Von Economo neurons are selectively targeted in frontotemporal dementia.

Von Economo neurons (VEN) are bipolar neurons located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI), areas affected early in behavioural variant frontotemporal dementia (bvFTD), in which VEN may constitute a selectively vulnerable cellular population. Aim A previous study has shown a selective loss of VEN in FTD above other neurons in the ACC of FTD. The aim of this study was to confirm this finding in a larger cohort, using a different methodology, and to examine VEN loss in relation to neuropathological severity and molecular pathology. Methods VEN and neighbouring neurons (NN) were quantified in layer Va and Vb of the right dorsal anterior cingulate cortex in 21 cases of behavioural variant FTD, 10 cases of Alzheimer's disease (AD) and 10 non-demented controls (NDC). Results A marked VEN reduction was seen in all FTD cases. In the neuropathologically early cases of FTD (n=13), VEN/10000 NN was significantly reduced by 53 % compared with NDC (p<0.001) and 41% compared with AD (p=0.019), whereas AD patients showed a non-significant 30% reduction of VEN/10000 NN compared with NDC. VEN reduction was present in all protein pathology subgroups. Discussion In conclusion, this study confirms selective sensitivity of VEN in FTD and suggests that VEN loss is an early event in the neurodegenerative process

Original Article Somatic complaints in frontotemporal dementia

Abstract: Frontotemporal dementia (FTD) is associated with a broad spectrum of clinical characteristics. The objective of this study was to analyze the prevalence of unexplained somatic complaints in neuropathologically verified FTD. We also examined whether the somatic presentations correlated with protein pathology or regional brain pathology and if the patients with these somatic features showed more depressive traits. Ninety-seven consecutively neuropathologically verified FTLD patients were selected. All 97 patients were part of a longitudinal study of FTD and all medical records were systematically reviewed. The somatic complaints focused on were headache, musculoskeletal, gastro/urogenital and abnormal pain response. Symptoms of somatic character (either somatic complaints and/or abnormal pain response) were found in 40.2%. These patients did not differ from the total group with regard to gender, age at onset or duration. Six patients showed exaggerated reactions to sensory stimuli, whereas three patients showed reduced response to pain. Depressive traits were present in 38% and did not correlate with somatic complaints. Suicidal behavior was present in 17 patients, in 10 of these suicidal behavior was concurrent with somatic complaints. No clear correlation between somatic complaints and brain protein pathology, regional pathology or asymmetric hemispherical atrophy was found. Our results show that many FTD patients suffer from unexplained somatic complaints before and/or during dementia where no clear correlation can be found with protein pathology or regional degeneration. Somatic complaints are not covered by current diagnostic criteria for FTD, but need to be considered in diagnostics and care. The need for prospective studies with neuropathological follow up must be stressed as these phenomena remain unexplained, misinterpreted, bizarre and, in many cases, excruciating

Swedish Version of the Hayling Test : Clinical Utility in Frontotemporal Dementia Syndromes

Objectives: The aim of this study was to assess the psychometric properties of a Swedish version of the Hayling test (HT-S) and its clinical utility in a group of patients with different frontotemporal dementia (FTD) syndromes. Early diagnosis of FTD is a challenge and requires a broad arsenal of assessment methods, neuropsychological tests not the least. The Hayling test assesses executive functions including initiation, efficiency and response inhibition. Methods: Seventy-six healthy controls were included as well as patients with the behavioral variant FTD (bvFTD; n = 17), semantic dementia (SD, n = 6), and progressive supranuclear palsy (n = 12). The Color Word Interference Test was administered to examine the construct validity. Results: Age showed a correlation with better performances in younger participants whereas the importance of sex and education were less evident. The split half reliability and internal consistency were equal to, or better, than reported for the original version. The interrater reliability was excellent. The construct validity was supported, nevertheless indicating partly different processes behind the performances of the two tests. The FTD group performed significantly worse than healthy controls on efficiency and response inhibition and there were also significant differences in performances between the syndromes despite small samples. Conclusions: The psychometric properties and clinical utility of the Swedish version are satisfactory for measuring efficiency and response inhibition with results indicating dissimilar profiles in the performances in the different syndromes. These results need to be corroborated in larger samples. (JINS, 2018, 22, 1-9

Association of Neuropathologically Confirmed Frontotemporal Dementia and Alzheimer Disease With Criminal and Socially Inappropriate Behavior in a Swedish Cohort

Importance Criminal and socially inappropriate behavior is encountered among patients with dementia, and it is sometimes the first sign of a dementing disorder. This behavior constitutes a significant burden to society, patients’ relatives, and patients themselves. Objectives To investigate and compare the prevalence and type of criminal and socially inappropriate behavior, as well as recurrence of criminal behavior, associated with Alzheimer disease (AD) and frontotemporal dementia (FTD) neuropathologically verified post mortem, and to assess whether there is a specific type of protein pathology more closely associated with criminal behavior in patients with FTD. Design, Setting, and Participants Cohort study using medical record review of 220 Swedish patients with a postmortem neuropathologic diagnosis of AD (n = 101) or frontotemporal lobar degeneration (n = 119) (hereinafter referred to as FTD) diagnosed between January 1, 1967, and December 31, 2017. Main Outcomes and Measures Patient notes containing reports of criminal and socially inappropriate behavior, as well as data on dominant protein pathology for patients with FTD, were duly reviewed and recorded. The Fisher exact test or logistic regression was used to assess possible differences between groups. Results Of the 220 patients studied, 128 (58.2%) were female, the median (range) age at disease onset was 63 (30-88) years and at death was 72 (34-96) years, and the median (range) disease duration was 9 (1-28) years. Instances of criminal behavior were found in 65 of the 220 patients (29.5%): in 15 of the 101 patients (14.9%) with AD and 50 of the 119 patients (42.0%) with FTD (P < .001). Recurrence of criminal behavior was significantly higher in the FTD group (89.0%) than in the AD group (53.3%) (P = .04). Instances of socially inappropriate behavior were found in 57 patients (56.4%) with AD and 89 (74.8%) with FTD (P = .004). An expression of non-tau pathology increased the odds for criminal behavior by a factor of 9.0 (95% CI, 3.4-24.0) among patients with FTD. Conclusions and Relevance These results suggest that criminal and socially inappropriate behaviors may be more prevalent and criminal behaviors may be more recurrent in patients with FTD than in those with AD. Non-tau pathology, but not tau pathology, appears to be associated with criminal behavior. These findings may help with the clinical diagnostic process

Grey and White Matter Clinico-Anatomical Correlates of Disinhibition in Neurodegenerative Disease.

Disinhibition is an important symptom in neurodegenerative diseases. However, the clinico-anatomical underpinnings remain controversial. We explored the anatomical correlates of disinhibition in neurodegenerative disease using the perspective of grey and white matter imaging. Disinhibition was assessed with a neuropsychological test and a caregiver information-based clinical rating scale in 21 patients with prefrontal syndromes due to behavioural variant frontotemporal dementia (n = 12) or progressive supranuclear palsy (n = 9), and healthy controls (n = 25). Cortical thickness was assessed using the Freesurfer software on 3T MRI data. The integrity of selected white matter tracts was determined by the fractional anisotropy (FA) from Diffusion Tensor Imaging. Disinhibition correlated with the cortical thickness of the right parahippocampal gyrus, right orbitofrontal cortex and right insula and the FA of the right uncinate fasciculus and right anterior cingulum. Notably, no relationship was seen with the thickness of ventromedial prefrontal cortex. Our results support an associative model of inhibitory control, distributed in a medial temporal lobe-insular-orbitofrontal network, connected by the intercommunicating white matter tracts. This reconciles some of the divergences among previous studies, but also questions the current conceptualisation of the "prefrontal" syndrome and the central role attributed to the ventromedial prefrontal cortex in inhibitory control

Diffusion Tensor Tractography versus Volumetric Imaging in the Diagnosis of Behavioral Variant Frontotemporal Dementia

MRI diffusion tensor imaging (DTI) studies of white matter integrity in behavioral variant frontotemporal dementia have consistently shown involvement of frontal and temporal white matter, corresponding to regional loss of cortical volume. Volumetric imaging has a suboptimal sensitivity as a diagnostic tool and thus we wanted to explore if DTI is a better method to discriminate patients and controls than volumetric imaging. We examined the anterior cingulum bundle in 14 patients with behavioral variant frontotemporal dementia and 22 healthy controls using deterministic manual diffusion tensor tractography, and compared DTI parameters with two measures of cortical atrophy, VBM and cortical thickness, of the anterior cingulate cortex (ACC). Statistically significant changes between patients and controls were detected in all DTI parameters, with large effect sizes. ROC-AUC was for the best DTI parameters: 0.92 (fractional anisotropy) to 0.97 (radial diffusivity), 0.82 for the best cortical parameter, VBM of the ACC. Results from the AUC were confirmed with binary logistic regression analysis including demographic variables, but only for fractional anisotropy and mean diffusivity. Ability to classify patient/nonpatient status was significantly better for mean diffusivity vs. VBM (p = 0.031), and borderline significant for fractional anisotropy vs. VBM (p = 0.062). The results indicate that DTI could offer advantages in comparison with the assessment of cortical volume in differentiating patients with behavioral variant frontotemporal dementia and controls

Diffusion Tensor Tractography versus Volumetric Imaging in the Diagnosis of Behavioral Variant Frontotemporal Dementia

MRI diffusion tensor imaging (DTI) studies of white matter integrity in behavioral variant frontotemporal dementia have consistently shown involvement of frontal and temporal white matter, corresponding to regional loss of cortical volume. Volumetric imaging has a suboptimal sensitivity as a diagnostic tool and thus we wanted to explore if DTI is a better method to discriminate patients and controls than volumetric imaging. We examined the anterior cingulum bundle in 14 patients with behavioral variant frontotemporal dementia and 22 healthy controls using deterministic manual diffusion tensor tractography, and compared DTI parameters with two measures of cortical atrophy, VBM and cortical thickness, of the anterior cingulate cortex (ACC). Statistically significant changes between patients and controls were detected in all DTI parameters, with large effect sizes. ROC-AUC was for the best DTI parameters: 0.92 (fractional anisotropy) to 0.97 (radial diffusivity), 0.82 for the best cortical parameter, VBM of the ACC. Results from the AUC were confirmed with binary logistic regression analysis including demographic variables, but only for fractional anisotropy and mean diffusivity. Ability to classify patient/nonpatient status was significantly better for mean diffusivity vs. VBM (p = 0.031), and borderline significant for fractional anisotropy vs. VBM (p = 0.062). The results indicate that DTI could offer advantages in comparison with the assessment of cortical volume in differentiating patients with behavioral variant frontotemporal dementia and controls

Regional structural hypo- and hyperconnectivity of frontal-striatal and frontal-thalamic pathways in behavioral variant frontotemporal dementia

Behavioral variant frontotemporal dementia (bvFTD) has been predominantly considered as a frontotemporal cortical disease, with limited direct investigation of frontal-subcortical connections. We aim to characterize the grey and white matter components of frontal-thalamic and frontal-striatal circuits in bvFTD. Twenty-four patients with bvFTD and 24 healthy controls underwent morphological and diffusion imaging. Subcortical structures were manually segmented according to published protocols. Probabilistic pathways were reconstructed separately from the dorsolateral, orbitofrontal and medial prefrontal cortex to the striatum and thalamus. Patients with bvFTD had smaller cortical and subcortical volumes, lower fractional anisotropy, and higher mean diffusivity metrics, which is consistent with disruptions in frontal-striatal-thalamic pathways. Unexpectedly, regional volumes of the striatum and thalamus connected to the medial prefrontal cortex were significantly larger in bvFTD (by 135% in the striatum, p =.032, and 217% in the thalamus, p =.004), despite smaller dorsolateral prefrontal cortex connected regional volumes (by 67% in the striatum, p =.002, and 65% in the thalamus, p =.020), and inconsistent changes in orbitofrontal cortex connected regions. These unanticipated findings may represent compensatory or maladaptive remodeling in bvFTD networks. Comparisons are made to other neuropsychiatric disorders suggesting a common mechanism of changes in frontal-subcortical networks; however, longitudinal studies are necessary to test this hypothesis