C9orf72 Repeat Expansion Does Not Affect the Phenotype in Primary Progressive Aphasia.

Primary progressive aphasia (PPA) forms the spectrum of language variants of frontotemporal lobar degeneration (FTLD), including three subtypes each consisting of distinctive speech and language features. Repeat expansion in C9orf72 gene is the most common genetic cause of FTLD. However, thus far only little is known about the effects of the C9orf72 repeat expansion on the phenotype of PPA. This retrospective study aimed at determining the differences between the PPA phenotypes of the C9orf72 expansion carriers and non-carriers. Our results demonstrated no significant differences between these groups, indicating that the C9orf72 repeat expansion does not substantially affect the phenotype of PPA.

Parkinsonism in frontotemporal dementias.

Frontotemporal dementia is a clinically and pathologically heterogeneous group of neurodegenerative disorders, with progressive impairment of behavior and language. They can be closely related to amyotrophic lateral sclerosis, clinically and through shared genetics and similar pathology. Approximately 40% of people with frontotemporal dementia report a family history of dementia, motor neuron disease or parkinsonism, and half of these familial cases are attributed to mutations in three genes (C9orf72, MAPT and PGRN). Akinetic-rigidity is a common feature in several types of frontotemporal dementia, particularly the behavioral variant and the non-fluent agrammatic variant of primary progressive aphasia, and the familial dementias. The majority of patients develop a degree of parkinsonism during the course of the illness, and signs may be present at the time of initial diagnosis. However, the parkinsonism of frontotemporal dementia is very different from that observed in idiopathic Parkinson's disease: it may be symmetric, axial, and poorly responsive to levodopa. Tremor is uncommon, and may be postural, action or occasionally rest tremor. The emergence of parkinsonism is often part of an evolving phenotype, in which frontotemporal dementia comes to resemble corticobasal syndrome or progressive supranuclear palsy. This chapter describes the prevalence and phenomenology of parkinsonism in each of the major syndromes, and according to the common genetic forms of frontotemporal dementia. We discuss the changing nosology and terminology surrounding the diagnoses, and the significance of parkinsonism as a core feature of frontotemporal dementia, relevant to clinical management and the design of future clinical trials.

Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia.

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA's relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.

Frontotemporal Dementia: A Clinical Review.

Frontotemporal dementias are a clinically, neuroanatomically, and pathologically diverse group of diseases that collectively constitute an important cause of young-onset dementia. Clinically, frontotemporal dementias characteristically strike capacities that define us as individuals, presenting broadly as disorders of social behavior or language. Neurobiologically, these diseases can be regarded as "molecular nexopathies," a paradigm for selective targeting and destruction of brain networks by pathogenic proteins. Mutations in three major genes collectively account for a substantial proportion of behavioral presentations, with far-reaching implications for the lives of families but also potential opportunities for presymptomatic diagnosis and intervention. Predicting molecular pathology from clinical and radiological phenotypes remains challenging; however, certain patterns have been identified, and genetically mediated forms of frontotemporal dementia have spearheaded this enterprise. Here we present a clinical roadmap for diagnosis and assessment of the frontotemporal dementias, motivated by our emerging understanding of the mechanisms by which pathogenic protein effects at the cellular level translate to abnormal neural network physiology and ultimately, complex clinical symptoms. We conclude by outlining principles of management and prospects for disease modification.

Hereditary primary lateral sclerosis and progressive nonfluent aphasia.

OBJECTIVE: To report a kindred with an association between hereditary primary lateral sclerosis (PLS) and progressive nonfluent aphasia. PATIENTS AND METHODS: Six members from a kindred with 15 affected individuals spanning three generations, suffered from spasticity without muscle atrophy or fasciculation, starting in the lower limbs and spreading to the upper limbs and bulbar musculature, followed by effortful speech, nonfluent language and dementia, in 5 deceased members. Disease onset was during the sixth decade of life, or later. Cerebellar ataxia was the inaugural manifestation in two patients, and parkinsonism, in another. RESULTS: Neuropathological examination in two patients demonstrated degeneration of lateral corticospinal tracts in the spinal cord, without loss of spinal, brainstem, or cerebral motor neurons. Greater loss of corticospinal fibers at sacral and lumbar, rather than at cervical or medullary levels was demonstrated, supporting a central axonal dying-back pathogenic mechanism. Marked reduction of myelin and nerve fibers in the frontal lobes was also present. Argyrophilic grain disease and primary age-related tauopathy were found in one case each, and considered incidental findings. Genetic testing, including exome sequencing aimed at PLS, ataxia, hereditary spastic paraplegia, and frontotemporal lobe dementia, triplet-repeated primed polymerase chain reaction aimed at dominant spinocerebellar ataxias, and massive sequencing of the human genome, yielded negative results. CONCLUSION: A central distal axonopathy affecting the corticospinal tract, exerted a pathogenic role in the dominantly inherited PLS-progressive nonfluent aphasia association, described herein. Further molecular studies are needed to identify the causative mutation in this disease.

Functional characterization of a novel progranulin mutation in a patient with progressive nonfluent aphasia.

Loss-of-function mutations in progranulin (PGRN) gene cause frontotemporal lobar degeneration. Here, we report a case of a 63-year-old woman with a 2-year history of speech impairment, diagnosed with a nonfluent variant of primary progressive aphasia, a subtype of frontotemporal lobar degeneration. In this patient, a novel heterozygous frameshift mutation, c.77delG, in exon 2 of PGRN gene, introducing premature stop codon, p.(C26SfsX28), has been identified. Cultured fibroblasts derived from the patient and her asymptomatic first-degree relative with c.77delG mutation had decreased levels of PGRN messenger RNA (mRNA) and protein. However, PGRN mRNA levels did not recover upon incubation with inhibitors of nonsense-mediated mRNA decay (cycloheximide or puromycin), suggesting involvement of other mRNA degradation pathways. In addition, we observed upregulated wingless-type mouse mammary tumor virus integration site (WNT) signaling pathway gene, WNT3A, in fibroblasts of the patient and her asymptomatic first-degree relative with c.77delG mutation. As reported previously, this is an early hallmark of PGRN deficiency.

GRN and MAPT Mutations in 2 Frontotemporal Dementia Research Centers in Brazil.

BACKGROUND: Mutations in GRN (progranulin) and MAPT (microtubule-associated protein tau) are among the most frequent causes of monogenic frontotemporal dementia (FTD), but data on the frequency of these mutations in regions such as Latin America are still lacking. OBJECTIVE: We aimed to investigate the frequencies of GRN and MAPT mutations in FTD cohorts from 2 Brazilian dementia research centers, the University of Sao Paulo and the Federal University of Minas Gerais medical schools. METHODS: We included 76 probands diagnosed with behavioral-variant FTD (n=55), semantic-variant Primary Progressive Aphasia (PPA) (n=11), or nonfluent-variant PPA (n=10). Twenty-five percent of the cohort had at least 1 relative affected with FTD. RESULTS: Mutations in GRN were identified in 7 probands, and in MAPT, in 2 probands. We identified 3 novel GRN mutations (p.Q130X, p.317Afs*12, and p.K259Afs*23) in patients diagnosed with nonfluent-variant PPA or behavioral-variant FTD. Plasma progranulin levels were measured and a cutoff value of 70 ng/mL was found, with 100% sensitivity and specificity to detect null GRN mutations. CONCLUSIONS: The frequency of GRN mutations was 9.6% and that of MAPT mutations was 7.1%. Among familial cases of FTD, the frequency of GRN mutations was 31.5% and that of MAPT mutations was 10.5%.

Clinical and MRI correlates of disease progression in a case of nonfluent/agrammatic variant of primary progressive aphasia due to progranulin (GRN) Cys157LysfsX97 mutation.

Little is known about the longitudinal changes of brain damage in patients with sporadic nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) and in progranulin (GRN) mutation carriers. This study reports the clinical and MRI longitudinal data of a patient with nfvPPA carrying GRN Cys157LysfsX97 mutation (GRN+). Voxel-based morphometry, tensor-based morphometry and diffusion tensor MRI were applied to evaluate gray matter (GM) and white matter (WM) changes over three years. The prominent clinical feature was motor speech impairment associated with only mild agrammatism. MRI demonstrated a progressive and severe GM atrophy of inferior fronto-insular-temporo-parietal regions with focal damage to frontotemporal and frontoparietal WM connections. This is the first report of longitudinal MRI data in a nfvPPA- GRN+ patient and this report offers new insights into the pathophysiology of the disease.

The presenilin 1 P264L mutation presenting as non-fluent/agrammatic primary progressive aphasia.

Primary progressive aphasia (PPA) represents a diverse group of language-led dementias most often due to frontotemporal lobar degeneration. We report clinical, neuropsychological, and neuroimaging data in the case of a 47-year-old woman presenting with non-fluent PPA due to a genetically confirmed pathogenic Presenilin 1 P264L mutation. This case highlights an unusual clinical presentation of familial Alzheimer's disease and a novel presentation of the P264L mutation. The case adds to accumulating evidence that particular mutations can promote specific brain network degeneration, with wider implications for understanding the sporadic forms of Alzheimer's disease and PPA.

Parálisis supranuclear progresiva / Progressive supranuclear palsy

Introducción. La parálisis supranuclear progresiva (PSP) es una enfermedad neurodegenerativa que se describió por primera vez en 1964 y en la que se produce una acumulación citoplasmática de proteína tau asociada a microtúbulos (MAPT) como consecuencia de su fosforilación anómala. Objetivo. El objetivo de este trabajo ha sido revisar los avances en el conocimiento de la PSP en los últimos años. Desarrollo. La PSP es la taupatía más frecuente, de aparición esporádica pero con algunos casos hereditarios por mutaciones en el gen MAPT. Las manifestaciones clínicas más características de esta enfermedad consisten en inestabilidad postural con caídas, deterioro cognitivo y parálisis supranuclear de la mirada. Se han descrito distintas variantes clínicas, entre las que destacan el Síndrome de Richardson, la PSP- Parkinsonismo, la acinesia pura con congelación de la marcha, la PSP-corticobasal y la afasia no fluente progresiva. Las diferentes características clínicas de estos subtipos vienen determinadas por la distinta densidad y localización de los agregados tau. El diagnóstico definitivo se realiza mediante confirmación anatomopatológica postmortem. Aunque se han producido algunos ensayos terapéuticos, en la actualidad no se dispone de tratamiento eficaz modificador de la enfermedad. Conclusiones. Los recientes avances han permitido un mejor conocimiento de la fisiopatología y genética de esta enfermedad. Existen distintas líneas de investigación abiertas en la actualidad siendo necesario que se profundice en estudios dirigidos a descubrir marcadores biológicos y agentes terapéuticos (AU)

Introduction. Progressive supranuclear palsy (PSP) is a neurodegenerative disease that was first reported in 1964 and which entails a cytoplasmic accumulation of microtubule-associated protein tau (MAPT) as a consequence of its abnormal phosphorylation. Aims. The objective of this research is to review the advances produced in the knowledge of PSP in recent years. Development. PSP is the most frequent tauopathy, which appears sporadically but with some hereditary cases due to mutations in the MAPT gene. The most characteristic clinical manifestations of this disease consist in postural instability with falls, cognitive impairment and supranuclear gaze palsy. Several different clinical variants have been described, including Richardson’s syndrome, Parkinsonism-PSP, pure akinesia with freezing of gait, corticobasal-PSP and progressive non-fluent aphasia. The different clinical features of these subtypes are determined by the different density and location of the tau aggregates. The definitive diagnosis is reached by confirmation from post-mortem pathological analyses. Although some therapeutic trials have been conducted, today there is still no effective disease-modifying treatment available. Conclusions. Recent advances have made it possible to gain a better understanding of the pathophysiology and genetics of this disease. Different lines of research are currently open, but there is a need for further in-depth studies aimed at discovering biological markers and therapeutic agents (AU)

A novel MAPT mutation associated with the clinical phenotype of progressive nonfluent aphasia.

A number of mutations in microtubule associated protein tau gene (MAPT), causing frontotemporal lobar degeneration (FTLD) with tau pathology, are located in the four-repeated microtubule (MT) binding domains and affect the ability of tau to bind MTs. Here, we describe a novel variant lying in the second MT domain, found in a female patient diagnosed clinically with progressive nonfluent aphasia (PNFA), with a positive family history for dementia. At 65 years, she started developing progressive language deficits, characterized by expression difficulties and word coordination impairment. She came to our attention at 67 years. Her MMSE score was 22/30. A Brain CT scan showed mild diffuse cortical atrophy, ventricles' asymmetry (left > right), and very mild signs of chronic vasculopathy. Cerebrospinal fluid analysis showed normal amyloid-ß42, tau, and P-tau levels. She was diagnosed with PNFA according to current diagnostic criteria. A novel exon 10 MAPT variant was identified (g.123798G > A), which leads to an amino acidic change (p.Gly304Ser) in the second MT microtubule binding domain. In silico analysis predicted that this variant is damaging on protein structure and function. Additional 168 FTLD patients and 503 controls screened (1342 chromosomes) did not carry the variant, suggesting that it is a mutation rather than a polymorphism. The amino acid change likely compromises the ability of tau to properly regulate the dynamic behavior of microtubules.

From FUS to Fibs: what's new in frontotemporal dementia?

Frontotemporal dementia (FTD) is an important cause of non-Alzheimer's dementia and is the second most common cause of young onset dementia. FTD presents with progressive changes in behavior and personality (behavioral variant FTD) or language deficits (also known as primary progressive aphasia), although both commonly coexist. Patients with progressive aphasia are subclassified according to the pattern of language deficits into those with progressive non-fluent aphasia (PNFA) and semantic dementia (SD). FTD is pathologically heterogeneous, both macroscopically and on a molecular level, with tau positive, TDP-43 positive, and FUS positive intraneuronal inclusions recognized on immunohistochemical analysis. TDP-43 positive inclusions are also a feature of amyotrophic lateral sclerosis pathology, corroborating the observation of overlapping clinical features between the two conditions and reaffirming the FTD-ALS disease spectrum. Most FTD cases are sporadic, but an important minority is inherited in an autosomal dominant fashion, most commonly due to MAPT or progranulin gene mutations. Familial clusters of FTD and amyotrophic lateral sclerosis are also recognized but poorly understood. This paper reviews the clinical phenotypes, assessment and treatment of FTD in light of recent pathological and genetic discoveries.