Neurofilaments and progranulin are related to atrophy in frontotemporal lobar degeneration - A transdiagnostic study cross-validating atrophy and fluid biomarkers.

INTRODUCTION: Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging. METHODS: Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry. RESULTS: FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects. DISCUSSION: Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy. HIGHLIGHTS: Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy.

Structural correlates of language processing in primary progressive aphasia.

Understanding the relationships between brain structure and language behaviour in primary progressive aphasia provides crucial information about these diseases' pathomechanisms. However, previous investigations have been limited from providing a statistically reliable view of broad language abilities by sample size, variant focus and task focus. In this study, the authors aimed to determine the relationship between brain structure and language behaviour in primary progressive aphasia, to determine the degree to which task-associated regions were atrophied across disease variants and to determine the degree to which task-related atrophy overlaps across disease variants. Participants were 118 primary progressive aphasia patients and 61 healthy, age-matched controls tested from 2011 to 2018 in the German Consortium for Frontotemporal Lobar Degeneration cohort. Diagnosis of primary progressive aphasia required progressive deterioration of mainly speech and language for ≥ 2 years, and variant was diagnosed by the criteria of Gorno-Tempini et al. (Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006-1014). Twenty-one participants not fulfilling a specific subtype were classified as mixed-variant and excluded. Language tasks of interest included the Boston naming test, a German adaptation of the Repeat and Point task, phonemic and category fluency tasks and the reading/writing subtest of the Aachen Aphasia Test. Brain structure was measured by cortical thickness. We observed networks of language task-associated temporal, frontal and parietal cortex. Overlapping task-associated atrophy was observed in the left lateral, ventral and medial temporal lobes, middle and superior frontal gyri, supramarginal gyrus and insula. Some regions, primarily in the perisylvian region, were associated with language behaviour despite showing no significant atrophy. The results crucially extend less powerful studies associating brain and language measures in primary progressive aphasia. Cross-variant atrophy in task-associated regions suggests partially shared underlying deficits, whereas unique atrophy reinforces variant-specific deficits. Language task-related regions that are not obviously atrophied suggest regions of future network disruption and encourage understanding of task deficits beyond clearly atrophied cortex. These results may pave the way for new treatment approaches.

The Behavioural Dysfunction Questionnaire discriminates behavioural variant frontotemporal dementia from Alzheimer's disease dementia and major depressive disorder.

BACKGROUND AND OBJECTIVES: Early-stage behavioural variant frontotemporal dementia (bvFTD) is often misdiagnosed, highlighting the need for new diagnostic instruments. Based on the revised diagnostic criteria for bvFTD, we developed the Behavioural Dysfunction Questionnaire (BDQ). In this explorative study, we aimed to determine the best scoring and analytical method for the BDQ to discriminate between bvFTD and non-bvFTD patients. MATERIALS AND METHODS: 34 patients with early-stage bvFTD, 56 with early-stage Alzheimer's disease dementia (ADD) and 41 with major depressive disorder (MDD) were recruited. We calculated BDQ-items with or without inclusion of a time criterion: (a) without time criterion, (b) with 10 years' time criterion (symptom presence less than 10 years), and (c) with 3 years' time criterion (symptom presentation within the first 3 years). Using these three differently calculated items, we generated six variables, i.e. 3*2 [BDQ-Global Score (BDQ-GS; domains average score); BDQ-Global Domain Score (BDQ-GDS; domains categorical score)]. Then, we performed univariate and bivariate (BDQ-GS and BDQ-GDS combined) ROC analyses. RESULTS: Models including BDQ-GS, BDQ-GDS or both variables combined discriminated similarly between groups. In contrast, models without time criterion or with 10 years' time criterion discriminated better than models including variables with 3 years' time criterion. These models discriminated highly (AUC = 85.98-87.78) between bvFTD and MDD and bvFTD and ADD, respectively. CONCLUSION: BDQ-scores without any time criterion discriminated highly between early-stage bvFTD and non-bvFTD groups, which could improve the early diagnosis of bvFTD. With its standardised procedure, the BDQ is also appropriate for repeated assessments.

Multiclass prediction of different dementia syndromes based on multi-centric volumetric MRI imaging.

INTRODUCTION: Dementia syndromes can be difficult to diagnose. We aimed at building a classifier for multiple dementia syndromes using magnetic resonance imaging (MRI). METHODS: Atlas-based volumetry was performed on T1-weighted MRI data of 426 patients and 51 controls from the multi-centric German Research Consortium of Frontotemporal Lobar Degeneration including patients with behavioral variant frontotemporal dementia, Alzheimer's disease, the three subtypes of primary progressive aphasia, i.e., semantic, logopenic and nonfluent-agrammatic variant, and the atypical parkinsonian syndromes progressive supranuclear palsy and corticobasal syndrome. Support vector machine classification was used to classify each patient group against controls (binary classification) and all seven diagnostic groups against each other in a multi-syndrome classifier (multiclass classification). RESULTS: The binary classification models reached high prediction accuracies between 71 and 95% with a chance level of 50%. Feature importance reflected disease-specific atrophy patterns. The multi-syndrome model reached accuracies of more than three times higher than chance level but was far from 100%. Multi-syndrome model performance was not homogenous across dementia syndromes, with better performance in syndromes characterized by regionally specific atrophy patterns. Whereas diseases generally could be classified vs controls more correctly with increasing severity and duration, differentiation between diseases was optimal in disease-specific windows of severity and duration. DISCUSSION: Results suggest that automated methods applied to MR imaging data can support physicians in diagnosis of dementia syndromes. It is particularly relevant for orphan diseases beside frequent syndromes such as Alzheimer's disease.

Incidence of Syndromes Associated With Frontotemporal Lobar Degeneration in 9 European Countries.

Importance: Diagnostic incidence data for syndromes associated with frontotemporal lobar degeneration (FTLD) in multinational studies are urgent in light of upcoming therapeutic approaches. Objective: To assess the incidence of FTLD across Europe. Design, Setting, and Participants: The Frontotemporal Dementia Incidence European Research Study (FRONTIERS) was a retrospective cohort study conducted from June 1, 2018, to May 31, 2019, using a population-based registry from 13 tertiary FTLD research clinics from the UK, the Netherlands, Finland, Sweden, Spain, Bulgaria, Serbia, Germany, and Italy and including all new FTLD-associated cases during the study period, with a combined catchment population of 11 023 643 person-years. Included patients fulfilled criteria for the behavioral variant of frontotemporal dementia (BVFTD), the nonfluent variant or semantic variant of primary progressive aphasia (PPA), unspecified PPA, progressive supranuclear palsy, corticobasal syndrome, or frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Data were analyzed from July 19 to December 7, 2021. Main Outcomes and Measures: Random-intercept Poisson models were used to obtain estimates of the European FTLD incidence rate accounting for geographic heterogeneity. Results: Based on 267 identified cases (mean [SD] patient age, 66.70 [9.02] years; 156 males [58.43%]), the estimated annual incidence rate for FTLD in Europe was 2.36 cases per 100 000 person-years (95% CI, 1.59-3.51 cases per 100 000 person-years). There was a progressive increase in FTLD incidence across age, reaching its peak at the age of 71 years, with 13.09 cases per 100 000 person-years (95% CI, 8.46-18.93 cases per 100 000 person-years) among men and 7.88 cases per 100 000 person-years (95% CI, 5.39-11.60 cases per 100 000 person-years) among women. Overall, the incidence was higher among men (2.84 cases per 100 000 person-years; 95% CI, 1.88-4.27 cases per 100 000 person-years) than among women (1.91 cases per 100 000 person-years; 95% CI, 1.26-2.91 cases per 100 000 person-years). BVFTD was the most common phenotype (107 cases [40.07%]), followed by PPA (76 [28.46%]) and extrapyramidal phenotypes (69 [25.84%]). FTD-ALS was the rarest phenotype (15 cases [5.62%]). A total of 95 patients with FTLD (35.58%) had a family history of dementia. The estimated number of new FTLD cases per year in Europe was 12 057. Conclusions and Relevance: The findings suggest that FTLD-associated syndromes are more common than previously recognized, and diagnosis should be considered at any age. Improved knowledge of FTLD incidence may contribute to appropriate health and social care planning and in the design of future clinical trials.

Relationship of serum beta-synuclein with blood biomarkers and brain atrophy.

BACKGROUND: Recent data support beta-synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD). METHODS: We provide a detailed comparison of serum beta-synuclein immunoprecipitation - mass spectrometry (IP-MS) with the established blood markers phosphorylated tau 181 (p-tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores. RESULTS: Serum beta-synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta-synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p-tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy. DISCUSSION: Serum beta-synuclein changes differ from those of NfL and p-tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta-synuclein can complement the existing panel of blood markers, thereby providing information on synaptic alterations. HIGHLIGHTS: Blood beta-synuclein is increased in Alzheimer's disease (AD) but not in frontotemporal lobar degeneration (FTLD) syndromes. Blood beta-synuclein correlates with temporal brain atrophy in AD. Blood beta-synuclein correlates with cognitive impairment in AD. The pattern of blood beta-synuclein changes in the investigated diseases is different to phosphorylated tau 181 (p-tau181) and neurofilament light (NfL).

Visinin-like protein 1 levels in blood and CSF as emerging markers for Alzheimer's and other neurodegenerative diseases.

BACKGROUND: Visinin-like protein 1 (VILIP-1) belongs to the group of emerging biomarkers with the potential to support the early diagnosis of Alzheimer's disease (AD). However, studies investigating the differential diagnostic potential in cerebrospinal fluid (CSF) are rare and are not available for blood. METHODS: We set up a novel, sensitive single molecule array (Simoa) assay for the detection of VILIP-1 in CSF and serum. In total, paired CSF and serum samples from 234 patients were investigated: 73 AD, 18 behavioral variant frontotemporal dementia (bvFTD), 26 parkinsonian syndromes, 20 amyotrophic lateral sclerosis (ALS), 22 Creutzfeldt-Jakob disease (CJD), and 75 non-neurodegenerative control (Con) patients. The differential diagnostic potential of CSF and serum VILIP-1 was assessed using the receiver operating characteristic curve analysis and findings were compared to core AD biomarkers. RESULTS: CSF and serum VILIP-1 levels correlated weakly (r=0.32 (CI: 0.20-0.43), p<0.0001). VILIP-1 concentrations in CSF and serum were elevated in AD compared to Con (p<0.0001 and p<0.01) and CJD (p<0.0001 for CSF and serum), and an increase in CSF was observed already in early AD stages (p<0.0001). In the discrimination of AD versus Con, we could demonstrate a strong diagnostic potential for CSF VILIP-1 alone (area under the curve (AUC): 0.87), CSF VILIP-1/CSF Abeta 1-42 (AUC: 0.98), and serum VILIP-1/CSF Abeta 1-42 ratio (AUC: 0.89). CONCLUSIONS: We here report on the successful establishment of a novel Simoa assay for VILIP-1 and illustrate the potential of CSF and serum VILIP-1 in the differential diagnosis of AD with highest levels in CJD.

Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning: Dementia Praecox Revisited.

Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. Objective: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). Design, Setting, and Participants: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022. Main Outcomes and Measures: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery. Results: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2 = 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2 = 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery. Conclusions and Relevance: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.

CSF levels of SNAP-25 are increased early in Creutzfeldt-Jakob and Alzheimer's disease.

BACKGROUND: Synaptosomal-associated protein 25 (SNAP-25) in cerebrospinal fluid (CSF) is an emerging synaptic biomarker for the early diagnosis of Alzheimer's disease (AD). However, comprehensive studies investigating the marker in Creutzfeldt-Jakob disease (CJD) and in the differential diagnosis of neurodegenerative diseases are still lacking. METHODS: We developed a novel, sensitive ELISA for the measurement of SNAP-25 in CSF. In total, we analysed 316 patients from 6 diagnostic groups comprising patients with AD (n=96), CJD (n=55), Parkinson's disease spectrum (n=41), frontotemporal lobar degeneration (n=25) and amyotrophic lateral sclerosis (n=24) and non-neurodegenerative control patients (n=75). Using receiver operating characteristic curve analysis, we analysed the differential diagnostic potential and compared the results with core AD biomarkers. RESULTS: SNAP-25 CSF concentrations were elevated in AD and CJD (p<0.0001) but not in the other neurodegenerative diseases. Increased levels were observed already at early AD and CJD stages (p<0.0001). In CJD, SNAP-25 levels correlated negatively with survival time (r=-0.33 (95% CI -0.57 to -0.04, p=0.02). For the discrimination of AD from all other diseases except CJD, we observed a good diagnostic performance for CSF SNAP-25 (area under the curve (AUC) 0.85) which was further improved by applying the ratio with CSF amyloid-ß 1-42 (AUC 0.95). For CJD, we could demonstrate a strong differential diagnostic potential against all other groups including AD (AUC 0.97). CONCLUSION: Using the novel established CSF SNAP-25 ELISA, we here demonstrate the applicability of SNAP-25 as an early synaptic biomarker for both AD and CJD with a possible prognostic value in patients with CJD.

Comparative analysis of machine learning algorithms for multi-syndrome classification of neurodegenerative syndromes.

IMPORTANCE: The entry of artificial intelligence into medicine is pending. Several methods have been used for the predictions of structured neuroimaging data, yet nobody compared them in this context. OBJECTIVE: Multi-class prediction is key for building computational aid systems for differential diagnosis. We compared support vector machine, random forest, gradient boosting, and deep feed-forward neural networks for the classification of different neurodegenerative syndromes based on structural magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS: Atlas-based volumetry was performed on multi-centric T1-weighted MRI data from 940 subjects, i.e., 124 healthy controls and 816 patients with ten different neurodegenerative diseases, leading to a multi-diagnostic multi-class classification task with eleven different classes. INTERVENTIONS: N.A. MAIN OUTCOMES AND MEASURES: Cohen's kappa, accuracy, and F1-score to assess model performance. RESULTS: Overall, the neural network produced both the best performance measures and the most robust results. The smaller classes however were better classified by either the ensemble learning methods or the support vector machine, while performance measures for small classes were comparatively low, as expected. Diseases with regionally specific and pronounced atrophy patterns were generally better classified than diseases with widespread and rather weak atrophy. CONCLUSIONS AND RELEVANCE: Our study furthermore underlines the necessity of larger data sets but also calls for a careful consideration of different machine learning methods that can handle the type of data and the classification task best.

Serum GFAP differentiates Alzheimer's disease from frontotemporal dementia and predicts MCI-to-dementia conversion.

OBJECTIVE: Reactive astrogliosis is a hallmark of Alzheimer's disease (AD) and frontotemporal dementia (FTD) but differences between the diseases and time course are unclear. Here, we used serum levels of the astroglial marker glial fibrillary acidic protein (GFAP) to investigate differences in patients with AD dementia, mild cognitive impairment (MCI)-AD and behavioural variant FTD (bvFTD). METHODS: This multicentre study included serum samples from patients diagnosed with AD dementia (n=230), MCI-AD (n=111), bvFTD (n=140) and controls (n=129). A subgroup of patients with MCI-AD (n=32) was longitudinally followed-up for 3.9±2.6 years after sample collection. Serum levels of GFAP, neurofilament light chain (NfL) and pTau181 were measured by Simoa (Quanterix) and Ella (ProteinSimple). RESULTS: In total, samples from 610 individuals from four clinical centres were investigated in this study. Serum GFAP levels in AD dementia were increased (median 375 pg/mL, IQR 276-505 pg/mL) compared with controls (167 pg/mL, IQR 108-234 pg/mL) and bvFTD (190 pg/mL, IQR 134-298 pg/mL, p<0.001). GFAP was already increased in the early disease phase (MCI-AD, 300 pg/mL, IQR 232-433 pg/mL, p<0.001) and was higher in patients with MCI-AD who developed dementia during follow-up (360 pg/mL, IQR 253-414 pg/mL vs 215 pg/mL, IQR 111-266 pg/mL, p<0.01, area under the curve (AUC)=0.77). Diagnostic performance of serum GFAP for AD (AUC=0.84, sensitivity 98%, specificity 60%, likelihood ratio 2.5) was comparable to serum pTau181 (AUC=0.89, sensitivity 80%, specificity 87%, likelihood ratio 6.0) but superior to serum NfL (AUC=0.71, sensitivity 92%, specificity 49%, likelihood ratio 1.8). CONCLUSIONS: Our data indicate a different type of reactive astrogliosis in AD and bvFTD and support serum GFAP as biomarker for differential diagnosis and prediction of MCI-to-dementia conversion.

Quantitative analysis of regional distribution of tau pathology with 11C-PBB3-PET in a clinical setting.

PURPOSE: The recent developments of tau-positron emission tomography (tau-PET) enable in vivo assessment of neuropathological tau aggregates. Among the tau-specific tracers, the application of 11C-pyridinyl-butadienyl-benzothiazole 3 (11C-PBB3) in PET shows high sensitivity to Alzheimer disease (AD)-related tau deposition. The current study investigates the regional tau load in patients within the AD continuum, biomarker-negative individuals (BN) and patients with suspected non-AD pathophysiology (SNAP) using 11C-PBB3-PET. MATERIALS AND METHODS: A total of 23 memory clinic outpatients with recent decline of episodic memory were examined using 11C-PBB3-PET. Pittsburg compound B (11C-PIB) PET was available for 17, 18F-flurodeoxyglucose (18F-FDG) PET for 16, and cerebrospinal fluid (CSF) protein levels for 11 patients. CSF biomarkers were considered abnormal based on Aß42 (< 600 ng/L) and t-tau (> 450 ng/L). The PET biomarkers were classified as positive or negative using statistical parametric mapping (SPM) analysis and visual assessment. Using the amyloid/tau/neurodegeneration (A/T/N) scheme, patients were grouped as within the AD continuum, SNAP, and BN based on amyloid and neurodegeneration status. The 11C-PBB3 load detected by PET was compared among the groups using both atlas-based and voxel-wise analyses. RESULTS: Seven patients were identified as within the AD continuum, 10 SNAP and 6 BN. In voxel-wise analysis, significantly higher 11C-PBB3 binding was observed in the AD continuum group compared to the BN patients in the cingulate gyrus, tempo-parieto-occipital junction and frontal lobe. Compared to the SNAP group, patients within the AD continuum had a considerably increased 11C-PBB3 uptake in the posterior cingulate cortex. There was no significant difference between SNAP and BN groups. The atlas-based analysis supported the outcome of the voxel-wise quantification analysis. CONCLUSION: Our results suggest that 11C-PBB3-PET can effectively analyze regional tau load and has the potential to differentiate patients in the AD continuum group from the BN and SNAP group.

Serum Beta-Synuclein Is Higher in Down Syndrome and Precedes Rise of pTau181.

This exploratory case-control study investigates the synaptic marker beta-synuclein in serum and plasma pTau181 in adults with Down syndrome (DS) with (sDS, n = 14) and without (aDS, n = 47) clinical symptoms of Alzheimer disease (AD) as well as euploid controls (n = 23). Beta-synuclein was higher in aDS and more pronounced in sDS (p < 0.0001), whereas pTau181 was only higher in sDS (p < 0.0001). Both markers showed good discriminatory power (area under the curve > 0.90) to distinguish symptomatic from asymptomatic AD. The data indicate that synaptic alterations belong to the earliest AD-associated events in DS and highlight the value of serum beta-synuclein as a potential early marker of AD. ANN NEUROL 2022;92:6-10.

Utility of the Repeat and Point Test for Subtyping Patients With Primary Progressive Aphasia.

BACKGROUND: Primary progressive aphasia (PPA) may present with three distinct clinical sybtypes: semantic variant PPA (svPPA), nonfluent/agrammatic variant PPA (nfvPPA), and logopenic variant PPA (lvPPA). OBJECTIVE: The aim was to examine the utility of the German version of the Repeat and Point (R&P) Test for subtyping patients with PPA. METHOD: During the R&P Test, the examiner reads out aloud a noun and the participants are asked to repeat the word and subsequently point to the corresponding picture. Data from 204 patients (68 svPPA, 85 nfvPPA, and 51 lvPPA) and 33 healthy controls were analyzed. RESULTS: Controls completed both tasks with >90% accuracy. Patients with svPPA had high scores in repetition (mean=9.2±1.32) but low scores in pointing (mean=6±2.52). In contrast, patients with nfvPPA and lvPPA performed comparably in both tasks with lower scores in repetition (mean=7.4±2.7 for nfvPPA and 8.2±2.34 for lvPPA) but higher scores in pointing (mean=8.9±1.41 for nfvPPA and 8.6±1.62 for lvPPA). The R&P Test had high accuracy discriminating svPPA from nfvPPA (83% accuracy) and lvPPA (79% accuracy). However, there was low accuracy discriminating nfvPPA from lvPPA (<60%). CONCLUSION: The R&P Test helps to differentiate svPPA from 2 nonsemantic variants (nfvPPA and lvPPA). However, additional tests are required for the differentiation of nfvPPA and lvPPA.

Differences in Sex Distribution Between Genetic and Sporadic Frontotemporal Dementia.

BACKGROUND: Reported sex distributions differ between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that has resulted in varying demographics. OBJECTIVE: Our aim was to determine the sex distribution of sporadic and genetic FTD cases and its subtypes in an international cohort. METHODS: We included 910 patients with behavioral variant frontotemporal dementia (bvFTD; n = 654), non-fluent variant primary progressive aphasia (nfvPPA; n = 99), semantic variant primary progressive aphasia (svPPA; n = 117), and right temporal variant frontotemporal dementia (rtvFTD; n = 40). We compared sex distribution between genetic and sporadic FTD using χ2-tests. RESULTS: The genetic FTD group consisted of 51.2% males, which did not differ from sporadic FTD (57.8% male, p = 0.08). In the sporadic bvFTD subgroup, males were predominant in contrast to genetic bvFTD (61.6% versus 52.9% males, p = 0.04). In the other clinical FTD subgroups, genetic cases were underrepresented and within the sporadic cases the sex distribution was somewhat equal. CONCLUSION: The higher male prevalence in sporadic bvFTD may provide important clues for its differential pathogenesis and warrants further research.

[Amyotrophic lateral sclerosis and frontotemporal dementia-On the way to common gene-specific treatment approaches]. / Amyotrophe Lateralsklerose und frontotemporale Demenz ­ auf dem Weg zu gemeinsamen genspezifischen Therapieansätzen.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share common neuropathological features and in the case of a gene mutation, also a genetic cause. To date five ALS-FTD genes are described in the literature in addition to other rare variants. OBJECTIVE: The current state of research on treatment options for ALS and FTD is presented and an outlook on possible gene-specific approaches for ALS-FTD is provided. MATERIAL AND METHODS: Analysis of the progression of ALS and FTD research by considering the increasing state of knowledge on the underlying pathomechanisms of the diseases. RESULTS: In addition to anti-inflammatory approaches and stabilization of protein folding, promising gene-specific treatment approaches are currently being developed, which target common causes of ALS and FTD and therefore have an effect on both diseases. CONCLUSION: So far there are no causal treatment options for ALS and FTD. The increasing importance of genetic causes directs the focus to the development of gene-specific treatment.

Clinico-genetic findings in 509 frontotemporal dementia patients.

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families.

Motor speech disorders in the nonfluent, semantic and logopenic variants of primary progressive aphasia.

OBJECTIVE: Motor speech disorders (MSDs) are characteristic for nonfluent primary progressive aphasia (nfvPPA). In primary progressive aphasia (PPA) of the semantic (svPPA) and of the logopenic type (lvPPA), speech motor function is considered typically intact. However, knowledge on the prevalence of MSDs in svPPA and lvPPA is mainly based on studies with a priori knowledge of PPA syndrome diagnosis. This fully blinded retrospective study aims to provide data on the prevalence of all types of MSDs in a large sample of German-speaking patients with different subtypes of PPA. METHOD: Two raters, blinded for PPA subtype, independently evaluated connected speech samples for MSD syndrome and severity from 161 patients diagnosed with nfvPPA, svPPA or lvPPA in the database of the German Consortium of Frontotemporal Lobar Degeneration (FTLDc). In case of disagreement, a third experienced rater re-evaluated the speech samples, followed by a consensus procedure. Consensus was reached for 160 patients (74 nfvPPA, 49 svPPA, 37 lvPPA). MAIN RESULTS: Across all PPA syndromes, 43.8% of the patients showed MSDs. Patients with nfvPPA demonstrated the highest proportion of MSDs (62.2%), but MSDs were also identified in svPPA (26.5%) and lvPPA (29.7%), respectively. Overall, dysarthria was the most common class of MSDs, followed by apraxia of speech. In addition, we identified speech abnormalities presenting as "syllabic speech", "dysfluent speech", and "adynamic speech". DISCUSSION: Our study confirmed MSDs as frequently occurring in PPA. The study also confirmed MSDs to be most common in patients with nfvPPA. However, MSDs were also found in substantial proportions of patients with svPPA and lvPPA. Furthermore, our study identified speech motor deficits that have not received attention in previous studies on PPA. The results are discussed against the background of the existing literature on MSDs in PPA, including theoretical considerations of the neuroanatomical conditions described for each of the different subtypes of PPA.

Quantifying progression in primary progressive aphasia with structural neuroimaging.

INTRODUCTION: The term primary progressive aphasia (PPA) sums up the non-fluent (nfv), the semantic (sv), and the logopenic (lv) variant. Up to now, there is only limited data available concerning magnetic resonance imaging volumetry to monitor disease progression. METHODS: Structural brain imaging and an extensive assessment were applied at baseline and up to 4-year(s) follow-up in 269 participants. With automated atlas-based volumetry 56 brain regions were assessed. Atrophy progression served to calculate sample sizes for therapeutic trials. RESULTS: At baseline highest atrophy appeared in parts of the left frontal lobe for nfvPPA (-17%) and of the left temporal lobe for svPPA (-34%) and lvPPA (-24%). Severest progression within 1-year follow-up occurred in the basal ganglia in nfvPPA (-7%), in the hippocampus/amygdala in svPPA (-9%), and in (medial) temporal regions in lvPPA (-6%). CONCLUSION: PPA presents as a left-dominant, mostly gray matter sensitive disease with considerable atrophy at baseline that proceeds variant-specific.

Comparison of MRI-based and PET-based image pre-processing for quantification of 11C-PBB3 uptake in human brain.

PURPOSE: Quantification of tau load using 11C-PBB3-PET has the potential to improve diagnosis of neurodegenerative diseases. Although MRI-based pre-processing is used as a reference method, not all patients have MRI. The feasibility of a PET-based pre-processing for the quantification of 11C-PBB3 tracer was evaluated and compared with the MRI-based method. MATERIALS AND METHODS: Fourteen patients with decreased recent memory were examined with 11C-PBB3-PET and MRI. The PET scans were visually assessed and rated as either PBB3(+) or PBB3(-). The image processing based on the PET-based method was validated against the MRI-based approach. The regional uptakes were quantified using the Mesial-temporal/Temporoparietal/Rest of neocortex (MeTeR) regions. SUVR values were calculated by normalizing to the cerebellar reference region to compare both methods within the patient groups. RESULTS: Significant correlations were observed between the SUVRs of the MRI-based and the PET-based methods in the MeTeR regions (rMe=0.91; rTe=0.98; rR=0.96; p<0.0001). However, the Bland-Altman plot showed a significant bias between both methods in the subcortical Me region (bias: -0.041; 95% CI: -0.061 to -0.024; p=0.003). As in the MRI-based method, the 11C-PBB3 uptake obtained with the PET-based method was higher for the PBB3(+) group in each of the cortical regions and for the whole brain than for the PBB3(-) group (PET-basedGlobal: 1.11 vs. 0.96; Cliff's Delta (d)=0.68; p=0.04; MRI-basedGlobal: 1.11 vs. 0.97; d=0.70; p=0.03). To differentiate between positive and negative scans, Youden's index estimated the best cut-off of 0.99 from the ROC curve with good accuracy (AUC: 0.88±0.10; 95% CI: 0.67-1.00) and the same sensitivity (83%) and specificity (88%) for both methods. CONCLUSION: The PET-based pre-processing method developed to quantify the tau burden with 11C-PBB3 provided comparable SUVR values and effect sizes as the MRI-based reference method. Furthermore, both methods have a comparable discrimination accuracy between PBB3(+) and PBB3(-) groups as assessed by visual rating. Therefore, the presented PET-based method can be used for clinical diagnosis if no MRI image is available.