TAF15 amyloid filaments in frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders1. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins2. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes3,4. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.

Long non-coding RNA NEAT1_1 ameliorates TDP-43 toxicity in in vivo models of TDP-43 proteinopathy.

Pathological changes involving TDP-43 protein ('TDP-43 proteinopathy') are typical for several neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD). FTLD-TDP cases are characterized by increased binding of TDP-43 to an abundant lncRNA, NEAT1, in the cortex. However it is unclear whether enhanced TDP-43-NEAT1 interaction represents a protective mechanism. We show that accumulation of human TDP-43 leads to upregulation of the constitutive NEAT1 isoform, NEAT1_1, in cultured cells and in the brains of transgenic mice. Further, we demonstrate that overexpression of NEAT1_1 ameliorates TDP-43 toxicity in Drosophila and yeast models of TDP-43 proteinopathy. Thus, NEAT1_1 upregulation may be protective in TDP-43 proteinopathies affecting the brain. Approaches to boost NEAT1_1 expression in the CNS may prove useful in the treatment of these conditions.

Frontotemporal dementia: an unusual cause.

Intracerebral pneumocephalus is commonly associated with head and facial trauma, ear infection, tumors and surgical interventions. Osteomas are relatively common, benign tumors that occur mainly in the paranasal sinuses, the frontal sinus in particular. Pneumocephalus has been commonly reported with frontal osteoma but isolated presentation as frontotemporal dementia is uncommon. Patient was admitted with complaints of change of behavior and forgetfulness for the last one year. He had progressively become more apathetic and presented with behavioral abnormalities. General physical examinations were within normal limits including the motor and sensory system although neuropsychiatry assessments were below the average level, with features of dementia. Further, MRI brain revealed pneumocephalus in bilateral frontal lobe. CT cisternography revealed a well defined lobulated densely sclerotic lesion of approximate size 20 × 17 × 27mm transverse and cranio-caudal axis respectively arising from right ethmoid sinus. Clinically, the association of pneumocephalus and isolated presentation as frontotemporal dementia has not been described to the best of our knowledge. A single case has been described with ethmoid osteoma. Radiological features were suggestive of osteoid osteoma. The uniqueness of the case is the development of dementia with frontotemporal involvement and resemblance with Frontotemporal Dementia. This is the only case with dementia and pneumocephalus (secondary to osteoid osteoma) to best of our knowledge.

Targeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement.

To identify genes associated with frontotemporal dementia (FTD) in South-East Asia, targeted exome sequencing and C9orf72 genotyping was performed in 198 subjects (52 patients with FTD and 146 healthy controls) who were screened for mutations in 12 FTD-associated genes. We detected a homozygous TREM2 R47C mutation in a patient with behavioral variant FTD without bone cysts or bone-associated phenotype. Two novel nonsense GRN mutations in 3 FTD patients from the Philippines were detected, but no known pathogenic mutations in other FTD-associated genes were found. In 45 subjects screened for C9orf72 repeat expansions, no pathogenic expansion (≥30 repeats) was identified, but there was a higher proportion of intermediate length (≥10-29 repeats) alleles in patients compared with controls (8/90 alleles, 8.9% vs. 9/164 alleles, 5.5%). Overall, we detected a mutation rate of 7.7% (4/52 patients) in our cohort. Given recent findings of enrichment of rare TREM2 variants (including R47C) in Alzheimer's disease, it is notable that we detected a homozygous TREM2 R47C carrier presenting with an FTD rather than an Alzheimer's disease phenotype.

Behavioral Variant Frontotemporal Dementia as a Serious Complication of Spontaneous Intracranial Hypotension.

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is a devastating early onset dementia. Symptoms of bvFTD may be caused by spontaneous intracranial hypotension (SIH), a treatable disorder, but no comprehensive study of such patients has been reported. OBJECTIVE: To describe detailed characteristics of a large cohort of patients with SIH and symptoms of bvFTD. METHODS: We identified patients with SIH who met clinical criteria for bvFTD. Patients were compared to a cohort of SIH patients without bvFTD. RESULTS: The mean age for the 21 men and 8 women was 52.9 yr (range, 37-65 yr). All 29 patients with bvFTD symptoms had hypersomnolence. Magnetic resonance imaging showed brain sagging in all patients, cerebrospinal fluid (CSF) opening pressure low in about half of patients, but a spinal CSF leak could not be detected in any patient. All patients underwent epidural blood patching, but 26 patients eventually underwent 1 or more surgical procedures. Overall, a good outcome was obtained in 21 patients (72%); 20 (91%) of 22 patients who had not undergone prior Chiari surgery compared to 1 (14%) of 7 patients who did undergo Chiari surgery (P < .003). Compared to SIH patients without symptoms of bvFTD (n = 547), those with bvFTD symptoms were older, more often male, less often demonstrated CSF leak on spinal imaging, and more often underwent surgery (P < .02). CONCLUSION: bvFTD in SIH is rare and associated with brain sagging and hypersomnolence. Spinal CSF leaks are rarely detected. bvFTD symptoms are often refractory to the usual percutaneous procedures but most patients can be cured.

ALS/FTD-Associated C9ORF72 Repeat RNA Promotes Phase Transitions In Vitro and in Cells.

Membraneless RNA granules originate via phase separation events driven by multivalent interactions. As RNA is the defining component of such granules, we examined how RNA contributes to granule assembly. Expansion of hexanucleotide GGGGCC (G4C2) repeats in the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). We describe a biophysical phenomenon whereby G4C2 RNA (rG4C2) promotes the phase separation of RNA granule proteins in vitro and in cells. The ability of rG4C2 to promote phase separation is dependent on repeat length and RNA structure because rG4C2 must assume a G-quadruplex conformation to promote granule assembly. We demonstrate a central role for RNA in promoting phase separations and implicate rG4C2 G-quadruplex structures in the pathogenesis of C9-ALS/FTD.

Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP•NPLOC4•UFD1L is enhanced by a mutation that causes multisystem proteinopathy.

p97 is a "segregase" that plays a key role in numerous ubiquitin (Ub)-dependent pathways such as ER-associated degradation. It has been hypothesized that p97 extracts proteins from membranes or macromolecular complexes to enable their proteasomal degradation; however, the complex nature of p97 substrates has made it difficult to directly observe the fundamental basis for this activity. To address this issue, we developed a soluble p97 substrate-Ub-GFP modified with K48-linked ubiquitin chains-for in vitro p97 activity assays. We demonstrate that WT p97 can unfold proteins and that this activity is dependent on the p97 adaptor NPLOC4-UFD1L, ATP hydrolysis, and substrate ubiquitination, with branched chains providing maximal stimulation. Furthermore, we show that a p97 mutant that causes inclusion body myopathy, Paget's disease of bone, and frontotemporal dementia in humans unfolds substrate faster, suggesting that excess activity may underlie pathogenesis. This work overcomes a significant barrier in the study of p97 and will allow the future dissection of p97 mechanism at a level of detail previously unattainable.

Frontal lobe dementia syndrome as a first manifestation of primary angiitis of the central nervous system (PACNS).

This case presents a clinical course of a frontal lobe dysexecutive syndrome with dementia caused by a primary angiitis of the central nervous system (PACNS) of exclusively very small vessels. An isolated frontal lobe dementia syndrome as a primary manifestation of PACNS highlights the diverse clinical manifestations of the disease. The patient presented with a progressive cognitive decline with loss of memory, disinhibited behavior, inappropriate affect and frontal release signs. The diagnostic workup essentially revealed a lymphocytic pleocytosis in the cerebrospinal fluid and a generalized cortical atrophy without any vascular abnormalities. To grasp a diagnosis for this enigmatic clinical picture of a frontal lobe syndrome with signs of inflammation we targeted a tissue-based diagnosis. A brain biopsy gave the decisive hint towards a microvasculitis. Although the histopathologic picture showed peculiarities, a destruction of the vascular bed of very small vessels by lymphocytic infiltration was evident. Our case illustrates an uncommon clinical picture of a PACNS and points to shortcomings of the current histopathologic criteria if only very small vessels are involved.

Progressive Supranuclear Palsy Syndrome and Semantic Dementia in Neuropathologically Proven Lewy Body Disease: A Report of Two Cases.

The impact of neuropathological lesions on the clinical symptoms and progression of Lewy body disease (LBD) remains unclear. To address this issue, we describe two illustrative cases of autopsy-proven LBD that presented atypical phenotypes of progressive supranuclear palsy syndrome and semantic dementia. Postmortem examination revealed diffuse LBD with massive brainstem involvement in case 1, whereas Lewy bodies predominated in the amygdala and neocortex in case 2. Alzheimer's disease pathology was present in both cases, and TDP-43 inclusions were noted in case 2. These cases illustrate two contrasted clinical presentations and highlight the heterogeneity within the underlying proteinopathies of neurodegenerative diseases.

Wild-type bone marrow transplant partially reverses neuroinflammation in progranulin-deficient mice.

Frontotemporal dementia (FTD) is a neurodegenerative disease with devastating changes in behavioral performance and social function. Mutations in the progranulin gene (GRN) are one of the most common causes of inherited FTD due to reduced progranulin expression or activity, including in brain where it is expressed primarily by neurons and microglia. Thus, efforts aimed at enhancing progranulin levels might be a promising therapeutic strategy. Bone marrow (BM)-derived cells are able to engraft in the brain and adopt a microglial phenotype under myeloablative irradiation conditioning. This ability makes BM-derived cells a potential cellular vehicle for transferring therapeutic molecules to the central nervous system. Here, we utilized BM cells from Grn(+/+) (wild type or wt) mice labeled with green fluorescence protein for delivery of progranulin to progranulin-deficient (Grn(-/-)) mice. Our results showed that wt bone marrow transplantation (BMT) partially reconstituted progranulin in the periphery and in cerebral cortex of Grn(-/-) mice. We demonstrated a pro-inflammatory effect in vivo and in ex vivo preparations of cerebral cortex of Grn(-/-) mice that was partially to fully reversed 5 months after BMT. Our findings suggest that BMT can be administered as a stem cell-based approach to prevent or to treat neurodegenerative diseases.

A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.

Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.

Cytokine profiling in patients with VCP-associated disease.

Valosin containing protein (VCP) disease (also known as Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia [IBMPFD] syndrome) is caused by mutations in the gene encoding VCP classically affecting the muscle, bone and brain. Although the genetic cause has been identified, details regarding the pathogenesis of IBMPFD have not been fully determined. Muscle wasting observed in VCP disease is suggestive of cytokine imbalance. We hypothesized that dysfunctional protein homeostasis caused by VCP mutations leads to cytokine imbalances thereby contributing to the muscle wasting phenotype. Circulating levels of interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF a) and epidermal growth factor (EGF) were measured in plasma of patients with VCP disease or controls. TNF a and EGF were significantly altered in VCP disease as compared to control. TNF a was up-regulated, consistent with a cachexia phenotype and EGF levels were increased. No significant differences were observed in IL-4 and IL-6. Cytokine imbalances may be associated with VCP disease and may play a contributory role in VCP myopathy. Further understanding of how VCP dysfunction leads to aberrant protein homeostasis and subsequent cytokine imbalances may also aid in the understanding of other proteinopathies and in the development of novel treatments.

[Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia].

Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disease caused by mutations in the VCP gene. VCP encodes a well-conserved multifunctional protein, valosin containing protein (VCP), which has important roles in protein quality control via proteasome and autophagy, protein aggregation, quality control of mitochondria, cell proliferation, and so on. Clinically, muscle weakness is the most common symptom of which disease onset is around 40 years. Affected muscles are variable, and the patients are sometimes diagnosed as limb girdle muscular dystrophy or GNE myopathy. Muscle pathology shows characteristic features including cytoplasmic/nuclear inclusions, rimmed vacuoles, and disorganized myofibrills, together with neurogenic changes. Paget's disease of bone is reported to be observed in a half of the patients around the age of 40 years, but less common in Japanese patients. Frontotemporal dementia is seen around one third of the patients which appears nearly 10 years later than muscle or bone disease. In addition to cognitive dysfunctions, motor neuron involvement and cerebellar signs were also seen in our series. IBMPFD is not so rare disease as previously thought, but complicate clinical findings may make its diagnosis difficult.

Psychiatric manifestations in cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare and severe, but treatable, inborn disorder of bile acid biosynthesis and sterol storage with autosomal recessive inheritance and variable clinical presentation. CTX treatment consists of chenodeoxycholic acid and must be started as early as possible to prevent permanent disability. Psychiatric manifestations are rare and non-specific, and often lead to significant diagnostic and treatment delay. Therefore, better recognition of the gamut of psychiatric manifestations in CTX can diminish the risk of misdiagnosis and irreversible neurological deterioration. We hereby describe the psychiatric features in CTX. A complete review of all published cases of CTX in the medical literature was undertaken and the case reports with psychiatric presentation were collected and analyzed. We also describe the psychiatric features in relation to the neurological semeiology in six patients with CTX diagnosed at the La Salpêtrière Hospital. We conclude that psychiatric manifestations in CTX follow a bimodal/bitemporal pattern, appearing early in the disease course in the form of a behavioral/personality disorder associated with learning difficulties or mental retardation, or manifesting in advanced disease in the setting of dementia as rich neuropsychiatric syndromes, such as frontal, orbitofrontal or frontotemporal syndromes of cortico-subcortical dementia encompassing behavioral/personality disturbance, affective/mood disorders or psychotic disorders. Behavioral/personality disturbance in childhood or adolescence, especially when accompanied by learning difficulties, should therefore lead to further investigation to exclude CTX, as early diagnosis and treatment is critical for prognosis.

La demencia frontotemporal en la consulta psiquiátrica / Frontotemporal Dementia in the Psychiatric Consultation

La Demencia Lobar Fronto Temporal (DFTL) variante frontal suele ser subdiagnosticada por presentar síntomas psiquiátricos y preservación de la memoria hasta etapas muy avanzadas de la enfermedad. Se inicia durante la mediana edad con trastornos conductuales, afectivos y del habla. Frecuentemente es tratada erróneamente como trastorno depresivo, esquizofrenia o psicosis funcional durante las primeras fases. Es la 3ra causa de demencia degenerativa y la 2da causa en menores de 65 años. Es por ello que considero importante el tener en cuenta su diagnóstico y diagnósticos diferenciales con patologías psiquiátricas y también orgánicas como la del Cerebro Hundido (FBSS) que suele diagnosticarse como DFTL. Se abordan las definiciones, prevalencia, incidencia, factores de riesgo, genética, clasificaciones, criterios diagnósticos, diagnósticos diferenciales y abordajes terapéuticas

Frontotemporal Dementia (FTD) with frontal variant is usually underdiagnosed for presenting psychiatric symptoms and the preservation of memory until very advanced stages of the disease. Its onset is during midlife with behavioral, affective and speech disorders. it is frequently mistreated as depressive disorder, schizophrenia or functional psychosis during the first phases. It's the third cause of degenerative dementia and the second cause among people below 65 years-old. This is why I consider it important to take into consideration its diagnosis and differential diagnoses with sychiatric as well as organic pathologies such as the "Sagging Brain" which is usually diagnosed as FTLD. This article includes definitions, prevalence, incidence, risk factors, genetics, classifications, diagnostic criteria, differential diagnoses and therapeutic approch

Clinical aspects of familial forms of frontotemporal dementia associated with parkinsonism.

Frontotemporal dementia is the second most common dementia among people under the age of 65. Fifty percent of affected patients have an associated family history. Several pathogenic genes have been identified for frontotemporal dementia associated with parkinsonism, including microtubule-associated protein tau, progranulin, and chromatin modifying protein 2B, and fused in sarcoma. It has also been reported that frontotemporal dementia associated with parkinsonism can be linked to chromosome 9p. In addition, there are families with frontotemporal dementia associated with a parkinsonian phenotype but unknown genetic status. Some of these kindreds have been diagnosed clinically as familial progressive supranuclear palsy, hereditary diffuse leukoencephalopathy with axonal spheroids, "overlap" syndrome, and others. Clinical presentation of frontotemporal dementia associated with parkinsonism is variable at age of symptomatic disease onset, disease duration, symptoms, and their occurrence during the disease course. Clinically, it is often difficult to sort out the different genetic forms of frontotemporal dementia associated with parkinsonism. However, with available clinical genetic testing for known genes, the precise diagnosis can be accomplished in some cases.

Hypoxia induces up-regulation of progranulin in neuroblastoma cell lines.

Progranulin (PGRN) is a widely expressed multifunctional protein, involved in regulation of cell growth and cell cycle progression with a possible involvement in neurodegeneration. We looked for PGRN regulation in three different human neuroblastoma cell lines, following exposure to two different stimuli commonly associated to neurodegeneration: hypoxia and oxidative stress. For gene and protein expression analysis we carried out a quantitative RT-PCR and western blotting analysis. We show that PGRN is strongly up-regulated by hypoxia, through the mitogen-actived protein kinase (MAPK)/extracellular signal-regulated kinase (MEK) signaling cascade. PGRN is not up-regulated by H(2)O(2)-induced oxidative stress. These results suggest that PGRN in the brain could exert a protective role against hypoxic stress, one of principal risk factors involved in frontotemporal dementia pathogenesis.