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Background Varoglutamstat (formerly PQ912) is a small molecule that inhibits the activity of the glutaminyl cyclase to reduce the level of pyroglutamate-A-beta (pGluAB42). Recent studies confirm that pGluAB42 is a particular amyloid form that is highly synaptotoxic and plays a significant role in the development of AD. Methods This paper describes the design and methodology behind the phase 2b VIVIAD-trial in AD. The aim of this study is to evaluate varoglutamstat in a state-of-the-art designed, placebo-controlled, double-blind, randomized clinical trial for safety and tolerability, efficacy on cognition, and effects on brain activity and AD biomarkers. In addition to its main purpose, the trial will explore potential associations between novel and established biomarkers and their individual and composite relation to disease characteristics. Results To be expected early 2023 Conclusion This state of the art phase 2b study will yield important results for the field with respect to trial methodology and for the treatment of AD with a small molecule directed against pyroglutamate-A-beta. Trial registration ClinicalTrials.gov Identifier: NCT04498650

Background: Behavioral variant frontotemporal dementia (bvFTD) is generally considered a young-onset dementia, although age at onset is highly variable. While several studies indicate clinical differences regarding age at onset, no biomarker validated cohort studies with updated clinical criteria have been performed. Objective: We aimed to examine behavior, cognition, and mortality over the full age spectrum in a cohort of bvFTD patients with neuroimaging, genetic, or histopathological confirmation and exclusion of positive Alzheimer’s disease biomarkers or severe cerebrovascular damage. Methods: In total, 315 patients with a clinical diagnosis of probable or definite bvFTD were included from the Amsterdam Dementia Cohort and grouped into quartiles by age-at-diagnosis. Neuropsychiatric symptoms and cognitive functioning were assessed with the neuropsychiatric inventory, the geriatric depression scale and a neuropsychological test battery. Data on mortality was obtained from the Dutch municipal register. Associations between age-at-diagnosis and clinical features and mortality risk were examined. Results: Age-at-diagnosis ranged from 26 to 85 years and established quartiles with mean ages of 52±6, 61±2, 66±2, and 74±3 years. In the total sample, 44.4%exceeded an age of 65 years at time of diagnosis. Earlier age-at-diagnosis was associated with more severe behavioral symptoms, while later age-at-diagnosis was associated with more severe memory impairment. Unexpectedly, mortality risk was not associated with age-at-diagnosis. Conclusion: In bvFTD, symptom profile is associated with age-at-diagnosis. This should be taken into account with regard to diagnostics, patient management, and trial design. Additionally, based on our sample, the prevalence of late-onset bvFTD is higher than generally thought.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5–6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

Background Neurofilament light in serum (sNfL) is a biomarker for axonal damage with elevated levels in many neurological disorders, including neurodegenerative dementias. Since within-group variation of sNfL is large and concentrations increase with aging, sNfL’s clinical use in memory clinic practice remains to be established. The objective of the current study was to evaluate the clinical use of serum neurofilament light (sNfL), a cross-disease biomarker for axonal damage, in a tertiary memory clinic cohort. Methods Six neurologists completed questionnaires regarding the usefulness of sNfL (n = 5–42 questionnaires/neurologist). Patients that visited the Alzheimer Center Amsterdam for the first time between May and October 2019 (n = 109) were prospectively included in this single-center implementation study. SNfL levels were analyzed on Simoa and reported together with normal values in relation to age, as part of routine diagnostic work-up and in addition to cerebrospinal fluid (CSF) biomarker analysis. Results SNfL was perceived as useful in 53% (n = 58) of the cases. SNfL was more often perceived as useful in patients p = 0.05) and males (41/65, 63%, p < 0.01). Availability of CSF biomarker results at time of result discussion had no influence. We observed non-significant trends for increased perceived usefulness of sNfL for patients with the diagnosis subjective cognitive decline (64%), psychiatric disorder (71%), or uncertain diagnosis (67%). SNfL was mostly helpful to neurologists in confirming or excluding neurodegeneration. Whether sNfL was regarded as useful strongly depended on which neurologist filled out the questionnaire (ranging from 0 to 73% of useful cases/neurologist). Discussion Regardless of the availability of CSF biomarker results, sNfL was perceived as a useful tool in more than half of the evaluated cases in a tertiary memory clinic practice. Based on our results, we recommend the analysis of the biomarker sNfL to confirm or exclude neurodegeneration in patients below 62 years old and in males.

Background Alzheimer’s disease (AD) is a devastating neurodegenerative disease leading to dementia. The field has made significant progress over the last 15 years. AD diagnosis has shifted from syndromal, based on signs and symptoms, to a biomarker construct based on the pathological hallmarks of the disease: amyloid β deposition, pathologic tau, and neurodegeneration. Numerous genetic risk factors for sporadic AD have been identified, providing further insight into the molecular underpinnings of the disease. For the last two decades, however, drug development for AD has been proven to be particularly challenging. Here, we provide a unique overview of the drug development landscape for AD. By comparing preclinical and clinical drug development pipelines, we aim to describe trends and differences regarding target classes and therapeutic modalities in preclinical and clinical development. Methods We analyzed proprietary and public databases and company websites for drugs in preclinical development for AD by the pharmaceutical industry and major clinical trial registries for drugs in clinical development for AD. Drugs were categorized by target class and treatment modality. Results We found a higher proportion of preclinical interventions targeting molecular pathways associated with sporadic AD genetic risk variants, compared to clinical stage interventions. These include apolipoprotein E (ApoE) and lipids, lysosomal/endosomal targets, and proteostasis. Further, we observed a trend suggesting that more traditional therapeutic modalities are developed for these novel targets, while more novel treatment modalities such as gene therapies and enzyme treatments are in development for more traditional targets such as amyloid β and tau. Interestingly, the percentage of amyloid β targeting therapies in preclinical development (19.2%) is even higher than the percentage in clinical development (10.7%), indicating that diversification away from interventions targeting amyloid-beta has not materialized. Inflammation is the second most popular target class in both preclinical and clinical development. Conclusions Our observations show that the AD drug development pipeline is diversifying in terms of targets and treatment modalities, while amyloid-targeting therapies remain a prominent avenue of development as well. To further advance AD drug development, novel companion diagnostics are needed that are directed at disease mechanisms related to genetic risk factors of AD, both for patient stratification and assessment of therapeutic efficacy in clinical trials.

A clinical syndrome with neuropsychiatric features of bvFTD without neuroimaging abnormalities and a lack of decline is a phenocopy of bvFTD (phFTD). Growing evidence suggests that psychological, psychiatric and environmental factors underlie phFTD. We describe a patient diagnosed with bvFTD prior to the revision of the diagnostic guidelines of FTD. Repeated neuroimaging was normal and there was no FTD pathology at autopsy, rejecting the diagnosis. We hypothesize on etiological factors that on hindsight might have played a role. This case report contributes to the understanding of phFTD and adds to the sparse literature of the postmortem assessment of phFTD.

ObjectiveTo examine the clinical value of neurofilament light chain (NfL) and the phospho-tau/total tau ratio (p/t-tau) across the entire frontotemporal dementia (FTD) spectrum in a large, well-defined cohort.MethodsCSF NfL and p/t-tau levels were studied in 361 patients with FTD: 179 behavioral variant FTD, 17 FTD with motor neuron disease (FTD-MND), 36 semantic variant primary progressive aphasia (PPA), 19 nonfluent variant PPA, 4 logopenic variant PPA (lvPPA), 42 corticobasal syndrome, and 64 progressive supranuclear palsy. Forty-five cognitively healthy controls were also included. Definite pathology was known in 68 patients (49 frontotemporal lobar degeneration [FTLD]-TDP, 18 FTLD-tau, 1 FTLD-FUS).ResultsNfL was higher in all diagnoses, except lvPPA (n = 4), than in controls, equally elevated in behavioral variant FTD, semantic variant PPA, nonfluent variant PPA, and corticobasal syndrome, and highest in FTD-MND. The p/t-tau was lower in all clinical groups, except lvPPA, than in controls and lowest in FTD-MND. NfL did not discriminate between TDP and tau pathology, while the p/t-tau ratio had a good specificity (76%) and moderate sensitivity (67%). Both high NfL and low p/t-tau were associated with poor survival (hazard ratio on tertiles 1.7 for NfL, 0.7 for p/t-tau).ConclusionNfL and p/t-tau similarly discriminated FTD from controls, but not between clinical subtypes, apart from FTD-MND. Both markers predicted survival and are promising monitoring biomarkers for clinical trials. Of note, p/t-tau, but not NfL, was specific to discriminate TDP from tau pathology in vivo.Classification of evidenceThis study provides Class III evidence that for patients with cognitive issues, CSF NfL and p/t-tau levels discriminate between those with and without FTD spectrum disorders.

Objective: Primary psychiatric disorders (PsD) can present with symptomatology identical to that of behavioral variant frontotemporal dementia (bvFTD). To date, clinical guidelines do not provide a solution for this diagnostic challenge. The aim of our study was to prospectively determine which demographic, clinical, neuropsychological, neuroimaging, and cerebrospinal fluid biomarkers are important in distinguishing PsD from bvFTD. Methods: Patients with late-onset behavioral disturbances (aged 45–75 years, 73% male) were included based on their scores on the Frontal Behavioral Inventory and the Stereotypy Rating Inventory and followed for 2 years from April 2011 to June 2015. Odds ratios (ORs) were calculated with backward stepwise logistic regression analyses to investigate the association between baseline clinical and demographic variables and the 2-year follow-up diagnosis of PsD (n = 46) (DSM-IV) versus probable/definite bvFTD (n = 27) (International Behavioral Variant FTD Criteria Consortium criteria). We separately measured the association between additional investigations and the 2-year followup diagnosis. Finally, we combined the selected variables to measure the predictive value of both clinical and additional investigations in a single model. Results: Male gender (OR = 5.9; 95% CI, 1.3–26.0), less stereotypy (OR = 0.08; 95% CI, 0.02–0.34), and more depressive symptoms (OR = 1.13; 95% CI, 1.04–1.24) explained 49% of the variance predicting PsD versus bvFTD (χ2 3 = 29.4, P< .001) and correctly classified 82.1% of the cases. Neuroimaging (OR = 0.02; 95% CI, 0.002–0.123) explained 55% of the variance (χ2 1 = 37.5, P< .001) and, in combination with clinical variables, 66.1% of the variance (χ2 3 = 44.06, P< .001). Conclusions: The present study demonstrated that PsD can be distinguished from probable/definite bvFTD with a thorough clinical evaluation by a psychiatrist and neurologist along with use of validated questionnaires for depression and stereotypy; these measures are even more effective in combination with neuroimaging.

Background: Dementia is generally characterized by cognitive impairment that can be accompanied by psychotic symptoms; for example, visual hallucinations are a core feature of dementia with Lewy bodies, and delusions are often seen in Alzheimer’s disease. However, for behavioral variant of frontotemporal dementia (bvFTD), studies on the broad spectrum of psychotic symptoms are still lacking. The aim of this study was to systematically and prospectively subtype the wide spectrum of psychotic symptoms in probable and definite bvFTD. Methods: In this study, a commonly used and validated clinical scale that quantifies the broad spectrum of psychotic symptoms (Positive and Negative Symptom Scale) was used in patients with probable and definite bvFTD (n=22) and with a primary psychiatric disorder (n=35) in a late-onset frontal lobe cohort. Median symptom duration was 2.8 years, and the patients were prospectively followed for 2 years. Results: In total, 22.7% of bvFTD patients suffered from delusions, hallucinatory behavior, and suspiciousness, although the majority of the patients exhibited negative psychotic symptoms such as social and emotional withdrawal and blunted affect (95.5%) and formal thought disorders (81.8%). “Difficulty in abstract thinking” and “stereotypical thinking” (formal thought disorders) differentiated bvFTD from psychiatric disorders. The combined predictors difficulty in abstract thinking, stereotypical thinking, “anxiety”, “guilt feelings,” and “tension” explained 75.4% of variance in the diagnosis of bvFTD versus psychiatric diagnoses (P

A late onset frontal lobe syndrome (LOF) refers to a clinical syndrome with apathy, disinhibition, or stereotypical behavior arising in middle or late adulthood. Diagnostics are challenging, and both clinicians and patients need reliable predictors of progression to improve clinical guidance. In this longitudinal multicenter and genetically screened prospective study, 137 LOF patients with frontal behavior (FBI score≥11) and/or stereotypical behavior (SRI≥10) were included. Progression was defined as institutionalization, death, or progression of frontal or temporal atrophy at magnetic resonance imaging (MRI) after two years of follow up. Absence of progression at MRI in addition to stable or improved Mini Mental State Examination and Frontal Assessment Battery scores after two years was indicative for non-progression. The presence of stereotypy and a neuropsychological profile with executive deficits at baseline were found to be predictive for progression, while a history and family history with psychiatric disorders were predictors for non-progression. The combination of these clinical markers had a predictive value of 80.4% (p < 0.05). In patients presenting with late onset behavioral symptoms, an appraisal of the rate of deterioration can be made by detailed mapping of clinical symptoms. Distinction of progressive discourses from non-progressive or treatable conditions is to be gained.

Patients with behavioral variant of frontotemporal dementia (bvFTD) initially may only show behavioral and/or cognitive symptoms that overlap with other neurological and psychiatric disorders. The diagnostic accuracy is dependent on progressive symptoms worsening and frontotemporal abnormalities on neuroimaging findings. Predictive biomarkers could facilitate the early detection of bvFTD. Objective: To determine the prognostic accuracy of clinical and structural MRI data using a support vector machine (SVM) classification to predict the 2-year clinical follow-up diagnosis in a group of patients presenting late-onset behavioral changes. Methods: Data from 73 patients were included and divided into probable/definite bvFTD (n=18), neurological (n=28), and psychiatric (n=27) groups based on 2-year follow-up diagnosis. Grey-matter volumes were extracted from baseline structural MRI scans. SVM classifiers were used to perform three binary classifications: bvFTD versus neurological and psychiatric, bvFTD versus neurological, and bvFTD versus psychiatric group(s), and one multi-class classification. Classification performance was determined for clinical and neuroimaging data separately and their combination using 5-fold cross-validation. Results: Accuracy of the binary classification tasks ranged from 72-82% (p

The authors apologize for misspelling the last name of the author Ratnavalli Ellajosyula. This has now been corrected.

Behavioural variant frontotemporal dementia (bvFTD) is characterized by behavioural and social cognitive disturbances, while various psychiatric and neurodegenerative disorders may have similar clinical symptoms. Since neurodegenerative disorders are eventually progressive, whereas primary psychiatric disorders are not, this study aimed to investigate whether the change in clinical symptoms over time differed between groups and which biomarkers predicted rate of decline. Disease trajectories (median follow-up = 3 years) of frontal and stereotyped behaviour, general and frontal cognitive functioning, and social cognition were examined in bvFTD (n = 34), other neurodegenerative (n = 28) and primary psychiatric disorders (n = 43), all presenting with late-onset frontal lobe syndrome (45-75 years), using linear mixed models. To gain more insight in underlying pathological processes driving disease progression, we studied the association of baseline cerebrospinal fluid (CSF) (neurofilament light (NfL) and YKL-40 levels, phosphotau181 to total tau ratio) and neuroimaging markers with disease trajectories. Frontal behavioural symptoms (e.g., disinhibition, apathy) worsened over time in bvFTD, whereas they improved in psychiatric disorders and remained stable in other neurodegenerative disorders. General and frontal cognitive decline was observed in bvFTD and other neurodegenerative disorders, but not in psychiatric disorders. None of the groups showed change in stereotypy and social cognition. For all diagnostic groups, higher CSF NfL levels were associated with faster frontal cognitive decline. A modest association was observed between caudate volume and stereotyped behaviour. Tracking frontal behavioural symptoms and cognition has potential to distinguish bvFTD from other disorders. CSF NfL levels seem to be associated with decline in frontal cognitive functioning.

The behavioral variant of Frontotemporal dementia (bvFTD) is an insidious neurodegenerative disease associated with progressive degeneration of the frontal lobes, anterior temporal lobes, or both [1]. Alterations in social cognition represent the core symptoms of bvFTD resulting in emotional disengagement and socially inappropriate responses or activities [2,3]. As is apparent in revised consortium criteria, additional neuropsychiatric symptoms including apathy and stereotypical and impulsive behavior are prominent in the clinical presentation [4]. Consequently, both neurodegenerative diseases and primary psychiatric disorders are crucial in the challenging differential diagnosis. The differentiation between bvFTD and Alzheimer’s disease (AD) has become easier by the use of biomarkers that are able to identify underlying AD pathology, such as the amyloid-β (Aβ) and tau [1,5]. However, to distinguish bvFTD from psychiatric disorders can still be difficult, particularly since biomarkers for bvFTD are less robust [6]. Previous studies indicated that as a result of symptomatic overlap between bvFTD and psychiatric disorders, bvFTD patients are clinically often mistaken for psychiatric patients and vice versa [7-10]. The current clinical criteria for bvFTD require that “if behavioral disturbance is better accounted for by a psychiatric diagnosis, a diagnosis of bvFTD has to be excluded” [4]. Despite clinical overlap, bvFTD patients do not often fulfill formal criteria for a psychiatric diagnosis, suggesting that it is valuable to apply formal criteria for psychiatric disorders [11]. Careful clinical phenotyping of overlapping symptoms can help to distinguish bvFTD from psychiatric disorders in clinical practice (Figure 1) [12,13]. Figure 1 Overlap and differentiation between bvFTD and psychiatric disorders in clinical practice. The value of different symptom rating scales and clinical tools has been proven useful in clinical practice in case of suspected bvFTD when a psychiatric disorder is also probable (Figure 2) [11,14,15]. Figure 2 Clinical hallmarks and supportive measuring instruments in the differential diagnosis bvFTD and psychiatric disorders. According to current criteria, the diagnostic certainty of bvFTD increases when Frontotemporal abnormalities are found on neuroimaging. In a large cohort of patients with late-onset behavioral changes, MRI had a sensitivity of 70% and a specificity of 93% for a bvFTD diagnosis [4]. The additional [18F]FDG-PET, when the MRI was inconclusive, had a sensitivity of 90% at the cost of a lower specificity (68%) [16]. [18F]FDG-PET is mainly useful when Frontotemporal hypo-metabolism is absent to exclude bvFTD diagnosis. The interpretation of neuroimaging results should especially be taken with caution in cases with a psychiatric differential diagnosis where [18F]FDG-PET is the only abnormal investigation and in cases with a genetic background where both MRI and [18F]FDG-PET can show a specific abnormalities [16-18]. Genetic screening especially for C9orf72 repeat expansion is emphasized [19,20]. particularly in cases with a remarkable (prolonged) disease course. In clinical practice, bvFTD has a broad differential diagnosis including both neurodegenerative diseases and primary psychiatric disorders. The current criteria for bvFTD have clearly improved diagnostics but differentiating bvFTD from psychiatric disorders remains difficult. The challenge for the next decade is finding specific biomarkers for bvFTD on the one hand, and optimizing the neuropsychiatric diagnosis of bvFTD on the other hand. To this end, patient care for suspected bvFTD patients would be largely improved in a setting where neurologists and psychiatrists work hand in hand, ideally applying a consensus set of clinical rating scales next to their clinical expertise.