methods.

Social cognition in the FTLD spectrum: evidence from MRI.

Over the past few years, there has been great interest in social cognition, a wide term referring to the human ability of understanding others' emotions, thoughts, and intentions, to empathize with them and to behave accordingly. While there is no agreement on the classification of social cognitive processes, they can broadly be categorized as consisting of theory of mind, empathy, social perception, and social behavior. The study of social cognition and its relative deficits is increasingly assuming clinical relevance. However, the clinical and neuroanatomical correlates of social cognitive alterations in neurodegenerative conditions, such as those belonging to the frontotemporal lobar (FTLD) spectrum, are not fully established. In this review, we describe the current understanding of social cognition impairments in different FTLD conditions with respect to MRI.

Intracortical diffusion tensor imaging signature of microstructural changes in frontotemporal lobar degeneration.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a neuropathological construct with multiple clinical presentations, including the behavioural variant of frontotemporal dementia (bvFTD), primary progressive aphasia-both non-fluent variant (nfvPPA) and semantic variant (svPPA)-progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), characterised by the deposition of abnormal tau protein in the brain. A major challenge for treating FTLD is early diagnosis and accurate discrimination among different syndromes. The main goal here was to investigate the cortical architecture of FTLD syndromes using cortical diffusion tensor imaging (DTI) analysis and to test its power to discriminate between different clinical presentations. METHODS: A total of 271 individuals were included in the study: 87 healthy subjects (HS), 31 semantic variant primary progressive aphasia (svPPA), 37 behavioural variant (bvFTD), 30 non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), 47 PSP Richardson's syndrome (PSP-RS) and 39 CBS cases. 3T MRI T1-weighted images and DTI scans were analysed to extract three cortical DTI derived measures (AngleR, PerpPD and ParlPD) and mean diffusivity (MD), as well as standard volumetric measurements. Whole brain and regional data were extracted. Linear discriminant analysis was used to assess the group discrimination capability of volumetric and DTI measures to differentiate the FTLD syndromes. In addition, in order to further investigate differential diagnosis in CBS and PSP-RS, a subgroup of subjects with autopsy confirmation in the training cohort was used to select features which were then tested in the test cohort. Three different challenges were explored: a binary classification (controls vs all patients), a multiclass classification (HS vs bvFTD vs svPPA vs nfvPPA vs CBS vs PSP-RS) and an additional binary classification to differentiate CBS and PSP-RS using features selected in an autopsy confirmed subcohort. RESULTS: Linear discriminant analysis revealed that PerpPD was the best feature to distinguish between controls and all patients (ACC 86%). PerpPD regional values were able to classify correctly the different FTLD syndromes with an accuracy of 85.6%. The PerpPD and volumetric values selected to differentiate CBS and PSP-RS patients showed a classification accuracy of 85.2%. CONCLUSIONS: (I) PerpPD achieved the highest classification power for differentiating healthy controls and FTLD syndromes and FTLD syndromes among themselves. (II) PerpPD regional values could provide an additional marker to differentiate FTD, PSP-RS and CBS.

Structural MRI Signatures in Genetic Presentations of the Frontotemporal Dementia/Motor Neuron Disease Spectrum.

BACKGROUND AND OBJECTIVES: To assess cortical, subcortical, and cerebellar gray matter (GM) atrophy using MRI in patients with disorders of the frontotemporal lobar degeneration (FTLD) spectrum with known genetic mutations. METHODS: Sixty-six patients carrying FTLD-related mutations were enrolled, including 44 with pure motor neuron disease (MND) and 22 with frontotemporal dementia (FTD). Sixty-one patients with sporadic FTLD (sFTLD) matched for age, sex, and disease severity with genetic FTLD (gFTLD) were also included, as well as 52 healthy controls. A whole-brain voxel-based morphometry (VBM) analysis was performed. GM volumes of subcortical and cerebellar structures were obtained. RESULTS: Compared with controls, GM atrophy on VBM was greater and more diffuse in genetic FTD, followed by sporadic FTD and genetic MND cases, whereas patients with sporadic MND (sMND) showed focal motor cortical atrophy. Patients carrying C9orf72 and GRN mutations showed the most widespread cortical volume loss, in contrast with GM sparing in SOD1 and TARDBP. Globally, patients with gFTLD showed greater atrophy of parietal cortices and thalami compared with sFTLD. In volumetric analysis, patients with gFTLD showed volume loss compared with sFTLD in the caudate nuclei and thalami, in particular comparing C9-MND with sMND cases. In the cerebellum, patients with gFTLD showed greater atrophy of the right lobule VIIb than sFTLD. Thalamic volumes of patients with gFTLD with a C9orf72 mutation showed an inverse correlation with Frontal Behavioral Inventory scores. DISCUSSION: Measures of deep GM and cerebellar structural involvement may be useful markers of gFTLD, particularly C9orf72-related disorders, regardless of the clinical presentation within the FTLD spectrum.

Amyotrophic lateral sclerosis features predict TDP-43 pathology in frontotemporal lobar degeneration.

Clinical and pathological heterogeneity is common in patients with frontotemporal lobar degeneration (FTLD) pathology. This investigated clinical or imaging characteristics that differentiate FTLD-TDP from FTLD-tau, FTLD-TDP subtypes from each other, or pathological stages of FTLD-TDP. Initial clinical, neuropsychological and neuroimaging characteristics were compared between pathologically defined FTLD-tau and FTLD-TDP groups. Voxel-based morphometry analyses contrasted grey matter atrophy patterns. Twenty-six FTLD-TDP, 28 FTLD-tau and 78 controls were included. Amyotrophic lateral sclerosis features, when present, were highly specific FTLD-TDP, which displayed greater cortical and subcortical atrophy than FTLD-tau. FTLD-TDP-43 type B had significantly shorter survival than type A. Type A patients were more cognitively impaired than type B, and basal ganglia atrophy appeared to distinguish type A from type B. Age at onset and survival duration were comparable between stages II and IV. In conclusion, Amyotrophic lateral sclerosis features may be useful in distinguishing FTLD-TDP from FTLD-tau. TDP-43 type A and B appear to present with distinct profiles. The relationship between clinical features and pathological staging in FTLD-TDP-43 is complex, and TDP-43 subtyping may have more clinical utility.