Progressive Personality Changes Research Articles

Very Young Onset Behavioral Variant Frontotemporal Dementia: A Case Series

ABSTRACT Frontotemporal dementia (FTD) is a clinical syndrome characterized by progressive changes in personality, behavior, and/or language with relative sparing of memory/learning. The behavioral variant of FTD (bvFTD) typically presents with insidious onset of changes in personality and behavior with a gradually progressive course. Such presentation can be easily attributed to other psychiatric disorders such as schizophrenia, obsessive compulsive disorder, or mood disorders. The most common age of presentation of bvFTD is in the fifth or sixth decades of life. However, in this case series, we present two rare cases of very early onset bvFTD with the onset of symptoms as early as third decade of life who were misdiagnosed as other psychiatric disorders.

Metabolic biomarkers for Alzheimer's disease: A mini review

Alzheimer's disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia worldwide, which characterized by progressive cognitive decline, memory impairment, and changes in behavior and personality. The prevalence of AD is expected to rise significantly in the coming decades due to the aging population, making it a major public health concern. Mounting evidence suggests that metabolic dysregulation plays a critical role in the pathogenesis of AD. In this mini review, we provide an overview of the current understanding of the interplay between metabolism and AD. Specifically, we explore the dysregulation of glucose metabolism, lipid metabolism, amino acid metabolism, and nitrogen oxide synthesis pathways in AD. These metabolic alterations have been identified as potential biomarkers for early diagnosis and prognosis of AD. Additionally, we discuss the current status of research in this field, including the advancements in metabolomics and imaging techniques that have allowed for the identification and validation of metabolic biomarkers.

New Approaches to the Treatment of Frontotemporal Dementia.

Frontotemporal dementia (FTD) comprises a diverse group of clinical neurodegenerative syndromes characterized by progressive changes in behavior, personality, executive function, language, and motor function. Approximately 20% of FTD cases have a known genetic cause. The three most common genetic mutations causing FTD are discussed. Frontotemporal lobar degeneration refers to the heterogeneous group of neuropathology underlying FTD clinical syndromes. While there are no current disease-modifying treatments for FTD, management includes off-label pharmacotherapy and non-pharmacological approaches to target symptoms. The utility of several different drug classes is discussed. Medications used in the treatment of Alzheimer's disease have no benefit in FTD and can worsen neuropsychiatric symptoms. Non-pharmacological approaches to management include lifestyle modifications, speech-, occupational-, and physical therapy, peer and caregiver support, and safety considerations. Recent developments in the understanding of the genetics, pathophysiology, neuropathology, and neuroimmunology underlying FTD clinical syndromes have expanded possibilities for disease-modifying and symptom-targeted treatments. Different pathogenetic mechanisms are targeted in several active clinical trials, opening up exciting possibilities for breakthrough advances in treatment and management of FTD spectrum disorders.

HEALTH COACHING FOR DEMENTIA CAREGIVERS: LESSONS LEARNED FROM THE ICARE4ME STUDY

Abstract Frontotemporal dementia (FTD) is a common cause of young-onset neurodegenerative disease that causes progressive changes in behavior and personality. FTD is often diagnosed around age 60, creating complex care needs that result in caregivers of persons with FTD experiencing high rates of depression, burden, and poor self-care. The iCare4Me for FTD study (NCT04686266) randomized 15 caregivers to receive a virtual health coaching intervention over 6 months (10 sessions) and 15 caregivers to the control group. To better understand the caregivers’ experience with the health coach intervention, two focus groups with intervention group caregivers (n=5) were held. Focus groups were recorded, transcribed and coded using content analysis. Caregivers reported the most valuable aspect was the relationship that was developed with their health coach. Caregivers particularly valued having someone to talk to who was outside their immediate social and support networks. It was noted the structured self-care curriculum served as a good backbone for discussions, but more specific coping conversations related to loss of patient empathy, prognostic uncertainty, and anticipatory grief are needed. One caregiver described being, “… awash in grief and it's affected my memory” while another described “grief is a big issue and I don't really find too many people understand it, because my husband is alive, but so many parts of him are gone”. These findings will be used to inform future studies utilizing health coaches for caregivers of persons with FTD. Implications for evidence-based virtual health coaching interventions with caregivers of persons living with FTD will be described.

Chronicling the diagnostic journey, symptom experiences, and disease impact in frontotemporal degeneration

AbstractBackgroundFrontotemporal degeneration (FTD) is an umbrella term encompassing a range of rare neurodegenerative disorders that cause progressive decline or changes in cognition, language, behavior, and personality. The FTD Insights Survey was created with the aim of gathering information on the lived experience of FTD. Here we present a subset of survey data chronicling the diagnostic journey, symptoms experienced, and the impact of FTD on distress, quality of life, and independence, in the mild to moderate stages of the disease course.MethodIn total, 1,796 individuals completed the survey. Persons reported as severe to profoundly impaired due to FTD, as well as past caregivers, were excluded for this analysis. The resulting cohort included 219 individuals diagnosed with FTD and 437 current care partners, representing a range of FTD diagnoses (n = 395 behavioral variant frontotemporal dementia or Pick’s disease; n = 155 primary progressive aphasia; n = 61 progressive supranuclear palsy or corticobasal syndrome; n = 13 FTD with amyotrophic lateral sclerosis; n = 32 unknown).ResultAround half of survey respondents saw three or more doctors before an FTD diagnosis was given, and a range of prior diagnoses, including primary psychiatric disorders, Parkinson’s disease, or Alzheimer’s disease, were noted. Most frequently endorsed symptoms tended to be consistent with clinical characteristics of the specific diagnosis, though there was significant variability in symptoms reported within diagnostic categories as well as considerable overlap in symptoms between diagnostic categories. Cognitive and language symptoms of FTD were generally most distressing to the person diagnosed, and a loss of independence was highly endorsed as affecting quality of life. The distinct perspectives of diagnosed persons and care partners regarding disease impact differed notably for bvFTD/Pick’s disease. Participating independently in activities, within the home, outside the home, and with other people, were reported as challenging for people living with FTD, underscoring the significant disruption to daily living even at the mild and moderate stages of disease.ConclusionOverall, by heeding the perspectives of those living with FTD, we can begin to design more meaningful research studies, provide better care, and develop new therapies that improve quality of life

Neuropathological and behavioral characterization of aged Grn R493X progranulin-deficient frontotemporal dementia knockin mice

Frontotemporal lobar degeneration (FTLD) causes a spectrum of clinical presentations of frontotemporal dementia (FTD), including progressive changes in behavior, personality, executive function, and language. Up to 20% of familial FTLD cases are caused by progranulin (GRN) haploinsufficiency (FTD-GRN), with one of the most common causal variant being a nonsense mutation at arginine 493 (R493X). Recently, a genetic knockin FTD-GRN mouse model was generated bearing this GrnR493X mutation, at the analogous arginine in murine Grn. Aged, homozygous GrnR493X mice (GrnR493X/R493X) have been shown to phenotypically replicate several neuropathological hallmarks previously demonstrated in Grn null mice. We conducted a comprehensive neuropathological and behavioral assessment of 18 month old GrnR493X/R493X mice, observing a striking lysosomal dysfunction and thalamic neurodegeneration not previously described in this model, as well as a male-specific increase in generalized anxiety. These findings provide additional phenotypic markers of pathogenesis in aged GrnR493X/R493X mice that will contribute to better defining mechanisms underlying FTD-GRN, and offer relevant outcome measures for preclinical efficacy testing of novel therapeutics that target nonsense mutations leading to this devastating disease.

A-072 Neuropsychological Case Study of Behavioral Variant Frontotemporal Neurocognitive Disorder​ in a Vietnamese Woman in a Community Health Setting

Abstract Objective Behavioral variant frontal temporal dementia (bvFTD) is characterized by progressive changes in behavior, personality, and cognition. Little is published on the presentation in non-English-speaking populations. Here is the case of a neuropsychological evaluation in a community health setting where language and cultural considerations were salient. Method A 73-year-old, right-handed, monolingual Vietnamese widowed female homemaker with five years of education and low literacy, was referred after gradual personality changes over five years caused family tension and a need for increased monitoring. History includes cardiovascular disease, hypertension, hypercholesterolemia, cholestatic hepatitis, and depression with remitting psychotic features and suicidal ideation. Neuroimaging shows right temporal encephalomalacia and mild diffuse atrophy commensurate with age. Results A bilingual phone interpreter was used. Test findings revealed low scores across all but two tasks (visuospatial processing speed, recognition memory). Several confrontation naming items were unknown to the patient or culturally irrelevant, per interpreter. Interview with an English-speaking daughter revealed declines in behavior and social comportment (e.g., unsympathetic, demanding, rigid, repetitive, disorganized, compulsive shopping and gaming, confabulatory) and modest declines in activities of daily living. Presentation was notably childlike, overly affectionate, “grabby”, insistent, restless, with poor conversational turn-taking (with interpreter), but generally intact expressive and receptive language. BvFTD was diagnosed. Conclusions Addressing needs of a diverse, multi-cultural population in a community health setting can present significant challenges. This case study highlights the importance of non-psychometric sources of data, including history, observation, and collateral interviews, along with consideration of education, language, and culture on the evaluation process and case conceptualization.

Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

18F-THK5351 PET Imaging in the Behavioral Variant of Frontotemporal Dementia.

Background and PurposeBehavioral variant frontotemporal dementia (bvFTD) is a subtype of frontotemporal dementia, which has clinical symptoms of progressive personality and behavioral changes with deterioration of social cognition and executive functions. The pathology of bvFTD is known to be tauopathy or TDP-43 equally. We analyzed the 18F-THK5351 positron emission tomography (PET) scans, which were recently developed tau PET, in patients with clinically-diagnosed bvFTD.MethodsForty-eight participants, including participants with behavioral variant frontotemporal dementia (bvFTD, n=3), Alzheimer's disease (AD, n=21) and normal cognition (NC, n=24) who completed 3T magnetic resonance images, 18F-THK5351 PET scans, and detailed neuropsychological tests were included in the study. Voxel-wise statistical analysis and region of interest (ROI)-based analyses were performed to evaluate the retention of THK in bvFTD patients.ResultsIn the voxel-based and ROI-based analyses, patients with bvFTD showed greater THK retention in the prefrontal, medial frontal, orbitofrontal, anterior cingulate, insula, anterior inferior temporal and striatum regions compared to NC participants. Left-right asymmetry was noted in the bvFTD patients. A patient with extrapyramidal symptoms showed much greater THK retention in the brainstem.ConclusionsThe distribution of THK retention in the bvFTD patients was mainly in the frontal, insula, anterior temporal, and striatum regions which are known to be the brain regions corresponding to the clinical symptoms of bvFTD. Our study suggests that 18F-THK5351 PET imaging could be a supportive tool for diagnosis of bvFTD.

Fronto-temporal Dementia with Early Onset

IntroductionEven though it is not the most common type of dementia, frontotemporal dementia (FTD) is a major health problem. It affects people younger than 65 with similar frequency as Alzheimer's dementia (AD) and has a progressive course that leads to inevitable deterioration in functioning. Still, FTD is not a unique entity in ICD- 10 classification.ObjectivesTo investigate the diagnostic and treatment difficulties in FTD.AimsTo show very rapid and progressive deterioration in people with early onset FTD.MethodsWe will present a series of cases showing progressive cognitive deterioration and prominent personality changes in patients with FTD hospitalised at University Psychiatric Hospital Vrapce since 2013 to 2015. Collected data included anamnestic and heteroanamnestic information, blood tests and neroimaging.ResultsOur findings showed a significance of early onset FTD, with subtle, untypical symptoms at the beginning, and galloping deterioration during the course of illness.ConclusionsPresented patients with FTD showed rapid and progressive nature of disease with infaust prognosis. Even though early onset patients make 20% of overall number of patients with FTD, we consider that it is necessary to separate them from late onset patients in future classification systems.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Frontotemporal Dementia: Identification and Management

Dementia is a disease primarily affecting older adults in their ability to carry out daily activities. Frontotemporal dementia (FTD), a leading cause of early-onset dementia, can present in the fourth and fifth decade by progressive changes in personality, affect, and behavior. The atypical presentation of FTD may resemble a midlife crisis, depression, schizophrenia, or a traumatic brain injury among its causes. The etiology of FTD is unknown, although genetic links have been suggested, thus treatment focuses on behavioral and symptom management. Early diagnosis of FTD is needed to better support the emotional and financial burdens of family and caregivers.

An Autopsy Confirmed Case of Behavioral Variant Frontotemporal Dementia with Corticobasal Degeneration Pathology

A 63-year-old man presented with a 1.5-year history of progressive personality changes. Clinical evaluations revealed severe frontal dysfunction and bilateral frontal atrophy/glucose hypometabolism. He was diagnosed as probable behavioral variant frontotemporal dementia. He continued to decline, and died at the age of 66. At autopsy, numerous tau-positive gilial threads and coiled bodies were observed in the white matter. Tau-positive astrocytic plaques and neuronal cytoplasmic inclusions were also seen in cerebral cortices, which were compatible with corticobasal degeneration. J Korean Neurol Assoc 33(3):178-182, 2015

Behavioural variant frontotemporal dementia: Clinical and therapeutic approaches

IntroductionBehavioural variant frontotemporal dementia (bvFTD) is the most frequent presentation in the clinical spectrum of frontotemporal dementia (FTD) and it is characterised by progressive changes in personality and conduct. Major breakthroughs in molecular biology and genetics made during the last two decades have lent us a better understanding of this syndrome, which may be the first manifestation in many different neurodegenerative diseases. DevelopmentWe reviewed the main epidemiological, clinical, diagnostic and therapeutic aspects of bvFTD. Most cases manifest sporadically and the average age of onset is 58 years. Current criteria for bvFTD propose three levels of diagnostic certainty: possible, probable, and definite. Clinical diagnosis is based on a detailed medical history provided by family members and caregivers, in conjunction with neuropsychological testing. Treatments which have been used in bvFDT to date are all symptomatic and their effectiveness is debatable. New drugs designed for specific molecular targets that are implicated in frontotemporal lobar degeneration are being developed. ConclusionsBvFDT is a frequent cause of dementia. It is a non-specific syndrome associated with heterogeneous histopathological and biomolecular findings. The definition of clinical subtypes complemented by biomarker identification may help predict the underlying pathology. This knowledge, along with the development of drugs designed for molecular targets, will offer new treatment possibilities.

ADULT ONSET LEUKOENCEPHALOPATHY DUE TO CSF1R GENE MUTATION

We report on a 44 year old Afro-Caribbean lady who presented with progressive personality change and cognitive impairment over one year. She had progressive difficulty managing household tasks, lost interest in her hobbies and spoke very little. Her family described her behaviour as ‘child-like’. She had been diagnosed with anti-Ro positive mild Lupus 10 years previously and was taking mepacrine. Examination suggested a predominantly frontal subcortical pattern of cognitive impairment. MRI/A revealed confluent symmetrical white matter changes in the frontal and parietal lobes with patchy restricted diffusion in the basal ganglia. Extensive other investigations including metabolic tests, autoimmune tests, and CSF analysis were unrevealing. A right frontal brain biopsy revealed non-specific gliosis. She was treated empirically with steroids and cyclophosphamide for the possibility of cerebral vasculitis but there was no subsequent clinical improvement. She tested positive for a heterozygous mutation in the CSF1R gene, first described in Hereditary Diffuse Leukoencephalopathy with Spheroids. Adult onset leukoencephalopathies are difficult to investigate given their broad clinical presentation and wide variety of acquired and rare genetic aetiologies. This case is instructive because it highlights a novel genetic test which may obviate the need for brain biopsy or harmful immunosuppressive agents in rapidly progressive leukoencephalopathies.

Human African trypanosomiasis with 7-year incubation period: Clinical, laboratory and neuroimaging findings

Human African trypanosomiasis (HAT), also referred to as “sleeping sickness”, is caused by the parasite Trypanosoma brucei. Diagnosing imported HAT outside endemic areas is difficult and diagnosis is often delayed. We report a case of imported human African trypanosomiasis caused by Trypanosoma brucei gambiense with an unusually long incubation period of at least 7years. A 33year old male African patient, a former resident of Cameroon, presented with a 4-month history of progressive personality changes. A few weeks before presentation the patient had first been admitted to a psychiatric ward and received antidepressant treatment, until a lumbar puncture showed pleocytosis and then antibiotic treatment for suspected neuroborreliosis was initiated. The patient continued to deteriorate during antibiotic treatment and became increasingly lethargic. Under antiparasitic and anti-inflammatory treatment, the condition of the patient gradually improved over the following months and he recovered completely after 24months of follow-up. This well-documented case illustrates typical difficulties in establishing the correct diagnosis outside endemic areas and provides an overview of typical clinical, neuropathological and neuroimaging findings in T. b. gambiense trypanosomiasis, guiding the clinician in establishing the correct diagnosis in this rare disease.

Pulvinar Sign in Sporadic Creutzfeldt-Jakob Disease: Exploring the Diagnostic Modalities of Prion Diseases

Creutzfeldt-Jakob disease ( CJD ) refers to the most common t ransmissible s pongiform e ncephalopathies. The distinction between a diagnosis of sporadically acquired CJD and the exogenously acquired CJD is important, and has previously been assisted by imaging modalities revealing the pulvinar sign. This case report describes a 71-year-old n ative-American female with rapidly deteriorating mental status, progressive personality changes, ataxia, and 50-pound weight loss. Non-contrast MRI of the brain was significant for symmetrical high diffusion signal in the bilateral pulvinar thalami. CSF studies performed by the National Prion Disease Surveillance Center showed a positive 14-3-3 level and an elevated tau conveying a positive predictive value of 72.6% for CJD. The case exemplifies commonality between sporadic CJD and variant CJD and challenges the utility of radiological findings differentiating the diseases. Our case emphasizes that the pulvinar sign may not be as specific for a diagnosing variant CJD as we once thought. doi: http://dx.doi.org/10.4021/jmc1278w

CADASIL presenting with a behavioural variant frontotemporal dementia phenotype

The behavioural variant of frontotemporal dementia (bvFTD) is characterised by personality change with a decline in cognition. We describe two patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL) who presented with behavioural phenotypes similar to bvFTD. The first patient presented with progressive personality and behavioural change, had florid white matter hyperintensity, and had a novel missense mutation C366W in exon 7 of the Notch3 gene. The second patient presented with progressive memory impairment and marked personality changes after a transient ischaemic attack. In this second patient, the radiological features were subtle and only the family history of stroke prompted testing for CADASIL using Notch3 genotyping. We present these patients to demonstrate that CADASIL may mimic bvFTD, with little clinical or radiological evidence to distinguish the two. CADASIL may be an under-recognised diagnosis in apparent bvFTD. Screening Notch3 in a substantial and unselected cohort of frontotemporal dementia patients might be appropriate to investigate this possibility.

Emerging Targets in Neurodegeneration: New Opportunities for Alzheimer's Disease Treatment?

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the brain associated with memory impairment, progressive cognitive decline and changes in personality and behavior, with rising incidence among elderly people. Reflecting the world population ageing, the scenario is expected to worsen in the next decades if novel drugs or mechanisms that help to counteract neurodegeneration will not be identified. The complex neuropathology of AD is characterized by cholinergic loss, extracellular deposition of amyloid-β plaques, formation of intracellular neurofibrillary tangles, chronic brain inflammation and oxidative damage. To date, there are no effective treatments that can slow or halt the disease, and currently approved drugs only seem to act as palliative by temporary ameliorating cognitive impairment. On the other hand, the role played by other biological systems in the pathogenetic process is now clearly growing and, as knowledge on how AD develops and triggers brain damage proceeds, drug discovery attempts to identify new potential therapeutic targets. This review will focus on these emerging strategies, some of which could open new therapeutic perspectives in Alzheimer's disease, adding new elements for the medicinal chemist to handle and combine for the design of novel multi-target-directed ligands able to simultaneously modulate 'old classic' and newly identified targets.

Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer

The aim of this study was to describe the clinical presentation of children and adolescents with anti-Hu antibodies (Hu-Abs). This was a retrospective study of children and adolescents with Hu-Abs collected by the French Paraneoplastic Neurological Syndrome (PNS) Reference Center between January 1, 2000 and December 31, 2011. The center identified 251 patients with Hu-Abs. Only 8 patients were younger than 18 years. All of the 243 adult patients had PNS. In contrast, of the 8 children, only 2 (25%, Fisher exact test p = 0.0003) had neuroblastoma and opsoclonus-myoclonus. The other 6 children (5 female and 1 male) presented with limbic encephalitis (progressive personality changes, memory loss, and seizure) and were free of cancer (mean follow-up time: 50 months; range: 34-72 months). Brain MRI scans were abnormal in 4 of the 6 patients, with left, right, or bitemporal T2/fluid-attenuated inversion recovery hyperintensity. Protein levels and cell counts in the CSF were normal in all patients, but numerous oligoclonal bands were observed in 4 patients. All 6 patients received antiepileptic drugs and immunotherapy, but management of epilepsy was difficult in all of them. Five of the children developed cognitive impairments. In children, as in adults, Hu-Abs can be a marker of PNS. However, in contrast to adults, Hu-Abs in children are also associated with an aggressive form of autoimmune nonparaneoplastic limbic encephalitis. Future studies should be conducted to determine the incidence of this syndrome and whether earlier diagnosis and T-cell-directed immunotherapies may improve its prognosis.

Demencia frontotemporal variante conductual: aproximación clínica y terapéutica

IntroductionBehavioural variant frontotemporal dementia (bvFTD) is the most frequent presentation in the clinical spectrum of frontotemporal dementia (FTD) and it is characterised by progressive changes in personality and conduct. Major breakthroughs in molecular biology and genetics made during the last two decades have lent us a better understanding of this syndrome, which may be the first manifestation in many different neurodegenerative diseases. DevelopmentWe reviewed the main epidemiological, clinical, diagnostic and therapeutic aspects of bvFTD. Most cases manifest sporadically and the average age of onset is 58 years. Current criteria for bvFTD propose three levels of diagnostic certainty: possible, probable, and definite. Clinical diagnosis is based on a detailed medical history provided by family members and caregivers, in conjunction with neuropsychological testing. Treatments which have been used in bvFDT to date are all symptomatic and their effectiveness is debatable. New drugs designed for specific molecular targets that are implicated in frontotemporal lobar degeneration are being developed. ConclusionsBvFDT is a frequent cause of dementia. It is a non-specific syndrome associated with heterogeneous histopathological and biomolecular findings. The definition of clinical subtypes complemented by biomarker identification may help predict the underlying pathology. This knowledge, along with the development of drugs designed for molecular targets, will offer new treatment possibilities.