Frontotemporal Dementia Syndromes Research Articles

Inappropriate trusting behaviour in dementia

BackgroundInappropriate trusting behaviour may have significant social, financial and other consequences for people living with dementia. However, its clinical associations and predictors have not been clarified. Here we addressed this issue in canonical syndromes of frontotemporal dementia (FTD) and Alzheimer’s disease (AD).MethodsIn 34 patients with AD and 73 with FTD (27 behavioural variant (bv)FTD, 22 semantic variant primary progressive aphasia (svPPA), 24 nonfluent/agrammatic variant (nfv)PPA) we recorded inappropriate trusting and other abnormal socio-emotional behaviours using a semi-structured caregiver survey. Patients were comprehensively characterised using a general cognitive assessment and the Revised Self-Monitoring Scale (RSMS; an informant index of socioemotional awareness).ResultsInappropriate trusting was more frequent in svPPA (55%) and bvFTD (44%) than nfvPPA (17%) or AD (24%). After adjusting for age, sex, education and Mini-Mental State Examination (MMSE) score, inappropriate trusting was significantly more likely in svPPA (odds ratio 3.61; 95% confidence interval 1.41–8.75) and bvFTD (3.01, 1.23–6.65) than AD. Significant predictors of inappropriate trusting comprised apathy in svPPA, disinhibition and altered pain responsiveness in bvFTD, and lower MMSE and RSMS (self-presentation) scores in AD.ConclusionDementia syndromes vary in prevalence and predictors of abnormal trusting behaviour, with implications for clinical counselling and safeguarding.

Cerebrospinal fluid and blood neurofilament light chain levels in amyotrophic lateral sclerosis and frontotemporal degeneration: A meta-analysis.

Neurofilament light chain (NFL) has been shown to be increased in amyotrophic lateral sclerosis (ALS) and, to a lesser extent, in frontotemporal dementia (FTD). A meta-analysis of NFL in ALS and FTD was performed. Available studies comparing cerebrospinal fluid and blood NFL levels in ALS versus neurologically healthy controls (NHCs), other neurological diseases (ONDs) and ALS mimics, as well as in FTD and related entities (behavioural variant of FTD and frontotemporal lobar degeneration syndromes) versus NHCs, ONDs and other dementias were evaluated. In ALS, both cerebrospinal fluid and blood levels of NFL were higher compared to other categories. In FTD, behavioural variant of FTD and frontotemporal lobar degeneration syndromes, NFL levels were consistently higher compared to NHCs; however, several comparisons with ONDs and other dementias did not demonstrate significant differences. Amyotrophic lateral sclerosis is characterized by higher NFL levels compared to most other conditions. In contrast, NFL is not as good at discriminating FTD from other dementias.

Profiles of motivational impairment and their relationship to functional decline in frontotemporal dementia

Motivational disturbances are pervasive in frontotemporal dementia (FTD) and impact negatively on everyday functioning. Despite mounting evidence of anhedonia in FTD, it remains unclear how such changes fit within the broader motivational symptom profile of FTD, or how anhedonia relates to functional outcomes. Here we sought to comprehensively characterize motivational disturbances in FTD and their respective relationships with functional impairment. A cross-sectional study design was used including 211 participants—68 behavioral-variant FTD (bvFTD), 32 semantic dementia (SD), 43 Alzheimer’s disease (AD), and 68 healthy older control participants. Anhedonia severity was measured using the Snaith–Hamilton Pleasure Scale while severity of apathy was assessed across Emotional, Executive, and Initiation dimensions using the Dimensional Apathy Scale. Functional impairment was established using the FTD Functional Rating Scale (FRS). Distinct motivational profiles emerged in each dementia syndrome: a domain-general motivational impairment in bvFTD; a predominantly anhedonic profile in SD; and more pronounced initiation and executive apathy in AD. Correlation analyses revealed differential associations between motivational symptoms and severity of functional impairment in each group. Executive apathy was associated with functional impairment in bvFTD, while anhedonia was strongly correlated with functional decline in SD. Finally, executive and emotional apathy were associated with functional decline in AD. Our study indicates distinct profiles of apathy and anhedonia in FTD syndromes, which in turn are differentially associated with functional decline. This detailed characterization of motivational phenotypes can inform patient stratification for targeted interventions to improve functional outcomes.

Examining the propensity and nature of criminal risk behaviours in frontotemporal dementia syndromes and Alzheimer's disease.

Some people with dementia develop changes in behaviour and cognition that may lead to interactions with police or the legal system. However, large, prospective case-control studies examining these behaviours are lacking. One hundred and forty-four people with dementia and 53 controls completed the Misdemeanours and Transgressions Screener. Criminal risk behaviours were reported in: 65.6% of behavioural-variant frontotemporal dementia, 46.2% of right-lateralised semantic dementia, and 27.0% of Alzheimer's disease patients. In 19.1% of patients these behaviours led to contact with police or authority figures. Compared to controls, people with dementia showed higher rates of physical assault (p=0.024), financial/professional recklessness (p=0.009), and inappropriate behaviours (p =0.052). Criminal risk behaviours are common across dementia subtypes and may be one of the first clinical signs of frontotemporal dementia. Further research to understand how to balance risk minimisation with an individual's liberties as well as the inappropriate criminalisation of people with dementia is needed. The Misdemeanours and Transgressions Screener is a new tool to assess criminal risk behaviours.Forty-seven percent of patients with dementia show criminal risk behaviour after dementia onset.Behaviours included verbal abuse, traffic violations, physical assault.New onset of criminal risk behaviours>50 years is a clinical sign for frontotemporal dementia.

A novel MAPT variant (E342K) as a cause of familial progressive supranuclear palsy.

MAPT variants are a known cause of frontotemporal dementia and Parkinsonian syndrome, of which progressive supranuclear palsy syndrome (PSP) is a rare manifestation. To report a novel MAPT variant in a PSP pedigree with autosomal dominant inheritance pattern, and to produce a literature review of PSP patients with MAPT variants. A comprehensive clinical, genetic, and molecular neuroimaging investigation was conducted on a 61 years-old female proband diagnosed with PSP. We also collected the clinical presentation data and history of the patient's pedigree, and performed further genetic analysis of 4 relatives, from two generations, with and without symptoms. The proband exhibited typical clinical manifestation of PSP. A cranial MRI revealed midbrain atrophy, and an FDG-PET scan suggested hypo-metabolic changes in caudate nucleus, left prefrontal lobe, both temporal poles, and midbrain. 18F-florzolo-tau-PET revealed tau-protein deposits in the thalamus and brainstem bilaterally. A gene test by whole-exome sequencing identified a novel MAPT variant [NM_005910.6, exon 11, c.1024G > A (p.E342K)], and the same variant was also identified in one affected relative and one asymptomatic relative, a probable pre-symptomatic carrier. The PSP pedigree caused by the novel MAPT (E342K) variant, expanded the mutational spectrum of MAPT.

Hearing symptom profiles in Alzheimer’s disease and frontotemporal dementia

AbstractBackgroundHearing loss has emerged as a marker of cognitive decline and potential treatment target in dementia, however the symptom profiles that characterise hearing impairment in different dementia syndromes are poorly characterised. Beyond sound detection, these diseases impair aspects of auditory perception that are crucial for communication in daily life. Here we addressed changes in everyday hearing function in Alzheimer’s disease and frontotemporal dementia syndromes, using standardised auditory symptom questionnaires completed by patients’ caregivers.MethodPrimary caregivers for patients with Alzheimer’s disease (n = 20), logopenic variant primary progressive aphasia (n = 8), nonfluent variant primary progressive aphasia (n = 13), semantic variant primary progressive aphasia (n = 13) and behavioural variant frontotemporal dementia (n = 18) completed the Hearing Impairment Impact – Significant Other Profile, adapted Amsterdam Inventory for Auditory Disability and Khalfa Hyperacusis questionnaires. The Amsterdam Inventory for Auditory Disability was also completed by 15 healthy age‐matched individuals. No participant had a past history of significant otological disease.ResultScores on the Hearing Impairment Impact – Significant Other Profile and Khalfa Hyperacusis Questionnaire respectively demonstrated greater carer burden and increased sensitivity to sound in the behavioural variant frontotemporal dementia group compared with the Alzheimer’s disease group. On the Amsterdam Inventory for Auditory Disability, multi‐domain hearing difficulties were endorsed for the behavioural variant frontotemporal dementia and primary progressive aphasia groups relative to healthy controls, and total scores in the logopenic and semantic variant primary progressive aphasia groups were significantly worse than both the healthy control and Alzheimer’s disease groups. Syndromic groups showed differentiable hearing profiles across hearing domains.ConclusionMajor dementia syndromes have distinct profiles of everyday hearing difficulty, and patients with frontotemporal dementia and progressive aphasia syndromes may have particularly marked (albeit often unrecognised) changes in their hearing. These findings should motivate the development of bespoke auditory tests to assess central hearing function and personalised hearing management strategies in these diseases.

Genetic screening of ANXA11 in Korean patients with Frontotemporal dementia syndrome

AbstractBackgroundPathogenic variants of ANXA11 have recently been identified in patients with ALS and ALS‐FTD in ALS cohorts. However, it is uncertain how prevalent the pathogenic variant of ANXA11 is in FTD syndrome. Thus, we performed genetic screening of ANXA11 in Korean patients with FTD to investigate the frequencies and clinical manifestations of ANXA11 mutations in Asian FTD population.MethodWe searched pathogenic variants of ANXA11 in whole exome database of Korean patients with FTD syndrome. Out of a total of 240 patients, 179 patients had been included in the previous Korean FTD genetic screening studies and the rest 61 patients have currently been enrolled in an ongoing longitudinal study of early onset dementia and family members‐FTD (LEAF‐FTD).ResultOne pathogenic variant in ANXA11, c.119A>G (p.D40G), was identified in three patients with right‐predominant svPPA. One of them has recently been reported elsewhere. They were all women and mean age of onset was 63 years old. Two of them had family history of dementia in first‐degree relatives. One patient showed dysarthria and motor weakness 3 years after the onset of symptoms who might have been presumed to have svPPA‐ALS, while the other two had no neurological deficits. Initial neuropsychological test results revealed selective impairments of naming and verbal memory. Brain MRIs demonstrated cortical atrophy in bilateral anterior temporal areas, worse on the right. One patient carried a pathogenic variant, p.V180I of PRNP as well as p.D40G of ANXA11, however, did not show any clinical features of CJD. Other than p.D40G variant, we found two variants of unknown significance of ANXA 11 in one patient with nfvPPA (c.1336‐6C>G) and the other with bvFTD (c.654G>A, p.T218 = ).ConclusionANXA11 mutations account for 0.8% of familial and 1.7% of sporadic ALS in European populations. The p.D40G variant identified in this study (1.25%, 3/240) had already been reported in both familial and sporadic ALS. Although the phenotypic variation of ANXA11 in FTD or FTD‐ALS syndrome remains unclear, our results suggest that right‐predominant svPPA may be a common FTD or FTD‐ALS manifestation in p.D40G variant. Further genetic screening of ANXA11 in Caucasian FTD cohort is needed.

The speech‐to‐song illusion in frontotemporal dementia and Alzheimer’s disease

AbstractBackgroundPerceptual plasticity depends on dynamic, coordinated synaptic tuning across neural circuits and is therefore likely to be vulnerable to neurodegenerative pathologies. However, the nature and limits of perceptual plasticity in dementia are largely unknown. Here we addressed this issue using a dramatic instance of auditory perceptual plasticity ‐ the speech‐to‐song illusion discovered by Diana Deutsch (2011), whereby a spoken phrase is perceived as sung after a few repetitions.MethodWe studied patients representing all major syndromes of frontotemporal dementia (FTD) (N = 22) and Alzheimer’s disease (AD) (N = 25) versus healthy age‐matched controls (N = 21). We asked each participant whether they experienced the Deutsch illusion, and separately assessed their ability to discriminate spoken and sung phrases. In patients who reported experiencing the illusion, we verified this using a forced‐choice procedure.ResultThe Deutsch illusion was reported by 76% of healthy controls, and by 44.4% with progressive non‐fluent aphasia (PNFA), 42.9% of patients with semantic dementia (SD), 20% with typical AD, 20% with logopenic aphasia (LPA), and none with behavioural variant FTD (bvFTD). Mean scores for speech/song discrimination were as follows: healthy controls, 99%; SD, 97.6%; AD, 95%; LPA, 94.7%; PNFA, 94%; bvFTD, 87%. bvFTD performed significantly lower than healthy controls at discrimination.ConclusionPerception of the speech‐to‐song illusion is reduced in canonical FTD and AD syndromes compared with healthy older people and stratifies dementia syndromes disproportionately to any underlying perceptual deficit. The illusion presents an interesting new model for assessing perceptual plasticity in these diseases.

Dementia is an auditory brain disorder

AbstractBackgroundWhile impaired hearing has emerged as a major potentiating factor for dementia, the basis for this relationship has not been defined. Most studies have emphasised the role of peripheral hearing loss. However, we hear with our brains: natural listening places immense computational demands on neural circuitry, and the neural networks pre‐eminently targeted by major dementias are essential for decoding and responding appropriately to the auditory environment. Auditory brain dysfunction is therefore predicted both to contribute importantly to hearing impairment in Alzheimer’s and other dementias and to be integral to the expression of neurodegenerative pathologies. Here I present an overview of evidence that speaks to this hypothesis.MethodsIn a series of linked experiments, we have assessed aspects of auditory cognition – the processes whereby the brain perceives, interprets and acts upon sounds ‐ in patient cohorts with Alzheimer’s disease and major syndromes of frontotemporal dementia, relative to healthy older individuals. We designed novel psychoacoustic tests to assess aspects of auditory scene analysis (the ‘cocktail party effect’ and localisation of sounds in space), comprehension of acoustically degraded speech and the processing of semantic and emotional information in sound in cognitively impaired people. Neuroanatomical mechanisms were assessed using voxel‐based morphometry and functional MRI.ResultsAcross experiments, after taking peripheral hearing function and general cognitive performance into account, patients with Alzheimer’s disease and frontotemporal dementias showed characteristic ‘auditory phenotypes’ or profiles of auditory cognitive impairment. Alzheimer’s disease is associated with impaired auditory scene analysis, linked to atrophy and dysfunction of temporo‐parietal cortical regions in the core ‘default mode network’ targeted by Alzheimer pathology. Frontotemporal dementia syndromes produce distinct impairments of auditory feature analysis, sound recognition and emotional valuation.ConclusionsAuditory brain dysfunction plays a key role in everyday hearing impairment and reflects core pathophysiology in major dementias. These findings raise the exciting prospect that auditory cognitive measures might be used in the early diagnosis of dementia, in guiding novel hearing interventions and as dynamic markers of therapeutic response in the dawning era of disease modification.

Plasma Neurofilament Light Chain predicts neuroimaging alterations and functional decline in frontotemporal dementia

AbstractBackgroundPlasma Neurofilament light chain (pNfL) is a promising biomarker to discriminate Frontotemporal dementia (FTD) from other diagnoses such as Alzheimer’s disease (AD) or psychiatric disorders. Currently, the diagnostic criteria for FTD syndromes are structured hierarchically into “Possible”, “Probable” and “Definite” levels depending on the degree of confidence set by biomarkers. We aim to study the diagnostic and prognostic values of pNfL in the different confidence levels of FTD diagnosis.MethodPatients fulfilling criteria for FTD were classified as “Possible”, “Probable” or “Definite” FTD based on the current diagnostic criteria. pNfL levels were determined with SiMoA, and then compared to Control and AD groups, as well as within the different levels of confidence in the FTD diagnosis.Result187 subjects were included: 37 controls, 79 AD and 71 FTD (11 Possible, 49 Probable and 11 Definite). The FTD group showed higher concentrations of pNfL than the Control (p < 0.001, AUC: 0.817) and the AD groups (p < 0.001, AUC: 0.677) (Figure 1A and 1B).Within the FTD group, pNfL levels differed across the different diagnostic confidence levels (Figure 1C). Subjects with Probable and Definite FTD showed higher levels of pNfL than subjects with Possible FTD (p < 0.001 and p < 0.01 respectively). By contrast, the Possible FTD group did not show differences in pNfL concentrations with the control group. In that sense, the diagnostic value of pNfL varied according to the different grades of diagnostic confidence (Figure 1D), with cases with probable or definite FTD exhibiting an excellent AUC to distinguish from controls (AUC 0.860 and 0.908 respectively), but with no discrimination between possible FTD and controls (AUC 0.583).pNfL presented an excellent performance in the differentiation of structural or functional impairment in the neuroimage (AUC 0.94, and AUC 0.86 respectively) (Figure 2). Finally, higher baseline pNfL levels were associated with worse clinical progression in FTD cases (Figure 3).ConclusionpNfL were higher in FTD patients compared to controls or AD patients. However, we found significant variation across the different confidence levels of FTD diagnosis. Finally, pNfL predicted neuroimage alterations and a worse clinical progression in FTD patients.

Motor neuron symptoms and pathology burden in de medulla oblongata of FTLD‐TDP brain donors

AbstractBackgroundmotor neuron symptoms (MNS) are the hallmark of amyotrophic lateral sclerosis (ALS), which is clinically and pathologically related to frontotemporal dementia (FTD). Up to 20% of FTD patients are diagnosed with ALS (1). However, MNS are observed in a larger proportion of FTD patients (FTD‐MNS), which do not fulfill clinical diagnostic criteria for concomitant ALS (FTD‐ALS) (2). The burden of TDP‐43 pathology in the hypoglossal nucleus (HN) is higher in FTD‐ALS compared to pure FTD brain donors (3), but little is known about the distribution of TDP‐43 pathology in the medulla oblongata in FTD‐MNS.MethodMNS occurring at any disease stage were assessed from the records of FTLD‐TDP brain donors from the Netherlands Brain Bank (n = 38). The total amount of neurons and the percentage of neurons showing TDP‐43 pathology were counted in the HN, nucleus ambiguus (NA) and inferior olivary nucleus (ION). ANOVA was performed between pure FTD, FTD‐ALS, and FTD‐MNS.Resulta pure FTD syndrome was recorded in 12/38 FTLD‐TDP brain donors. A concomitant FTD‐ALS diagnosis had been established during life for 4/38 brain donors, while 16/38 had FTD‐MNS. The most common MNS were dysphagia (63%), spasticity (29%) and wasting (24%). A higher TDP‐43 burden in the HN and NA was observed in FTD‐ALS compared to FTD (p < 0.05). TDP‐43 burden in the HN and in the ION was significantly higher in FTD‐MNS compared to FTD brain donors (p < 0.05).ConclusionMNS are common in FTD, even in the absence of ALS. MNS in FTD are linked to TDP‐43 burden in the HN, NA and ION.

Familial FTD in India

AbstractBackgroundThe burden of dementia in India is estimated to increase by 197% by 2050, and Frontotemporal dementia (FTD) is among the leading causes of young‐onset dementia. With recent advances in molecular pathology, genetic mechanisms and emerging therapies in FTD, it is important to understand familial FTD patterns in the heterogeneous sociocultural context of India. High genetic diversity is characteristic of India, and its population bears genetic imprints of European, Asian and even African genomes. The objective of this presentation is to provide an account of FTD in India, with a focus on familial FTD and genetic mechanisms recently being identified.MethodThe prevalence of FTD in clinical dementia cohorts across different geographic regions in India, frequency of familial FTD, clinical presentations in the context of sociolinguistic and ethnic diversity, and genetic mechanisms are reported.ResultThe reported prevalence of FTD in clinical and research groups across India varies from 7% to 26%. The proportion of familial FTD ranges from 9.5% in Kolkata in the east, 15% in Trivandrum in the south, 24.6% from Hyderabad and more recently, as high as 40% in a recent study from Bangalore. Few genetic mutations were reported in early studies. In a recent large effort from Bangalore, India, 200 patients with FTD syndromes underwent three generation pedigree analysis, clinical and neuropsychological evaluation and MRI according to ADNI protocol. Nearly half underwent genetic analysis by next generation sequencing and RT‐PCR was done to analyse C9orf 11 in a subset. Novel gene mutations including SQSTM1, GRN, MAPT, PSEN2, TBK1 and C9orf were detected. Of these mutations, 11 were pathogenic in 11 and 26 were variants of unknown significance (VUS). Apart from abnormal protein accumulation due to MAPT and GRN, we also identified CSF1R, TREM2 and TYROBP, that are recognised as primary microgliopathies. A few examples of VUS include PRNP, LRRK2, GBA and PANK2 mutations.ConclusionResearch from familial FTD cohorts in India is contributing to growing evidence of a wider spectrum of genetic mechanisms for FTD. Our findings provide compelling evidence to increase harmonised global efforts to reduce risk and develop novel treatment strategies for FTD.

Trajectories of white matter degeneration in frontotemporal dementia: new insights using fixel‐based analysis

AbstractBackgroundThe three clinical presentations of frontotemporal dementia (FTD), behavioral‐variant FTD (bvFTD), progressive non‐fluent aphasia (PNFA), and semantic dementia (SD), are caused by abnormal aggregation of protein pathologies and progressive brain atrophy that precede the emergence of clinical symptoms. Neuropathology shows a ‘prion‐like’ propagation along white matter pathways before aggregating in the neuronal cell bodies of the grey matter. The in‐vivo mapping of upstream white matter trajectories of degeneration can improve disease staging and understanding of disease mechanisms in FTD, but longitudinal white matter studies are rare due to methodological challenges. Here, we develop a novel neuroimaging approach to map white matter changes in FTD using fixel‐based analysis (FBA), a new diffusion weighted imaging technique.MethodSixty FTD patients (23 bvFTD, 15 PNFA and 22 SD) were matched with 30 heathy controls. Participants underwent a comprehensive annual clinical assessment and high‐resolution multimodal MRI (median 2 years; range 1‐6 years). Time‐varying changes in white matter fibre density and cross‐section were computed with MRtrix3, FreeSurfer 7.1.1 and Spatiotemporal Linear Mixed Effects models.ResultAll FTD syndromes showed more extensive white matter changes at baseline than previously reported. In bvFTD, atrophy extended posteriorly over time, encroaching in tracts connecting subcortical and motor‐associations regions (Fig 1). In PNFA, baseline left‐lateralized atrophy extended anteriorly and inferiorly and into the contralateral hemisphere, eventually mirroring patterns of atrophy at presentation (Fig 2). In SD, the focal left temporal baseline atrophy extended posteriorly and laterally along the inferior and superior longitudinal fasculi, and involving the right hemisphere with disease progression (Fig 3).ConclusionThe FBA approach enabled the identification of new white matter bundles in FTD, with syndrome‐specific effects and improved biological interpretability compared to traditional tensor imaging methods. Our method can be extended beyond FTD to other neurodegenerative disorders to inform better models of disease staging and provide useful targets for patient stratification and monitoring in trials of disease‐monitoring interventions.

Clinical Manifestations.

Despite considerable interest in music as an index of brain function and a therapeutic modality in dementia, the neural correlates of music processing in different dementias remain poorly defined. In the frontotemporal dementia spectrum, behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA) are often associated with striking changes in musical function and/or retained musical skills, suggesting frontotemporal dementia may be an instructive disease model in which to assess brain mechanisms of music processing in neurodegenerative pathologies. Here we addressed this issue using activation fMRI in patients with frontotemporal dementia. Nineteen patients (10 svPPA, nine bvFTD) and 26 healthy age-matched controls underwent 3-Tesla 'sparse' fMRI in which they listened passively to musical melodies. In a 2×2 factorial design, stimulus conditions were manipulated to probe two key dimensions of music processing: semantic memory (familiarity: familiar vs. novel melodies) and perceptual features (temporal structure: isochronous vs. anisochronous melodies). Post-scan behavioral testing assessed participants' ability to discriminate melodies under each of the two manipulated stimulus dimensions. Information about participant demographics and musical background was also collected. The healthy older control group showed separable profiles of activation in posterior superior temporal cortex for processing musical temporal structure, and in anterior temporal and inferior frontal cortices for processing musical familiarity. Compared with healthy older listeners, syndromic groups showed differential patterns of engagement of these distributed neural networks. In post-scan behavioral testing, patients with bvFTD also exhibited significantly impaired musical familiarity judgments relative to healthy controls. Frontotemporal dementia syndromes show distinct functional neuroanatomical signatures of music perception. Future work should explore fMRI of music processing as a probe of neural function in particular molecular pathologies and a candidate marker of therapeutic potential in dementia.

Clinical profile of primary progressive Aphasia in Peru: Case series from a Neurological care center

AbstractBackgroundPrimary Progressive Aphasia (PPA) is one of the clinical syndromes of frontotemporal dementia (1). The frequency of PPA syndromes is low (16%) in this Latin America, with just one published report in Peruvian population (2). We aim to describe clinical features of PPA patients followed up at a Neurological healthcare center in Peru.MethodRetrospective review of clinical records of patients diagnosed with probable PPA (based on 2011 diagnostic criteria) during the 2010‐2020 period. Local IRB approval was obtained for this study.ResultWe included 11 cases that fulfilled the selection criteria. Nine cases (75%) were categorized as nfvPPA, and 3 (25%) svPPA. There was slightly female predominance (58%). The average of education was 10.8±4.8 years. Six cases (54.5%) declared place of birth from northern Peru. We found 4.2±1.8 years of diagnostic delay for PPA. The mean age at onset for nfvPPA and svPPA groups was 63 ±12.4, and 52(52‐64) respectively. The first symptom identified in the nfvPPA group was effortful, halting speech 7 (77.8%), while svPPA was impaired confrontation naming 3 (100%). nfvPPA group showed agrammatism in language production and effortful speech in 8 patients (88.9%) and impaired in comprehension of syntactically complex sentences and spared single ‐word comprehension 3(33.3%). Parkinsonism was present in 6 patients (66.7%) and only one patient reported coexistence of amyotrophic lateral sclerosis. Depression was present in most of the 50% of cases. svPPA group also presented impaired in single word‐ comprehension, in object knowledge, and spared repetition 3(100%), 3 (100%) and 2(66.8%) respectively. Less than 50% of PPA cases were in speech therapy.ConclusionThe main clinical features of the PPA reported are mostly consistent with previous reports. In our medical records review, no cases of apraxia of speech were found. There is a significant delay of PPA diagnosis. Further studies with prospective design are required to obtain a better description. Implementing training strategies for clinicians will allow to improve the timely and accurate diagnosis of PPA in Peru.

CSF Aβ42 and Aβ42/Aβ40 Ratio in Alzheimer's Disease and Frontotemporal Dementias.

Alzheimer's disease dementia (ADD) may manifest with atypical phenotypes, resembling behavioral variant frontotemporal dementia (bvFTD) and corticobasal syndrome (CBS), phenotypes which typically have an underlying frontotemporal lobar degeneration with tau proteinopathy (FTLD-tau), such as Pick's disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or FTLD with TDP-43 proteinopathy (FTLD-TDP). CSF biomarkers total and phosphorylated tau (τT and τP-181), and amyloid beta with 42 and 40 amino acids (Aβ42 and Aβ40) are biomarkers of AD pathology. The primary aim of this study was to compare the diagnostic accuracy of Aβ42 to Aβ42/Aβ40 ratio in: (a) differentiating ADD vs. frontotemporal dementias; (b) patients with AD pathology vs. non-AD pathologies; (c) compare biomarker ratios and composite markers to single CSF biomarkers in the differentiation of AD from FTD; Methods: In total, 263 subjects were included (ADD: n = 98; bvFTD: n = 49; PSP: n = 50; CBD: n = 45; controls: n = 21). CSF biomarkers were measured by commercially available ELISAs (EUROIMMUN). Multiple biomarker ratios (Aβ42/Aβ40; τT/τP-181; τT/Aβ42; τP-181/Aβ42) and composite markers (t-tau: τT/(Aβ42/Aβ40); p-tau: τP-181/(Aβ42/Aβ40) were calculated. ROC curve analysis was performed to compare AUCs of Aβ42 and Aβ42/Aβ40 ratio and relevant composite markers between ADD and FTD, as defined clinically. BIOMARKAPD/ABSI criteria (abnormal τT, τP-181 Aβ42, and Aβ42/Aβ40 ratio) were used to re-classify all patients into AD pathology vs. non-AD pathologies, and ROC curve analysis was repeated to compare Aβ42 and Aβ42/Aβ40; Results: Aβ42 did not differ from Aβ42/Aβ40 ratio in the differentiation of ADD from FTD (AUCs 0.752 and 0.788 respectively; p = 0.212). The τT/Aβ42 ratio provided maximal discrimination between ADD and FTD (AUC:0.893; sensitivity 88.8%, specificity 80%). BIOMARKAPD/ABSI criteria classified 60 patients as having AD pathology and 211 as non-AD. A total of 22 had discrepant results and were excluded. Aβ42/Aβ40 ratio was superior to Aβ42 in the differentiation of AD pathology from non-AD pathology (AUCs: 0.939 and 0.831, respectively; p < 0.001). In general, biomarker ratios and composite markers were superior to single CSF biomarkers in both analyses. Aβ42/Aβ40 ratio is superior to Aβ42 in identifying AD pathology, irrespective of the clinical phenotype. CSF biomarker ratios and composite markers provide higher diagnostic accuracy compared to single CSF biomarkers.

The architecture of abnormal reward behaviour in dementia: multimodal hedonic phenotypes and brain substrate.

Abnormal reward processing is a hallmark of neurodegenerative diseases, most strikingly in frontotemporal dementia. However, the phenotypic repertoire and neuroanatomical substrates of abnormal reward behaviour in these diseases remain incompletely characterized and poorly understood. Here we addressed these issues in a large, intensively phenotyped patient cohort representing all major syndromes of sporadic frontotemporal dementia and Alzheimer's disease. We studied 27 patients with behavioural variant frontotemporal dementia, 58 with primary progressive aphasia (22 semantic variant, 24 non-fluent/agrammatic variant and 12 logopenic) and 34 with typical amnestic Alzheimer's disease, in relation to 42 healthy older individuals. Changes in behavioural responsiveness were assessed for canonical primary rewards (appetite, sweet tooth, sexual activity) and non-primary rewards (music, religion, art, colours), using a semi-structured survey completed by patients' primary caregivers. Changes in more general socio-emotional behaviours were also recorded. We applied multiple correspondence analysis and k-means clustering to map relationships between hedonic domains and extract core factors defining aberrant hedonic phenotypes. Neuroanatomical associations were assessed using voxel-based morphometry of brain MRI images across the combined patient cohort. Altered (increased and/or decreased) reward responsiveness was exhibited by most patients in the behavioural and semantic variants of frontotemporal dementia and around two-thirds of patients in other dementia groups, significantly (P < 0.05) more frequently than in healthy controls. While food-directed changes were most prevalent across the patient cohort, behavioural changes directed toward non-primary rewards occurred significantly more frequently (P < 0.05) in the behavioural and semantic variants of frontotemporal dementia than in other patient groups. Hedonic behavioural changes across the patient cohort were underpinned by two principal factors: a 'gating' factor determining the emergence of altered reward behaviour and a 'modulatory' factor determining how that behaviour is directed. These factors were expressed jointly in a set of four core, trans-diagnostic and multimodal hedonic phenotypes: 'reward-seeking', 'reward-restricted', 'eating-predominant' and 'control-like'-variably represented across the cohort and associated with more pervasive socio-emotional behavioural abnormalities. The principal gating factor was associated (P < 0.05 after correction for multiple voxel-wise comparisons over the whole brain) with a common profile of grey matter atrophy in anterior cingulate, bilateral temporal poles, right middle frontal and fusiform gyri: the cortical circuitry that mediates behavioural salience and semantic and affective appraisal of sensory stimuli. Our findings define a multi-domain phenotypic architecture for aberrant reward behaviours in major dementias, with novel implications for the neurobiological understanding and clinical management of these diseases.

Mapping behavioural, cognitive and affective transdiagnostic dimensions in frontotemporal dementia.

Two common clinical variants of frontotemporal dementia are the behavioural variant frontotemporal dementia, presenting with behavioural and personality changes attributable to prefrontal atrophy, and semantic dementia, displaying early semantic dysfunction primarily due to anterior temporal degeneration. Despite representing independent diagnostic entities, mounting evidence indicates overlapping cognitive-behavioural profiles in these syndromes, particularly with disease progression. Why such overlap occurs remains unclear. Understanding the nature of this overlap, however, is essential to improve early diagnosis, characterization and management of those affected. Here, we explored common cognitive-behavioural and neural mechanisms contributing to heterogeneous frontotemporal dementia presentations, irrespective of clinical diagnosis. This transdiagnostic approach allowed us to ascertain whether symptoms not currently considered core to these two syndromes are present in a significant proportion of cases and to explore the neural basis of clinical heterogeneity. Sixty-two frontotemporal dementia patients (31 behavioural variant frontotemporal dementia and 31 semantic dementia) underwent comprehensive neuropsychological, behavioural and structural neuroimaging assessments. Orthogonally rotated principal component analysis of neuropsychological and behavioural data uncovered eight statistically independent factors explaining the majority of cognitive-behavioural performance variation in behavioural variant frontotemporal dementia and semantic dementia. These factors included Behavioural changes, Semantic dysfunction, General Cognition, Executive function, Initiation, Disinhibition, Visuospatial function and Affective changes. Marked individual-level overlap between behavioural variant frontotemporal dementia and semantic dementia was evident on the Behavioural changes, General Cognition, Initiation, Disinhibition and Affective changes factors. Compared to behavioural variant frontotemporal dementia, semantic dementia patients displayed disproportionate impairment on the Semantic dysfunction factor, whereas greater impairment on Executive and Visuospatial function factors was noted in behavioural variant frontotemporal dementia. Both patient groups showed comparable magnitude of atrophy to frontal regions, whereas severe temporal lobe atrophy was characteristic of semantic dementia. Whole-brain voxel-based morphometry correlations with emergent factors revealed associations between fronto-insular and striatal grey matter changes with Behavioural, Executive and Initiation factor performance, bilateral temporal atrophy with Semantic dysfunction factor scores, parietal-subcortical regions with General Cognitive performance and ventral temporal atrophy associated with Visuospatial factor scores. Together, these findings indicate that cognitive-behavioural overlap (i) occurs systematically in frontotemporal dementia; (ii) varies in a graded manner between individuals and (iii) is associated with degeneration of different neural systems. Our findings suggest that phenotypic heterogeneity in frontotemporal dementia syndromes can be captured along continuous, multidimensional spectra of cognitive-behavioural changes. This has implications for the diagnosis of both syndromes amidst overlapping features as well as the design of symptomatic treatments applicable to multiple syndromes.

Diagnostic Performance and Clinical Applicability of Blood-Based Biomarkers in a Prospective Memory Clinic Cohort.

Blood-based biomarkers have emerged as minimally invasive options for evaluating cognitive impairment. Most studies to date have assessed them in research cohorts, limiting their generalization to everyday clinical practice. We evaluated their diagnostic performance and clinical applicability in a prospective, real-world, memory clinic cohort. All patients referred with suspected cognitive impairment between July 2019 and June 2021 were prospectively invited to participate. Five plasma biomarkers (tau phosphorylated at threonine 181 [p-tau181], glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], total tau [t-tau], and ubiquitin C-terminal hydrolase L1 [UCH-L1]) were determined with single-molecule array. Performance was assessed in comparison to clinical diagnosis (blinded to plasma results) and amyloid status (CSF/PET). A group of cognitively unimpaired (CU) controls was also included. Three hundred forty-nine participants (mean age 68, SD 8.3 years) and 36 CU controls (mean age 61.7, SD 8.2 years) were included. In the subcohort with available Alzheimer disease (AD) biomarkers (n = 268), plasma p-tau181 and GFAP had a high diagnostic accuracy to differentiate AD from non-neurodegenerative causes (area under the receiver operating characteristic curve 0.94 and 0.92, respectively), with p-tau181 systematically outperforming GFAP. Plasma p-tau181 levels predicted amyloid status (85% sensitivity and specificity) with accurate individual prediction in approximately 60% of the patients. Plasma NfL differentiated frontotemporal dementia (FTD) syndromes from CU (0.90) and non-neurodegenerative causes (0.93), whereas the discriminative capacity with AD and between all neurodegenerative and non-neurodegenerative causes was less accurate. A combination of p-tau181 and NfL identified FTD with 82% sensitivity and 85% specificity and had a negative predictive value for neurodegenerative diagnosis of 86%, ruling out half of the non-neurodegenerative diagnoses. In the subcohort without AD biomarkers, similar results were obtained. T-tau and UCH-L1 did not offer added diagnostic value. Plasma p-tau181 predicted amyloid status with high accuracy and could have potentially avoided CSF/amyloid PET testing in approximately 60% of subjects in a memory clinic setting. NfL was useful for identifying FTD from non-neurodegenerative causes but behaved worse than p-tau181 in all other comparisons. Combining p-tau181 and NfL improved diagnostic performance for FTD and non-neurodegenerative diagnoses. However, the 14% false-negative results suggest that further improvement is needed before implementation outside memory clinics. This study provides Class I evidence that plasma p-tau181 correlates with the presence or absence of AD and a combination of plasma p-tau181 and NfL correlates moderately well with a diagnosis of FTD.

The many faces of globular glial tauopathy: A clinical and imaging study.

Globular glial tauopathy (GGT) has been associated with frontotemporal dementia syndromes; little is known about the clinical and imaging characteristics of GGT and how they differ from other non-globular glial 4-repeat tauopathies (N4GT) such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). For this case-control study the Mayo Clinic brain banks were queried for all cases with an autopsy-confirmed diagnosis of GGT between 1 January 2011 and 31 October 2021. Fifty patients with N4GT (30 PSP, 20 CBD) were prospectively recruited and followed by the Neurodegenerative Research Group at Mayo Clinic, Minnesota. Magnetic resonance imaging was used to characterize patterns of gray/white matter atrophy, MR-parkinsonism index, midbrain volume, and white matter hyperintensities.18 F-Fluorodeoxyglucose-, 11 C Pittsburg compound-, and 18 F-flortaucipir-positron emission tomography scans were reviewed. Twelve patients with GGT were identified: 83% were women compared to 42% in NG4T (p=0.02) with median age at death 76.5 years (range: 55-87). The most frequent clinical features were eye movement abnormalities, parkinsonism, behavioral changes followed by pyramidal tract signs and motor speech abnormalities. Lower motor neuron involvement was present in 17% and distinguished GGT from NG4T (p=0.035). Primary progressive apraxia of speech was the most frequent initial diagnosis (25%); 50% had a Parkinson-plus syndrome before death. Most GGT patients had asymmetric frontotemporal atrophy with matching hypometabolism. GGT patients had more gray matter atrophy in temporal lobes, normal MR-parkinsonism index, and larger midbrain volumes. Female sex, lower motor neuron involvement in the context of a frontotemporal dementia syndrome, and asymmetric brain atrophy with preserved midbrain might be suggestive of underlying GGT.