Progressive anomia revisited: focal degeneration associated with progranulin gene mutation

In 2003 we reported a case study of a patient, Newton who presented with a progressive circumscribed anomia in association with focal left hemisphere atrophy. Remarkably, he could spell aloud the names of objects that he could not name, indicating dissociated access to phonology and orthography. We now present follow-up clinical data, post-mortem histopathological findings, and results of molecular genetic analysis. Newton showed tau-negative ubiquitin-positive histology consistent with frontotemporal lobar degeneration (FTLD) and a mutation in the progranulin (PGRN) gene. The case exemplifies the heterogeneity of clinical expression of FTLD and contributes to understanding of primary progressive aphasia.     

Clinical,Cognitive and Anatomical Evolution from Nonfluent Progressive Aphasia to Corticobasal Syndrome: A Case Report

Abstract

Recent clinical and pathological studies have suggested that frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS) show clinical and pathological overlap. We present four years of longitudinal clinical, cognitive and anatomical data in the case of a 56-year-old woman, AS, whose clinical picture evolved from FTLD to CBS. For the first three years, AS showed a progressive speech and language disorder compatible with a diagnosis of the nonfluent aphasia variant of FTLD. At year four, 10 years after her first symptom, AS developed the classical clinical signs of CBS, including alien limb phenomenon and dystonia. Voxel-based morphometry (VBM) applied to AS's four annual scans showed progression of atrophy from the inferior posterior frontal gyrus, to the left insula and finally to the medial frontal lobe. This case demonstrates the clinical overlap between FTLD and CBS and shows that the two can appear in the same patient at different stages of the disease in relation to the progression of anatomical damage.     

The genetics of frontotemporal lobar degeneration

The clinical disorders associated with frontotemporal lobar degeneration (FTLD) are increasingly recognized as an important cause of early-onset dementia. Patients usually present with progressive changes in personality, behavior, or language, progressing to general cognitive impairment and ultimately death. In the past decade, improved clinical and histopathologic characterization uncovered extensive heterogeneity, and multiple clinical and pathologic FTLD subtypes were defined. Simultaneously, the discovery of four causal FTLD genes emphasized the genetic complexity associated with FTLD. More recently, the field of FTLD has gained increased attention as a result of two major findings. First, mutations in the progranulin gene (PGRN) were recognized as a major cause of FTLD with ubiquitin-positive and tau-negative inclusions (FTLDU), and subsequently the TAR DNA-binding protein-43 (TDP-43) was identified as a key protein within the ubiquitinated inclusions in FTLD-U and amyotrophic lateral sclerosis (ALS). In this report, we outline the progress made in the study of the genetic etiologies and neuropathologic substrates in FTLD.     

MRI signatures of the frontotemporal lobar degeneration continuum

Objective. To identify overlapping and unique grey (GM) and white matter (WM) signatures within the frontotemporal lobar degeneration (FTLD) continuum, and discriminate likely FTLD‐TAU and FTLD‐TDP patients using structural and diffusion tensor (DT) magnetic resonance imaging (MRI). Methods. T1‐weighted and DT MRI were collected from 121 subjects: 35 motor neuron disease (MND), 14 behavioral variant of frontotemporal dementia, 12 semantic and 11 nonfluent primary progressive aphasia, 21 progressive supranuclear palsy syndrome patients, and 28 healthy controls. Patterns of GM atrophy were established using voxel‐based morphometry. Tract‐based spatial statistics was used to perform a WM voxelwise analysis of mean diffusivity and fractional anisotropy. Results. In all clinical FTLD phenotypes, the pattern of WM damage was more distributed than that of GM atrophy. All patient groups, with the exception of MND cases with a pure motor syndrome, shared a focal GM atrophy centered around the dorsolateral and medial frontal cortex and a largely overlapping pattern of WM damage involving the genu and body of the corpus callosum and ventral frontotemporal and dorsal frontoparietal WM pathways. Surrounding this common area, phenotype (symptom)‐specific GM and WM regions of damage were found in each group. Conclusions. In the FTLD spectrum, WM disruption is more severe than GM damage. Frontal cortex and WM pathways represent the common target of neurodegeneration in these conditions. The topographic pattern of damage supports a “prion‐like” protein propagation through WM connections as underlying mechanism of the stereotyped progression of FTLD. Hum Brain Mapp 36:2602–2614, 2015. © 2015 Wiley Periodicals, Inc.     

Increase in the relative expression of tau with four microtubule binding repeat regions in frontotemporal lobar degeneration and progressive supranuclear palsy brains

Some cases of familial frontotemporal dementia (FTD) leading to frontotemporal lobar degeneration (FTLD) are caused by mutations in tau on chromosome 17 (FTDP-17). Certain mutations alter the ratio between four (4R tau) and three (3R tau) repeat tau isoforms whereas cases with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) mainly have 4R tau brain pathology. We assessed tau mRNA and protein levels in frontal cortex from 15 sporadic FTLD, 21 PSP, 5 CBD, 15 Alzheimer’s disease (AD) and 16 control brains. Moreover, we investigated the disease association and possible tau splicing effects of the tau H1 haplotype. Cases with FTLD and PSP had lower tau mRNA levels than control brains. When analyzing 4R tau and 3R tau mRNA separately, control subjects displayed a 4R tau/3R tau ratio of 0.48. Surprisingly, FTLD brains displayed a more elevated ratio (1.32) than PSP brains (1.12). Also, several FTLD and PSP cases had higher 4R tau/3R tau mRNA than FTDP-17 cases, included as reference tissues, and the ratio increase was seen regardless of underlying histopathology, i.e. both for tau-positive and tau-negative FTLD cases. Furthermore, total tau protein levels were slightly decreased in both FTLD and AD as compared to control subjects. Finally, we confirmed the association of tau H1 with PSP, but could not find any haplotype-related effect on tau exon 10 splicing. In conclusion, we demonstrated increased but largely variable 4R tau/3R tau mRNA ratios in FTLD and PSP cases, suggesting heterogeneous pathophysiological processes within these disorders.     

Atypical parkinsonian syndromes: a general neurologist's perspective

The differential diagnosis of atypical parkinsonian syndromes is challenging. These severe and often rapidly progressive neurodegenerative disorders are clinically heterogeneous and show significant phenotypic overlap. Here, clinical, imaging, neuropathological and genetic features of multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and frontotemporal lobar degeneration (FTLD) are reviewed. The terms corticobasal degeneration and FTLD refer to pathologically confirmed cases of corticobasal syndrome and frontotemporal dementia (FTD). Frontotemporal lobar degeneration clinically presents as the behavioral variant FTD, semantic variant primary progressive aphasia (PPA), non‐fluent agrammatic variant PPA, logopenic variant PPA and FTD associated with motor neuron disease. While progressive supranuclear palsy and corticobasal syndrome have been called Parkinson‐plus syndromes in the past, they are now classified as FTD‐related disorders, reflecting that they pathologically differ from α‐synucleinopathies like multiple system atrophy and Parkinson disease. The contribution of genetic factors to atypical parkinsonian syndromes is increasingly recognized. Genes involved in the etiology of FTLD include MAPT, GRN and C9orf72. Novel neuroimaging techniques, including tau positron emission tomography imaging, are being investigated. Multimodal magnetic resonance imaging approaches and automated magnetic resonance imaging volume segmentation techniques are being evaluated for optimized differential diagnosis. Current treatment options are symptomatic, and disease modifying therapies are under active investigation.     

Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration

The aim of this study was to improve the neuropathologic recognition and provide criteria for the pathological diagnosis in the neurodegenerative diseases grouped as frontotemporal lobar degeneration (FTLD); revised criteria are proposed. Recent advances in molecular genetics, biochemistry, and neuropathology of FTLD prompted the Midwest Consortium for Frontotemporal Lobar Degeneration and experts at other centers to review and revise the existing neuropathologic diagnostic criteria for FTLD. The proposed criteria for FTLD are based on existing criteria, which include the tauopathies [FTLD with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, sporadic multiple system tauopathy with dementia, argyrophilic grain disease, neurofibrillary tangle dementia, and FTD with microtubule-associated tau (MAPT) gene mutation, also called FTD with parkinsonism linked to chromosome 17 (FTDP-17)]. The proposed criteria take into account new disease entities and include the novel molecular pathology, TDP-43 proteinopathy, now recognized to be the most frequent histological finding in FTLD. TDP-43 is a major component of the pathologic inclusions of most sporadic and familial cases of FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Molecular genetic studies of familial cases of FTLD-U have shown that mutations in the progranulin (PGRN) gene are a major genetic cause of FTLD-U. Mutations in valosin-containing protein (VCP) gene are present in rare familial forms of FTD, and some families with FTD and/or MND have been linked to chromosome 9p, and both are types of FTLD-U. Thus, familial TDP-43 proteinopathy is associated with defects in multiple genes, and molecular genetics is required in these cases to correctly identify the causative gene defect. In addition to genetic heterogeneity amongst the TDP-43 proteinopathies, there is also neuropathologic heterogeneity and there is a close relationship between genotype and FTLD-U subtype. In addition to these recent significant advances in the neuropathology of FTLD-U, novel FTLD entities have been further characterized, including neuronal intermediate filament inclusion disease. The proposed criteria incorporate up-to-date neuropathology of FTLD in the light of recent immunohistochemical, biochemical, and genetic advances. These criteria will be of value to the practicing neuropathologist and provide a foundation for clinical, clinico-pathologic, mechanistic studies and in vivo models of pathogenesis of FTLD.     

An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies

The pathological distinctions between the various clinical and pathological manifestations of frontotemporal lobar degeneration (FTLD) remain unclear. Using monoclonal antibodies specific for 3- and 4-repeat isoforms of the microtubule associated protein, tau (3R- and 4R-tau), we have performed an immunohistochemical study of the tau pathology present in 14 cases of sporadic forms of FTLD, 12 cases with Pick bodies and two cases without and in 27 cases of familial FTLD associated with 12 different mutations in the tau gene (MAPT), five cases with Pick bodies and 22 cases without. In all 12 cases of sporadic FTLD where Pick bodies were present, these contained only 3R-tau isoforms. Clinically, ten of these cases had frontotemporal dementia and two had progressive apraxia. Only 3R-tau isoforms were present in Pick bodies in those patients with familial FTLD associated with L266V, Q336R, E342V, K369I or G389R MAPT mutations. Patients with familial FTLD associated with exon 10 N279K, N296H or +16 splice site mutations showed tau pathology characterised by neuronal neurofibrillary tangles (NFT) and glial cell tangles that contained only 4R-tau isoforms, as did the NFT in P301L MAPT mutation. With the R406W mutation, NFT contained both 3R- and 4R-tau isoforms. We also observed two patients with sporadic FTLD, but without Pick bodies, in whom the tau pathology comprised only of 4R-tau isoforms. We have therefore shown by immunohistochemistry that different specific tau isoform compositions underlie the various kinds of tau pathology present in sporadic and familial FTLD. The use of such tau isoform specific antibodies may refine pathological criteria underpinning FTLD.     

Clinical, cognitive and anatomical evolution from nonfluent progressive aphasia to corticobasal syndrome: a case report

Recent clinical and pathological studies have suggested that frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS) show clinical and pathological overlap. We present four years of longitudinal clinical, cognitive and anatomical data in the case of a 56-year-old woman, AS, whose clinical picture evolved from FTLD to CBS. For the first three years, AS showed a progressive speech and language disorder compatible with a diagnosis of the nonfluent aphasia variant of FTLD. At year four, 10 years after her first symptom, AS developed the classical clinical signs of CBS, including alien limb phenomenon and dystonia. Voxel-based morphometry (VBM) applied to AS's four annual scans showed progression of atrophy from the inferior posterior frontal gyrus, to the left insula and finally to the medial frontal lobe. This case demonstrates the clinical overlap between FTLD and CBS and shows that the two can appear in the same patient at different stages of the disease in relation to the progression of anatomical damage.     

Caudate atrophy on MRI is a characteristic feature of FTLD‐FUS

Background and purpose: Frontotemporal lobar degeneration (FTLD) can be subdivided into those in which the abnormal protein is tau (FTLD‐TAU), the TAR DNA binding protein 43 (FTLD‐TDP) and the fused in sarcoma protein (FTLD‐FUS). We have observed severe caudate atrophy at autopsy in FTLD‐FUS, and hence, we aimed to determine whether caudate atrophy on MRI is a feature that can distinguish FTLD‐FUS from FTLD‐TDP and FTLD‐TAU. Methods: From a cohort of 207 cases of FTLD, we identified all cases of FTLD‐FUS that had a volumetric antemortem head MRI (n = 3). Caudate and frontal lobe volumes were measured in all three cases using atlas‐based parcellation and SPM5 and were compared to 10 randomly selected cases of FTLD‐TDP and 10 randomly selected cases of FTLD‐TAU. Total grey matter volumes were also calculated for all cases. Results: The FTLD‐FUS cases had significantly smaller caudate volumes (P = 0.02) yet similar frontal lobe grey matter volumes (P = 0.12) compared to FTLD‐TDP and FTLD‐TAU. Caudate volumes when corrected for total grey matter volume (P = 0.01) or frontal lobe grey matter volume (P = 0.01) were significantly smaller in FTLD‐FUS than in FTLD‐TDP and FTLD‐TAU and showed no overlap with the other two groups. Conclusions: Caudate atrophy on MRI appears to be significantly greater in FTLD‐FUS compared with FTLD‐TDP and FTLD‐TAU, suggesting that severe caudate atrophy may be a useful clinical feature to predict FTLD‐FUS pathology.     

Right Temporal Lobe Atrophy: A Case That Initially Presented as Excessive Piety

Objective: Variants of frontotemporal lobar degeneration (FTLD) are associated with distinct clinical, pathological, and neuroanatomical profiles. Lines of emerging research indicate a rare variant with focal atrophy of the right temporal lobe (RTLA). The objective was to present case data and discussion of an individual with RTLA in order to assist with conceptualization of this variant. Method: A 60-year-old, right-handed, college-educated Protestant minister with RTLA was evaluated. This patient presented with several hallmark behavioral and psychiatric features with personality changes, including hyper-religiosity, depression, and social disinhibition. Given the profession of the patient, the observed personality alterations (e.g., religiosity and pietism) were initially excused, which delayed diagnosis. Results: In addition to cognitive deficits, an examination of affect processing within visual and auditory channels revealed severe impairment in emotion recognition with features of prosopagnosia. These impairments were in general more severe than the cognitive impairment observed on traditional neuropsychological measures. Conclusions: This case provides support for an FTLD right temporal lobe variant. This case also illustrates the importance of neuropsychological evaluation of affect processing in the differential diagnosis and treatment planning for FTLD and its subtypes.     

A visual [18F]FDG-PET rating scale for the differential diagnosis of frontotemporal lobar degeneration

This study presents a visual rating scale for the assessment of cerebral [¹⁸F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scans to characterize typical findings in dementias associated with frontotemporal lobar degeneration (FTLD) and to differentiate individual patients with FTLD compared to Alzheimer’s disease (AD) and mild cognitive impairment (MCI). A total of 43 cerebral PET scans from patients with FTLD (n = 16, mean age 58.4 years), AD (n = 16, 59.9 years) and MCI (n = 11, 57.9 years) were analysed. Every PET data set was visually rated for seven brain regions on each hemisphere (frontal lobe, temporal lobe, parietal lobe, occipital lobe, basal ganglia, thalamus and cerebellum). The extent of the impairment in metabolism was classified as absent, mild, medium or strong. Using this four-stage visual rating scale, characteristic profiles of metabolic impairment in FTLD, AD, MCI and the FTLD-subgroup FTD (n = 9) could be demonstrated. Patients with FTLD showed a significantly lower metabolism in the left frontal lobe and in the left basal ganglia when compared to AD and to MCI. Complementary analyses using statistical parametric mapping (SPM2) supported the findings of the visual analysis. In detecting FTLD with visual rating, sensitivity/specificity was 81/94% compared to AD and 81/64% compared to MCI. Patients with FTD were correctly attributed to a diagnosis of FTLD with a sensitivity of 89%. This visual rating scale may facilitate the differential diagnosis of FTLD in clinical routine.     

Broadening the phenotype of <Emphasis Type="Italic">TARDBP</Emphasis> mutations: the <Emphasis Type="Italic">TARDBP</Emphasis> Ala382Thr mutation and Parkinson’s disease in Sardinia

Mutations in the TARDBP gene are a cause of autosomal dominant amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration (FTLD), but they have not been found so far in patients with Parkinson’s disease (PD). A founder TARDBP mutation (p.Ala382Thr) was recently identified as the cause of ~30% of ALS cases in Sardinia, a Mediterranean genetic isolate. We studied 327 consecutive Sardinian patients with clinically diagnosed PD (88 familial, 239 sporadic) and 578 Sardinian controls. One family with FTLD and parkinsonism was also included. The p.Ala382Thr heterozygous mutation was detected in eight unrelated PD patients (2.5%). The three patients from the FTLD/parkinsonism family also carried this mutation. Within the control group, there were three heterozygous mutation carriers. During follow-up, one of these individuals developed motoneuron disease and another, a rapidly progressive dementia; the third remains healthy at the age of 79 but two close relatives developed motoneuron disease and dementia. The eight PD patients carrying the p.Ala382Thr mutation had all sporadic disease presentation. Their average onset age was 70.0 years (SD 9.4, range 51–79), which is later but not significantly different from that of the patients who did not carry this mutation. In conclusion, we expand the clinical spectrum associated with TARDBP mutations to FTLD with parkinsonism without motoneuron disease and to clinically definite PD. The TDP-43 protein might be directly involved in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD but also PD.     

Hospital admission circumstances and prevalence of frontotemporal lobar degeneration: a multicenter psychiatric state hospital study in Germany

Frontotemporal lobar degeneration (FTLD) is a heterogenous, non-Alzheimer's disease, dementia complex with variable clinical presentation. We carried out a prospective nationwide hospital-based clinico-epidemiologic study in geriatric psychiatry to estimate the prevalence and admission circumstances of patients with FTLD. During a 4-week period 33 patients with clinical FTLD were prospectively ascertained in 36 psychiatric state hospitals in Germany with a total catchment area of >20,000,000 people. The relative portion of FTLD patients within the primary dementia population accounted for 1.9%. The estimated prevalence of FTLD in Germany was 47.9/100,000 population aged between 45 and 79 years. The admission circumstances were mainly behavioral disturbances (54.5%), unclear syndromes of dementia (18.1%) and further remarkably heterogeneous psychiatric syndromes. FTLD is a common cause of dementia in geriatric psychiatry with a variable clinical presentation that could mimic most of the major psychiatric diseases. Patients with FTLD may be older than previously assumed (mean age at admission 63.9 years) and show their maximum age-related prevalence between 60 and 70 years (78.7/100,000).     

<Emphasis Type="Italic">TMEM106B</Emphasis> a Novel Risk Factor for Frontotemporal Lobar Degeneration

Recently, the first genome-wide association (GWA) study in frontotemporal lobar degeneration (FTLD) identified common genetic variability at the TMEM106B gene on chromosome 7p21.3 as a potential important risk-modifying factor for FTLD with pathologic inclusions of TAR DNA-binding protein (FTLD-TDP), the most common pathological subtype in FTLD. To gather additional evidence for the implication of TMEM106B in FTLD risk, multiple replication studies in geographically distinct populations were set up. In this review, we revise all recent replication and follow-up studies of the FTLD-TDP GWA study and summarize the growing body of evidence that establish TMEM106B as a bona fide risk factor for FTLD. With the TMEM106B gene, a new player has been identified in the pathogenic cascade of FTLD which could hold important implications for the future development of disease-modifying therapies.     

Mutations in CHMP2B are not a cause of frontotemporal lobar degeneration in Finnish patients

Background: Frontotemporal lobar degeneration (FTLD) is a genetically complex disorder. The majority of mutations linked to FTLD families are found in the microtubule‐associated protein tau (MAPT) and progranulin (PGRN) genes. Mutations in the chromatin‐modifying protein 2B gene (CHMP2B) have been identified in a few families. However, CHMP2B has been showed to be a rare cause of FTLD. Our aim was to determine the frequency of CHMP2B mutations in a clinical series of patients with FTLD in Northern Finland. Patients and methods: We examined 72 (36 men) Finnish patients with FTLD. The mean age at onset was 58.9 (range 43–80). Symptoms of motor neuron disease (FTLD‐MND) were present in 12 patients (17%). Positive family history was detected in 28% of the patients. Mutations in MAPT and PGRN were excluded from these patients. All exons and exon–intron boundaries of the CHMP2B gene were sequenced. Results: No pathogenic CHMP2B mutations were found. A rare polymorphism in the non‐coding region of exon 1 (rs36098294) and three other previously reported polymorphisms were detected. Conclusions: Our results confirm that mutations in CHMP2B are not a common cause of FTLD. MAPT and PGRN mutations are also rare in Finnish population, suggesting that other, still unknown genetic factors may play a role in the pathogenesis of FTLD in Finnish population.     

The molecular genetics and neuropathology of frontotemporal lobar degeneration: recent developments

The past year has seen a number of significant advances in our understanding of the neuropathological and molecular genetic basis of frontotemporal lobar degeneration (FTLD). Whereas, in the past, most attention focused on FTLD associated with tau-based pathology and microtubule associated protein tau gene (MAPT) mutations, there has recently been greater attention paid to non-tau FTLD. FTLD with tau-negative, ubiquitinated inclusions (FTLD-U) is now recognized as the most common pathology associated with clinical FTLD. Mutations in the progranulin gene (PGRN) have been identified as the cause of FTLD-U linked to chromosome 17. A rapidly growing number of PGRN mutations have been identified, and to date, all appear to cause FTLD by reducing the amount of functional PGRN protein (haploinsufficiency). The neuropathology associated with each of the known non-MAPT FTLD genes and loci (PGRN, valosin-containing protein gene, CHMP2B and 9p), has been shown to be a specific subtype of FTLD-U. The ubiquitinated pathological protein in FTLD-U has been identified as TAR deoxyribonucleic acid-binding protein with M _r 43 kDa (TDP-43). Immunohistochemical and biochemical studies of TDP-43 have helped to clarify the relationship between different sub-types of FTLD-U and related conditions. It is anticipated that these discoveries will facilitate the development of new diagnostic tests and therapeutics.     

The genetics and neuropathology of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of disorders characterized by disturbances of behavior and personality and different types of language impairment with or without concomitant features of motor neuron disease or parkinsonism. FTLD is characterized by atrophy of the frontal and anterior temporal brain lobes. Detailed neuropathological studies have elicited proteinopathies defined by inclusions of hyperphosphorylated microtubule-associated protein tau, TAR DNA-binding protein TDP-43, fused-in-sarcoma or yet unidentified proteins in affected brain regions. Rather than the type of proteinopathy, the site of neurodegeneration correlates relatively well with the clinical presentation of FTLD. Molecular genetic studies identified five disease genes, of which the gene encoding the tau protein (MAPT), the growth factor precursor gene granulin (GRN), and C9orf72 with unknown function are most frequently mutated. Rare mutations were also identified in the genes encoding valosin-containing protein (VCP) and charged multivesicular body protein 2B (CHMP2B). These genes are good markers to distinguish underlying neuropathological phenotypes. Due to the complex landscape of FTLD diseases, combined characterization of clinical, imaging, biological and genetic biomarkers is essential to establish a detailed diagnosis. Although major progress has been made in FTLD research in recent years, further studies are needed to completely map out and correlate the clinical, pathological and genetic entities, and to understand the underlying disease mechanisms. In this review, we summarize the current state of the rapidly progressing field of genetic, neuropathological and clinical research of this intriguing condition.     

Synaptic changes in frontotemporal lobar degeneration: correlation with MAPT haplotype and APOE genotype

S. J. Connelly, E. B. Mukaetova‐Ladinska, Z. Abdul‐All, J. Alves da Silva, C. Brayne, W. G. Honer and D. M. A. Mann (2011) Neuropathology and Applied Neurobiology 37, 366–380
Synaptic changes in frontotemporal lobar degeneration: correlation with MAPT haplotype and APOE genotype Aims: This immunohistochemical study quantified synaptic changes (synaptophysin and SNAP‐25) in the frontal lobe of subjects with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD), and related these to APOE genotype and MAPT haplotype. Methods: Frontal neocortex (BA9) of post mortem brains from subjects with FTLD (n = 20), AD (n = 10) and age‐matched controls (n = 9) were studied immunohistochemically for synaptophysin and SNAP‐25. Results: We report that patients with FTLD have a significant increase in synaptophysin and depletion in SNAP‐25 proteins compared to both control subjects and individuals with AD (P < 0.001). The FTLD up‐regulation of synaptophysin is disease specific (P < 0.0001), and is not influenced by age (P = 0.787) or cortical atrophy (P = 0.248). The SNAP‐25 depletion is influenced by a number of factors, including family history and histological characteristics of FTLD, APOE genotype, MAPT haplotype and gender. Thus, more profound loss of SNAP‐25 occurred in tau‐negative FTLD, and was associated with female gender and lack of family history of FTLD. Presence of APOEε4 allele and MAPT H2 haplotype in FTLD had a significant influence on the expression of synaptic proteins, specifically invoking a decrease in SNAP‐25. Conclusions: Our results suggest that synaptic expression in FTLD is influenced by a number of genetic factors which need to be taken into account in future neuropathological and biochemical studies dealing with altered neuronal mechanisms of the disease. The selective loss of SNAP‐25 in FTLD may be closely related to the core clinical non‐cognitive features of the disease.     

Are frontotemporal lobar degeneration, progressive supranuclear palsy and corticobasal degeneration distinct diseases?

New findings relating to the clinical, genetic and molecular bases of neurodegenerative disorders have led to a shift away from traditional nomenclatures of clinical syndromes. Historically, frontotemporal lobar degeneration (FTLD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) were classified on the basis of distinct clinical and pathological features. In recent years, however, advances in molecular and genetic research have led clinicians to suggest that the similar etiologies of the three disorders warrant their amalgamation into a single disorder with three subtypes. In this Review, we consider the utility and validity of combining FTLD, CBD and PSP. The earliest reports of these disorders demonstrate their distinctiveness, whereas recent findings challenge traditional nomenclatures by showing etiological overlap. For example, tau inclusions have been confirmed in patients with CBD and those with PSP, and in some patients with FTLD, implying that all three disorders are 'tauopathies'. Furthermore, most patients with progressive nonfluent aphasia, a subtype of FTLD, show PSP or CBD post-mortem. Even tau-related cases of FTLD, CBD and PSP are distinguishable on the basis of other criteria, however, and many FTLD cases do not show tau pathology. We argue, therefore, that FTLD, CBD and PSP should be considered as pathologically similar but distinct syndromes. New research criteria for CBD and PSP should note that progressive nonfluent aphasia is often a precursor of these conditions.