Behavioral Variant FTD Research Articles

Clinical features that differentiate young‐onset AD from young‐onset FTLD: An examination of the NACC UDS 3.0 and FTLD Module

AbstractBackgroundClinicopathologic studies reported that the NACC Uniform Dataset (UDS) 2.0 core measures do not adequately differentiate patients who ultimately died of Frontotemporal Lobar Degeneration (FTLD) from Alzheimer’s disease (AD). The FTLD Module (FTLD‐MOD) assesses core features of behavioral variant FTD (bvFTD) and primary progressive aphasia (PPA). Initial investigations suggest that the FTLD‐MOD improves discrimination between biomarker‐supported bvFTD and typical late‐onset AD, and that clinically diagnosed PPA participants performed worse than bvFTD on all FTLD‐MOD language tasks. However, the utility of these measures in the differential diagnosis of AD vs. major FTLD syndromes in young‐onset cases remains underexplored.MethodWe examined participants with age‐of‐onset < 65 years in the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) consortium and the Longitudinal Early Onset AD Study (LEADS). 115 bvFTD, 53 semantic variant PPA (svPPA), 29 non‐fluent variant PPA (nfvPPA) and 124 early‐onset AD (eoAD) cases completed the UDS3 and FLTD‐MOD. Linear regression analyses measured group differences in FLTD‐MOD raw scores and UDS3 neuropsychological z‐scores after accounting for group differences in demographic variables and global severity ratings. Alpha was 0.05 with Bonferroni corrections.ResultsParticipants with eoAD demonstrated the most impaired scores on tasks of attention, working memory, and processing speed, including Digit Span Backward (z=‐1.87) and Trails A (z=‐3.82). They also demonstrated difficulty on FTLD‐MOD language tasks with a working memory requirement (sentence repetition raw=3.68/5) and, as expected, memory (story delayed recall z=‐2.4z). svPPA performed the worst on FTLD‐MOD and UDS3 tasks assessing semantic memory, especially naming (all p’s ≤ 0.03). nfvPPA performed worst on sentence reading, sentence repetition, and letter fluency (all p’s ≤ 0.02). Consistent with previous work, these measures differentiate between bvFTD and PPA variants. However, relative to eoAD, bvFTD was equivalent (Trails B: bvFTDz=‐3.8, eoADz=‐3.82; p=0.12) or outperformed (sentence repetition: bvFTD=4.22/5, eoAD=3.68/5; p<0.001) the eoAD group on all tasks.ConclusionsWe undertook this analysis to compare performance of the major young‐onset sporadic AD and FTLD clinical syndromes in the ALLFTD and LEADS studies. Results demonstrate relatively distinct cognitive profiles among eoAD, svPPA, and nfvPPA, but not in bvFTD. Future analyses will include FTLD‐MOD behavioral symptom questionnaires to assess their utility in differentiating bvFTD.

Altered music processing phenotypes in patients with frontotemporal dementia

AbstractBackgroundFrontotemporal dementia (FTD) can present with changes in music appreciation. The aim of the present study was to determine the prevalence and nature of music appreciation phenotypes among FTD syndromes in a memory clinic population.MethodForty‐seven FTD patients (44.7% female, mean age 65.0±8.4, 31 behavioral variant FTD (bvFTD), 10 semantic dementia (SD), 6 progressive nonfluent aphasia (PNFA)) who consecutively visited our memory clinic were included in this study. Forty‐six caregivers (54.3% female, mean age 61.8±9.2) were included as a control group. Based on reported musical changes in the literature, we developed an informant‐based questionnaire by extending a previously used questionnaire (Fletcher et al., 2015). Music‐emotion recognition was assessed with a live music test in which both participants and caregivers were played 9 guitar chords, and rated if these were major, minor or dissonant (i.e. happy, sad or disharmonic). Visual emotion recognition was examined with the Ekman 60 faces test in a subgroup of patients (n= 23). Non‐parametric tests were used for group comparisons.ResultMusic appreciation phenotypes were observed in 79% of the FTD patients. Musicophilia was most often present (in 12/47 patients, 26%), followed by music anhedonia (23%), change of music taste (21%), increased singing (21%), sound‐aversion (19%), music‐aversion (13%), music agnosia (9%) and increased dancing (5%). Musicophilia was present in a third of bvFTD patients, but only in 10% of the semantic dementia and none of PNFA patients. The other reported music changes were more evenly distributed. The presence of music changes was not associated with lower performance on the music emotion recognition task (p = 0.62) or visual emotion recognition task (p = 0.87). However, compared to controls, bvFTD performed worse on the music emotion recognition task (p< .003), SD performed worse at trend level (p = .06) and no differences were found with PNFA (p = .8) patients (figure 1).ConclusionMusic appreciation phenotypes are highly prevalent in the FTD population, consist of a variety of symptoms, differ between syndromes and do not do not correlate with emotion recognizing capacities. Furthermore, compared to controls, bvFTD performed worse on a music emotion recognition test.

Infratentorial pathology in frontotemporal dementia: cerebellar grey and white matter alterations in FTD phenotypes

The contribution of cerebellar pathology to cognitive and behavioural manifestations is increasingly recognised, but the cerebellar profiles of FTD phenotypes are relatively poorly characterised. A prospective, single-centre imaging study has been undertaken with a high-resolution structural and diffusion tensor protocol to systematically evaluate cerebellar grey and white matter alterations in behavioural-variant FTD(bvFTD), non-fluent variant primary progressive aphasia(nfvPPA), semantic-variant primary progressive aphasia(svPPA), C9orf72-positive ALS-FTD(C9 + ALSFTD) and C9orf72-negative ALS-FTD(C9-ALSFTD). Cerebellar cortical thickness and complementary morphometric analyses were carried out to appraise atrophy patterns controlling for demographic variables. White matter integrity was assessed in a study-specific white matter skeleton, evaluating three diffusivity metrics: fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD). Significant cortical thickness reductions were identified in: lobule VII and crus I in bvFTD; lobule VI VII, crus I and II in nfvPPA; and lobule VII, crus I and II in svPPA; lobule IV, VI, VII and Crus I and II in C9 + ALSFTD. Morphometry revealed volume reductions in lobule V in all groups; in addition to lobule VIII in C9 + ALSFTD; lobule VI, VIII and vermis in C9-ALSFTD; lobule V, VII and vermis in bvFTD; and lobule V, VI, VIII and vermis in nfvPPA. Widespread white matter alterations were demonstrated by significant fractional anisotropy, axial diffusivity and radial diffusivity changes in each FTD phenotype that were more focal in those with C9 + ALSFTD and svPPA. Our findings indicate that FTD subtypes are associated with phenotype-specific cerebellar signatures with the selective involvement of specific lobules instead of global cerebellar atrophy.

Etiology of Dementia in Thai Patients

Introduction: Molecular imaging has been developed and validated in Thai patients, comprising a portion of patients in the dementia registry. This should provide a more accurate diagnosis of the etiology of dementia, which was the focus of this study. Methods: This was a multicenter dementia study. The baseline characteristics, main presenting symptoms, and results of investigations and cognitive tests of the patients were electronically collected in the registry. Functional imaging and/or molecular imaging were performed in patients with an equivocal diagnosis of the causes of dementia, especially in atypical dementia or young onset dementia (YOD). Results: There were 454 patients in the study. The mean age of the patients was 78 years, with 60% female. Functional imaging and/or molecular imaging were performed in 57 patients (57/454 patients, 13%). The most common cause of dementia was Alzheimer’s disease (AD; 50%), followed by vascular dementia (VAD; 24%), dementia with Lewy bodies (6%), Parkinson’s disease dementia (6%), frontotemporal dementia (FTD; 2.6%), progressive supranuclear palsy (2%), multiple system atrophy (0.8%), and corticobasal syndrome (0.4%). YOD accounted for 17% (77/454 patients), with a mean age of 58 years. The causes of YOD were early onset amnestic AD (44%), VAD (16%), behavioral variant FTD (8%), posterior cortical atrophy (6.5%), and logopenic variant primary progressive aphasia (5.2%). Conclusion: AD was the most common cause of dementia in Thai patients and the distribution of other types of dementia and main presenting symptoms were similar to previous reports in Western patients; however, the proportion of YOD was higher.

Heterogeneity of behavioural and language deficits in FTD-MND.

To comprehensively examine the clinical presentation of patients diagnosed with frontotemporal dementia-motor neuron disease (FTD-MND) compared to FTD subtypes. To clarify the heterogeneity of behavioural and language deficits in FTD-MND using a data-driven approach. Patients with FTD-MND (n = 31), behavioural variant FTD (n = 119), non-fluent variant primary progressive aphasia (n = 47), semantic variant primary progressive aphasia (n = 42), and controls (n = 127) underwent comprehensive clinical, cognitive and behavioural assessments. Two-step cluster analysis examined patterns of behavioural and language impairment. Voxel-based morphometry and tract-based spatial statistics were used to investigate differences across the subgroups that emerged from cluster analysis. More than half of FTD-MND patients initially presented with variable combinations of deficits (e.g., mixed behaviour/cognitive, mixed behaviour/cognitive/motor deficits), with 74% of them meeting criteria for FTD-MND within 24months with a median of 12months. The frequency and severity of behavioural and language abnormalities in FTD-MND lie between that seen in the three FTD phenotypes. Cluster analysis identified three patterns of behavioural and language impairment in FTD-MND. The three FTD-MND subgroups demonstrated different profiles of white matter tract disruption, but did not differ in age at onset, disease duration or patterns of cortical atrophy. While highly heterogeneous, in terms of behavioural and language deficits, and disease severity, the presentation of FTD-MND may be distinct to that of FTD. Distinct white matter degeneration patterns may underpin heterogeneous clinical profiles in FTD-MND. FTD presenting with mixed behavioural-language disturbances should be monitored closely for at least 12-24months for the emergence of MND symptoms/signs.

Regional prefrontal cortical atrophy predicts specific cognitive-behavioral symptoms in ALS-FTD.

Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD) may present typical behavioral variant FTD symptoms. This study aims to determine whether profile and severity of cognitive-behavioral symptoms in ALS/ALS-FTD are predicted by regional cortical atrophy. The hypothesis is that executive dysfunction can be predicted by dorsolateral prefrontal cortical (dlPFC) atrophy, apathy by dorsomedial PFC (dmPFC) and anterior cingulate cortical (ACC) atrophy, disinhibition by orbitofrontal cortical (OFC) atrophy. 3.0 Tesla MRI scans were acquired from 22 people with ALS or ALS-FTD. Quantitative cortical thickness analysis was performed with FreeSurfer. A priori-defined regions of interest (ROI) were used to measure cortical thickness in each participant and calculate magnitude of atrophy in comparison to 115 healthy controls. Spearman correlations were used to evaluate associations between frontal ROI cortical thickness and cognitive-behavioral symptoms, measured by Neuropsychiatric Inventory Questionnaire (NPI-Q) and Clinical Dementia Rating (CDR) scale. ALS-FTD participants exhibited variable degrees of apathy (NPI-Q/apathy: 1.6 ± 1.2), disinhibition (NPI-Q/disinhibition: 1.2 ± 1.2), executive dysfunction (CDR/judgment-problem solving: 1.7 ± 0.8). Within the ALS-FTD group, executive dysfunction correlated with dlPFC atrophy (ρ:-0.65;p < 0.05); similar trends were seen for apathy with ACC (ρ:-0.53;p < 0.10) and dmPFC (ρ:-0.47;p < 0.10) atrophy, for disinhibition with OFC atrophy (ρ:-0.51;p < 0.10). Compared to people with ALS, those with ALS-FTD showed more diffuse atrophy involving precentral gyrus, prefrontal, temporal regions. Profile and severity of cognitive-behavioral symptoms in ALS-FTD are predicted by regional prefrontal atrophy. These findings are consistent with established brain-behavior models and support the role of quantitative MRI in diagnosis, management, counseling, monitoring and prognostication for a neurodegenerative disorder with diverse phenotypes.

Screening for cognition in amyotrophic lateral sclerosis: test characteristics of a new screen

Cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS) negatively influences the quality of life and survival, and, therefore, screening for these impairments is recommended. We developed a cognitive screening tool, the amyotrophic lateral sclerosis–frontotemporal dementia–cognitive screen (ALS–FTD–Cog) and aimed to validate it in patients with ALS. During the current study, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was published and we, therefore, decided to compare these two cognitive screening methods. The ALS–FTD–Cog was administered to 72 patients with ALS, 21 patients with behavioural variant FTD (bvFTD) and 34 healthy controls. Twenty-nine patients with ALS underwent the ECAS. ROC curve analyses were performed and sensitivity and specificity of the ALS–FTD–Cog and ECAS were calculated, with a neuropsychological examination (NPE) as the gold standard. Cognitive impairment was present in 28% of patients with ALS. ROC curve analyses of the ALS–FTD–Cog and ECAS showed an area under the curve (AUC) of 0.72 (95% CI 0.58–0.86) and 0.95 (95% CI 0.86–1.03), respectively. Compared to a full NPE, sensitivity and specificity of the ALS–FTD–Cog were 65.0% and 63.5% and of the ECAS 83.3% and 91.3%, respectively. The sensitivity and specificity of the ALS–FTD–Cog in patients with bvFTD were 94.4% and 100%, respectively. Test characteristics of the ALS–FTD–Cog were moderate, suggesting restricted practical value, as compared to a comprehensive NPE. The ECAS had an excellent AUC and high sensitivity and specificity, indicating that it is a valid screening instrument for cognitive impairment in ALS.

Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia

ObjectiveProgranulin-related frontotemporal dementia (FTD-GRN) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation...

A comparison of automated atrophy measures across the frontotemporal dementia spectrum: Implications for trials

BackgroundFrontotemporal dementia (FTD) is a common cause of young onset dementia, and whilst there are currently no treatments, there are several promising candidates in development and early phase trials. Comprehensive investigations of neuroimaging markers of disease progression across the full spectrum of FTD disorders are lacking and urgently needed to facilitate these trials. ObjectiveTo investigate the comparative performance of multiple automated segmentation and registration pipelines used to quantify longitudinal whole-brain atrophy across the clinical, genetic and pathological subgroups of FTD, in order to inform upcoming trials about suitable neuroimaging-based endpoints. MethodsSeventeen fully automated techniques for extracting whole-brain atrophy measures were applied and directly compared in a cohort of 226 participants who had undergone longitudinal structural 3D T1-weighted imaging. Clinical diagnoses were behavioural variant FTD (n = 56) and primary progressive aphasia (PPA, n = 104), comprising semantic variant PPA (n = 38), non-fluent variant PPA (n = 42), logopenic variant PPA (n = 18), and PPA-not otherwise specified (n = 6). 49 of these patients had either a known pathogenic mutation or postmortem confirmation of their underlying pathology. 66 healthy controls were included for comparison. Sample size estimates to detect a 30% reduction in atrophy (80% power; 0.05 significance) were computed to explore the relative feasibility of these brain measures as surrogate markers of disease progression and their ability to detect putative disease-modifying treatment effects. ResultsMultiple automated techniques showed great promise, detecting significantly increased rates of whole-brain atrophy (p<0.001) and requiring sample sizes of substantially less than 100 patients per treatment arm. Across the different FTD subgroups, direct measures of volume change consistently outperformed their indirect counterparts, irrespective of the initial segmentation quality. Significant differences in performance were found between both techniques and patient subgroups, highlighting the importance of informed biomarker choice based on the patient population of interest. ConclusionThis work expands current knowledge and builds on the limited longitudinal investigations currently available in FTD, as well as providing valuable information about the potential of fully automated neuroimaging biomarkers for sporadic and genetic FTD trials.

Prevalence of FTD clinical diagnostic features in patients with TDP‐43 pathology

AbstractBackgroundFrontotemporal dementia (FTD) is a heterogeneous syndrome which includes three main clinical subtypes, behavioural variant FTD (bvFTD) and the non‐fluent and semantic variants of primary progressive aphasia (nfvPPA, svPPA). The pathology underlying clinical FTD, referred to as frontotemporal lobar degeneration (FTLD), is also heterogenous with transactive response DNA binding protein Mw 43 (FTLD‐TDP) present in ∼50%. In this study we investigate the proportion of FTLD‐TDP cases that fulfil diagnostic criteria for each of the clinical FTD subtypes.MethodWe retrospectively reviewed charts of patients with autopsy proven FTLD‐TDP. Patients with additional pathology, (e.g. Alzheimer’s disease, AD), were excluded. We extracted clinical data regarding behaviour, language and cognition, and compared these against the current FTD clinical diagnostic criteria.ResultFifteen of 24 patients (62.5%) with autopsy‐confirmed FTLD‐TDP pathology met diagnostic criteria for possible bvFTD (n=9), nfvPPA (n=3) or svPPA(n=3). The clinical diagnosis of the nine patients who did not match criteria for any of the three FTD syndromes included FTD with motor neuron disease (n=5), AD type dementia (n=3), progressive supranuclear palsy (n=1), corticobasal syndrome (n=1) and FTD with Parkinsonism linked to chromosome 17 (n=1). Patients with motor neuron disease developed 1 (n=2) or 2 (n=3) diagnostic features of bvFTD.Among the bvFTD diagnostic features, executive dysfunction was the commonest (79.2%), followed by apathy (37.5%) and disinhibition (33.3%). 70.8% of all patients and 42.9% of bvFTD patients developed clinical features of aphasia. Cognitive screening tests revealed a high prevalence of impaired short‐term recall (79.2%) and language dysfunction (83.3%) irrespective of the clinical diagnosis.ConclusionbvFTD is the commonest presentation of FTLD‐TDP; however, a significant proportion of patients do not match diagnostic criteria for FTD. Additionally, the high prevalence of impaired short‐term recall suggests it may not be practical to use this as an exclusionary criteria for FTD. We recognize the selection bias in our sample which was derived exclusively from a dementia clinic population.

A clinical-radiological framework of the right temporal variant of frontotemporal dementia.

The concept of the right temporal variant of frontotemporal dementia (rtvFTD) is still equivocal. The syndrome accompanying predominant right anterior temporal atrophy has previously been described as memory loss, prosopagnosia, getting lost and behavioural changes. Accurate detection is challenging, as the clinical syndrome might be confused with either behavioural variant FTD (bvFTD) or Alzheimer’s disease. Furthermore, based on neuroimaging features, the syndrome has been considered a right-sided variant of semantic variant primary progressive aphasia (svPPA). Therefore, we aimed to demarcate the clinical and neuropsychological characteristics of rtvFTD versus svPPA, bvFTD and Alzheimer’s disease. Moreover, we aimed to compare its neuroimaging profile against svPPA, which is associated with predominant left anterior temporal atrophy. Of 619 subjects with a clinical diagnosis of frontotemporal dementia or primary progressive aphasia, we included 70 subjects with a negative amyloid status in whom predominant right temporal lobar atrophy was identified based on blinded visual assessment of their initial brain MRI scans. Clinical symptoms were assessed retrospectively and compared with age- and sex-matched patients with svPPA (n = 70), bvFTD (n = 70) and Alzheimer’s disease (n = 70). Prosopagnosia, episodic memory impairment and behavioural changes such as disinhibition, apathy, compulsiveness and loss of empathy were the most common initial symptoms, whereas during the disease course, patients developed language problems such as word-finding difficulties and anomia. Distinctive symptoms of rtvFTD compared to the other groups included depression, somatic complaints, and motor/mental slowness. Aside from right temporal atrophy, the imaging pattern showed volume loss of the right ventral frontal area and the left temporal lobe, which represented a close mirror image of svPPA. Atrophy of the bilateral temporal poles and the fusiform gyrus were associated with prosopagnosia in rtvFTD. Our results highlight that rtvFTD has a unique clinical presentation. Since current diagnostic criteria do not cover specific symptoms of the rtvFTD, we propose a diagnostic tree to be used to define diagnostic criteria and call for an international validation.

Emotion recognition of morphed facial expressions in presymptomatic and symptomatic frontotemporal dementia, and Alzheimer\u2019s dementia

BackgroundThe emotion recognition task (ERT) was developed to overcome shortcomings of static emotion recognition paradigms, by identifying more subtle deficits in emotion recognition across different intensity levels. In this study, we used the ERT to investigate emotion recognition deficits across the frontotemporal (FTD) and Alzheimer’s Dementia (AD) spectrum.MethodsWith the ERT, we assessed the recognition of facial emotional expressions (anger-disgust-fear-happiness-sadness-surprise) across four intensities (40–60–80–100%) in patients with behavioural variant FTD (bvFTD; n = 32), and AD (n = 32), presymptomatic FTD mutation carriers (n = 47) and controls (n = 49). We examined group differences using multilevel linear regression with age, sex and education level as covariates, and performed post hoc analyses on presymptomatic (MAPT, GRN and C9orf72) mutation carriers. Classification abilities were investigated by means of logistic regression.ResultsLowest ERT total scores were found in patients with bvFTD and AD, whereas equal highest performance was found in presymptomatic mutation carriers and controls. For all emotions, significantly lower subscores were found in patients with bvFTD than in presymptomatic mutation carriers and in controls (highest p value = 0.025). Patients with bvFTD performed lower than patients with AD on anger (p = 0.005) and a trend towards significance was found for a lower performance on happiness (p = 0.065). Task performance increased with higher emotional intensity, and classification was better at the lowest than at the highest intensity. C9orf72 mutation carriers performed worse on recognizing anger at the lowest intensity than GRN mutation carriers (p = 0.047) and controls (p = 0.038). The ERT differentiated between patients with bvFTD and controls, and between patients with AD and controls (both p < 0.001).DiscussionOur results demonstrate emotion recognition deficits in both bvFTD and AD, and suggest the presence of subtle emotion recognition changes in presymptomatic C9orf72-FTD. This highlights the importance of incorporating emotion recognition paradigms into standard neuropsychological assessment for early differential diagnosis, and as clinical endpoints in upcoming therapeutic trials.

Automated analysis of natural speech in amyotrophic lateral sclerosis spectrum disorders.

We implemented automated methods to analyze speech and evaluate the hypothesis that cognitive and motor factors impair prosody in partially distinct ways in patients with amyotrophic lateral sclerosis (ALS). We recruited 213 participants, including 67 with ALS (44 with motor ALS, 23 with ALS and frontotemporal degeneration [FTD]), 33 healthy controls, and neurodegenerative reference groups with behavioral variant FTD (n = 90) and nonfluent/agrammatic primary progressive aphasia (n = 23). Digitized, semistructured speech samples obtained from picture descriptions were automatically segmented with a Speech Activity Detector; continuous speech segments were pitch-tracked; and duration measures for speech and silent pause segments were extracted. Acoustic measures were calculated, including fundamental frequency (f0) range, mean speech and pause segment durations, total speech duration, and pause rate (pause count per minute of speech). Group comparisons related performance on acoustic measures to clinical scales of cognitive and motor impairments and explored MRI cortical thinning in ALS and ALS-FTD. The f0 range was significantly impaired in ALS spectrum disorders and was related to bulbar motor disease, and regression analyses related this to cortical thickness in primary motor cortex and perisylvian regions. Impaired speech and pause duration measures were related to the degree of cognitive impairment in ALS spectrum disorders, and regressions related duration measures to bilateral frontal opercula and left anterior insula. Automated analyses of acoustic speech properties dissociate motor and cognitive components of speech deficits in ALS spectrum disorders.

Pick's disease: clinicopathologic characterization of 21 cases.

Pick's disease (PiD) is a unique subtype of frontotemporal lobar degeneration characterized pathologically by aggregates of 3-Repeat tau. Few studies have examined the clinical variability and disease progression in PiD. We describe the clinical features, neuropsychological profiles and coexistent pathologies in 21 cases of autopsy-confirmed PiD. This study was a retrospective analysis of patients with Pick's disease evaluated at Mayo Clinic, Rochester or Jacksonville (1995-2018), and identified through an existing database. Twenty-one cases with sufficient clinical data were identified. Behavioral variant FTD (bvFTD; 12/21) was the most common phenotype, followed by primary progressive aphasia (PPA; 7/21), corticobasal syndrome (CBS; 1/21) and amnestic dementia (1/21). Median age at disease onset was 54years, with PPA cases (median = 52years) presenting earlier than bvFTD (median = 59). Median disease duration (onset-death) overall was 10years and did not differ significantly between bvFTD (median = 9.5years) and PPA (median = 13). Age at death was not significantly different in PPA (median = 66) compared to bvFTD (median = 68.5). A third of the cases (n = 7/21) demonstrated pure PiD pathology, while the remainder showed co-existent other pathologies including Alzheimer's type (n = 6), cerebral amyloid angiopathy (n = 3), combined Alzheimer's and amyloid angiopathy (n = 4), and Lewy body disease (n = 1). Our study shows that bvFTD and PPA are the most common clinical phenotypes associated with PiD, although rare presentations such as CBS were also seen. Coexisting non-Pick's pathology was also present in many cases. Our study highlights the clinical and pathologic heterogeneity in PiD.

Physiological, behavioral and subjective sadness reactivity in frontotemporal dementia subtypes.

Frontotemporal dementia (FTD), a neurodegenerative disease broadly characterized by socioemotional impairments, includes three clinical subtypes: behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA) and non-fluent variant primary progressive aphasia (nfvPPA). Emerging evidence has shown emotional reactivity impairments in bvFTD and svPPA, whereas emotional reactivity in nfvPPA is far less studied. In 105 patients with FTD (49 bvFTD, 31 svPPA and 25 nfvPPA) and 27 healthy controls, we examined three aspects of emotional reactivity (physiology, facial behavior and subjective experience) in response to a sad film. In a subset of the sample, we also examined the neural correlates of diminished aspects of reactivity using voxel-based morphometry. Results indicated that all three subtypes of FTD showed diminished physiological responding in respiration rate and diastolic blood pressure; patients with bvFTD and svPPA also showed diminished subjective experience, and no subtypes showed diminished facial behavior. Moreover, there were differences among the clinical subtypes in brain regions where smaller volumes were associated with diminished sadness reactivity. These results show that emotion impairments extend to sadness reactivity in FTD and underscore the importance of considering different aspects of sadness reactivity in multiple clinical subtypes for characterizing emotional deficits and associated neurodegeneration in FTD.

Thalamic nuclei in frontotemporal dementia: Mediodorsal nucleus involvement is universal but pulvinar atrophy is unique to C9orf72.

Thalamic atrophy is a common feature across all forms of FTD but little is known about specific nuclei involvement. We aimed to investigate in vivo atrophy of the thalamic nuclei across the FTD spectrum. A cohort of 402 FTD patients (age: mean(SD) 64.3(8.2) years; disease duration: 4.8(2.8) years) was compared with 104 age‐matched controls (age: 62.5(10.4) years), using an automated segmentation of T1‐weighted MRIs to extract volumes of 14 thalamic nuclei. Stratification was performed by clinical diagnosis (180 behavioural variant FTD (bvFTD), 85 semantic variant primary progressive aphasia (svPPA), 114 nonfluent variant PPA (nfvPPA), 15 PPA not otherwise specified (PPA‐NOS), and 8 with associated motor neurone disease (FTD‐MND), genetic diagnosis (27 MAPT, 28 C9orf72, 18 GRN), and pathological confirmation (37 tauopathy, 38 TDP‐43opathy, 4 FUSopathy). The mediodorsal nucleus (MD) was the only nucleus affected in all FTD subgroups (16–33% smaller than controls). The laterodorsal nucleus was also particularly affected in genetic cases (28–38%), TDP‐43 type A (47%), tau‐CBD (44%), and FTD‐MND (53%). The pulvinar was affected only in the C9orf72 group (16%). Both the lateral and medial geniculate nuclei were also affected in the genetic cases (10–20%), particularly the LGN in C9orf72 expansion carriers. Use of individual thalamic nuclei volumes provided higher accuracy in discriminating between FTD groups than the whole thalamic volume. The MD is the only structure affected across all FTD groups. Differential involvement of the thalamic nuclei among FTD forms is seen, with a unique pattern of atrophy in the pulvinar in C9orf72 expansion carriers.

Use of the CDR® plus NACC FTLD in mild FTLD: Data from the ARTFL/LEFFTDS consortium

IntroductionBehavior/Comportment/Personality (BEHAV) and Language (LANG) domains were added to the Clinical Dementia Rating (CDR®) for improving evaluation of patients with frontotemporal lobar degeneration (FTLD) (CDR® plus NACC FTLD). MethodsWe analyzed the CDR® plus NACC FTLD among participants from the baseline visit of the Advancing Research and Treatment for Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Consortium. ResultsThe CDR® plus NACC FTLD was able to detect early symptoms in the mildly impaired participants who were rated as CDR® sum of boxes (CDR®-SB) = 0. The CDR®-SB was not sensitive, particularly in participants with mild nonfluent/agrammatic primary progressive aphasia. Participants with familial and sporadic behavioral variant FTD exhibited similar CDR® plus NACC FTLD profiles except that language impairment was more frequent in participants with mild sporadic behavioral variant FTD. Adding the BEHAV and/or LANG domains to the CDR®-SB significantly enhanced discriminatory power in differentiating among the FTLD spectrum disorders. DiscussionThe BEHAV and LANG domains enable the CDR® plus NACC FTLD to capture early symptomatology of FTLD.

The role of MAPT gene in Chinese dementia patients: a P301L pedigree study and brief literature review.

Background and purposeFrontotemporal dementia (FTD) is the second most common presenile dementia characterized by behavioral changes and language impairment. The diagnosis of FTD relies heavily on neuroimaging, and sometimes on genetic screening. However, the genetic components in Chinese FTD patients remain largely unknown. Only a few FTD cases with established mutations have been reported in China. This study reported the detailed clinical and neuroimaging features in a Chinese behavioral variant FTD family. The role of MAPT gene mutation in Chinese dementia patients was also reviewed.MethodsBy detailed inquiry of all affected individuals in the family, this study summarized the main clinical features of the disease. Four candidate genes (MAPT, PSEN1, PSEN2, and APP) were screened by direct sequencing. Structural magnetic resonance imaging (MRI), functional imaging of cerebral blood flow with arterial spin-labeled MRI (ASL-MRI), and cerebral metabolism with fluorodeoxyglucose positron emission tomography (FDG-PET) were collected in the proband and healthy mutation carriers.ResultsBy direct sequencing of candidate genes (MAPT, PSEN1, PSEN2, and APP), this study identified the P301L mutation in the MAPT gene in the proband and three unaffected family members. The phenotype of the affected cases was consistent within the pedigree. In this genetically proven behavioral variant FTD (bvFTD) patient, the maps of hypoperfusion on ASL-MRI look fairly similar to the hypometabolism on FDG-PET. The clinical feature for this bvFTD was in line with the hypoperfusion or hypometabolism pattern on functional neuroimagings. The phenotype of P301L in east Asia seems similar to western countries.ConclusionFor the inherited FTD patients, ASL-MRI and genetic identification were strongly recommended for the final diagnosis. In case of being underestimated, the role of MAPT gene mutation in Chinese FTD patients warrants further investigation.

Plasma tau is increased in frontotemporal dementia

BackgroundFrontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder presenting clinically with personality change (behavioural variant FTD (bvFTD)) or language deficits (primary progressive aphasia (PPA)). About a third of FTD is...

FDG-PET and CSF biomarker accuracy in prediction of conversion to different dementias in a large multicentre MCI cohort.

Background/aimsIn this multicentre study in clinical settings, we assessed the accuracy of optimized procedures for FDG-PET brain metabolism and CSF classifications in predicting or excluding the conversion to Alzheimer's disease (AD) dementia and non-AD dementias.MethodsWe included 80 MCI subjects with neurological and neuropsychological assessments, FDG-PET scan and CSF measures at entry, all with clinical follow-up. FDG-PET data were analysed with a validated voxel-based SPM method. Resulting single-subject SPM maps were classified by five imaging experts according to the disease-specific patterns, as “typical-AD”, “atypical-AD” (i.e. posterior cortical atrophy, asymmetric logopenic AD variant, frontal-AD variant), “non-AD” (i.e. behavioural variant FTD, corticobasal degeneration, semantic variant FTD; dementia with Lewy bodies) or “negative” patterns. To perform the statistical analyses, the individual patterns were grouped either as “AD dementia vs. non-AD dementia (all diseases)” or as “FTD vs. non-FTD (all diseases)”. Aβ42, total and phosphorylated Tau CSF-levels were classified dichotomously, and using the Erlangen Score algorithm. Multivariate logistic models tested the prognostic accuracy of FDG-PET-SPM and CSF dichotomous classifications. Accuracy of Erlangen score and Erlangen Score aided by FDG-PET SPM classification was evaluated.ResultsThe multivariate logistic model identified FDG-PET “AD” SPM classification (Expβ = 19.35, 95% C.I. 4.8–77.8, p < 0.001) and CSF Aβ42 (Expβ = 6.5, 95% C.I. 1.64–25.43, p < 0.05) as the best predictors of conversion from MCI to AD dementia. The “FTD” SPM pattern significantly predicted conversion to FTD dementias at follow-up (Expβ = 14, 95% C.I. 3.1–63, p < 0.001). Overall, FDG-PET-SPM classification was the most accurate biomarker, able to correctly differentiate either the MCI subjects who converted to AD or FTD dementias, and those who remained stable or reverted to normal cognition (Expβ = 17.9, 95% C.I. 4.55–70.46, p < 0.001).ConclusionsOur results support the relevant role of FDG-PET-SPM classification in predicting progression to different dementia conditions in prodromal MCI phase, and in the exclusion of progression, outperforming CSF biomarkers.