Degeneration Of Temporal Lobes Research Articles

Sleep disturbance associated with temporal lobe degeneration in frontotemporal dementia

AbstractBackgroundSleep abnormalities are increasingly recognized as markers and potential drivers of neurodegenerative proteinopathies. However, the sleep phenotype of less common dementias remains poorly characterised. In particular, clinical experience suggests that patients with focal temporal lobe degeneration in the frontotemporal dementia spectrum can experience sometimes striking sleep disruption. We recently had the opportunity to corroborate this clinical impression in a small series of representative patients participating in a larger cohort study.MethodsTo date, we have studied seven patients and three healthy age‐matched controls. The patients’ diagnoses comprise behavioural variant frontotemporal dementia associated with focal right temporal lobe atrophy (n = 3), semantic dementia associated with focal left temporal lobe atrophy (n = 2), young onset Alzheimer’s disease and logopenic aphasia (each n = 1). No participant had a past history of a clinical sleep disorder. Detailed data on sleep patterns, adapted standard sleep questionnaires (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale), overnight oximetry and neuropsychological test scores (covering domains of executive function, emotion processing, memory, and auditory perceptual learning) pre‐/post‐overnight sleep were collected with the assistance of patients’ caregivers.ResultsTwo patients with right temporal lobe atrophy and one with left temporal lobe atrophy had marked sleep fragmentation, in one right temporal case accompanied by frequent sleep attacks, with increased overall time in bed and/or attempting to sleep. Epworth and Pittsburgh indices in these patients indicated significant daytime sleepiness and reduced sleep quality; none had evidence of significant sleep apnoea on overnight oximetry. Comparatively mild clinical sleep disturbances were reported in patients with other dementia diagnoses. However, there was evidence for reduced auditory perceptual learning benefit from overnight sleep relative to healthy older controls, particularly in the patients with underlying Alzheimer pathology.ConclusionsThese preliminary findings suggest that focal temporal lobe degeneration may be associated with clinically relevant sleep disruption, as part of the more pervasive derangement of homeostasis in these syndromes. Further work is indicated to define the hypnic phenotype in detail, with sleep electrophysiology and correlative behavioural, neuroimaging and laboratory data in larger patient cohorts.

Association between basal forebrain and medial temporal lobe tau, and gray matter volume

AbstractBackgroundTau pathology is a hallmark of Alzheimer’s disease (AD). The basal forebrain (BF) is a significant cholinergic projection site with cholinergic groups 1‐3 (Ch1‐3) projecting to the hippocampus, hypothalamus, and olfactory bulb, and group 4 (Ch4) projecting to the cortical mantle and amygdala. Braak stage 1 includes BF tau and recent literature suggests BF degeneration precedes medial temporal lobe (MTL) degeneration, thus implicating early involvement of the BF in AD. This study examines BF 18F‐flortaucipir (FTP) retention and gray matter (GM) volume, and their associations with MTL FTP retention and GM volume.MethodData were acquired for 111 older adults (Table 1) in the Baltimore Longitudinal Study of Aging. Binary masks for BF subregions Ch1‐3 and Ch4 were generated using a probabilistic atlas (Figure 1). We computed mean standardized uptake value ratio (SUVR) using an inferior cerebellar GM reference region and mean GM volume using average voxel‐based morphometry values for each BF subregion. Colocalized relationships between BF tau and volume were assessed using Pearson correlations. Proximal relationships between BF tau/GM and MTL tau/GM were assessed at the voxel level controlling for age, sex, and intracranial volume and corrected for multiple comparisons using non‐parametric permutations.ResultsWithin the BF, FTP‐SUVR in Ch1‐3 was strongly related to FTP‐SUVR in Ch4, and FTP‐SUVR was associated with larger volume in Ch1‐3, but not Ch4 (Figure 2). Voxelwise analyses showed strong BF‐MTL associations with higher Ch1‐3 and Ch4 FTP‐SUVR associated with higher FTP‐SUVR throughout the MTL. The strongest associations were observed anteriorly (amygdala, peri/entorhinal cortices) and medially along the longitudinal axis of the hippocampus/parahippocampal gyrus. Moreover, for both BF Ch groups, larger volume was associated with larger MTL volume. This association was strongest in the amygdala and hippocampal head and body.ConclusionAs expected, BF FTP‐SUVR was positively associated with MTL FTP‐SUVR, and BF volume was positively associated with MTL GM volume, supporting the use of these BF measures. Further analysis is necessary to better understand the positive associations between BF FTP‐SUVR and GM volume and to assess the temporal ordering of FTP‐SUVR accumulation in the BF and MTL.

The eyes speak when the mouth cannot: Using eye movements to interpret omissions in primary progressive aphasia

Though it may seem simple, object naming is a complex multistage process that can be impaired by lesions at various sites of the language network. Individuals with neurodegenerative disorders of language, known as primary progressive aphasias (PPA), have difficulty with naming objects, and instead frequently say “I don't know” or fail to give a vocal response at all, known as an omission. Whereas other types of naming errors (paraphasias) give clues as to which aspects of the language network have been compromised, the mechanisms underlying omissions remain largely unknown. In this study, we used a novel eye tracking approach to probe the cognitive mechanisms of omissions in the logopenic and semantic variants of PPA (PPA-L and PPA-S). For each participant, we identified pictures of common objects (e.g., animals, tools) that they could name aloud correctly, as well as pictures that elicited an omission. In a separate word-to-picture matching task, those pictures appeared as targets embedded among an array with 15 foils. Participants were given a verbal cue and tasked with pointing to the target, while eye movements were monitored. On trials with correctly-named targets, controls and both PPA groups ceased visual search soon after foveating the target. On omission trials, however, the PPA-S group failed to stop searching, and went on to view many foils “post-target”. As further indication of impaired word knowledge, gaze of the PPA-S group was subject to excessive “taxonomic capture”, such that they spent less time viewing the target and more time viewing related foils on omission trials. In contrast, viewing behavior of the PPA-L group was similar to controls on both correctly-named and omission trials. These results indicate that the mechanisms of omission in PPA differ by variant. In PPA-S, anterior temporal lobe degeneration causes taxonomic blurring, such that words from the same category can no longer be reliably distinguished. In PPA-L, word knowledge remains relatively intact, and omissions instead appear to be caused by downstream factors (e.g., lexical access, phonological encoding). These findings demonstrate that when words fail, eye movements can be particularly informative.

Accounting for word production, comprehension, and repetition in semantic dementia, Alzheimer’s dementia, and mild cognitive impairment

It has been known since Pick (1892, 1904) that word retrieval is commonly impaired in left temporal lobe degeneration. Individuals with semantic dementia (SD), Alzheimer’s dementia (AD), and mild cognitive impairment (MCI) present with word retrieval difficulty, while comprehension is less affected and repetition is preserved. Whereas computational models have elucidated performance in poststroke and progressive aphasias, including SD, simulations are lacking for AD and MCI. Here, the WEAVER++/ARC model, which has provided neurocognitive computational accounts of poststroke and progressive aphasias, is extended to AD and MCI. Assuming a loss of activation capacity in semantic memory in SD, AD, and MCI, the simulations showed that severity variation accounts for 99% of the variance in naming, comprehension, and repetition at the group level and 95% at the individual patient level (N = 49). Other plausible assumptions do less well. This supports a unified account of performance in SD, AD, and MCI.

Pathological 25 kDa C-Terminal Fragments of TDP-43 Are Present in Lymphoblastoid Cell Lines and Extracellular Vesicles from Patients Affected by Frontotemporal Lobar Degeneration and Neuronal Ceroidolipofuscinosis Carrying a GRN Mutation.

Frontotemporal lobar degeneration (FTLD) is a complex disease, characterized by progressive degeneration of frontal and temporal lobes. Mutations in progranulin (GRN) gene have been found in up to 50% of patients with familial FTLD. Abnormal deposits of post-translationally-modified TAR DNA-binding protein of 43 kDa (TDP-43) represent one of the main hallmarks of the brain pathology. To investigate in peripheral cells the presence of the different TDP-43 forms, especially the toxic 25 kDa fragments, we analyzed lymphoblastoid cell lines (LCLs) and the derived extracellular vesicles (EVs) from patients carrying a GRN mutation, together with wild-type (WT) healthy controls. After characterizing EV sizes and concentrations by nanoparticle tracking analysis, we investigated the levels of different forms of the TDP-43 protein in LCLs and respective EVs by Western blot. Our results showed a trend of concentration decreasing in EVs derived from GRN-mutated LCLs, although not reaching statistical significance. A general increase in p-TDP-43 levels in GRN-mutated LCLs and EVs was observed. In particular, the toxic 25 kDa fragments of p-TDP-43 were only present in GRN-mutated LCLs and were absent in the WT controls. Furthermore, these fragments appeared to be more concentrated in EVs than in LCLs, suggesting a relevant role of EVs in spreading pathological molecules between cells.

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.

Distinct performance profiles on the Brixton test in frontotemporal dementia

The Brixton Spatial Anticipation Test is a well-established test of executive function that evaluates the capacity to abstract, follow, and switch rules. There has been remarkably little systematic analysis of Brixton test performance in the prototypical neurodegenerative disorder of the frontal lobes: behavioural variant frontotemporal dementia (bvFTD) or evaluation of the test's ability to distinguish frontal from temporal lobe degenerative disease. We carried out a quantitative and qualitative analysis of Brixton performance in 76 patients with bvFTD and 34 with semantic dementia (SD) associated with temporal lobe degeneration. The groups were matched for demographic variables and illness duration. The bvFTD group performed significantly more poorly (U=348, p<.0001, r=.58), 53% of patients scoring in the poor-impaired range compared with 6% of SD patients. Whereas bvFTD patients showed problems in rule acquisition and switching, SD patients did not, despite their impaired conceptual knowledge. Error analysis revealed more frequent perseverative errors in bvFTD, particularly responses unconnected to the stimulus, as well as random responses. Stimulus-bound errors were rare. Within the bvFTD group, there was variation in performance profile, which could not be explained by demographic, neurological, or genetic factors. The findings demonstrate sensitivity and specificity of the Brixton test in identifying frontal lobe degenerative disease and highlight the clinical value of qualitative analysis of test performance. From a theoretical perspective, the findings provide evidence that semantic knowledge and the capacity to acquire rules are dissociable. Moreover, they exemplify the separable functional contributions to executive performance.

Spectrum of Frontotemporal Lobar Degeneration on 18F-FDG PET/CT Scan.

FTLD (Frontotemporal lobar degeneration) is a clinically and pathologically heterogeneous group of degenerative disorders, characterized by predominantly asymmetric degeneration of frontal and temporal lobes with selective neuronal loss and gliosis. The disease presents with variable degrees of impairment in behavior, language, executive control, and motor symptoms with progressive loss of cognition. On the basis of presenting clinical symptoms, FTLD is further divided into behavioral variant, nonfluent/agrammatic variant primary progressive aphasia (PPA), semantic variant PPA, logopenic variant PPA, progressive supranuclear palsy, and corticobasal ganglionic degeneration. Here we illustrate the utility of FDG PET with statistical parametric analysis for evaluation of these patients.

Quantitative EEG Differences in Subtypes of Frontotemporal Dementia

Frontotemporal dementia (FTD) is the second most common group of neurodegenerative disorder following Alzheimer’s Disease (AD); and characterized by degeneration of frontal and/or temporal lobes. FTD can be classified as behavioral variant FTD (bvFTD) and primary progressive aphasia (PPA). The aim of this study is to investigate electrophysiological differences in bvFTD and nonfluent/agrammatic PPA (naPPA), one of three forms of PPA. Twelve patients with bvFTD and 15 patients with naPPA were included in the study. EEG was recorded from 19 electrode sites based on international 10-20 system. Each participant's data were averaged across the recording epochs for each electrode, and the mean absolute power values were computed for delta, theta, beta and alpha frequency bands. For all frequency bands, inter-hemispheric and intrahemispheric coherence was calculated. In absolute power; decreased theta power at all regions was found in bvFTD group as compared to naPPA group. Regarding coherence; increased beta coherence at left centoparietal region and increased alpha coherence at inter-hemispheric frontal region was found in bvFTD as compared to naPPA group. Our findings suggests that subtypes of FTD vary in resting-state EEG especially indexed by the decreased theta power reflecting bvFTD.

Incidence of frontotemporal disorders in Olmsted County: A population-based study

IntroductionFrontotemporal dementia disorders (FTDs) are heterogeneous phenotypical behavioral and language disorders usually associated with frontal and/or temporal lobe degeneration. We investigated their incidence in a population-based cohort. MethodsUsing a records-linkage system, we identified all patients with a diagnostic code for dementia in Olmsted County, MN, 1995–2010, and confirmed the diagnosis of FTD. A behavioral neurologist verified the clinical diagnosis and determined phenotypes. ResultsWe identified 35 FTD cases. Overall, the incidence of FTDs was 4.3/100,000/year (95% CI: 2.9, 5.7). Incidence was higher in men (6.3/100,000, 95% CI 3.6, 9.0) than women (2.9/100,000; 95% CI: 1.3, 4.5); we observed an increased trend over time (B = 0.83, 95% CI: 0.54, 1.11, P < .001). At autopsy, clinical diagnosis was confirmed in eight (72.7%) cases. DiscussionWe observed an increased incidence and trends of FTDs over time. This may reflect a better recognition by clinicians and improvement of clinical criteria and diagnostic tools.

Naming and Knowing Revisited: Eyetracking Correlates of Anomia in Progressive Aphasia.

Progressive naming impairment (i.e., anomia) is a core diagnostic symptom of numerous pathologies that impact anterior and inferior portions of the temporal lobe. For patients who experience such regional temporal lobe degeneration, patterns of language loss often parallel the degradation of semantic memory, an etiology of naming impairment known as semantic anomia. Previous studies of semantic anomia have focused extensively on the output of naming attempts by contrasting errors, omissions, and distortions as a function of item-level characteristics (e.g., prototypicality, semantic category). An alternative approach involves evaluating visual confrontation naming as the naming process unfolds. Techniques with high temporal resolution (e.g., eyetracking) offer a potentially sensitive mode of delineating the locus of impairment during naming. For example, a lexical retrieval disorder would hypothetically elicit normal gaze patterns associated with successful visual object recognition regardless of naming accuracy. In contrast, we hypothesize that semantic anomia would be distinguished by aberrant gaze patterns as a function of reduced top-down conceptually guided search. Here we examined visual object recognition during picture confrontation naming by contrasting gaze patterns time locked to stimulus onset. Patients included a cohort of patients with anomia associated with either primary progressive aphasia (N = 9) or Alzheimer’s disease (N = 1) who attempted to name 200 pictures over the course of 18–24 months. We retrospectively isolated correct and incorrect naming attempts and contrasted gaze patterns for accurate vs. inaccurate attempts to discern whether gaze patterns are predictive of language forgetting. Patients tended to show a lower fixation count, higher saccade count, and slower saccade velocity for items that were named incorrectly. These results hold promise for the utility of eyetracking as a diagnostic and therapeutic index of language functioning.

Detection of Frontotemporal Dementia using Artificial Intelligence Techniques

Atrophy (degeneration) of frontal and temporal lobes in human brain causes a dysfunctionality in Language, Emotion, Executive abilities and these losses are irreversible. If Atrophy is detected at an early age it is beneficial for the patient. A detailed diagnosis of the patient in terms of physical, physiological, psychological and neuropsychological aspects are mandatory to trace the possibility. There is a continuous increase in population of the disease and limited number of specialists. Frontotemporal Dementia (FTD) happens due to the frontal and/or temporal lobe degeneration. The proposed system helps in the identification of the FTD in the brain using various Artificial Intelligence (AI) techniques. The study makes use of the MR brain images for the purpose of the detection of the FTD.

Damage of the temporal lobe and APOE status determine neural compensation in mild cognitive impairment

In mild cognitive impairment (MCI), the APOE4 genotype is associated with accelerated memory decline, likely due to the impact of neuropathology on main cerebral networks required for successful memory retrieval and/or to decreased capacity for recruiting secondary networks that might compensate for that brain damage. Here, we tested this hypothesis in twenty-six healthy older adults and thirty-four MCI patients, of which sixteen were APOE4 carriers. Compared to controls, MCI showed hippocampal volume reduction, cortical thinning in frontal, temporal and parietal regions, and dysfunctional EEG oscillations across fronto-temporal networks. But importantly, APOE4 status was the critical factor in determining the impact of temporal lobe degeneration on memory in MCI individuals. Specifically, path analyses revealed that hippocampal damage in MCI was responsible for memory deterioration in APOE4 carriers, a relationship mediated by the serial intervention of three related factors in noncarriers. Temporal cortical thickness (first mediator) accounted for activation of functional networks through synchronized theta activity across temporal regions (second mediator), which, in turn, coordinated memory reactivation through desynchronized alpha/beta activity across sensorimotor areas (third mediator). Results revealed that, contrary to APOE4-carrier patients, noncarriers are successful in recruiting secondary cortical networks to improve memory performance as long as the integrity and functionality of the temporal lobe is preserved, a fact primarily dependent on hippocampal degeneration.

Laminar degeneration of frontal and temporal cortex in Parkinson disease dementia.

To investigate cortical laminar degeneration in Parkinson's disease (PD) with dementia (PDD). Changes in density of α-synuclein-immunoreactive Lewy bodies (LB), Lewy neurites (LN), and Lewy grains (LG) together with surviving neurons, abnormally enlarged neurons (EN), vacuoles, and glial cell nuclei were measured across cortical laminae of frontal and temporal cortex in fifteen cases of PDD using quantitative methods and polynomial curve-fitting. Most frequently, LB and LN were distributed across all laminae, while LG were distributed in upper cortical laminae. Low densities of EN were present in most cases distributed across all cortical laminae. Densities of vacuoles and glia were greatest in upper and lower cortical laminae, respectively. In most gyri, there were no spatial correlations between the densities of LB, LN, and LG. Cortical degeneration of frontal and temporal lobes in PDD affects all cortical laminae. Laminar distributions may result from the spread of α-synuclein pathology from subcortical regions and subsequent spread via the cortico-cortical pathways. This spread may be a major factor in the development of dementia in PD.

Genetics of FTLD: overview and what else we can expect from genetic studies.

Frontotemporal lobar degeneration (FTLD) comprises a highly heterogeneous group of disorders clinically associated with behavioral and personality changes, language impairment, and deficits in executive functioning, and pathologically associated with degeneration of frontal and temporal lobes. Some patients present with motor symptoms including amyotrophic lateral sclerosis. Genetic research over the past two decades in FTLD families led to the identification of three common FTLD genes (microtubule-associated protein tau, progranulin, and chromosome 9 open reading frame 72) and a small number of rare FTLD genes, explaining the disease in almost all autosomal dominant FTLD families but only a minority of apparently sporadic patients or patients in whom the family history is less clear. Identification of additional FTLD (risk) genes is therefore highly anticipated, especially with theemerging use of next-generation sequencing. Common variants in the transmembrane protein 106 B were identified as a genetic risk factor of FTLD and disease modifier in patients with known mutations. This review summarizes for each FTLD gene what we know about the type and frequency of mutations, their associated clinical and pathological features, and potential disease mechanisms. We also provide an overview of emerging disease pathways encompassing multiple FTLD genes. We further discuss how FTLD specific issues, such as disease heterogeneity, the presence of an unclear family history and the possible role of an oligogenic basis of FTLD, can pose challenges for future FTLD gene identification and risk assessment of specific variants. Finally, we highlight emerging clinical, genetic, and translational research opportunities that lie ahead. Genetic research led to the identification of three common FTLD genes with rare variants (MAPT, GRN, and C9orf72) and a small number of rare genes. Efforts are now ongoing, which aimed at the identification of rare variants with high risk and/or low frequency variants with intermediate effect. Common risk variants have also been identified, such as TMEM106B. This review discusses the current knowledge on FTLD genes and the emerging disease pathways encompassing multiple FTLD genes.

DEFICITS IN VISUAL RECOGNITION MEMORY: A MARKER OF EARLY MESIAL TEMPORAL LOBE DEGENERATION IN NONDEMENTED OUTPATIENTS FROM MEMORY CLINICS?

DEFICITS IN VISUAL RECOGNITION MEMORY: A MARKER OF EARLY MESIAL TEMPORAL LOBE DEGENERATION IN NONDEMENTED OUTPATIENTS FROM MEMORY CLINICS?

Surface errors without semantic impairment in acquired dyslexia: a voxel-based lesion–symptom mapping study

Patients with surface dyslexia have disproportionate difficulty pronouncing irregularly spelled words (e.g. pint), suggesting impaired use of lexical-semantic information to mediate phonological retrieval. Patients with this deficit also make characteristic 'regularization' errors, in which an irregularly spelled word is mispronounced by incorrect application of regular spelling-sound correspondences (e.g. reading plaid as 'played'), indicating over-reliance on sublexical grapheme-phoneme correspondences. We examined the neuroanatomical correlates of this specific error type in 45 patients with left hemisphere chronic stroke. Voxel-based lesion-symptom mapping showed a strong positive relationship between the rate of regularization errors and damage to the posterior half of the left middle temporal gyrus. Semantic deficits on tests of single-word comprehension were generally mild, and these deficits were not correlated with the rate of regularization errors. Furthermore, the deep occipital-temporal white matter locus associated with these mild semantic deficits was distinct from the lesion site associated with regularization errors. Thus, in contrast to patients with surface dyslexia and semantic impairment from anterior temporal lobe degeneration, surface errors in our patients were not related to a semantic deficit. We propose that these patients have an inability to link intact semantic representations with phonological representations. The data provide novel evidence for a post-semantic mechanism mediating the production of surface errors, and suggest that the posterior middle temporal gyrus may compute an intermediate representation linking semantics with phonology.

Phenotypic Heterogeneity of Monogenic Frontotemporal Dementia.

Frontotemporal dementia (FTD) is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment, and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e., the behavioral variant of FTD, the agrammatic variant of primary progressive aphasia, and the semantic variant of PPA. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Genetic studies have identified several genes associated with monogenic FTD: microtubule-associated protein tau, progranulin, TAR DNA-binding protein 43, valosin-containing protein, charged multivesicular body protein 2B, fused in sarcoma, and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological, and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease.

Identification of environmental sounds and melodies in syndromes of anterior temporal lobe degeneration

Recognition of nonverbal sounds in semantic dementia and other syndromes of anterior temporal lobe degeneration may determine clinical symptoms and help to define phenotypic profiles. However, nonverbal auditory semantic function has not been widely studied in these syndromes. Here we investigated semantic processing in two key nonverbal auditory domains – environmental sounds and melodies – in patients with semantic dementia (SD group; n=9) and in patients with anterior temporal lobe atrophy presenting with behavioural decline (TL group; n=7, including four cases with MAPT mutations) in relation to healthy older controls (n=20). We assessed auditory semantic performance in each domain using novel, uniform within-modality neuropsychological procedures that determined sound identification based on semantic classification of sound pairs. Both the SD and TL groups showed comparable overall impairments of environmental sound and melody identification; individual patients generally showed superior identification of environmental sounds than melodies, however relative sparing of melody over environmental sound identification also occurred in both groups. Our findings suggest that nonverbal auditory semantic impairment is a common feature of neurodegenerative syndromes with anterior temporal lobe atrophy. However, the profile of auditory domain involvement varies substantially between individuals.

Investigation of the Role Played by the RNA G-Quadruplex Structure in ALS/FTD Pathology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in motor neuron loss in brain and spinal cord. Frontotemporal dementia (FTD) is one of the most common forms of young onset dementia and second most common form of dementia overall, after Alzheimer's, resulting in degeneration of temporal lobes along with personality changes and language impairment. ALS and FTD are now recognized as members of a broad continuum of neurodegenerative disorders, linked by similar pathology, mechanisms, and overlapping clinical symptoms. Two RNA-binding proteins of interest that link the two diseases are TAR DNA-binding protein 43 (TDP-43) and the fused in sarcoma/translocated in liposarcoma protein (FUS), which are the major protein components in over 90% of ALS and over 50% of FTD inclusions. We hypothesize that the G-quadruplex RNA structure might play an essential role in the pathogenic mechanisms of FUS in ALS and FTD. In this study, the G-quadruplex RNA binding properties of the wild type and C-terminal NLS mutant FUS protein implicated in ALS/FTD will be analyzed.