Progressive Nonfluent Aphasia Research Articles

Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease

We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2, and HTT genes in several neurodegenerative diseases. The study included 1126 patients with Alzheimer's disease (AD), 440 patients with frontotemporal dementia (FTD), and 610 patients with Parkinson's disease. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. In addition, in the FTD cohort, we determined the number of HTT CAG repeats. The frequency of HTT IAs was higher in patients with FTD (6.9%) versus controls (2.9%) and in the C9orf72 expansion noncarriers (7.2%) versus controls (2.9%), although the difference was nonsignificant after correction for multiple testing. Compared with controls, progressive nonfluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs (13.6% vs. 2.9% controls). For the ATXN2 gene, we observed an increase in IA frequency in AD cases (AD 4.1% vs. controls 1.8%) and in the behavioral FTD group (4.8% vs. 1.8%). For the ATXN1 gene, we found a significant increase of IAs in patients with PNFA (18.6%) versus controls (6.7%). In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD.

Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Amyotrophic lateral sclerosis (ALS) is often comorbid with frontotemporal dementia (FTD). Patients may exhibit language deficits as seen in progressive non-fluent aphasia (PNFA) or semantic dementia (SD). In behavioral variant FTD (bvFTD), cognitive impairments such as executive function, verbal fluency and language abnormalities are frequently seen, while apathy and disinhibition are major behavioral changes. Further, there are many ALS patients who do not fulfill the criteria for FTD but have mild cognitive and/or behavioral impairments. Appropriate evaluation of these conditions is necessary for non-pharmacological and pharmacological interventions.

The Cerebellum in Frontotemporal Dementia: a Meta-Analysis of Neuroimaging Studies.

Frontotemporal dementia (FTD) is a neurodegenerative brain disorder primarily affecting the frontal and/or temporal lobes. Three main subtypes have been recognized: behavioural-variant FTD (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA), each of which has a distinct clinical and cognitive profile. Although the role of the cerebellum in cognition is increasingly accepted, knowledge of cerebellar changes across neuroimaging modalities and their contribution to behavioural and cognitive changes in FTD syndromes is currently scant. We conducted an anatomical/activation likelihood estimation (ALE) meta-analysis in 53 neuroimaging studies (structural MRI: 42; positron emission tomography: 6; functional MRI: 4; single-photon emission computed tomography: 1) to identify the patterns of cerebellar changes and their relations to profiles of behavioural and cognitive deficits in FTD syndromes. Overall, widespread bilateral cerebellar changes were found in FTD and notably the patterns were subtype specific. In bvFTD, ALE peaks were identified in the bilateral Crus, left lobule VI, right lobules VIIb and VIIIb. In SD, focal cerebellar changes were located in the left Crus I and lobule VI. A separate ALE meta-analysis on PNFA studies was not performed due to the limited number of studies available. In addition, the ALE analysis indicated that bilateral Crus I and Crus II were associated with behavioural disruption and cognitive dysfunction. This ALE meta-analysis provides the quantification of the location and extent of cerebellar changes across the main FTD syndromes, which in turn provides evidence of cerebellar contributions to behavioural and cognitive changes in FTD. These results bring new insights into the mechanisms mediating FTD symptomatology.

Orphan designation: Methylthioninium, treatment of progressive non-fluent aphasia

Orphan designation: Methylthioninium, treatment of progressive non-fluent aphasia

Orphan designation: Methylthioninium, treatment of progressive non-fluent aphasia

Orphan designation: Methylthioninium, treatment of progressive non-fluent aphasia

Hereditary primary lateral sclerosis and progressive nonfluent aphasia.

To report a kindred with an association between hereditary primary lateral sclerosis (PLS) and progressive nonfluent aphasia. 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. 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. 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.

Clinical and neuroimaging investigations of language disturbance in frontotemporal dementia-motor neuron disease patients.

This study systematically investigated the neuropsychological profile of language disturbance in frontotemporal dementia-motor neuron disease (FTD-MND) using a data-driven approach. Neuroanatomical correlates of language profiles were also examined. Patients with FTD-MND (N = 26), pure motor neuron disease (N = 34), progressive non-fluent aphasia (N = 30), semantic dementia (N = 17), and controls (N = 31) underwent comprehensive language assessments. Clinical assessments were complemented with the Sydney Language Battery (SYDBAT), to assess semantic abilities, and the Test for Reception of Grammar (TROG), to assess syntactic comprehension. Two-step cluster analysis examined patterns of language impairment in FTD-MND and voxel-based morphometry investigated neuroanatomical differences between clusters. Almost all (88.5%) FTD-MND patients had language impairment, with anomia in 73.1% and impaired sentence comprehension in 56%. Cluster analysis revealed two main profiles of language impairment in FTD-MND; a mild mixed semantic and syntactic impairment (mild mixed subgroup) seen in 12 cases and a subgroup with more marked impairment particularly of syntactic comprehension (PNFA-like subgroup) seen in 7 cases. VBM revealed disproportionate atrophy of the caudate head and putamen bilaterally in the PNFA-like subgroup. In conclusion, language disturbances in FTD-MND are heterogeneous and more mixed than seen in FTD language phenotypes. Atrophy of the caudate and putamen was correlated with disproportionate impairment of syntactic comprehension. A pure semantic dementia like syndrome appears to be rare in FTD-MND.

SA44WHAT CPGS CAN TELL: AN APPROACH TO THE METHYLATION PATTERN OF BDNF PROMOTER IV IN MAJOR DEPRESSION DISORDER AND ITS RELATION TO STRESS

Progranulin gene (GRN) mutations are among the leading causes of frontotemporal lobar degeneration, a group of neurodegenerative diseases characterized by remarkable clinical heterogeneity. In this article, we report the new GRN 708+4A>T splicing mutation, identified in 2 siblings of a family with several members affected by cognitive, behavioral, and motor disorders. Plasma progranulin dosage and GRN expression analysis, together with in silico prediction studies, supported the pathogenicity of the mutation. Both the patients displayed a clinical syndrome in which language impairment was largely predominant. However, motor speech deficits were the major feature in one case, diagnosed as progressive nonfluent aphasia, whereas marked semantic alterations were present in the other, whose clinical phenotype was in favor of a mixed aphasia. The profile of neuroanatomical alterations from imaging studies was in line with the clinical phenotypes. Therefore, also this novel GRN mutation is associated with haploinsufficiency and phenotypic heterogeneity, which are both typical features of progranulinopathies.

Chapter 12 - Neuroimaging in aging and neurologic diseases

Neuroimaging biomarkers for neurologic diseases are important tools, both for understanding pathology associated with cognitive and clinical symptoms and for differential diagnosis. This chapter explores neuroimaging measures, including structural and functional measures from magnetic resonance imaging (MRI) and molecular measures primarily from positron emission tomography (PET), in healthy aging adults and in a number of neurologic diseases. The spectrum covers neuroimaging measures from normal aging to a variety of dementias: late-onset Alzheimer's disease [AD; including mild cognitive impairment (MCI)], familial and nonfamilial early-onset AD, atypical AD syndromes, posterior cortical atrophy (PCA), logopenic aphasia (lvPPA), cerebral amyloid angiopathy (CAA), vascular dementia (VaD), sporadic and familial behavioral-variant frontotemporal dementia (bvFTD), semantic dementia (SD), progressive nonfluent aphasia (PNFA), frontotemporal dementia with motor neuron disease (FTD-MND), frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), Parkinson's disease (PD) with and without dementia, and multiple systems atrophy (MSA). We also include a discussion of the appropriate use criteria (AUC) for amyloid imaging and conclude with a discussion of differential diagnosis of neurologic dementia disorders in the context of neuroimaging.

Network localization of heterogeneous neuroimaging findings.

Studies of the same disease often implicate different brain regions, contributing to a perceived reproducibility crisis in neuroimaging. Here, we leverage the normative human brain connectome to test whether seemingly heterogeneous neuroimaging findings localize to connected brain networks. We use neurodegenerative disease, and specifically Alzheimer's disease, as our example as it is one of the diseases that has been studied the most using neuroimaging. First, we show that neuroimaging findings in Alzheimer's disease occur in different brain regions across different studies but localize to the same functionally connected brain network. Second, we show that neuroimaging findings across different neurodegenerative diseases (Alzheimer's disease, frontotemporal dementia, corticobasal syndrome, and progressive non-fluent aphasia) localize to different disease-specific brain networks. Finally, we show that neuroimaging findings for a specific symptom within a disease (delusions in Alzheimer's disease) localize to a symptom-specific brain network. Our results suggest that neuroimaging studies that appear poorly reproducible may identify different regions within the same connected brain network. Human connectome data can be used to link heterogeneous neuroimaging findings to common neuroanatomy, improving localization of neuropsychiatric diseases and symptoms.

History of Pick's disease

History of Pick's disease

Identification of a novel mutation in APP gene in a Thai subject with early-onset Alzheimer's disease.

IntroductionEarly-onset Alzheimer’s disease (AD) accounts for than less 1% of all AD cases, with large variation in the reported genetic contributions of known dementia genes. Mutations in the amyloid precursor protein (APP) gene were the first to be recognized as the cause of AD.MethodsHere, a male patient with probable early-onset AD at the age of 55 years from Thailand was investigated by next-generation sequencing.ResultsA novel mutation in exon 14 of APP (c.1810C>T, p.V604M) was found. He initially illustrated the clinical manifestations of progressive nonfluent aphasia in 2011. However, he was finally diagnosed with AD presenting logopenic aphasia in 2013. The follow-up magnetic resonance imaging scan showed progression of hippocampal trophy compared with the initial image. A 3D protein structure model revealed that V604M exchange could result in significant changes in the APP protein due to the increased hydrophobicity of methionine in the helix, which could result in altering of the APP functions.ConclusionAdditional studies to characterize APP p.V604M are necessary to further understand the effects of this mutation.

Pathogenesis of Frontotemporal Lobar Degeneration: Insights From Loss of Function Theory and Early Involvement of the Caudate Nucleus.

Frontotemporal lobar degeneration (FTLD) is a group of clinically, pathologically and genetically heterogeneous neurodegenerative disorders that involve the frontal and temporal lobes. Behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA) are three major clinical syndromes. TDP-43, FUS, and tau are three major pathogenetic proteins. In this review, we first discuss the loss-of-function mechanism of FTLD. We focus on FUS-associated pathogenesis in which FUS is linked to tau by regulating its alternative splicing machinery. Moreover, FUS is associated with abnormalities in post-synaptic formation, which can be an early disease marker of FTLD. Second, we discuss clinical and pathological aspects of FTLD. Recently, FTLD and amyotrophic lateral sclerosis (ALS) have been recognized as the same disease entity; indeed, nearly all sporadic ALS cases show TDP-43 pathology irrespective of FTD phenotype. Thus, investigating early structural and network changes in the FTLD/ALS continuum can be useful for developing early diagnostic markers of FTLD. MRI studies have revealed the involvement of the caudate nucleus and its anatomical networks in association with the early phase of behavioral/cognitive decline in FTLD/ALS. In particular, even ALS patients with normal cognition have shown a significant decrease in structural connectivity between the caudate head networks. In pathological studies, FTLD/ALS has shown striatal involvement of both efferent system components and glutamatergic inputs from the cerebral cortices even in ALS patients. Thus, the caudate nucleus may be primarily associated with behavioral abnormality and cognitive involvement in FTLD/ALS. Although several clinical trials have been conducted, there is still no therapy that can change the disease course in patients with FTLD. Therefore, there is an urgent need to establish a strategy for predominant sporadic FTLD cases.

CSF Biomarkers of Neurodegeneration in Progressive Non-fluent Aphasia and Other Forms of Frontotemporal Dementia: Clues for Pathomechanisms?

Frontotemporal Dementia (FTD) encompasses distinct pathophysiologically heterogenous disorders with different genetic and cellular disease mechanisms. The objective of this study is to compare the constellation of biomarkers of neurodegeneration in the cerebrospinal fluid (CSF) to the FTD type categorized by clinical symptoms. We investigated the levels of Phospho181-tau, Total-tau, Beta-amyloid1−42, Neurofilament light chain, and Progranulin in the CSF of n = 99 FTD patients regarding to the different subtypes of FTD, including semantic dementia (SD), progressive non-fluent aphasia (PNFA), behavioral variant FTD (bvFTD). We compared these groups to patients without neurodegenerative disorders and another cohort encompassing tauopathies with distinct clinical syndromes (Cortico basal syndrome and progressive supranuclear palsy) and logopenic PNFA (lPPA) as another disorder with predominant speech disturbance. CSF-Progranulin levels were significantly lower in FTD type patients with semantic dementia and behavioral variant FTD mainly attributed to the Tar-DNA-Binding-Protein (TDP) 43 compared to predominantly Tau-mediated PNFA (p < 0.05). Also, neurofilament light chain was significantly higher (p < 0.036) in all FTD patients especially in SD patients (p < 0.01). CSF-Nfl levels also distinguished SD patients from logopenic Alzheimers patients (p < 0.05). In sum, CSF-Neurofilament light chain and CSF-Progranulin seem to be promising biomarkers for FTD, the latter predominantly for assumed TDP43-mediated FTD.

Cerebellar atrophy and its contribution to cognition in frontotemporal dementias.

Increasing evidence suggests that cerebellar damage impacts on cognitive functions. Frontotemporal dementias (FTDs) are neurodegenerative brain conditions, primarily affecting the frontal and/or temporal lobe. Three main phenotypes are recognized, each with a distinct clinical and cognitive profile: behavioral-variant FTD (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). The severity of cerebellar changes and their relation to cognition in FTD, however, remain unclear. This study aimed to establish cerebellar gray matter changes on magnetic resonance imaging (MRI) and their relation to profiles of cognitive deficits in FTD subtypes. Ninety-six FTD patients (45 bvFTD, 28 SD, and 23 PNFA), meeting current clinical diagnostic criteria, and 35 age-, sex-, and education-matched controls underwent brain MRI and cognitive assessment. Cerebral and cerebellar gray matter integrity were investigated using voxel-based morphometry. Compared with controls, widespread bilateral cerebellar changes were observed in all FTD subtypes, with the greatest atrophy present in bvFTD. Significant associations were found between cerebellar integrity and cognitive performance in attention and working memory in bvFTD, visuospatial function in SD, and language-motor function in PNFA. Bilateral atrophy of crus and lobule VI were most commonly associated with cognitive deficits, irrespective of FTD phenotype. This study is the first to identify distinct patterns of cerebellar atrophy across FTD syndromes, which in turn relate to discrete cognitive dysfunctions, after accounting for the effect of cerebral atrophy. These findings extend our understanding of the cerebellum and point to its involvement across an array of processes beyond the domain of motor function. Ann Neurol 2018;83:98-109.

EARLY ONSET DEGENERATIVE DEMENTIAS: ETIOLOGICAL CLASSIFICATION AND DEMOGRAPHIC CHARACTERISTICS IN SERBIAN TERTIARY REFERRAL CENTER

Early-onset dementia (EOD), conventionally considered to include patients with disease onset before 65 years of age, represents a major diagnostic challenge. Degenerative dementias (Alzheimer's disease (AD), frontotemporal dementia (FTD), Dementia with lewy bodies (DLB)), traditionally considered to affect older population, are a main cause of EOD as well. Our aim was to make etiological classification and to determine demographic characteristics of consecutive degenerative EOD patients. Between april 2012 and april 2017, 256 patients were reffered to Neurology Clinic, Clinical Centre of Serbia with the diagnosis of possible EOD. After detailed examination, 207 patients fulfilled current criteria for degenerative demetias- AD, FTD spectrum and DLB. In our investigated EOD cohort, 129(62,2%) patients were diagnosed with AD, 78(36,2%) with FTD spectrum and 3(1,4%) patients with DLB. According to dominant presenting cognitive symptom, AD patients were further classified into AD with amnestic presentation (95 patients, 73%) and non-amnestic presentation (34 patients, 27%). Among FTD spectrum, 60(75.6%) patients met criteria for behavioural variant (FTDbv), 13(16,7%) for primary progressive aphasia (PPA)-progressive nonfluent aphasia (PPA-PNFA) and 5(7.7%) for semantic variant of PPA. Furthermore, 5(2,4%) patients (all FTDbv) developed symptoms consistent with progressive supranuclear palsy, 5(2,4%) patients (1 FTDbv, 2 PPA-PNFA and 2 AD) had corticobasal syndrome and 4(1,9%) patients developed concomitant motor neuron disease (3 FTDbv, 1 PPA-PNFA) Demographic characteristics did not differ significantly among diagnostic categories in our EOD group. Degenerative disorders as causes of EOD are not rare. High clinical alertness is warranted to achieve correct and timely diagnosis.

Speech Therapy for Progressive Non-fluent Aphasia: On a Case of Apraxia of Speech, Pure Word Deafness and Amusia

Speech Therapy for Progressive Non-fluent Aphasia: On a Case of Apraxia of Speech, Pure Word Deafness and Amusia

Neuropathologic Subtypes of Frontotemporal Lobar Degeneration

Frontotemporal lobar degeneration (FTLD) is a heterogeneous disease entity encompassing a wide variety of histopathological features and genetic backgrounds. The last two decades have seen the discovery of causative genes and the identification of relevant proteins. The current histopathological classification is based on the major types of protein deposition in the brain, and most FTLD cases can be placed into one of three pathological subgroups: FTLD-tau, FTLD-TDP, and FTLD-FUS. Further sub-classification within each subgroup is based on the morphology of neuronal and glial inclusions and lesion distribution. Affected patients, including some from the same subgroups, show considerable heterogeneity in their clinical presentations, suggesting that the subgroups represent a variety of well-defined clinical syndromes, including variants of frontotemporal dementia (behavioral variant frontotemporal dementia, progressive non-fluent aphasia, and semantic dementia) and motor disorders (amyotrophic lateral sclerosis, corticobasal syndrome, and supranuclear palsy syndrome). On the other hand, patients with MAPT mutations always show the FTLD-tau phenotype, whereas patients with progranulin, C9orf72, VCP or TARDBP usually present the FTLD-TDP phenotype. In this review, we describe the histopathologic features of the main FTLD subtypes and summarize the clinical presentations and genetic characteristics of affected patients.

Cerebrospinal fluid in the differential diagnosis of Alzheimer\u2019s disease: clinical utility of an extended panel of biomarkers in a specialist cognitive clinic

BackgroundCerebrospinal fluid (CSF) biomarkers are increasingly being used to support a diagnosis of Alzheimer’s disease (AD). Their clinical utility for differentiating AD from non-AD neurodegenerative dementias, such as dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD), is less well established. We aimed to determine the diagnostic utility of an extended panel of CSF biomarkers to differentiate AD from a range of other neurodegenerative dementias.MethodsWe used immunoassays to measure conventional CSF markers of amyloid and tau pathology (amyloid beta (Aβ)1–42, total tau (T-tau), and phosphorylated tau (P-tau)) as well as amyloid processing (AβX-38, AβX-40, AβX-42, soluble amyloid precursor protein (sAPP)α, and sAPPβ), large fibre axonal degeneration (neurofilament light chain (NFL)), and neuroinflammation (YKL-40) in 245 patients with a variety of dementias and 30 controls. Patients fulfilled consensus criteria for AD (n = 156), DLB (n = 20), behavioural variant frontotemporal dementia (bvFTD; n = 45), progressive non-fluent aphasia (PNFA; n = 17), and semantic dementia (SD; n = 7); approximately 10% were pathology/genetically confirmed (n = 26). Global tests based on generalised least squares regression were used to determine differences between groups. Non-parametric receiver operating characteristic (ROC) curves and area under the curve (AUC) analyses were used to quantify how well each biomarker discriminated AD from each of the other diagnostic groups (or combinations of groups). CSF cut-points for the major biomarkers found to have diagnostic utility were validated using an independent cohort which included causes of AD (n = 104), DLB (n = 5), bvFTD (n = 12), PNFA (n = 3), SD (n = 9), and controls (n = 10).ResultsThere were significant global differences in Aβ1–42, T-tau, T-tau/Aβ1–42 ratio, P-tau-181, NFL, AβX-42, AβX-42/X-40 ratio, APPα, and APPβ between groups. At a fixed sensitivity of 85%, AβX-42/X-40 could differentiate AD from controls, bvFTD, and SD with specificities of 93%, 85%, and 100%, respectively; for T-tau/Aβ1–42 these specificities were 83%, 70%, and 86%. AβX-42/X-40 had similar or higher specificity than Aβ1–42. No biomarker or ratio could differentiate AD from DLB or PNFA with specificity > 50%. Similar sensitivities and specificities were found in the independent validation cohort for differentiating AD and other dementias and in a pathology/genetically confirmed sub-cohort.ConclusionsCSF AβX-42/X-40 and T-tau/Aβ1–42 ratios have utility in distinguishing AD from controls, bvFTD, and SD. None of the biomarkers tested had good specificity at distinguishing AD from DLB or PNFA.

Repetitive transcranial magnetic stimulation for the treatment of cognitive impairment in frontotemporal dementia: an open-label pilot study.

BackgroundFrontotemporal dementia (FTD) is one of the most frequent dementia types in patients under 65 years of age. Currently, no therapy can effectively improve the cognitive deficits associated with FTD. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method of inducing brain plasticity with therapeutic potential in neurodegenerative diseases. The purpose of this study was to evaluate the effect of rTMS on cognitive, behavioral, and emotional function in FTD.MethodsNine patients (seven women, four men, mean age 61.7±10.1 years) with the behavioral variant of FTD, one with nonfluent/agrammatic variant primary progressive aphasia, and one with progressive nonfluent aphasia (subtypes of FTD) underwent 10 daily sessions of 10 Hz rTMS over the bilateral dorsolateral prefrontal cortex. Cognitive and behavioral assessments were administered before and after therapy.ResultsAfter rTMS, the Montreal Cognitive Assessment and letter and digit cancellation test scores, as well as reading time and error number in the Stroop test improved. The caregivers’ impression of the daily functioning of patients improved in the Frontal Behavioral Inventory scores. These changes were not paralleled by an improvement of mood.ConclusionThe results indicate that rTMS may improve the cognitive performance of patients with FTD and warrant sham-controlled trials.