Behavioral variant frontotemporal dementia (bvFTD) is the second leading cognitive disorder caused by neurodegeneration in patients under 65 years of age. Characterized by frontal, insular, and/or ...temporal brain atrophy, patients present with heterogeneous constellations of behavioral and psychological symptoms among which progressive changes in social conduct, lack of empathy, apathy, disinhibited behaviors, and cognitive impairments are frequently observed. Since the histopathology of the disease is heterogeneous and identified genetic mutations only account for ~30% of cases, there are no reliable biomarkers for the diagnosis of bvFTD available in clinical routine as yet. Early detection of bvFTD thus relies on correct application of clinical diagnostic criteria. Their evaluation however, requires expertise and in-depth assessments of cognitive functions, history taking, clinical observations as well as caregiver reports on behavioral and psychological symptoms and their respective changes. With this review, we aim for a critical appraisal of common methods to access the behavioral and psychological symptoms as well as the cognitive alterations presented in the diagnostic criteria for bvFTD. We highlight both, practical difficulties as well as current controversies regarding an overlap of symptoms and particularly cognitive impairments with other neurodegenerative and primary psychiatric diseases. We then review more recent developments and evidence on cognitive, behavioral and psychological symptoms of bvFTD beyond the diagnostic criteria which may prospectively enhance the early detection and differential diagnosis in clinical routine. In particular, evidence on specific impairments in social and emotional processing, praxis abilities as well as interoceptive processing in bvFTD is summarized and potential links with behavior and classic cognitive domains are discussed. We finally outline both, future opportunities and major challenges with regard to the role of clinical neuropsychology in detecting bvFTD and related neurocognitive disorders.
Many choice situations require imagining potential outcomes, a capacity that was shown to involve memory brain regions such as the hippocampus. We reasoned that the quality of hippocampus-mediated ...simulation might therefore condition the subjective value assigned to imagined outcomes. We developed a novel paradigm to assess the impact of hippocampus structure and function on the propensity to favor imagined outcomes in the context of intertemporal choices. The ecological condition opposed immediate options presented as pictures (hence directly observable) to delayed options presented as texts (hence requiring mental stimulation). To avoid confounding simulation process with delay discounting, we compared this ecological condition to control conditions using the same temporal labels while keeping constant the presentation mode. Behavioral data showed that participants who imagined future options with greater details rated them as more likeable. Functional MRI data confirmed that hippocampus activity could account for subjects assigning higher values to simulated options. Structural MRI data suggested that grey matter density was a significant predictor of hippocampus activation, and therefore of the propensity to favor simulated options. Conversely, patients with hippocampus atrophy due to Alzheimer's disease, but not patients with Fronto-Temporal Dementia, were less inclined to favor options that required mental simulation. We conclude that hippocampus-mediated simulation plays a critical role in providing the motivation to pursue goals that are not present to our senses.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective: The frontal variant of frontotemporal degeneration (fvFTD) is characterized by a predominant behavioral syndrome, which is mostly attributable to an orbital-medial prefrontal dysfunction. ...The orbital and ventral medial prefrontal functions in humans are difficult to assess in clinical practice. Here, we propose a new tool, the SEA (Social cognition and Emotional Assessment), for use in evaluating the functions of the orbital and ventral-medial portions of the prefrontal cortex. Method: The SEA is composed of five subtests, each assessing a specific orbitofrontal-related function: a test of identification of facial emotions, a reversal/extinction task, a behavioral control task, a theory of mind test, and an apathy scale. The maximum score is 55. Three groups have been tested: 22 fvFTD patients, 22 patients with Alzheimer's disease (AD) or amnesic mild cognitive impairment (aMCI), and 30 healthy control subjects, all matched for age and educational level. Results: FvFTD patients showed significantly lower performances in all subtests of the SEA. A cut-off score of 39.4/55 was proposed to separate normal controls from fvFTD patients, with a maximum sensitivity and specificity of 100%. A very high specificity (88.5%) was obtained using the same cut-off with AD/aMCI patients and normal controls versus fvFTD patients. FvFTD patients' performance in the SEA did not correlate with any other neuropsychological scores, particularly the classical cognitive executive tests. Conclusions: The SEA is a new and useful tool for diagnosing fvFTD and, more generally, all of the diseases affecting the orbital and medial prefrontal functions.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
Behavioural variant of frontotemporal dementia (bvFTD) is a neurodegenerative disease that is clinically characterised by progressive behavioural changes and social interpersonal dysfunctions. Its ...diagnosis remains a clinical challenge, and depression is one of the main causes of misdiagnoses due to the prevalence of apathy in bvFTD.
To evaluate the sensitivity and specificity of the Social Cognition and Emotional Assessment (SEA) and the mini-SEA for differentiating bvFTD from major depressive disorder (MDD).
Scores for the SEA and mini-SEA for 37 patients with bvFTD (divided into subgroups of 17 with early bvFTD and 20 with moderate bvFTD according to the normal range of the Mattis Dementia Rating Scale), 19 MDD patients and 30 control subjects were compared to define the discrimination power of these tools compared with other standard neuropsychological tests.
SEA and mini-SEA scores were significantly lower for both the early and moderate bvFTD groups compared with control subjects and the MDD group, and very few scores overlapped between patients in the bvFTD subgroups and patients in the MDD and control subgroups. SEA and mini-SEA scores distinguished early bvFTD from MDD with sensitivity and specificity rates above 94%.
Unlike standard executive neuropsychological tests, SEA and the mini-SEA can differentiate MDD from bvFTD in the early stages of the disease. The mini-SEA is an easy tool that can be utilised in neurological or psychiatric departments.
Measuring the morphology of brain sulci has been recently proposed as a novel imaging approach in Alzheimer's disease (AD). We aimed to investigate the relevance of such an approach in AD, by ...exploring its (1) clinical relevance in comparison with traditional imaging methods, (2) relationship with amyloid deposition, (3) association with cognitive functions. Here, 51 patients (n = 32 mild cognitive impairment/mild dementia-AD, n = 19 moderate/severe dementia-AD) diagnosed according to clinical-biological criteria (CSF biomarkers and amyloid-PET) and 29 controls (with negative amyloid-PET) underwent neuropsychological and 3T-MRI examinations. Mean sulcal width (SW) and mean cortical thickness around the sulcus (CT-S) were automatically measured. We found higher SW and lower CT-S in patients with AD than in controls. These differences were more pronounced at later stages of the disease and provided the best diagnostic accuracies among the imaging markers. Correlations were not found between CT-S or SW and amyloid deposition but between specific cognitive functions and regional CT-S/SW in key associated regions. Sulcal morphology is a good supporting diagnosis tool that reflects the main cognitive impairments in AD. It could be considered as a good surrogate marker to evaluate the efficacy of new drugs.
•Examination of sulcal morphology alterations is a good diagnosis tool for Alzheimer's disease.•This imaging marker is more accurate than traditional imaging tools such as hippocampal volume.•Sulcal morphology alterations are correlated to specific cognitive impairment observed.•Sulcal morphology alterations are related to disease severity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Whether theory of mind (ToM) is preserved in Alzheimer's disease (AD) remains a controversial subject. Recent studies have showed that performance on some ToM tests might be altered in AD, though to ...a lesser extent than in behavioural-variant Frontotemporal Dementia (bvFTD). It is however, unclear if this reflects a genuine impairment of ToM or a deficit secondary to the general cognitive decline observed in AD. Aiming to investigate the cognitive determinants of ToM performance in AD, a data-mining study was conducted in 29 AD patients then replicated in an independent age-matched group of 19 AD patients to perform an independent replication of the results. 44 bvFTD patients were included as a comparison group. All patients had an extensive neuropsychological examination. Hierarchical clustering analyses showed that ToM performance clustered with measures of executive functioning (EF) in AD. ToM performance was also specifically correlated with the executive component extracted from a principal component analysis. In a final step, automated linear modelling conducted to determine the predictors of ToM performance showed that 48.8% of ToM performance was significantly predicted by executive measures. Similar findings across analyses were observed in the independent group of AD patients, thereby replicating our results. Conversely, ToM impairments in bvFTD appeared independent of other cognitive impairments. These results suggest that difficulties of AD patients on ToM tests do not reflect a genuine ToM deficit, rather mediated by general (and particularly executive) cognitive decline. They also suggest that EF has a key role in mental state attribution, which support interacting models of ToM functioning. Finally, our study highlights the relevancy of data-mining statistical approaches in clinical and cognitive neurosciences.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Due to heterogeneous clinical presentation, difficult differential diagnosis with Alzheimer's disease (AD) and psychiatric disorders, and evolving clinical criteria, the epidemiology and natural ...history of frontotemporal lobar degeneration (FTD) remain elusive. In order to better characterize FTD patients, we relied on the database of a regional memory clinic network with standardized diagnostic procedures and chose AD patients as a comparator.
Patients that were first referred to our network between January 2010 and December 2016 and whose last clinical diagnosis was degenerative or vascular dementia were included. Comparisons were conducted between FTD and AD as well as between the different FTD syndromes, divided into language variants (lvFTD), behavioral variant (bvFTD), and FTD with primarily motor symptoms (mFTD). Cognitive progression was estimated with the yearly decline in Mini Mental State Examination (MMSE).
Among the patients that were referred to our network in the 6-year time span, 690 were ultimately diagnosed with FTD and 18,831 with AD. Patients with FTD syndromes represented 2.6% of all-cause dementias. The age-standardized incidence was 2.90 per 100,000 person-year and incidence peaked between 75 and 79 years. Compared to AD, patients with FTD syndromes had a longer referral delay and delay to diagnosis. Patients with FTD syndromes had a higher MMSE score than AD at first referral while their progression was similar. mFTD patients had the shortest survival while survival in bvFTD, lvFTD, and AD did not significantly differ. FTD patients, especially those with the behavioral variant, received more antidepressants, anxiolytics, and antipsychotics than AD patients.
FTD syndromes differ with AD in characteristics at baseline, progression rate, and treatment. Despite a broad use of the new diagnostic criteria in an organized memory clinic network, FTD syndromes are longer to diagnose and account for a low proportion of dementia cases, suggesting persistent underdiagnosis. Congruent with recent publications, the late peak of incidence warns against considering FTD as being exclusively a young-onset dementia.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Behavioral variant frontotemporal dementia (bvFTD) has only recently been associated with significant striatal atrophy, whereas the striatum appears to be relatively preserved in Alzheimer's disease ...(AD). Considering the critical role the striatum has in cognition and behavior, striatal degeneration, together with frontal atrophy, could be responsible of some characteristic symptoms in bvFTD and emerges therefore as promising novel diagnostic biomarker to distinguish bvFTD and AD. Previous studies have, however, only taken either cortical or striatal atrophy into account when comparing the two diseases. In this study, we establish for the first time a profile of fronto-striatal atrophy in 23 bvFTD and 29 AD patients at presentation, based on the structural connectivity of striatal and cortical regions. Patients are compared to 50 healthy controls by using a novel probabilistic connectivity atlas, which defines striatal regions by their cortical white-matter connectivity, allowing us to explore the degeneration of the frontal and striatal regions that are functionally linked. Comparisons with controls revealed that bvFTD showed substantial fronto-striatal atrophy affecting the ventral as well as anterior and posterior dorso-lateral prefrontal cortices and the related striatal subregions. In contrast, AD showed few fronto-striatal atrophy, despite having significant posterior dorso-lateral prefrontal degeneration. Direct comparison between bvFTD and AD revealed significantly more atrophy in the ventral striatal-ventromedial prefrontal cortex regions in bvFTD. Consequently, deficits in ventral fronto-striatal regions emerge as promising novel and efficient diagnosis biomarker for bvFTD. Future investigations into the contributions of these fronto-striatal loops on bvFTD symptomology are needed to develop simple diagnostic and disease tracking algorithms.
Memory impairment in behavioral variant frontotemporal dementia (bvFTD) is traditionally considered to be mild and attributed to prefrontal cortex dysfunction. Recent studies, however, indicated that ...some patients can present with a memory impairment of the hippocampal type, showing storage and consolidation deficits in addition to the more executive/prefrontal related encoding and strategic difficulties.
This study aimed to study the relationship between executive functions (EF) and memory processes in bvFTD via a data-driven approach.
Participants consisted of 71 bvFTD (among which 60.6% had a lumbar puncture showing non-Alzheimer biomarker profile) and 60 controls (among which 45% had amyloid imaging showing a normal profile). EF were assessed by the Frontal Assessment Battery, semantic/lexical verbal fluency tests, and forward/backward digit spans. Patients were split into amnestic (n = 33) and non-amnestic (n = 38) subgroups based on normative data (total recall score) from the Free and Cued Selective Reminding Test (FCSRT). Relationships between FCSRT subscores and EF measures were explored through hierarchical clustering analysis, partial correlation analysis with an EF component, and automated linear modeling.
Convergent findings across the statistical approaches show that, overall, memory performance was independent from EF in bvFTD whereas the relationship was stronger in controls. Indeed, in bvFTD, memory performance did not cluster with EF, was not correlated with the EF component, and was only partially (4% - 12.7%) predicted by EF.
These findings show that executive dysfunctions cannot solely explain the memory deficits occurring in bvFTD. Indeed, some patients present with a genuine amnesia affecting storage and consolidation abilities, which are independent from executive dysfunctions. On the clinical level, this study highlights the importance of revising the neuropsychological diagnosis criteria for bvFTD.
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