Early Frontotemporal Dementia Research Articles

Neuroanatomy of FTD: Whole‐brain correlations between symptoms and pathologies

Distinct pathologies accumulate in multiple brain regions (BR) and shape the heterogeneous clinical presentation of frontotemporal dementia (FTD). It is unknown how regional pathological burden links to symptoms, what the role of co-occurring pathologies is, and whether the localization of pathology might be a bigger contributor to symptoms than the type of pathology. Our aim is to investigate how early FTD symptoms correlate to the burden of multiple pathologies throughout the brain.Post-mortem brain tissue of frontotemporal lobar degeneration (FTLD) donors from the Netherlands brain bank was dissected into twenty standard BR and stained for TAR DNA-binding protein 43 (TDP-43), tau, fused-in-sarcoma (FUS), amyloid-beta (Aβ), and alpha-synuclein. The burden of each pathological protein in each BR was quantified. All clinical records were reviewed to assess psychiatric, behavioral, language, and motor symptoms in the first three years from disease onset. Whole-brain clinico-pathological partial correlations were assessed using the heterogeneous correlation function (R 3.6.1). The local false discovery rate threshold was set at 0.01.Eighty-eight FTLD brain donors were studied, including 46 TDP-43, 35 tau, and 7 FUS. Significant positive partial correlations (p < 0.01) were found between hippocampal TDP-43 pathology and hallucinations (R = 0.23), perseverative-compulsive behavior (R = 0.25), depression (R = 0.28), and mania (R = 0.32). Tau pathology in the substantia nigra and locus coeruleus was linked to depression (R = 0.25, R = 0.24). Both TDP-43 and Aβ in the subthalamus were associated with severe disinhibition (R = 0.23, R = 0.25), while apathy correlated with both TDP-43 and tau burden in the parietal lobe (R = 0.27, R = 0.24). Parkinsonism was linked to TDP-43 burden in the substantia nigra (R = 0.33).Neuropsychiatric symptoms of FTD are linked to pathology burden in BR beyond the frontal lobes, including subcortical structures such as the hippocampus, the substantia nigra and locus coeruleus. Co-occurring pathologies are not simple bystanders, but could play a role in configuring FTD clinical phenotype. Different pathologies in the same BR correlate with the same symptoms.

Early detection of frontotemporal dementia (EDoF): A digital biomarker study

AbstractBackgroundWith the commencement of clinical trials in frontotemporal dementia (FTD), robust biomarkers that can detect the earliest signs of the disease and also measure treatment effect, are essential. Pen and paper assessments are laborious, administered infrequently, and can rely on subjective reporting. Using digital devices allows for more frequent, often continuous, assessment from home, whilst producing a wealth of objective data. The Early Detection of Frontotemporal dementia (EDoF) study aims to develop a series of digital measures that may be useful for the diagnosis of FTD and for outcome measures in trials.MethodThe EDoF study includes: a computerised cognitive battery, a mobile eye tracking device, a novel app that passively measures cognitive function by monitoring smartphone metadata, speech and language analysis using machine learning algorithms, actigraphy, and gait analysis. These measures are being validated in a large control population before being tested in symptomatic and presymptomatic genetic FTD within the Genetic FTD Initiative (GENFI) study.ResultWe are currently recruiting participants to the initial arms of the study, with over 1,300 healthy controls having already completed the computerized cognitive battery. The mobile eye tracking device measures eye movement abnormalities but also uses instructionless eye movement tasks to measure executive function and social cognition. Pilot eye tracking data shows abnormalities of these tasks in symptomatic FTD, and also for antisaccadic eye movements in presymptomatic FTD. Normative data for all of the measures will be generated helping to assess construct validity and retest reliability.ConclusionEDoF is the first study aiming to use a comprehensive set of digital measures to detect early FTD. It may also prove useful for home monitoring within future therapeutic trials of FTD.

Premorbid de novo artistic creativity in frontotemporal dementia (FTD) syndromes.

The emergence of new artistic activities or shifts in artistic style in patients with frontotemporal dementia (FTD) syndromes is well documented at or after disease onset. However, a closer look in the literature reveals emerging artistic creativity also before FTD onset, although the significance and underlying pathology of such creative endeavors remain elusive. Here, we systematically review relevant studies and report an additional FTD case to elaborate on artistic activities that developed years before disease manifestation by paying particular attention to the sequence of events in individual patients' biography and clinical history. We further discuss the FTD patient's creative activities in the context of their life events, other initial or "premorbid" dementia symptoms or risk factors described in the literature such as mental illness and mild behavioral impairment (MBI), as well as changes in neuronal systems (i.e., neuroimaging and neuropathology). In addition to our FTD patient, we identified five published cases with an FTD syndrome, including three with FTD, one with primary progressive aphasia (PPA), and one with the behavioral variant of PPA (bvPPA). Premorbid novel creativity emerged across different domains (visual, musical, writing), with the FTD diagnosis ensuing artistic productivity by a median of 8years. Data on late-life and pre-dementia life events were available in four cases. The late creative phase in our case was accompanied by personality changes, accentuation of personality traits, and cessation of painting activities occurred with the onset of memory complaints. Thus, premorbid personality changes in FTD patients can be associated with de novo creative activity. Stressful life events may also contribute to the burgeoning of creativity. Moreover, primary neocortical areas that are largely spared by pathology at early FTD stages may facilitate the engagement in artistic activities, offering a window of opportunity for art therapy and other therapeutic interventions during the MBI stage or even earlier.

A multimodal MRI-based classification signature emerges just prior to symptom onset in frontotemporal dementia mutation carriers

BackgroundMultimodal MRI-based classification may aid early frontotemporal dementia (FTD) diagnosis. Recently, presymptomatic FTD mutation carriers, who have a high risk of developing FTD, were separated beyond chance level from controls...

Frontotemporal dementia misdiagnosed as schizophrenia or other psychotic disorder

IntroductionFrontotemporal dementia (FTD) encompasses a group of clinical features that include personality and behavior changes (disinhibition, social isolation, antisocial behavior, compulsion) and executive dysfunction (poor planning, loss of judgment and loss of insight). These features may lead to an incorrect diagnosis of a primary psychiatric disorder.ObjectivesTo emphasize the difficulties in making a clinical distinction between early frontotemporal dementia and other psychiatric diseases.MethodsWe describe 11 patients who suffered from FTD, while initially had diagnosed with primary psychiatric disorders. The correct diagnosis was achieved by psychiatric and neuropsychological evaluations (WAIS SCALE, ACE-R, MMSE), neuroimaging studies (MRI 7/11, SPECT 8/11) and applying the international consensus criteria for FTD.ResultsAll patients (5 males and 6 females) were initially diagnosed with psychiatric disorders: schizophrenia (2/11), bipolar disorders (4/11), depression (5/11), schizoaffective disorder (1/11), somatization disorder (1/11), personality disorders (2/11), malingering (1/11), alcohol dependence (1/11), while 5 patients had more than one diagnosis. The age of onset varied from 19 to 53 years old. Final diagnosis of FTD was delayed on average 6,5 years from the onset of symptoms.ConclusionClinicians should be familiar with the clinical entity of FTD and its difficult distinction from other psychiatric disorders. A possible hospitalization of a patient with FTD in a psychiatric department and the social impact that it brings may be avoided. On the other hand, the proper care of FTD patients (pharmacological and psychosocial) improves the quality of life of patients and their caregivers.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia.

We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of MAPT (microtubule-associated protein tau) or GRN (progranulin) mutations. In this case-control study, 75 healthy individuals (aged 20-70 years) with 50% risk of frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, structural MRI, and fMRI. We used voxel-based morphometry and tract-based spatial statistics for voxel-wise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsular, anterior midcingulate, and posterior cingulate cortices. Carriers (n = 39) and noncarriers (n = 36) had similar neuropsychological performance, except for lower Letter Digit Substitution Test scores in carriers. Worse performance on Stroop III, Rivermead Behavioral Memory Test, and Happé Cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy in the right uncinate fasciculus was found in carriers compared with controls. Reductions in functional connectivity between anterior midcingulate cortex and frontoinsula and several other brain regions were found in carriers compared with controls and correlated with higher age in carriers, but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found, except for a small cluster of higher volume in the precentral gyrus in carriers. This study demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.

Microstructural Characterization of Motor Pathway Disruption in Early Frontotemporal Dementia: A DTI Investigation on the FTD-ALS Continuum (P06.059)

Microstructural Characterization of Motor Pathway Disruption in Early Frontotemporal Dementia: A DTI Investigation on the FTD-ALS Continuum (P06.059)

Episodic memory in frontotemporal dementia: a critical review

This review offers a critical appraisal of the literature on episodic memory performance in frontotemporal dementia. Historically, description of patients diagnosed with what was then known as Pick's disease included the presence of memory deficits and an underlying amnestic syndrome was noted in some of these patients. Over the last 20 years, however, the clinical view has been that episodic memory processing is relatively intact in the frontotemporal dementia syndrome. In particular, patients with the subtypes of behavioural variant frontotemporal dementia and progressive non-fluent aphasia are reported to perform within normal limits on standard memory tests. In the third clinical presentation of frontotemporal dementia, semantic dementia, relatively intact episodic memory against a significantly impaired semantic memory was regarded as the hallmark. This position was instrumental in the development of clinical diagnostic criteria for frontotemporal dementia in which amnesia was explicitly listed as an exclusion criterion for the disease. The relative intactness of episodic memory, therefore, appeared to be a useful diagnostic marker to distinguish early frontotemporal dementia from Alzheimer's disease, in which early episodic memory disturbance remains the most common clinical feature. We argue that recent evidence questions the validity of preserved episodic memory in frontotemporal dementia, particularly in behavioural variant frontotemporal dementia. In semantic dementia, a complex picture emerges with preservation of some components of episodic memory, notably recognition-based visual memory and recall of recent autobiographical events. We propose a critical synthesis of recent neuropsychological evidence on retrograde and anterograde memory in light of neuroimaging and neuropathological findings, demonstrating involvement of medial temporal structures in frontotemporal dementia, structures known to be critical for episodic memory processing. We further argue that the multifactorial nature of most memory tests commonly used clinically fail to capture the memory deficits in frontotemporal dementia and that sensitive assessment tools of memory are needed. Together, recent clinical and experimental findings and the historical evidence represent a strong case for a re-evaluation of the importance of memory disturbance in the clinical diagnosis of frontotemporal dementia.

Conflict monitoring in early frontotemporal dementia

Despite the extensive frontal atrophy and behavioral disinhibition that characterizes behavioral variant frontotemporal dementia (bvFTD), many studies of early bvFTD suggest normal executive functioning (EF). The current study examined cognitive control in patients with bvFTD who otherwise seemed cognitively normal. Subjects included 7 patients with bvFTD with normal neuropsychological test scores, 7 patients with bvFTD matched for Mini-Mental State Examination score but with impaired neuropsychological test scores, and 14 normal controls. A flanker paradigm and other measures of EF were administered to participants. A semiautomated parcellation program was used to analyze structural MRI scans. On the flanker task, multivariate analysis of variance revealed a significant condition X diagnosis interaction. Both bvFTD groups showed a larger congruency effect than normal controls, i.e., they displayed disproportionately reduced speed and accuracy on incongruent trials relative to congruent trials. Imaging data illustrated significant orbitofrontal atrophy in patients with early bvFTD as compared with controls. Patients with behavioral variant frontotemporal dementia (bvFTD) who performed within normal limits on clinical tests of executive functioning demonstrated a select impairment on an experimental test of cognitive control, suggesting a subtle impairment in inhibiting attention or response to the irrelevant stimuli. Measures of neuropsychological functioning sensitive to the ventromedial prefrontal cortex may be useful in early diagnosis of patients with bvFTD. Our understanding of this syndrome may be increased by considering the efficiency of selective inhibition, a fundamental component of executive cognitive control.

A neuropsychological battery to detect specific executive and social cognitive impairments in early frontotemporal dementia

Traditional cognitive tests may not be sensitive for the early detection of executive and social cognitive impairments in the behavioural variant of frontotemporal dementia. The aim of this study was to detect specific executive and social cognitive deficits in patients with early behavioural variant frontotemporal dementia using a battery of tests previously shown to be sensitive to frontal lobe dysfunction. Behavioural variant frontotemporal dementia patients and paired controls were assessed with a complete standard neuropsychological battery evaluating attention, memory, visuospatial abilities, language and executive functions. All participants were then assessed with our Executive and Social Cognition Battery, which included Theory of Mind tests (Mind in the Eyes, Faux Pas), the Hotel Task, Multiple Errands Task-hospital version and the Iowa Gambling Task for complex decision-making. Patients were divided into two groups according to their Addenbrooke's Cognitive Examination scores, a measure of general cognitive status. Low Addenbrooke's Cognitive Examination patients differed from controls on most tasks of the standard battery and the Executive and Social Cognition Battery. While high Addenbrooke's Cognitive Examination patients did not differ from controls on most traditional neuropsychological tests, significant differences were found between this high-functioning behavioural variant of frontotemporal dementia group and controls on most measures of our Executive and Social Cognition Battery. Our results suggest that the Executive and Social Cognition Battery used in this study is more sensitive in detecting executive and social cognitive impairment deficits in early behavioural variant of frontotemporal dementia than the classical cognitive measures.

Changes in dietary or eating behavior in frontotemporal dementia versus Alzheimer's disease.

Changes in dietary or eating behavior are common in dementia and may help distinguish between different dementing illnesses. To evaluate and characterize differences in dietary and eating behavior among patients with early frontotemporal dementia (FTD) versus Alzheimer's disease (AD). This study administered the Food-Related Problems Questionnaire (FRPQ) to caregivers of 16 patients with FTD and 16 comparable patients with AD. The FRPQ was evaluated at initial presentation when patients presented for a diagnostic evaluation. Compared with the AD patients, the FTD patients had significantly more changes on the FRPQ. Subscale analysis indicated that the FTD patients showed impairment of observed satiety, improper taking of food, and inappropriate responses when food was not available. The use of food-related questionnaires, such as the FRPQ, can help distinguish FTD patients, early in their course, from those with AD and can further characterize the altered dietary and eating behavior.

Symptoms of Frontotemporal Dementia Provide Insights into Orbitofrontal Cortex Function and Social Behavior

Recent investigations into the brain substrates of behavioral changes in frontotemporal dementia (FTD) demonstrate that the orbitofrontal cortex (OFC) plays a crucial role in normal social and emotional behavior. The initial symptoms of FTD reflect the early involvement of OFC as well as the disruption of an associated network involving the insula, striatum, and medial frontal lobes. As predicted by patients with other types of OFC lesions, FTD patients show impairments involving stimulus-reward reversal learning, response inhibition, and ability to judge the appropriateness of their behavior in the social context. While the natural reward system remains intact in these patients, that is, patients will seek out directly rewarding stimuli, such as food and sex, with progressive OFC dysfunction they lose the ability to process complex stimulus-reward contingencies. These abnormalities are apparent in their social interactions, which break down early in the disease. Also, deficits in emotion recognition and empathy have been directly linked to OFC atrophy in these patients. In contrast, some patients with early FTD show intact cognitive skills, including memory and executive functioning. Here, we review the behavioral and neuropsychological changes that accompany OFC atrophy in FTD and argue that phylogenetically new neurons found in this region, called von Economo neurons, are selectively vulnerable in FTD.

Early frontotemporal dementia targets neurons unique to apes and humans

Frontotemporal dementia (FTD) is a neurodegenerative disease that erodes uniquely human aspects of social behavior and emotion. The illness features a characteristic pattern of early injury to anterior cingulate and frontoinsular cortex. These regions, though often considered ancient in phylogeny, are the exclusive homes to the von Economo neuron (VEN), a large bipolar projection neuron found only in great apes and humans. Despite progress toward understanding the genetic and molecular bases of FTD, no class of selectively vulnerable neurons has been identified. Using unbiased stereology, we quantified anterior cingulate VENs and neighboring Layer 5 neurons in FTD (n = 7), Alzheimer's disease (n = 5), and age-matched nonneurological control subjects (n = 7). Neuronal morphology and immunohistochemical staining patterns provided further information about VEN susceptibility. FTD was associated with early, severe, and selective VEN losses, including a 74% reduction in VENs per section compared with control subjects. VEN dropout was not attributable to general neuronal loss and was seen across FTD pathological subtypes. Surviving VENs were often dysmorphic, with pathological tau protein accumulation in Pick's disease. In contrast, patients with Alzheimer's disease showed normal VEN counts and morphology despite extensive local neurofibrillary pathology. VEN loss links FTD to its signature regional pattern. The findings suggest a new framework for understanding how evolution may have rendered the human brain vulnerable to specific forms of degenerative illness.

The Scale for Emotional Blunting in Patients with Frontotemporal Dementia

Emotional blunting may underlie many of the behavioral features of frontotemporal dementia (FTD). The Scale for Emotional Blunting (SEB) was evaluated in 12 patients with early FTD, 12 patients with Alzheimer's disease (AD), and 12 normal controls. There were overall group differences on the SEB, and the FTD patients had greater emotional blunting than the AD patients. The SEB had good inter-rater reliability and a sensitivity of 92%, and a specificity of 83.5% for FTD. These findings suggest that the SEB may be a good instrument for the early detection and quantification of emotional blunting in patient with FTD.

P4-112: Is early frontotemporal dementia a dementia?

In the absence of a biomarker, the diagnosis of frontotemporal dementia (FTD) depends on recognizing the neuropsychiatric symptoms of this disease. The traditional model of cognitive loss of Alzheimer's disease (AD) may not apply in the beginning stages of FTD, when patients have predominant behavioral symptoms. Patients with early FTD often lack the multiple cognitive impairments or memory loss necessary to meet established criteria (DSM–IV or ICD–10) for dementia. To determine whether patients with FTD meet criteria for dementia on presentation within two years of onset of their disease. We reviewed all patients meeting Consensus Criteria for FTD (Neary et al, 1998) and having corroborative frontal or frontotemporal changes on functional neuroimaging (either PET or SPECT). All FTD patients in this study presented for evaluation in university–based neurological clinics. All patients were within two years of onset of their first symptoms. This study included only the behavioral variant of frontotemporal lobar degeneration and excluded patients with primary progressive aphasia or semantic dementia. All patients underwent initial neurobehavioral and neuropsychological testing at baseline and again at two years. On initial presentation, 23 (36.5%) patients met all core criteria for FTD and were diagnosed with the disorder; an additional 40 patients met all core criteria at two years from the initial presentation. Of these 63 patients eventually diagnosed with FTD, none met criteria (DSM–IV or ICD–10) for dementia at baseline by neurobehavioral or neuropsychological testing, and 43 (68.3%) met dementia criteria at two years from the initial presentation. Most FTD patients initially lacked sufficient memory and other cognitive deficits to characterize as “dementia.” FTD is often difficult to diagnose. Patients with FTD present with subtle personality or behavioral changes rather than cognitive deficits typical of AD. Although neuropsychological studies report abnormalities in frontal–executive functions and language, with less impaired memory and visuospatial skills than AD, the non–cognitive behavioral changes are actually the earliest and most characteristic features of FTD. This report suggests that early FTD defies the neuropsychological model of dementia and that clinicians need better diagnostic tools for recognizing this neuropsychiatric disorder.

Frontotemporal Dementia, Semantic Dementia, and Alzheimer’s Disease: The Contribution of Standard Neuropsychological Tests to Differential Diagnosis

CERAD-NAB (Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery) data were compared between 51 patients with frontotemporal dementia, 13 with semantic dementia, and 69 with Alzheimer's disease. There were statistically significant differences between the 3 groups. Compared with patients with Alzheimer's disease, patients with frontotemporal dementia were more impaired on Animal Fluency but not on any other CERAD-NAB subtest. Patients with semantic dementia performed worse in Animal Fluency and Boston Naming Test compared with frontotemporal dementia and Alzheimer's disease. Multiple logistic regression analysis revealed that in the differentiation between frontotemporal dementia and Alzheimer's disease, the combination of Animal Fluency and Boston Naming Test correctly classified 90.5% of patients. In segregating semantic dementia and Alzheimer's disease, the combination of Boston Naming Test and Mini Mental State Examination resulted in a correct classification of 96.3%. These findings demonstrate that the Mini Mental State Examination and the language subtests of the CERAD-NAB are valuable clinical instruments for the differential diagnosis between early frontotemporal dementia, semantic dementia, and Alzheimer's disease.

Frontotemporal Behavioral Scale

At autopsy, frontotemporal dementia (FTD) account for up to 20% of degenerative dementia cases, although FTDs are underrecognized in memory clinics. FTDs are confused with Alzheimer disease (AD) or vascular dementia (VaD). These misdiagnosis may affect the results of AD pharmacological trials. The first manifestations of FTD are behavioral abnormalities. The aim of this study was to assess a behavioral scale of frontal lobe dysfunction and to determine a behavioral cutoff to diagnose early FTD and distinguish it from AD and VaD. The score of the behavioral frontotemporal lobe dysfunction assessment scale was higher in FTD than in other dementias (p < 0.0001). With a cutoff of 3 points on the scale, FTD patients were diagnosed with a specificity of 95% and sensitivity of 91%. Noncognitive symptoms known to be institutionalization factors could contribute to differences between etiologies of mild dementia.