Progressive Nonfluent Aphasia Research Articles

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.

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.

Associations between brain TSPO and [18F]FDG‐PET signals in neurodegenerative disorders

AbstractBackgroundRecent evidence indicates that activated microglial cells contribute to the brain FDG‐PET signal changes in neurodegenerative disorders. Radiopharmaceuticals targeting the 18‐kDa translocator protein (TSPO) have been used to measure microglial activation. The combination of FDG‐PET and TSPO‐PET allows for assessing, in‐vivo and non‐invasively, whether they associate in brain regions vulnerable to neurodegeneration. So far, multiple studies have used FDG‐PET and TSPO‐PET concomitantly, but to our knowledge, no systematic evaluation has been conducted to assess whether they are associated. We aimed to systematically summarize the current data on brain TSPO‐PET and FDG‐PET signals in individuals with neurodegenerative disorders.MethodStudies performing TSPO‐ and FDG‐PET in neurodegenerative disorders were searched in PubMed and Web of Science. Included articles must have performed PET images concomitantly with both tracers in healthy controls and individuals presenting with neurodegenerative disorders. This review complied with PRISMA (2020) guidelines and was registered at PROSPERO (CRD42022354523).ResultA total of 272 articles were found after a search on PubMed and Web of Science, with eight meeting the inclusion criteria. We included clinical studies with individuals presenting Alzheimer’s Disease (AD), Parkinson’s Disease (PD), corticobasal syndrome and progressive supranuclear palsy, behavioral variant frontotemporal dementia, and progressive nonfluent aphasia. In AD, five studies presented negative associations, and one presented a positive association between TSPO and FDG signals in brain regions vulnerable to AD. In PD (3 studies) and the other related neurodegenerative disorders (2 studies) evaluated, we found a negative correlation between FDG‐PET and TSPO‐PET signals in vulnerable regions.ConclusionAll studies presented associations between FDG‐ and TSPO‐PET signals. These findings suggest that microglia, indexed by TSPO binding, negatively impacts brain glucose metabolism indexed by FDG‐PET. Further studies are needed to address associations between TSPO‐PET and FDG‐PET in the asymptomatic and early stages of neurodegenerative disorders.

FC24: Transcranial Magnetic Stimulation (TMS) as a Treatment for Dementia due to non-Alzheimer’s disease (non-AD): What is the Evidence?

Objective:There is no cure for dementia due to non-Alzheimer’s disease (non-AD), and current treatments are symptomatic. Noninvasive brain stimulation therapies such as transcranial magnetic stimulation (TMS) are increasingly being investigated to improve cognitive function in dementia. We conducted a systematic review to investigate the effectiveness of TMS on cognition in non-AD dementia.Methods:Comprehensive search of databases (Medline, Embase, Cochrane, APA PsycINFO, Web of Science, and Scopus) from 2000 to February 2023 using keywords related to TMS and dementia (PROSPERO, CRD42022326423). Here we report outcomes from randomized controlled trials (RCTs) of TMS on non-AD dementia populations.Results:In total, 20 RCTs comprised of 660 patients, mean age 62 years (range 46-71). Diagnostic groups include stroke (n=8), Parkinson’s disease (n=6), Frontotemporal dementia (n=3), Huntington’s disease (n=2) and Progressive non-fluent aphasia (n=1). The most common site of stimulation was left (L) dorsolateral prefrontal cortex (DLPFC, n=13); other sites were primary motor cortex (n=2); Right (R) Broca's area, Brodmann area, Contralesional pars triangularis, R Inferior Frontal Gyrus (IFG) (all n=1); and multiple sites in 1 RCT (L and R IFG, L superior frontal gyrus, L DLPFC, L and R right anterior temporal lobe, supplementary motor area, anterior cingulate, and vertex). Studies used both low (1Hz, n=5) and high (50Hz, n=5) frequencies, or other high (5Hz, 10Hz, 20Hz) or combination low/high frequencies. Frequent duration of treatment was 10 days (n=7), range 1-40. Of 20 studies, 19 (95%) demonstrated improvement of global cognition (on MoCA, MMSE) and specific cognitive domains (learning and memory, language, executive function, problem-solving, attention, reaction time). The only RCT with no effect utilized a single session intermittent theta burst stimulation on the LDLPFC on PD patients. Adverse events in 7 studies included headaches (most common), dull skull pain, dizziness, insomnia, fatigue, anxiety, temporary decrease in hearing, and temporary decreased mental clarity.Conclusion:There is favorable evidence that rTMS improves global and specific cognitive domains in non-AD dementia. Left DLPFC is the most common stimulation site, both low- and high-frequency are utilized, and 10 sessions is frequently used. Further studies are needed to determine optimal TMS treatments in cognitively impaired populations

B - 83 A Case Study of Suspected Progressive Non-Fluent Aphasia in an Older Adult with a Prior History of Seizures.

Progressive non-fluent aphasia (PNFA) is a neurodegenerative disorder characterized by agrammatism and apraxia of speech. Other features include impaired comprehension of syntactically complex structures, intact object knowledge, and spared single-word comprehension. Given the complexity of primary progressive aphasia (PPA) syndromes, neuropsychologists can play a vital role in differential diagnosis, particularly when there are comorbid medical factors. This case study presents on a 74-year-old female with progressive language and cognitive impairment over the past 8years whose care was jointly managed in specialty neurology clinics (e.g., Epilepsy and Memory Disorders) at a university medical center. She had a history of generalized convulsive seizures but with none occurring in several years. She was weaned off phenobarbital over the course of a few months to help rule out any adverse effects on functioning but her deficits persisted. Follow-up MRI showed mild-to-moderate diffuse atrophy. Her cognitive neurologist raised concerns for PPA which prompted the neuropsychological evaluation 3-4months later. Testing showed prominent impairments in fluency, naming, repetition, oral reading, and comprehension for grammatically complex questions while semantic knowledge for objects was preserved. Conversational language was halting, effortful, dysfluent, and anomic. Broader cognitive deficits were also observed during testing which was suggestive of more generalized cerebral dysfunction. The patient's profile was highly concerning for PNFA. Further work-up at the institution's Frontotemporal Dementia Clinic along with an FDG-PET scan were recommended to help further clarify her profile. Overall, this case highlights the utility of neuropsychology in the differential diagnosis of complex neurodegenerative disorders with comorbid medical factors.

Error profiles of facial emotion recognition in frontotemporal dementia and Alzheimer's disease.

To identify the patterns of errors in facial emotion recognition in frontotemporal dementia (FTD) subtypes compared with Alzheimer's disease (AD) and healthy controls. Retrospective analysis. Participants were recruited from FRONTIER, the frontotemporal dementia research group at the University of Sydney, Australia. A total of 356 participants (behavioral-variant FTD (bvFTD): 62, semantic dementia (SD)-left: 29, SD-right: 14, progressive non-fluent aphasia (PNFA): 21, AD: 76, controls: 90) were included. Facial emotion recognition was assessed using the Facial Affect Selection Task, a word-face matching task measuring recognition of the six basic emotions (anger, disgust, fear, happiness, sadness, and surprise), as well as neutral emotion, portrayed by black and white faces. Overall, all clinical groups performed significantly worse than controls with the exception of the PNFA subgroup (p = .051). The SD-right group scored worse than all other clinical groups (all p values < .027) and the bvFTD subgroup performed worse than the PNFA group (p < .001). The most frequent errors were in response to the facial emotions disgust (26.1%) and fear (22.9%). The primary error response to each target emotion was identified; patterns of errors were similar across all clinical groups. Facial emotion recognition is impaired in FTD and AD compared to healthy controls. Within FTD, bvFTD and SD-right are particularly impaired. Dementia groups cannot be distinguished based on error responses alone. Implications for future clinical diagnosis and research are discussed.

Evaluation of Plasma Phosphorylated Tau217 for Differentiation Between Alzheimer Disease and Frontotemporal Lobar Degeneration Subtypes Among Patients With Corticobasal Syndrome

Plasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)-associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology. To validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS. This multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort. Plasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling. Of 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P < .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P < .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005). In this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aβ or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials.

Analysis of positron emission tomography hypometabolic patterns and neuropsychiatric symptoms in patients with dementia syndromes.

To estimate the proportions of specific hypometabolic patterns and their association with neuropsychiatric symptoms (NPS) in patients with cognitive impairment (CI). This multicenter study with 1037 consecutive patients was conducted from December 2012 to December 2019. 18 F-FDG PET and clinical/demographic information, NPS assessments were recorded and analyzed to explore the associations between hypometabolic patterns and clinical features by correlation analysis and multivariable logistic regression models. Patients with clinical Alzheimer's disease (AD, 81.6%, 605/741) and dementia with Lewy bodies (67.9%, 19/28) mostly had AD-pattern hypometabolism, and 76/137 (55.5%) of patients with frontotemporal lobar degeneration showed frontal and anterior temporal pattern (FT-P) hypometabolism. Besides corticobasal degeneration, patients with behavioral variant frontotemporal dementia (36/58), semantic dementia (7/10), progressive non-fluent aphasia (6/9), frontotemporal lobar degeneration and amyotrophic lateral sclerosis (3/5), and progressive supranuclear palsy (21/37) also mostly showed FT-P hypometabolism. The proportion of FT-P hypometabolism was associated with the presence of hallucinations (R=0.171, p=0.04), anxiety (R=0.182, p=0.03), and appetite and eating abnormalities (R=0.200, p=0.01) in AD. Specific hypometabolic patterns in FDG-PET are associated with NPS and beneficial for the early identification and management of NPS in patients with CI.

Anatomical MRI staging of frontotemporal dementia variants.

The three clinical variants of frontotemporal dementia (behavioral variant [bvFTD], semantic dementia, and progressive non-fluent aphasia [PNFA]) are likely to develop over decades, from the preclinical stage to death. To describe the long-term chronological anatomical progression of FTD variants, we built lifespan brain charts of normal aging and FTD variants by combining 8022 quality-controlled MRIs from multiple large-scale data-bases, including 107 bvFTD, 44 semantic dementia, and 38 PNFA. We report in this manuscript the anatomical MRI staging schemes of the three FTD variants by describing the sequential divergence of volumetric trajectories between normal aging and FTD variants. Subcortical atrophy precedes focal cortical atrophy in specific behavioral and/or language networks, with a "radiological" prodromal phase lasting 8-10 years (time elapsed between the first structural alteration and canonical cortical atrophy). Amygdalar and striatal atrophy can be candidate biomarkers for future preclinical/prodromal FTD variants definitions. We describe the chronological MRI staging of the most affected structures in the three frontotemporal dementia (FTD) syndromic variants. In behavioral variant of FTD (bvFTD): bilateral amygdalar, striatal, and insular atrophy precedes fronto-temporal atrophy. In semantic dementia: bilateral amygdalar atrophy precedes left temporal and hippocampal atrophy. In progressive non-fluent aphasia (PNFA): left striatal, insular, and thalamic atrophy precedes opercular atrophy.

[A case of non-fluent/agrammatic variant of primary progressive aphasia with logoclonia].

We report a case of non-fluent/agrammatic variant of primary progressive aphasia in a 79-year-old right-handed man who was admitted with a 5-year history of non-fluent speech and apraxia of speech. He also presented with agrammatism and logoclonia (the meaningless repetition of the middle or final syllable of a word). Furthermore, brain MRI revealed atrophy of the bilateral frontal and temporal lobes, while N-isopropyl-p-123I-iodoamphetamine single-photon emission computed tomography (SPECT) revealed relative hypoperfusion in the right basal ganglia. In addition, dopamine transporter SPECT revealed a decrease in specific binding ratio values, indicating neural dopamine dysfunction, which led to his diagnosis of progressive non-fluent aphasia with logoclonia. Logoclonia is a severe linguistic dysfunction usually observed in the advanced stages of Alzheimer's disease. However, based on the clinical course and cerebrospinal fluid evaluation results, our patient did not show any features of Alzheimer's disease. Thus, logoclonia might be associated with lesions involving the basal ganglia, right hemisphere, and left frontotemporal lobe.

A Patient with Corticobasal Syndrome and Progressive Non-Fluent Aphasia (CBS-PNFA), with Variants in ATP7B, SETX, SORL1, and FOXP1 Genes.

Our aim was to analyze the phenotypic-genetic correlations in a patient diagnosed with early onset corticobasal syndrome with progressive non-fluent aphasia (CBS-PNFA), characterized by predominant apraxia of speech, accompanied by prominent right-sided upper-limb limb-kinetic apraxia, alien limb phenomenon, synkinesis, myoclonus, mild cortical sensory loss, and right-sided hemispatial neglect. Whole-exome sequencing (WES) identified rare single heterozygous variants in ATP7B (c.3207C&gt;A), SORL1 (c.352G&gt;A), SETX (c.2385_2387delAAA), and FOXP1 (c.1762G&gt;A) genes. The functional analysis revealed that the deletion in the SETX gene changed the splicing pattern, which was accompanied by lower SETX mRNA levels in the patient's fibroblasts, suggesting loss-of-function as the underlying mechanism. In addition, the patient's fibroblasts demonstrated altered mitochondrial architecture with decreased connectivity, compared to the control individuals. This is the first association of the CBS-PNFA phenotype with the most common ATP7B pathogenic variant p.H1069Q, previously linked to Wilson's disease, and early onset Parkinson's disease. This study expands the complex clinical spectrum related to variants in well-known disease genes, such as ATP7B, SORL1, SETX, and FOXP1, corroborating the hypothesis of oligogenic inheritance. To date, the FOXP1 gene has been linked exclusively to neurodevelopmental speech disorders, while our study highlights its possible relevance for adult-onset progressive apraxia of speech, which guarantees further study.

Altered reward processing underpins emotional apathy in dementia

IntroductionWhile apathy is broadly defined as a loss of motivation, it is increasingly recognised as a multidimensional syndrome spanning executive, emotional, and initiation domains. Emotional apathy is purportedly driven by deficits in using socioemotional rewards to guide behaviour, yet the link between these symptoms and reward processing, and their common neural correlates, has not been directly examined.MethodsSixty-four patients (33 behavioural-variant frontotemporal dementia, 14 Alzheimer’s disease, 8 semantic dementia, 6 progressive nonfluent aphasia, 3 logopenic progressive aphasia) were classified into high (HEA; n = 36) and low (LEA; n = 28) emotional apathy groups based on emotional apathy subscale scores on the Dimensional Apathy Scale. Patients and age-matched healthy controls (n = 27) performed an instrumental reward learning task where they learned to associate cues with either social or monetary outcomes.ResultsHEA patients showed impaired learning on both the social and monetary reward conditions, relative to LEA patients (p = 0.016) and controls (p = 0.005). Conversely, the LEA group did not differ from controls (p = 0.925). Importantly, multiple regression analyses indicated that social reward learning significantly predicted emotional apathy. Voxel-based morphometry analyses revealed that emotional apathy and social reward learning were both associated with orbitofrontal cortex, ventral striatum, and insula atrophy.DiscussionOur results demonstrate a unique link between impaired social reward learning and emotional apathy in dementia and reveal a shared neurobiological basis. Greater understanding of these neurocognitive mechanisms of reward processing will help improve the identification of emotional apathy in dementia and inform the development of novel interventions to address these symptoms.

Remote versus face-to-face neuropsychological testing for dementia research: a comparative study in people with Alzheimer’s disease, frontotemporal dementia and healthy older individuals

ObjectivesWe explored whether adapting neuropsychological tests for online administration during the COVID-19 pandemic was feasible for dementia research.DesignWe used a longitudinal design for healthy controls, who completed face-to-face assessments 3–4...

Primary progressive aphasia and motor neuron disease: A review.

BackgroundThis study aims at reviewing, within the framework of motor neuron disease-frontotemporal degeneration (MND-FTD)-spectrum disorders, evidence on the co-occurrence between primary progressive aphasia (PPA) and MND in order to profile such a complex at pathological, genetic and clinical levels.MethodsThis review was pre-registered (osf.io/ds8m4) and performed in accordance with the 2020 PRISMA guidelines. Case reports/series and group studies were included if addressing (1) progressive non-fluent aphasia (PNFA) or semantic dementia (SD) with MND or (2) MND patients with co-morbid PNFA/SD.ResultsOut of 546 initial records, 56 studies were included. As to case reports/series (N = 35), which included 61 PPA-MND patients, the following findings yielded: (1) PNFA is more frequent than SD in PPA-MND; (2) in PPA-MND, the most prevalent motor phenotypes are amyotrophic lateral sclerosis and predominant-upper MND, with bulbar involvement being ubiquitous; (3) extrapyramidal features are moderately frequent in PPA-MND; (4) PPA-MND patients usually display frontotemporal, left-greater-than-right involvement; (5) TDP-43-B is the typical pathological substrate of PPA-MND; (6) TBK1 mutations represent the most frequent genetic risk factors for PPA-MND.As to group studies, including 121 patients, proportional meta-analytic procedures revealed that: (1) the lifetime prevalence of MND in PPA is 6%; (2) PPA occurs in 19% of patients with co-morbid MND and FTD; (3) MND is more frequent in PNFA (10%) than in SD patients (3%).DiscussionInsights herewith delivered into the clinical, neuropathological and genetic features of PPA-MND patients prompt further investigations aimed at improving clinical practice within the MND-FTD spectrum.

Olfactory Bulb Integrity in Frontotemporal Dementia and Alzheimer’s Disease

Olfactory dysfunction is highly prevalent in dementia syndromes, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). The structural integrity of the olfactory bulb (OB) is thought to play a critical role in odor detection and identification, but no MRI study has measured OB volume in FTD, or measured OB volume longitudinally in AD. To measure OB volume in FTD and AD patients longitudinally using MRI. This study measured OB volumes using MRI in patients diagnosed with behavioral-variant FTD (n = 55), semantic dementia (n = 34), progressive non-fluent aphasia (n = 30), AD (n = 50), and healthy age-matched controls (n = 55) at their first visit to a dementia research clinic ('baseline'). Imaging data in patients 12-months later were analyzed where available (n = 84) for longitudinal assessment. Volumes of subcortical and cortical olfactory regions ('olfactory network') were obtained via surface-based morphometry. Results revealed that in AD and FTD at baseline, OB volumes were similar to controls, whereas volumes of olfactory network regions were significantly reduced in all patient groups except in progressive non-fluent aphasia. Longitudinal data revealed that OB volume became significantly reduced (10-25% volume reduction) in all dementia groups with disease progression. Olfactory dysfunction is common in patients diagnosed with AD or FTD, but our results indicate that there is no detectable volume loss to the OBs upon first presentation to the clinic. Our findings indicate that the OBs become detectably atrophied later in the disease process. OB atrophy indicates the potential usefulness for OBs to be targeted in interventions to improve olfactory function.

Music appreciation phenotypes in patients with frontotemporal dementia: A pilot study.

ObjectivesFrontotemporal dementia (FTD) can present with changes in music appreciation. Research has suggested a relationship of altered music appreciation phenotypes with typical socio‐emotional changes. We aimed to determine the prevalence and severity of music appreciation phenotypes in FTD and study the relationship with emotion recognition capacities in order to examine whether they could serve as a proxy for changes in socio‐emotional functioning.Methods/DesignBased on reported musical changes in the literature, we developed an informant‐based questionnaire to assess musical changes and a music test to assess music emotion recognition. Social cognition was assessed with the Ekman 60 faces test in a subgroup of patients (n = 23). Relationships between measures were assessed with linear regressions.ResultsWe included 47 patients (44.7% female, mean age 65.0 ± 8.4, 31 behavioral variant FTD (bvFTD), 10 semantic dementia (SD), and six progressive nonfluent aphasia (PNFA)). Thirty‐six caregivers were included in the music emotion recognition test as controls. Altered music appreciation phenotypes were observed in 79% of the FTD patients. Musicophilia was present in a third of bvFTD patients, and only in up to 10% in language FTD variants. Changes in music appreciation were not associated with decreased music emotion recognition or visual emotion recognition. Compared to controls, bvFTD performed worse on the music emotion recognition task (p < 0.003), and no differences were found with SD (p = 0.06) and PNFA patients (p = 0.8).ConclusionsMusic appreciation phenotypes are highly prevalent in FTD patients. Future studies should further investigate the potential diagnostic value of changes in music processing.

Biological basis and psychiatric symptoms in frontotemporal dementia.

Frontotemporal dementia is a neurodegenerative disease characterized by focal degeneration of the frontal and temporal lobes, clinically presenting with disinhibited behavior, personality changes, progressive non-fluent aphasia and/or impaired semantic memory. Research progress has been made in re-organizing the clinical concept of frontotemporal dementia and neuropathological classification based on multiple accumulating proteins. Alongside this progress a list of genetic mutations or variants that are causative or increase the risk of frontotemporal dementia have been identified and some of these gene products are extensively studied. However, there are still a lot of points that need to be overcome, including lack of specific diagnostic biomarker which enable antemortem diagnosis of underlying neurodegenerative process, and lack of disease modifying therapy which could prevent disease progression. Early and precise diagnosis of frontotemporal dementia is urgently required. In this context, how to define prodromal frontotemporal dementia and early differential diagnosis from primary psychiatric disorders are also important issues. In this review we will summarize and discuss current understanding of biological basis and psychiatric symptoms in frontotemporal dementia.

Anosognosia in Dementia: Evaluation of Perfusion Correlates Using 99mTc-HMPAO SPECT and Automated Brodmann Areas Analysis.

(1) Background: Considerable inconsistency exists regarding the neural substrates of anosognosia in dementia in previous neuroimaging studies. The purpose of this study was the evaluation of anosognosia perfusion correlates across various types of dementia using automated Brodmann areas (BAs) analysis and comparison with a database of normal subjects. (2) Methods: We studied 72 patients: 32 with Alzheimer’s disease, 26 with frontotemporal dementia—FTD (12 behavioral FTD, 9 semantic FTD, 5 Progressive Non-Fluent Aphasia), 11 with corticobasal syndrome, and 3 with progressive supranuclear palsy. Addenbrook’s Cognitive Examination—Revised (ACE-R) mean(±SD) was 55.6(±22.8). For anosognosia measurement, the Anosognosia Questionnaire—Dementia was used. Total anosognosia score mean(±SD) was 22.1(±17.9), cognitive anosognosia score mean(±SD) was 18.1(±15.1) and behavioral–mood anosognosia score mean(±SD) was 3.3(±4.7). (3) Results: Higher anosognosia total score was associated with hypoperfusion in the inferior temporal, anterior cingulate, and inferior frontal cortices of the right hemisphere (BAs 20R, 24R, 32R, 45R). Higher anosognosia cognitive score was correlated with hypoperfusion in the left middle and anterior temporal cortices, and right dorsal anterior cingulate cortex (BAs 21L, 22L, 32R). No association was found with behavioral–mood anosognosia. (4) Conclusions: Automated analysis of brain perfusion Single Photon Emission Computed Tomography could be useful for the investigation of anosognosia neural correlates in dementia.

Stroke-induced and progressive forms of apraxia of speech

Background: Stylistic differences in language use, as described by sociolinguists, have also been shown to occur in disordered speech and language. In this article, we describe apraxia of speech, and compare stroke-induced and progressive forms of this neurogenic disorder. Method: Audio recordings were made of a client, CS, who had progressive apraxia of speech and progressive nonfluent aphasia. Information from control participants was also available, and use was made of published data from clients with stroke-induced apraxia of speech. Results: A range of results are reported, but in particular the comparative difficulty of spontaneous connected speech as compared to reading or repetition for the client with progressive apraxia of speech. This differed from the findings of those with apraxia of speech from stroke, in that connected speech was much more difficult in the progressive form of the disorder. Discussion/conclusion: We discuss the importance of obtaining a wide range of speech styles when collecting data from clients with a range of communication problems, and how – in the specific case of apraxia of speech – these style differences aid in analysis and diagnosis.

Rare variants in TP73 in a frontotemporal dementia cohort link this gene with primary progressive aphasia phenotypes.

TP73 was recently reported to cause amyotrophic lateral sclerosis (ALS). ALS and frontotemporal dementia (FTD) are considered to form part of a continuum. We aimed to investigate whether TP73 variants may be associated with FTD. We studied a thoroughly investigated cohort of 65 Portuguese patients with frontotemporal dementia using whole-exome sequencing. The patients had no other known genetic cause for their disease (C9orf72 expansion was also excluded). Of the 65 patients studied, two had rare variants in TP73 (p.Gly605Ser and p.Arg347Trp). Both variants had minor allele frequency <0.001 and were predicted to be pathogenic in silico. The two patients displayed a phenotype that included predominant language impairment, suggestive of non-fluent progressive aphasia. We show that two thoroughly studied patients without other known genetic changes harbored TP73 rare variants, which are pathogenic in silico. This adds evidence to support the role of TP73 in the ALS-FTD spectrum, especially in primary progressive aphasia cases.