Prevalence and motor-functional correlates of frontotemporal-spectrum disorders in a large cohort of non-demented ALS patients.

BACKGROUND: This study aimed at (1) delivering generalizable estimates of the prevalence of frontotemporal-spectrum disorders (FTSDs) in non-demented ALS patients and (2) exploring their motor-functional correlates. METHODS: N = 808 ALS patients without FTD were assessed for motor-functional outcomes-i.e., disease duration, severity (ALSFRS-R), progression rate (ΔFS), and stage (King's and Milano-Torino-MiToS-systems)-cognition-via the cognitive section of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS)-and behaviour-via the ECAS-Carer Interview. Neuropsychological phenotypes were retrieved via Strong's revised criteria-i.e., ALS cognitively and behaviourally normal (ALScbn) or cognitively and/or behaviourally impaired (ALSci/bi/cbi). RESULTS: Defective ECAS-Total performances were detected in ~ 29% of patients, with the ECAS-Executive being failed by the highest number of patients (~ 30%), followed by the ECAS-Language, -Fluency, and -Memory (~ 15-17%) and -Visuospatial (~ %8). Apathy was the most frequent behavioural change (~ 28%), followed by loss of sympathy/empathy (~ 13%); remaining symptoms were reported in < 4% of patients. The distribution of Strong's classifications was as follows: ALScbn: 46.7%; ALSci/bi/cbi: 22.9%/20.0%/10.4%. Multinomial regressions on Strong's classifications revealed that lower ALSFRS-R scores were associated with a higher probability of ALSbi and ALScbi classifications (p ≤ .008). Higher King's and MiToS stages were associated with a higher probability of ALSbi classification (p ≤ .031). CONCLUSIONS: FTSDs affect ~ 50% of non-demented ALS patients, with cognitive deficits being as frequent as behavioural changes. A higher degree of motor-functional involvement is associated with worse behavioural outcomes-with this link being weaker for cognitive deficits.

Establishing and evaluating the gradient of item naming difficulty in post-stroke aphasia and semantic dementia.

Anomia is a common consequence following brain damage and a central symptom in semantic dementia (SD) and post-stroke aphasia (PSA), for instance. Picture naming tests are often used in clinical assessments and experience suggests that items vary systematically in their difficulty. Despite clinical intuitions and theoretical accounts, however, the existence and determinants of such a naming difficulty gradient remain to be empirically established and evaluated. Seizing the unique opportunity of two large-scale datasets of semantic dementia and post-stroke aphasia patients assessed with the same picture naming test, we applied an Item Response Theory (IRT) approach and we (a) established that an item naming difficulty gradient exists, which (b) partly differs between patient groups, and is (c) related in part to a limited number of psycholinguistic properties - frequency and familiarity for SD, frequency and word length for PSA. Our findings offer exciting future avenues for new, adaptive, time-efficient, and patient-tailored approaches to naming assessment and therapy.

Cognitive dispersion and its functional relevance in behavioral variant frontotemporal dementia and prodromal behavioral variant frontotemporal dementia.

OBJECTIVE: Executive dysfunction is characteristic of behavioral variant frontotemporal dementia (bvFTD) but can be challenging to detect. Dispersion-based intraindividual variability (IIV-d) is hypothesized to reflect a sensitive index of executive dysfunction and has demonstrated relevance to functional decline but has not been evaluated in bvFTD. METHOD: We report on 477 demographically matched participants (159 cognitively healthy [CH], 159 clinical Alzheimer's disease [AD], 159 clinical bvFTD/prodromal bvFTD) who completed the Uniform Data Set 3.0 Neuropsychological Battery. IIV-d was measured using the coefficient of variance (CoV; raw and demographically adjusted) across 12 Uniform Data Set 3.0 Neuropsychological Battery indicators and the informant-rated Functional Activities Questionnaire assessed daily functioning. RESULTS: Analysis of covariance showed that participants in the bvFTD/prodromal bvFTD group exhibited higher raw and demographically adjusted CoV compared to CH participants, at a very large effect size (d = 1.28-1.47). Demographically adjusted (but not raw) CoV was lower in the bvFTD/prodromal bvFTD group than the AD group, though the effect size was small (d = .38). Both CoV metrics accurately differentiated the bvFTD/prodromal bvFTD and CH groups (areas under the curve = .84), but not bvFTD/prodromal bvFTD and AD groups (areas under the curve = .59). Regression analyses in the bvFTD/prodromal bvFTD group indicated that higher IIV-d on both metrics was associated with greater daily functioning impairment, over and above covariates. CONCLUSIONS: Compared to healthy adults, individuals with bvFTD/prodromal bvFTD show greater levels of performance variability across a battery of neuropsychological measures, which interferes with everyday functioning. These data demonstrate the clinical utility and ecological validity of IIV-d in bvFTD/prodromal bvFTD, though these findings should be replicated in more diverse samples. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Basal parasympathetic deficits in C9orf72 hexanucleotide repeat expansion carriers relate to smaller frontoinsula and thalamus volume and lower empathy.

Diminished basal parasympathetic nervous system activity is a feature of frontotemporal dementia that relates to left frontoinsula dysfunction and empathy impairment. Individuals with a pathogenic expansion of the hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72), the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis, provide a unique opportunity to examine whether parasympathetic activity is disrupted in genetic forms of frontotemporal dementia and to investigate when parasympathetic deficits manifest in the pathophysiological cascade. We measured baseline respiratory sinus arrhythmia, a parasympathetic measure of heart rate variability, over two minutes in a sample of 102 participants that included 19 asymptomatic expansion carriers (C9+ asymp), 14 expansion carriers with mild cognitive impairment (C9+ MCI), 16 symptomatic expansion carriers with frontotemporal dementia (C9+ FTD), and 53 expansion-negative healthy controls (C9- HC) who also underwent structural magnetic resonance imaging. In follow-up analyses, we compared baseline respiratory sinus arrhythmia in the C9+ FTD group with an independent age-, sex-, and clinical severity-matched group of 26 people with sporadic behavioral variant frontotemporal dementia. The Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating-Sum of Boxes score was used to quantify behavioral symptom severity, and informant ratings on the Interpersonal Reactivity Index provided measures of participants' current emotional (empathic concern) and cognitive (perspective-taking) empathy. Results indicated that the C9+ FTD group had lower baseline respiratory sinus arrhythmia than the C9+ MCI, C9+ asymp, and C9- HC groups, a deficit that was comparable to that of sporadic behavioral variant frontotemporal dementia. Linear regression analyses indicated that lower baseline respiratory sinus arrhythmia was associated with worse behavioral symptom severity and lower empathic concern and perspective-taking across the C9orf72 expansion carrier clinical spectrum. Whole-brain voxel-based morphometry analyses in participants with C9orf72 pathogenic expansions found that lower baseline respiratory sinus arrhythmia correlated with smaller gray matter volume in the left frontoinsula and bilateral thalamus, key structures that support parasympathetic function, and in the bilateral parietal lobes, occipital lobes, and cerebellum, regions that are also vulnerable in individuals with C9orf72 expansions. This study provides novel evidence that basal parasympathetic functioning is diminished in FTD due to C9orf72 expansions and suggests that baseline respiratory sinus arrhythmia may be a potential non-invasive biomarker that is sensitive to behavioral symptoms in the early stages of disease.

Beta-to-Theta Entropy Ratio of EEG in Aging, Frontotemporal Dementia, and Alzheimer's Dementia.

BACKGROUND: Aging, frontotemporal dementia (FTD), and Alzheimer's dementia (AD) manifest electroencephalography (EEG) alterations, particularly in the beta-to-theta power ratio derived from linear power spectral density (PSD). Given the brain's nonlinear nature, the EEG nonlinear features could provide valuable physiological indicators of aging and cognitive impairment. Multiscale dispersion entropy (MDE) serves as a sensitive nonlinear metric for assessing the information content in EEGs across biologically relevant time scales. OBJECTIVE: To compare the MDE-derived beta-to-theta entropy ratio with its PSD-based counterpart to detect differences between healthy young and elderly individuals and between different dementia subtypes. METHODS: Scalp EEG recordings were obtained from two datasets: 1) Aging dataset: 133 healthy young and 65 healthy older adult individuals; and 2) Dementia dataset: 29 age-matched healthy controls (HC), 23 FTD, and 36 AD participants. The beta-to-theta ratios based on MDE vs. PSD were analyzed for both datasets. Finally, the relationships between cognitive performance and the beta-to-theta ratios were explored in HC, FTD, and AD. RESULTS: In the Aging dataset, older adults had significantly higher beta-to-theta entropy ratios than young individuals. In the Dementia dataset, this ratio outperformed the beta-to-theta PSD approach in distinguishing between HC, FTD, and AD. The AD participants had a significantly lower beta-to-theta entropy ratio than FTD, especially in the temporal region, unlike its corresponding PSD-based ratio. The beta-to-theta entropy ratio correlated significantly with cognitive performance. CONCLUSION: Our study introduces the beta-to-theta entropy ratio using nonlinear MDE for EEG analysis, highlighting its potential as a sensitive biomarker for aging and cognitive impairment.

Socioemotional Dysfunction From Temporal Lobe Involvement in Frontotemporal Dementia: A Preliminary Report.

OBJECTIVE: Socioemotional changes, rather than cognitive impairments, are the feature that defines behavioral variant frontotemporal dementia (bvFTD). Investigators have attributed the socioemotional changes in bvFTD and other dementias to frontal lobe dysfunction; however, recent work implies a further contribution from right anterior temporal disease. The authors evaluated relationships between regional brain atrophy and socioemotional changes in both bvFTD and early-onset Alzheimer's disease (EOAD). METHODS: This study explored the neuroanatomical correlations of performance on the Socioemotional Dysfunction Scale (SDS), an instrument previously shown to document socioemotional changes in bvFTD, among 13 patients with bvFTD not preselected for anterior temporal involvement and 16 age-matched patients with early-onset Alzheimer's disease (EOAD). SDS scores were correlated with volumes of regions of interest assessed with tensor-based morphometric analysis of MRI images. RESULTS: As expected, the bvFTD group had significantly higher SDS scores overall and smaller frontal regions compared with the EOAD group, which in turn had smaller volumes in temporoparietal regions. SDS scores significantly correlated with lateral anterior temporal lobe (ATL) atrophy, and a regression analysis that controlled for diagnosis indicated that SDS scores predicted lateral ATL volume. Within the bvFTD group, higher SDS scores were associated with smaller lateral and right ATL regions, as well as a smaller orbitofrontal cortex. Within the EOAD group, higher SDS scores were associated with a smaller right parietal cortex. CONCLUSIONS: This study confirms that, in addition to orbitofrontal disease, there is a prominent right and lateral ATL origin of socioemotional changes in bvFTD and further suggests that right parietal involvement contributes to socioemotional changes in EOAD.

Describing and assessing behavioural symptoms in amyotrophic lateral sclerosis with and without frontotemporal dementia: a scoping review.

PURPOSE OF REVIEW: Alongside motor and cognitive symptoms, amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal dementia (ALSFTD) present with behavioural symptoms, which can be challenging for all affected by the disease. A scoping review of studies published between 2011 and 2024 was conducted to present the breadth of behavioural symptoms in ALS and ALSFTD, explore how they are described and assessed, and identify patterns in the literature. FINDINGS: This scoping review identified 3939 articles, with 111/3939 meeting eligibility criteria. Most studies were from Australia (23.22%), Italy (16.94%) and the UK (14.29%); 75.67% were cross-sectional. Sample size ranged from 1 to 1013, as case studies were included. Overall mean age (100/111 studies) was 61.32 (SD = 4.15). Proportion of male patients (reported 102/111 studies) was 61.49%; mean disease duration (reported in 86/111 records) was 32.63 months (SD = 24.72). Papers described a broad range of behavioural symptoms (465 examples), which were thematically collated into seven categories: disinhibition (27.74%), apathy (25.16%), perseverative/compulsive behaviours (17.42%), hyperorality (10.53%), loss of sympathy or empathy (8.6%), psychotic symptoms (7.74%), and loss of insight about disease and changes (2.8%). Most studies (78.37%) used validated behavioural assessments that elicited carer's perspectives. SUMMARY: Despite extensive evidence of behavioural symptoms in ALS, implementation of assessments and management of behavioural symptoms in clinical care remain limited. Clinicians must assess behavioural symptoms, as these can negatively affect disease prognosis, patient treatment engagement and increase family distress. Measures capturing carers' perspectives through interviews are ideal as they can reveal anosognosia, lack of sympathy and lack of empathy.

Changes of brain functional network in Alzheimer's disease and frontotemporal dementia: a graph-theoretic analysis.

BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias, presenting with similar clinical features that challenge accurate diagnosis. Despite extensive research, the underlying pathophysiological mechanisms remain unclear, and effective treatments are limited. This study aims to investigate the alterations in brain network connectivity associated with AD and FTD to enhance our understanding of their pathophysiology and establish a scientific foundation for their diagnosis and treatment. METHODS: We analyzed preprocessed electroencephalogram (EEG) data from the OpenNeuro public dataset, comprising 36 patients with AD, 23 patients with FTD, and 29 healthy controls (HC). Participants were in a resting state with eyes closed. We estimated the average functional connectivity using the Phase Lag Index (PLI) for lower frequencies (delta and theta) and the Amplitude Envelope Correlation with leakage correction (AEC-c) for higher frequencies (alpha, beta, and gamma). Graph theory was applied to calculate topological parameters, including mean node degree, clustering coefficient, characteristic path length, global and local efficiency. A permutation test was then utilized to assess changes in brain network connectivity in AD and FTD based on these parameters. RESULTS: Both AD and FTD patients showed increased mean PLI values in the theta frequency band, along with increases in average node degree, clustering coefficient, global efficiency, and local efficiency. Conversely, mean AEC-c values in the alpha frequency band were notably diminished, which was accompanied by decreases average node degree, clustering coefficient, global efficiency, and local efficiency. Furthermore, AD patients in the occipital region showed an increase in theta band node degree and decreased alpha band clustering coefficient and local efficiency, a pattern not observed in FTD. CONCLUSIONS: Our findings reveal distinct abnormalities in the functional network topology and connectivity in AD and FTD, which may contribute to a better understanding of the pathophysiological mechanisms of these diseases. Specifically, patients with AD demonstrated a more widespread change in functional connectivity, while those with FTD retained connectivity in the occipital lobe. These observations could provide valuable insights for developing electrophysiological markers to differentiate between the two diseases.

Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown. OBJECTIVE: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD. METHODS: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age. RESULTS: The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases). CONCLUSIONS: These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change.

Advances in semantic dementia: Neuropsychology, pathology & neuroimaging.

Semantic dementia is a kind of neurodegenerative disorder, characterized by prominent semantic impairments and anterior temporal lobe atrophy. Since 2010, more studies have devoted to this rare disorder, revealing that it is more complex than we think. Clinical advances include more specific findings of semantic impairments and other higher order cognitive deficits. Neuroimaging techniques can help revealing the different brain networks affected (both structurally and functionally) in this condition. Pathological and genetic studies have also found more complex situations of semantic dementia, which might explain the huge variance existing in semantic dementia. Moreover, the current diagnosis criteria mainly focus on semantic dementia's classical prototype. We further delineated the features of three subtypes of semantic dementia based on atrophy lateralization with three severity stages. In a broader background, as a part of the continuum of neurodegenerative disorders, semantic dementia is commonly compared with other resembling conditions. Therefore, we summarized the differential diagnosis between semantic dementia and them. Finally, we introduced the challenges and achievements of its diagnosis, treatment, care and cross cultural comparison. By providing a comprehensive picture of semantic dementia on different aspects of advances, we hope to deepen the understanding of semantic dementia and promote more inspirations on both clinical and theoretical studies about it.

Analysis of the alpha activity envelope in electroencephalography in relation to the ratio of excitatory to inhibitory neural activity.

Alpha waves, one of the major components of resting and awake cortical activity in human electroencephalography (EEG), are known to show waxing and waning, but this phenomenon has rarely been analyzed. In the present study, we analyzed this phenomenon from the viewpoint of excitation and inhibition. The alpha wave envelope was subjected to secondary differentiation. This gave the positive (acceleration positive, Ap) and negative (acceleration negative, An) values of acceleration and their ratio (Ap-An ratio) at each sampling point of the envelope signals for 60 seconds. This analysis was performed on 36 participants with Alzheimer's disease (AD), 23 with frontotemporal dementia (FTD) and 29 age-matched healthy participants (NC) whose data were provided as open datasets. The mean values of the Ap-An ratio for 60 seconds at each EEG electrode were compared between the NC and AD/FTD groups. The AD (1.41 ±0.01 (SD)) and FTD (1.40 ±0.02) groups showed a larger Ap-An ratio than the NC group (1.38 ±0.02, p<0.05). A significant correlation between the envelope amplitude of alpha activity and the Ap-An ratio was observed at most electrodes in the NC group (Pearson's correlation coefficient, r = -0.92 ±0.15, mean for all electrodes), whereas the correlation was disrupted in AD (-0.09 ±0.21, p<0.05) and disrupted in the frontal region in the FTD group. The present method analyzed the envelope of alpha waves from a new perspective, that of excitation and inhibition, and it could detect properties of the EEG, Ap-An ratio, that have not been revealed by existing methods. The present study proposed a new method to analyze the alpha activity envelope in electroencephalography, which could be related to excitatory and inhibitory neural activity.

Visuospatial working memory in behavioural variant frontotemporal dementia: a comparative analysis with Alzheimer's disease using the box task.

OBJECTIVE: This study investigated the visuospatial working memory profiles of behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) using a novel computerised test of visuospatial working memory: the Box Task. METHODS: Twenty-eight bvFTD and 28 AD patients, as well as 32 age-matched control participants were recruited. All participants completed the Box Task and conventional neuropsychological tests of working memory, episodic memory, and visuospatial function. RESULTS: Both the bvFTD and AD groups exhibited significantly more Box Task between-search errors than the control group across all set sizes. Notably, the AD group demonstrated a significantly higher error rate compared to the bvFTD group. Regression analysis revealed that whilst episodic memory impairment significantly predicted Box Task error performance in AD, this was not the case for bvFTD. Additionally, a noticeable trend was observed for attention in predicting Box Task errors in both bvFTD and AD groups. The Box Task demonstrated high utility in differentiating between bvFTD and AD, with a decision tree correctly classifying 82.1% of bvFTD patients and 75% of AD patients. CONCLUSIONS: Our findings reveal significant visuospatial working memory impairments in bvFTD, albeit of lesser severity compared to disease-matched AD patients. The Box Task, a novel measure of visuospatial working memory, proved effective in differentiating between bvFTD and AD, outperforming many traditional neuropsychological measures. Overall, our findings highlight the utility of assessing visuospatial memory when differentiating between bvFTD and AD in the clinical setting.

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.

Frontal allographic agraphia in a patient with behavioral variant frontotemporal dementia.

We report a patient with behavioral variant frontotemporal dementia who developed agraphia, irritability, perseverative and stereotyped behavior, and dietary changes. MRI revealed bilateral frontal convexity atrophy. Neuropsychological examination showed fluent aphasia with perseverative allographic agraphia, mild semantic impairment, and dysexecutive syndrome. Allographic agraphia featured unidirectional conversion from hiragana (cursive form of Japanese phonograms) and kanji (Japanese morphograms) to katakana (square form of Japanese phonograms), as opposed to mutual (bidirectional) conversion between hiragana and katakana in parieto-occipital gyri lesions. Furthermore, all letters of the word were converted and this whole-word conversion may be characteristic of perseverative behavior in frontotemporal dementia.

Clinical heterogeneity within the ALS-FTD spectrum in a family with a homozygous optineurin mutation.

OBJECTIVE: Mutations in the gene encoding for optineurin (OPTN) have been reported in the context of different neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. Based on single case reports, neuropathological data in OPTN mutation carriers have revealed transactive response DNA-binding protein 43 kDa (TDP-43) pathology, in addition to accumulations of tau and alpha-synuclein. Herein, we present two siblings from a consanguineous family with a homozygous frameshift mutation in the OPTN gene and different clinical presentations. METHODS: Both affected siblings underwent (i) clinical, (ii) neurophysiological, (iii) neuropsychological, (iv) radiological, and (v) laboratory examinations, and (vi) whole-exome sequencing (WES). Postmortem histopathological examination was conducted in the index patient, who deceased at the age of 41. RESULTS: The index patient developed rapidly progressing clinical features of upper and lower motor neuron dysfunction as well as apathy and cognitive deterioration at the age of 41. Autopsy revealed an ALS-FTLD pattern associated with prominent neuronal and oligodendroglial TDP-43 pathology, and an atypical limbic 4-repeat tau pathology reminiscent of argyrophilic grain disease. The brother of the index patient exhibited behavioral changes and mnestic deficits at the age of 38 and was diagnosed with behavioral FTD 5 years later, without any evidence of motor neuron dysfunction. WES revealed a homozygous frameshift mutation in the OPTN gene in both siblings (NM_001008212.2: c.1078_1079del; p.Lys360ValfsTer18). INTERPRETATION: OPTN mutations can be associated with extensive TDP-43 pathology and limbic-predominant tauopathy and present with a heterogeneous clinical phenotype within the ALS-FTD spectrum within the same family.

Plasma Neurofilament Light Relates to Divergent Default and Salience Network Connectivity in Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia.

Background: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) show differential vulnerability to large-scale brain functional networks. Plasma neurofilament light (NfL), a promising biomarker of neurodegeneration, has been linked in AD patients to glucose metabolism changes in AD-related regions. However, it is unknown whether plasma NfL would be similarly associated with disease-specific functional connectivity changes in AD and bvFTD. Objective: Our study examined the associations between plasma NfL and functional connectivity of the default mode and salience networks in patients with AD and bvFTD. Methods: Plasma NfL and neuroimaging data from patients with bvFTD (n = 16) and AD or mild cognitive impairment (n = 38; AD + MCI) were analyzed. Seed-based functional connectivity maps of key regions within the default mode and salience networks were obtained and associated with plasma NfL in these patients. RESULTS: We demonstrated divergent associations between NfL and functional connectivity in AD + MCI and bvFTD patients. Specifically, AD + MCI patients showed lower default mode network functional connectivity with higher plasma NfL, while bvFTD patients showed lower salience network functional connectivity with higher plasma NfL. Further, lower NfL-related default mode network connectivity in AD + MCI patients was associated with lower Montreal Cognitive Assessment scores and higher Clinical Dementia Rating sum-of-boxes scores, although NfL-related salience network connectivity in bvFTD patients was not associated with Neuropsychiatric Inventory Questionnaire scores. CONCLUSIONS: Our findings indicate that plasma NfL is differentially associated with brain functional connectivity changes in AD and bvFTD.

Symptomatic progression of frontotemporal dementia with the TARDBP I383V variant.

We present a longitudinal description of a man with the TARDBP I383V variant of frontotemporal dementia (FTD). His progressive changes in behavior and language resulted in a diagnosis of the right temporal variant of FTD, also called the semantic behavioral variant (sbvFTD). We also present data from a small series of patients with the TARDBP I383V variant who were enrolled in a nationwide FTD research collaboration (ALLFTD). These data support slowly progressive loss of semantic function. While semantic dementia is infrequently considered genetic, the TARDBP I383V variant seems to be an exception. Longitudinal analyses in larger samples are warranted.

Amyotrophic lateral sclerosis; clinical features, differential diagnosis and pathology.

Amyotrophic lateral sclerosis (ALS) is a late-onset syndrome characterized by the progressive degeneration of both upper motor neurons (UMN) and lower motor neurons (LMN). ALS forms a clinical continuum with frontotemporal dementia (FTD), in which there are progressive language deficits or behavioral changes. The genetics and pathology underlying both ALS and FTD overlap as well, with cytoplasmatic misvocalization of TDP-43 as the hallmark. ALS is diagnosed by exclusion. Over the years several diagnostic criteria have been proposed, which in essence all require a history of slowly progressive motor symptoms, with UMN and LMN signs on neurological examination, clear spread of symptoms through the body, the exclusion of other disorder that cause similar symptoms and an EMG that it is compatible with LMN loss. ALS is heterogeneous disorder that may present in multitude ways, which makes the diagnosis challenging. Therefore, a systematic approach in the diagnostic process is required in line with the most common presentations. Subsequently, assessing whether there are cognitive and/or behavioral changes within the spectrum of FTD and lastly determining the cause is genetic. This chapter, an outline on how to navigate this 3 step process.

Cognitive trajectories preluding the onset of different dementia entities: a descriptive longitudinal study using the NACC database.

OBJECTIVE: To describe the 10-year preclinical cognitive trajectories of older, non-demented individuals towards the onset of the four most prevalent types of dementia, i.e., Alzheimer's disease(AD), Lewy body(LBD), vascular(VD) and frontotemporal dementia(FTD). METHODS: Our analysis focused on data from older (≥ 60years) NACC (National Alzheimer's Coordinating Center) participants. Four distinct presymptomatic dementia groups (AD-LBD-VD-FTD) and a comparison group of cognitively unimpaired(CU) participants were formed. Comprehensive cognitive assessments involving verbal episodic memory, semantic verbal fluency, confrontation naming, mental processing speed - attention and executive function - cognitive flexibility were conducted at baseline and on an approximately yearly basis. Descriptive analyses (adjusted general linear models) were performed to determine and compare the yearly cognitive scores of each group throughout the follow-up. Exploratory analyses were conducted to estimate the rates of cognitive decline. RESULTS: There were 3343 participants who developed AD, 247 LBD, 108 FTD, 155 VD and 3398 composed the CU group. Participants with AD performed worse on episodic memory than those with VD and LBD for about 3 to 4 years prior to dementia onset (the FTD group documented an intermediate course). Presymptomatic verbal fluency and confrontation naming trajectories differentiated quite well between the FTD group and the remaining dementia entities. Participants with incident LBD and VD performed worse than those with AD on executive functions and mental processing speed-attention since about 5 years prior to the onset of dementia, and worse than those with FTD more proximally to the diagnosis of the disorder. CONCLUSIONS: Heterogeneous cognitive trajectories characterize the presymptomatic courses of the most prevalent dementia entities.