Frontotemporal Dementia (Frontotemporal Lobar Degeneration)

The frontotemporal disorders are a group of rare diseases that involve shrinkage of specific areas of the brain that regulate behavior, personality, and language, a process termed frontotemporal lobar degeneration (FTLD). Frontotemporal disorders usually develop between ages 40 and 60, with early symptoms that can include personality or behavior changes, loss of ability to use or comprehend language, or difficulties with movement, followed by more general cognitive impairment and, ultimately, death. A frontotemporal disorder may sometimes be diagnosed in combination with another neurological disorder such as amyotrophic lateral sclerosis (ALS) or Parkinson’s disease. The exact prevalence of these disorders is unknown, but some researchers estimate that as many as 10 percent of all cases of dementia are actually frontotemporal disorders. [Source: National Institutes of Health Fact Sheet]

Latest Frontotemporal Dementia PubMed Abstracts. Some citations may include links to full-text content from PubMed Central and publisher web sites. [Source: National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine (NLM) via HubMed.org interface. NCBI Copyright and Disclaimers]
• Self-projection and the default network in frontotemporal dementia.

  Nat Rev Neurol. 2012 Feb 14;
  Irish M, Piguet O, Hodges JR

  Converging evidence suggests that when individuals are left to think to themselves, a so-called default network of the brain is engaged, allowing the individual to daydream, reflect on their past, imagine possible future scenarios, and consider the viewpoints of others. These flexible self-relevant mental explorations enable the anticipation and evaluation of events before they occur, and are essential for successful social interactions. Such self-projective efforts are particularly vulnerable to disruption in frontotemporal dementia (FTD), a neurodegenerative disorder involving damage to the frontal and temporal lobes of the brain. In this Review, we explore how the progressive degeneration of the neural networks in two subtypes of FTD-the behavioral variant and semantic dementia-affects key structures of the default network and putative self-projective functions. We examine the available evidence from studies of autobiographical memory, episodic future thinking, theory of mind, moral reasoning, and economic decision-making in these neurodegenerative diseases. Finally, we propose that the mapping of default-network functions onto discrete subsystems of the default network may need revision in light of neuropsychological and clinical evidence from studies in patients with FTD.

• The Impact of Dementia Severity on Caregiver Burden in Frontotemporal Dementia and Alzheimer Disease.

  Alzheimer Dis Assoc Disord. 2012 Feb 6;
  Mioshi E, Foxe D, Leslie F, McLinneuro SS, Hsieh S, Miller L, Hodges JR, Piguet O

  Caregiver burden is greater in frontotemporal dementia (FTD) than in Alzheimer disease (AD). However, little is known of the impact of the 3 main clinical variants of FTD- behavioral-variant frontotemporal dementia (bvFTD), semantic dementia (SemDem), and progressive nonfluent aphasia (PNFA)-or the role of disease severity in caregiver burden. The Zarit Burden Inventory was used to measure caregiver burden of bvFTD (n=17), SemDem (n=20), PNFA (n=20), and AD (n=19) patients. Symptom duration, caregiver age, and relationship type were matched across groups. Moreover, a number of caregiver (mood, social network) and patient variables (functional disability, behavioral changes, relationship with caregiver, and dementia stage) were addressed to investigate their impact on caregiver burden. Caregivers of bvFTD patients reported the highest burden, whereas SemDem and PNFA caregivers reported burden similar to AD. A regression analysis revealed that caregiver burden in FTD, regardless of subtype, was explained by a model combining disease staging, relationship changes, and caregiver depression. Burden increased with disease severity in FTD. This study is the first to show that caregivers of SemDem, PNFA, and AD patients show similar burden, while confirming that bvFTD caregivers show higher burden than AD caregivers. More importantly, this study demonstrates that burden worsens with disease progression in FTD.

• [Advances in Biological Psychiatry Research on Dementia: AD-FTLD Spectrum].

  Brain Nerve. 2012 Feb; 64(2): 149-61
  Takeda M

  Abstract Neurodegenerative dementia, including Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD), is one of the main target areas for research in biological psychiatry. In this review, the historical view, present situation, and further development in dementia research have been discussed from the viewpoint of biological psychiatry. Considering the rapidly increasing number of dementia patients in Japan, the importance of dementia in clinical psychiatry service will keep increasing in the near future. Biological as well as psychosocial knowledge is required to elucidate the mechanism underlying dementia. Although the molecular mechanism underlying the pathological features of AD has not yet been fully elucidated, it can be placed under the concept of the AD-FTLD spectrum, in which loss of function of an important gene may result in accumulation of insoluble proteins inside and outside neurons. To develop disease-modifying drugs for AD and FTLD, elucidation of pathological events that occur earlier than abnormal protein deposition is essential. Early diagnosis and early intervention are important for overcoming these neurodegenerative dementia.

• Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations.

  Brain. 2012 Feb 2;
  Snowden JS, Rollinson S, Thompson JC, Harris JM, Stopford CL, Richardson AM, Jones M, Gerhard A, Davidson YS, Robinson A, Gibbons L, Hu Q, Duplessis D, Neary D, Mann DM, Pickering-Brown SM

  The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients' clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients' delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all cases of frontotemporal dementia with motor neuron disease. Other mutations remain to be discovered. C9ORF72 mutations are associated with variable clinical presentations and pathology. Nevertheless, the findings highlight a powerful association between C9ORF72 mutations and psychosis and suggest that the behavioural characteristics of patients with C9ORF72 mutations are qualitatively distinct. Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.

• Social Cognition and Emotional Assessment differentiates frontotemporal dementia from depression.

  J Neurol Neurosurg Psychiatry. 2012 Jan 29;
  Bertoux M, Delavest M, de Souza LC, Funkiewiez A, Lépine JP, Fossati P, Dubois B, Sarazin M

  BackgroundBehavioural variant of frontotemporal dementia (bvFTD) is a neurodegenerative disease that is clinically characterised by progressive behavioural changes and social interpersonal dysfunctions. Its diagnosis remains a clinical challenge, and depression is one of the main causes of misdiagnoses due to the prevalence of apathy in bvFTD.ObjectiveTo evaluate the sensitivity and specificity of the Social Cognition and Emotional Assessment (SEA) and the mini-SEA for differentiating bvFTD from major depressive disorder (MDD).MethodsScores for the SEA and mini-SEA for 37 patients with bvFTD (divided into subgroups of 17 with early bvFTD and 20 with moderate bvFTD according to the normal range of the Mattis Dementia Rating Scale), 19 MDD patients and 30 control subjects were compared to define the discrimination power of these tools compared with other standard neuropsychological tests.ResultsSEA and mini-SEA scores were significantly lower for both the early and moderate bvFTD groups compared with control subjects and the MDD group, and very few scores overlapped between patients in the bvFTD subgroups and patients in the MDD and control subgroups. SEA and mini-SEA scores distinguished early bvFTD from MDD with sensitivity and specificity rates above 94%.ConclusionUnlike standard executive neuropsychological tests, SEA and the mini-SEA can differentiate MDD from bvFTD in the early stages of the disease. The mini-SEA is an easy tool that can be utilised in neurological or psychiatric departments.

• Neuroimaging in frontotemporal lobar degeneration-predicting molecular pathology.

  Nat Rev Neurol. 2012 Jan 31;
  Whitwell JL, Josephs KA

  Frontotemporal lobar degeneration (FTLD) encompasses a group of diseases characterized by neuronal loss and gliosis of the frontal and temporal lobes. Almost all cases of FTLD can be classified into three categories on the basis of deposition of one of three abnormal proteins: the microtubule-associated protein tau, TAR DNA-binding protein 43, or fused in sarcoma. The specific diagnoses within each of these three categories are further differentiated by the distribution and morphological appearance of the protein-containing inclusions. Future treatments are likely to target these abnormal proteins; the clinical challenge, therefore, is to be able to predict molecular pathology during life. Clinical diagnosis alone has had variable success in helping to predict pathology, and is particularly poor in the diagnosis of behavioral variant frontotemporal dementia, which can be associated with all three abnormal proteins. Consequently, other biomarkers of disease are needed. This Review highlights how patterns of atrophy assessed on MRI demonstrate neuroanatomical signatures of the individual FTLD pathologies, independent of clinical phenotype. The roles of these patterns of atrophy as biomarkers of disease, and their potential to help predict pathology during life in patients with FTLD, are also discussed.

• Diminished disgust reactivity in behavioral variant frontotemporal dementia.

  Neuropsychologia. 2012 Jan 20;
  Eckart JA, Sturm VE, Miller BL, Levenson RW

  Frontotemporal dementia is a neurodegenerative disease that impacts emotion and social behavior. Using laboratory measures of emotional reactivity, our past work has found that reactivity to loud noises and to thematically simple happy and sad emotional films are preserved in the early stages of the disease while other emotional responses (e.g., embarrassment) are severely compromised. In the present study we examined disgust, an emotion whose function is to distance us from offending objects and situations. We measured disgust reactivity in 21 patients with behavioral variant frontotemporal dementia (bvFTD, a subtype of frontotemporal dementia characterized by emotional blunting) and 25 neurologically healthy controls. Disgust is an emotion of particular interest in bvFTD, due to caregiver and clinician reports that patients engage in acts that suggest this emotion may be compromised; in addition, the pattern of neurodegeneration in bvFTD includes atrophy of key frontotemporal structures (e.g., anterior insula) with known roles in visceral emotions such as disgust. In the present study, participants had their emotional facial behavior, physiology, and self-reported emotional experience measured while watching a disgust-eliciting film. We found that behavioral, physiological, and self-reported experiential responses were all reduced in bvFTD patients compared to controls (with behavioral and physiological differences still found after controlling for patients' cognitive deficits). We discuss the implications of these findings for bvFTD patients' problems in social functioning and their typical patterns of neurodegeneration.

• Voxel-based morphometry in patients with obsessive-compulsive behaviors in behavioral variant frontotemporal dementia.

  Eur J Neurol. 2012 Jan 28;
  Perry DC, Whitwell JL, Boeve BF, Pankratz VS, Knopman DS, Petersen RC, Jack CR, Josephs KA

  Background and purpose:  Obsessions and compulsive (OC) behaviors are a frequent feature of behavioral variant frontotemporal dementia (bvFTD), but their structural correlates have not been definitively established. Methods:  Patients with bvFTD presenting to the Mayo Clinic Alzheimer's Disease Research Center were recruited. Each patient's caregiver was given the Yale-Brown Obsessive-Compulsive scale (YBOCS) to document the type and presence of OC behaviors and to rate their severity. All subjects underwent standardized magnetic resonance imaging (MRI) that was evaluated using voxel-based morphometry (VBM). Seventeen patients with bvFTD were recruited, and 11 were included in the study and compared with 11 age- and gender-matched controls. Six were excluded for lack of MRI at the time of survey or a pre-existing neurodegenerative condition. Results:  Nine of the 11 reported OC behaviors, with the most frequent compulsions being checking, hoarding, ordering/arranging, repeating rituals, and cleaning. In the VBM analysis, total YBOCS score correlated with gray matter loss in the bilateral globus pallidus, left putamen, and in the lateral temporal lobe, particularly the left middle and inferior temporal gyri (P < 0.001 uncorrected for multiple comparisons). Conclusions:  Obsessive-compulsive behaviors were frequent among these patients. The correlation with basal ganglia atrophy may point to involvement of frontal subcortical neuronal networks. Left lateral temporal lobe volume loss probably reflects the number of MAPT mutation patients included but also provides additional data implicating temporal lobe involvement in OC behaviors.

• Frontotemporal lobar degeneration: new understanding brings new approaches.

  Neuroimaging Clin N Am. 2012 Feb; 22(1): 83-97
  Tartaglia MC

  Frontotemporal dementia (FTD) describes a group of clinical syndromes united by underlying frontotemporal lobar degeneration (FTLD) pathology. The clinical syndromes associated with FTLD are heterogeneous and are based on whether the patients present with behavioral, language, or motor impairments. FTLD is at the center of a paradigm shift in neurodegenerative diseases, with thought being given at diagnosis of underlying disease. There is pathologic heterogeneity of certain clinical syndromes such as behavioral variant FTD. Differentiation between the proteinopathies will become imperative as protein-specific treatments become available. This review provides an overview of FTLD, with an update of recent discoveries.

• Frontotemporal lobar degeneration (FTLD) concept and classification update.

  Rinsho Shinkeigaku. 2011 Nov; 51(11): 844-7
  Nakano I

  FTLD is a neuroanatomical disease concept defined only by the presence of degeneration of the frontal and temporal lobes regardless of the underlying histopathological features, and therefore inevitably includes heterogeneous diseases that affect those cerebral regions. The ambiguous idea of Pick disease, the prototype of FTLD, constantly caused great nosological confusion as to FTLD. Progress in molecular neuropathology aimed at clarification of the protein constituents of the inclusion bodies seen in conditions causing FTLD, however, has resolved this problem by providing FTLD with a new concise nomenclature and classification based on the inclusion body proteins. The substances in inclusions in FTLD with ubiquitin-only inclusions (FTLD-U) have been discovered one after another; TDP-43 was the first, being found in inclusions in ALS and ALS with dementia (ALSD) too, and soon FUS/TLS was identified in some TDP-43-negative FTLD-U groups. Thus, FTLD has been divided into three main subgroups; 1) FTLD-tau, which includes Pick disease, PSP, CBD, etc., 2) FTLD-TDP, which is further divided to types A-D, ALSD belonging to type B, and 3) FTLD-FUS, which includes aFTLD-U, NIFID, and BIBD. Further deciphering of yet-unidentified proteins of some FTLD-U subsets will add more subclasses.

• Progranulin axis and recent developments in frontotemporal lobar degeneration.

  Alzheimers Res Ther. 2012 Jan 23; 4(1): 4
  Nicholson AM, Gass J, Petrucelli L, Rademakers R

  ABSTRACT: Frontotemporal lobar degeneration (FTLD) is a devastating neurodegenerative disease that is the second most common form of dementia affecting individuals under age 65. The most common pathological subtype, FTLD with transactive response DNA-binding protein with a molecular weight of 43 kDa inclusions (FTLD-TDP), is often caused by autosomal dominant mutations in the progranulin gene (GRN) encoding the progranulin protein (PGRN). GRN pathogenic mutations result in haploinsufficiency, usually by nonsense-mediated decay of the mRNA. Since the discovery of these mutations in 2006, several groups have published data and animal models that provide further insight into the genetic and functional relevance of PGRN in the context of FTLD-TDP. These studies were critical in initiating our understanding of the role of PGRN in neural development, degeneration, synaptic transmission, cell signaling, and behavior. Furthermore, recent publications have now identified the receptors for PGRN, which will hopefully lead to additional therapeutic targets. Additionally, drug screens have been conducted to identify pharmacological regulators of PGRN levels to be used as potential treatments for PGRN haploinsufficiency. Here we review recent literature describing relevant data on GRN genetics, cell culture experiments describing the potential role and regulators of PGRN in the central nervous system, animal models of PGRN deficiency, and potential PGRN-related FTLD therapies that are currently underway. The present review aims to underscore the necessity of further elucidation of PGRN biology in FTLD-related neurodegeneration.

• Characterization of Apathy in Persons Wth Frontotemporal Dementia and the Impact on Family Caregivers.

  Alzheimer Dis Assoc Disord. 2012 Jan 17;
  Merrilees J, Dowling GA, Hubbard E, Mastick J, Ketelle R, Miller BL

  This study characterized daytime activity and apathy in patients with behavioral variant frontotemporal dementia (bvFTD) and semantic dementia (SD) and their family caregivers. Twenty-two patient-caregiver dyads were enrolled: 13 bvFTD and 9 SD. Data were collected on behavior and movement. Patients and caregivers wore Actiwatches for 2 weeks to record activity. We predicted that bvFTD patients would show greater caregiver report of apathy and less daytime activity compared with patients diagnosed with SD. Patients with bvFTD spent 25% of their day immobile, whereas patients with SD spent 16% of their day inactive. BvFTD caregivers spent 11% of their day immobile and SD caregivers were immobile 9% of their day. Apathy was present in all of the patients with bvFTD and in all but one patient with SD; the severity of apathy was greater in bvFTD compared with SD. Apathy correlated with caregiver emotional distress in both groups. In conclusion, apathy has been defined as a condition of diminished motivation that is difficult to operationalize. Among patients with frontotemporal dementia, apathy was associated with lower levels of activity, greater number of bouts of immobility, and longer immobility bout duration. Apathy and diminished daytime activity appeared to have an impact on the caregiver. Objective measures of behavioral output may help in formulation of a more precise definition of apathy.

• FET proteins in frontotemporal dementia and amyotrophic lateral sclerosis.

  Brain Res. 2011 Dec 13;
  Mackenzie IR, Neumann M

  Mutations in the fused in sarcoma gene (FUS) cause amyotrophic lateral sclerosis (ALS) with TDP-43-negative, FUS-positive pathology. FUS is also the pathological protein in most tau/TDP-43-negative subtypes of frontotemporal lobar degeneration (FTLD-FUS). FUS, together with Ewing's sarcoma protein (EWS) and TATA-binding protein associated factor 15 (TAF15), make up the FET family of DNA/RNA binding proteins that share functional homology and have the potential to interact. We recently investigated the role of the other FET proteins in the clinicopathological spectrum of FUS-opathies. In all FTLD-FUS subtypes, FUS-positive pathology was also labeled for TAF15 and EWS and cells with inclusions showed a reduction in the normal nuclear staining of all FET proteins. In contrast, in cases of ALS-FUS, TAF15 and EWS remained localized to the nucleus and did not label FUS-positive inclusions. Cell culture models replicated the human diseases. These findings indicate that ALS-FUS and FTLD-FUS have different pathomechanisms and add TAF15 and EWS to the growing list of RNA-binding proteins involved in neurodegeneration. This article is part of a Special Issue entitled: RNA-Binding Proteins.

• Disease-Modifying Therapies in Frontotemporal Lobar Degeneration.

  Curr Med Chem. 2012 Jan 17;
  Bigni B, Premi E, Pilotto A, Padovani A, Borroni B

  Frontotemporal Lobar Degeneration (FTLD) is characterized by behavioral changes, executive dysfunctions, and language impairment, sustained by different neuropathological patterns. The collective efforts of clinical, pathological and genetic studies have recently opened new insights into the underpinnings of pathological mechanisms of this complex disorder. Different types of inclusions define the new conceptual framework for FTLD classification. Up to now, Tau (FTLDTau-positive), TAR DNA-binding protein (TDP43, FTLD Tau-negative TDP43-positive) have been recognized as the most frequent neuropathological hallmarks of FTLD. In some clinical cases, monogenic forms are identified, mainly due to Microtubule Associated Protein (MAPT) or Granulin (GRN) mutations. No treatments for FTLD are available yet, and off-label medications are commonly used to treat behavioralsymptoms. However, several studies testing potential modifying treatments on the basis of neuropathological inclusions are ongoing. With regard to FTLD-Tau positive, inhibitors of Tau kinases or manipulation of Tau-processing pathways have been proposed. On the other hand, progranulin haploinsuffciency associated with GRN mutations, has been counteracted by specific pharmacological treatments. Finally, new insights into pathological processing of TDP-43 and other key-molecules involved in FTLD, such as hyperphosphorylation and ubiquitination, and their consequent translocation from nucleus to cytoplasm, and their role as RNA-binding proteins, open new perspectives for a growing number of potential therapeutic targets. In this continuously evolving field, the aim of the present review is to summarize the new findings on molecular targets and modifying therapies in FTLD.

• UBQLN2/P62 cellular recycling pathways in amyotrophic lateral sclerosis and frontotemporal dementia.

  Muscle Nerve. 2012 Feb; 45(2): 157-62
  Fecto F, Siddique T

  Recent findings highlight a pathologic and functional convergence in amyotrophic lateral sclerosis (ALS) and amyotrophic lateral sclerosis with frontotemporal dementia (ALS-FTD) at the level of protein recycling and disposal. Genes linked to rare cases of familial ALS and ALS-FTD, like UBQLN2, OPTN, SQSTM1/p62, and VCP, may converge onto a unifying pathogenic pathway and thereby provide novel therapeutic targets common to a spectrum of etiologically diverse forms of ALS and ALS-FTD. Interactions between these genes need to be further explored to understand their common molecular pathways. Future efforts should be directed toward generation and characterization of in vivo models to dissect the pathogenic mechanisms of ALS and ALS-FTD and the role of protein degradation pathways, both centrally, at the cell body, and peripherally, at the level of the synapse. Such efforts will rapidly accelerate the discovery of new drugs that regulate accumulation of pathogenic proteins and their downstream consequences in ALS and ALS-FTD and, possibly, other neurodegenerative diseases as well. Muscle Nerve, 2012.