Semantic dementia with lower motor neuron disease showing FTLD‐TDP type 3 pathology (sensu Mackenzie)

We describe a case of frontotemporal lobar degeneration with semantic dementia and lower motor neuron disease. A 63‐year‐old man presented with the full clinical picture of semantic dementia, including semantic anomia, surface alexia, lexical agraphia, associative agnosia, prosopagnosia and phonagnosia. Flaccid dysarthria, bulbar dysphagia and fasciculations developed 7 years after onset, followed by death within a year. The neuropathological examination showed heavy neuronal loss in the anterior temporal lobe cortex, dorsal vagal and hypoglossal nuclei and anterior horns of the spinal cord. Ubiquitin‐ and TDP‐43‐positive cytoplasmic inclusions were abundant in layer II of affected cortices and in granular cells of the hippocampal dentate gyrus, whereas dystrophic neurites were sparse and intranuclear inclusions absent. It is concluded that FTLD‐TDP type 3 can be associated with semantic dementia and lower motor neuron disease in combination.     

Atypical FTLD‐FUS associated with ALS‐TDP: A case report

A 30‐year‐old Japanese woman without relevant family history presented with a behavioral abnormality followed by motor weakness about 14 years later. The patient died at age 45. Post mortem examination revealed degeneration of the frontal and temporal lobes, as well as lower motor neurons in the brainstem and spinal cord. These features were reported previously as being consistent with a diagnosis of frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS). In the present study, we show abundant fused in sarcoma (FUS)‐positive dystrophic neurites but only a few neuronal cytoplasmic inclusions in the frontal and temporal cortices. TAR DNA‐binding protein 43 (TDP‐43)‐positive inclusions were absent in the cerebrum. However, TDP‐43‐positive inclusions were present in the lower motor neurons of the brainstem and spinal cord. To our knowledge, this is the first report of a case in which FTLD‐FUS pathology is of a dystrophic neurites‐predominant type and FTLD‐FUS is associated with ALS‐TDP.     

Review: Neuropathology of non‐tau frontotemporal lobar degeneration

Frontotemporal dementia (FTD) is a heterogeneous clinical syndrome associated with frontotemporal lobar degeneration (FTLD) as a relatively consistent neuropathological hallmark feature. However, the discoveries in the past decade of many of the relevant pathological proteins aggregating in human FTD brains in addition to several new FTD causing gene mutations underlined that FTD is a diverse condition on the neuropathological and genetic basis. This resulted in a novel molecular classification of these conditions based on the predominant protein abnormality and allows most cases of FTD to be placed now into one of three broad molecular subgroups; FTLD with tau, TAR DNA‐binding protein 43 or FET protein accumulation (FTLD‐tau, FTLD‐TDP and FTLD‐FET respectively). This review will provide an overview of the molecular neuropathology of non‐tau FTLD, insights into disease mechanisms gained from the study of human post mortem tissue as well as discussion of current controversies in the field.     

Frontotemporal lobar degeneration with ubiquitinated tau‐negative inclusions and additional α‐synuclein pathology but also unusual cerebellar ubiquitinated p62‐positive,TDP‐43‐negative inclusions

Mutations in the progranulin (PGRN) gene on chromosome 17 have been shown to be responsible for one non‐tauopathy subtype of familial frontotemporal lobar degeneration – frontotemporal lobar degeneration with ubiquitinated, tau‐negative inclusions (FTLD‐U). Such cases have pathological similarities to sporadic cases with neuronal inclusions positive for ubiquitin, the ubiquitin binding protein, p62 and the newly recognised protein TDP‐43 but negative for hyperphosphorylated (HP) tau. There has been a recent report on two families with a novel progranulin mutation where the neuropathology showed not only TDP‐43 neuronal positivity but separate tau and/or α‐synuclein pathology. We describe an unusual case with some family history but no mutation in the progranulin gene. The pathological features were typical for FTLD‐U but with additional significant α‐synuclein pathology, and unusual ubiquitin‐positive, p62‐positive, TDP‐43‐negative inclusions in the cerebellum. This case may represent a further pathological phenotype for familial FTLD‐U. It also highlights the need for further investigations on the ubiquitin binding protein p62 as a marker in FTLD‐U. It is certainly possible that the presence or absence of these ubiquitinated p62‐positive yet TDP‐43‐negative cerebellar inclusions may act as a useful correlative factor in the future.     

Senile onset frontotemporal lobar degeneration with TAR‐DNA binding protein 43 proteinopathy primarily presenting with wasteful habits

We present an autopsied case of a senile Japanese woman with sporadic frontotemporal lobar degeneration (FTLD) presenting as frontotemporal dementia. Disease onset was at the age of 70 and presented as a behaviour disorder, particularly involving wasteful habits. The patient had repeated incidents of making expensive purchases and then had difficulty making payments. Following these symptoms, she showed other changes of character such as lethargy and apathy. She gradually showed signs of parkinsonism including rigidity and bradykinesia, and in the terminal stage, an akinetic mutism state with quadriplegia in flexion was observed. Head magnetic resonance imaging revealed severe frontotemporal lobe atrophy with severe lateral ventricular dilatation and frontal white matter degeneration. At autopsy, the brain weighed 930 g and the frontotemporal cerebral cortex showed neuron loss with gliosis, tissue rarefaction and spongiform change, particularly in the superficial layers. Pathologic degeneration was more severe in the anterior portion of the frontal lobe with extensive white matter degeneration. Immunostaining for phosphorylated TAR‐DNA binding protein 43 (TDP‐43) revealed numerous neuronal cytoplasmic inclusions and extensive short dystrophic neuritis, particularly in the frontotemporal cortex. Many TDP‐43‐positive cytoplasmic inclusions were also observed in the dentate gyrus of the hippocampus. The patient was pathologically diagnosed with FTLD with TDP‐43‐positive inclusions (FTLD‐TDP) without motor neuron disease. The immunohistochemical findings corresponded to type A of the FTLD‐TDP pathology classification system.     

Invited review: Neuropathology of tauopathies: principles and practice

Tauopathies are clinically, morphologically and biochemically heterogeneous neurodegenerative diseases characterized by the deposition of abnormal tau protein in the brain. The neuropathological phenotypes are distinguished based on the involvement of different anatomical areas, cell types and presence of distinct isoforms of tau in the pathological deposits. The nomenclature of primary tauopathies overlaps with the modern classification of frontotemporal lobar degeneration. Neuropathological phenotypes comprise Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age‐related tauopathy, formerly called also as neurofibrillary tangle‐only dementia, and a recently characterized entity called globular glial tauopathy. Mutations in the gene encoding the microtubule‐associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17. In addition, further neurodegenerative conditions with diverse aetiologies may be associated with tau pathologies. Thus, the spectrum of tau pathologies and tauopathy entities expands beyond the traditionally discussed disease forms. Detailed multidisciplinary studies are still required to understand their significance.     

Primary lateral sclerosis: Upper‐motor‐predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration – immunohistochemical and biochemical analyses of TDP‐43

Primary lateral sclerosis (PLS) is clinically defined as a disorder selectively affecting the upper motor neuron (UMN) system. However, recently it has also been considered that PLS is heterogeneous in its clinical presentation. To elucidate the association of PLS, or disorders mimicking PLS, with 43‐kDa TAR DNA‐binding protein (TDP‐43) abnormality, we examined two adult patients with motor neuron disease, which clinically was limited almost entirely to the UMN system, and was followed by progressive frontotemporal atrophy. In the present study, the distribution and severity, and biochemical profile of phosphorylated TDP‐43 (pTDP‐43) in the brains and spinal cords were examined immunohistochemically and biochemically. Pathologically, in both cases, frontotemporal lobar degeneration with ubiquitin inclusions (FTLD‐U) was evident, with the most severe degeneration in the motor cortex. An important feature in both cases was the presence of Bunina bodies and/or ubiquitin inclusions, albeit very rarely, in the well preserved lower motor neurons. The amygdala and neostriatum were also affected. pTDP‐43 immunohistochemistry revealed the presence of many positively stained neuronal cytoplamic inclusions (NCIs) and dystrophic neurites/neuropil threads in the affected frontotemporal cortex and subcortical gray matter. By contrast, such pTDP‐43 lesions, including NCIs, were observed in only a few lower motor neurons. pTDP‐43 immunoblotting revealed that fragments of ～25‐kDa were present in the cortices, but not in the spinal cord in both cases. Genetically, neither of the patients had any mutation in the TDP‐43 gene. In conclusion, we consider that although PLS may be a clinically significant disease entity, at autopsy, the majority of such clinical cases would present as upper‐motor‐predominant amyotrophic lateral sclerosis with FTLD‐TDP.     

Distribution of basal ganglia lesions in Pick's disease with Pick bodies: A topographic neuropathological study of eight autopsy cases

The distribution of the basal ganglia lesions, including the amygdala, striatum, and pallidum, were investigated neuropathologically in eight Japanese autopsy cases of Pick's disease with Pick bodies. The lesions were classified as mild, moderate or severe. The degree and distribution of basal ganglia lesions in all eight cases were uniform: the amygdala showed severe to moderate lesions, the caudate nucleus and putamen showed moderate to mild lesions, and the pallidum showed mild lesions. Furthermore, the lesions in the amygdala were more prominent in the basolateral group than in the corticomedial group. In Pick's disease with Pick bodies, the degree and distribution of the lesions within the basal ganglia differs from those reported in both ‘Pick's disease without Pick bodies’ and corticobasal degeneration (CBD), in which severe lesions were present in the pallidum. These neuropathological findings may contribute to the morphological differential diagnosis among Pick's disease with Pick bodies, ‘Pick's disease without Pick bodies’, and CBD.     

Degeneration of Pick bodies visualized by methenamine‐silver staining and immunohistochemistry

The degeneration process of Pick's bodies (PB) was investigated using methenamine‐silver (MS) staining and immunohistochemistry. Methenamine‐silver staining sensitively detected extracellular PB as well as intracellular PB in the granular cell layer of the dentate gyrus. Extracellular PB appeared as granular masses with ill‐defined boundaries in the neuropil. For MS electron microscopy, the extracellular PB were composed of randomly oriented fibrillary components measuring 9–12 nm in diameter with astroglial processes and degenerated organelles. Tau immunoreactivity of extracellular PB was reduced or abolished. These findings indicate that MS staining is a convenient method for detecting extracellular PB. In addition, it was shown that microglial involvement was associated with PB‐bearing neurons at the late stage of the degeneration process and that extracellular PB remained in the neuropil with astroglial reaction.     

Possible concurrence of TDP‐43, tau and other proteins in amyotrophic lateral sclerosis/frontotemporal lobar degeneration

Transactivation response DNA‐binding protein 43 kDa (TDP‐43) has been regarded as a major component of ubiquitin‐positive/tau‐negative inclusions of motor neurons and the frontotemporal cortices in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Neurofibrillary tangles (NFT), an example of tau‐positive inclusions, are biochemically and morphologically distinguished from TDP‐43‐positive inclusions, and are one of the pathological core features of Alzheimer disease (AD). Although ALS/FTLD and AD are distinct clinical entities, they can coexist in an individual patient. Whether concurrence of ALS/FTLD‐TDP‐43 and AD‐tau is incidental is still controversial, because aging is a common risk factor for ALS/FTLD and AD development. Indeed, it remains unclear whether the pathogenesis of ALS/FTLD is a direct causal link to tau accumulation. Recent studies suggested that AD pathogenesis could cause the accumulation of TDP‐43, while abnormal TDP‐43 accumulation could also lead to abnormal tau expression. Overlapping presence of TDP‐43 and tau, when observed in a brain during autopsy, should attract attention, and should initiate the search for the pathological substrate for this abnormal protein accumulation. In addition to tau, other proteins including α‐synuclein and amyloid β should be also taken into account as candidates for an interaction with TDP‐43. Awareness of a possible comorbidity between TDP‐43, tau and other proteins in patients with ALS/FTLD will be useful for our understanding of the influence of these proteins on the disease development and its clinical manifestation.     

Comparison of extent of tau pathology in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with Pick bodies and early onset Alzheimer's disease

In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene (MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer's disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly (P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% (P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration - whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell.     

Review: Transactive response DNA‐binding protein 43 (TDP‐43): mechanisms of neurodegeneration

T. F. Gendron, K. A. Josephs and L. Petrucelli (2010) Neuropathology and Applied Neurobiology 36, 97–112
Transactive response DNA‐binding protein 43 (TDP‐43): mechanisms of neurodegeneration Since the identification of phosphorylated and truncated transactive response DNA‐binding protein 43 (TDP‐43) as a primary component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin‐positive inclusions, and the discovery that mutations in the TDP‐43 gene cause ALS, much effort has been directed towards establishing how TDP‐43 contributes to the development of neurodegeneration. Although few in vivo models are presently available, findings thus far strongly support the involvement of abnormally modified TDP‐43 in promoting TDP‐43 aggregation and cellular mislocalization. Therefore, TDP‐43‐mediated neurotoxicity is likely to result from a combination of toxic gains of function conferred by TDP‐43 inclusions as well as from the loss of normal TDP‐43 function. Nonetheless, the exact neurotoxic TDP‐43 species remain unclear, as do the mechanism(s) by which they cause neuronal death. Moreover, little is currently known about the roles of TDP‐43, both in the nucleus and the cytoplasm, making it difficult to truly appreciate the detrimental consequences of aberrant TDP‐43 function. This review will summarize what is currently understood regarding normal TDP‐43 function and the involvement of TDP‐43 in neurodegeneration, and will also highlight some of the many remaining questions in need of further investigation.     

Nuclear carrier and RNA‐binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes

Y. S. Davidson, A. C. Robinson, Q. Hu, M. Mishra, A. Baborie, E. Jaros, R. H. Perry, N. J. Cairns, A. Richardson, A. Gerhard, D. Neary, J. S. Snowden, E. H. Bigio and D. M. A. Mann (2013) Neuropathology and Applied Neurobiology 39, 157–165 Nuclear carrier and RNA‐binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes Aims: We aimed to investigate the role of the nuclear carrier and binding proteins, transportin 1 (TRN1) and transportin 2 (TRN2), TATA‐binding protein‐associated factor 15 (TAF15) and Ewing's sarcoma protein (EWS) in inclusion body formation in cases of frontotemporal lobar degeneration (FTLD) associated with fused in sarcoma protein (FTLD‐FUS). Methods: Eight cases of FTLD‐FUS (five cases of atypical FTLD‐U, two of neuronal intermediate filament inclusion body disease and one of basophilic inclusion body disease) were immunostained for FUS, TRN1, TRN2, TAF15 and EWS. Ten cases of FTLD associated with TDP‐43 inclusions served as reference cases. Results: The inclusion bodies in FTLD‐FUS contained TRN1 and TAF15 and, to a lesser extent, EWS, but not TRN2. The patterns of immunostaining for TRN1 and TAF15 were very similar to that of FUS. None of these proteins was associated with tau or TDP‐43 aggregations in FTLD. Conclusions: Data suggest that FUS, TRN1 and TAF15 may participate in a functional pathway in an interdependent way, and imply that the function of TDP‐43 may not necessarily be in parallel with, or complementary to, that of FUS, despite each protein sharing many similar structural elements.     

Vulnerability to neuroleptic side effects in frontotemporal lobar degeneration

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is commonly associated with behavioural disturbances such as disinhibition and aggression; these often result in the use of neuroleptic medication. METHODS: All available case notes of patients attending a specialist cognitive disorders clinic with a diagnosis of FTLD were selected. This gave 100 subjects (62 male, 38 female). RESULTS: In 61 patients significant behavioural disturbances were present. Of these patients, 24 had been prescribed neuroleptics. Significant extrapyramidal side effects were reported in eight patients (33%); in five patients these were severe enough to cause severe mobility problems and in one patient resulted in impaired consciousness. In some instances the extrapyramidal side effects took weeks to wear off. CONCLUSION: These results suggest that patients with FTLD may, as in Lewy body dementia, be particularly sensitive to the extrapyramidal side effects of neuroleptics. We suggest that neuroleptics should be used cautiously in FTLD and treatment should be started at low doses avoiding depot preparations until further prospective studies have been performed.     

Alpha‐synuclein polymorphisms are associated with Parkinson's disease in a Saskatchewan population

Alpha‐synuclein gene (SNCA) mutations cause familial Parkinsonism but the role of SNCA variability in idiopathic Parkinson's disease (PD) remains incompletely defined. We report a study of SNCA genetic variation in 452 idiopathic PD cases and 245 controls. SNCA copy number mutations were not associated with early‐onset disease in this population. The minor allele “G” at rs356165 was associated with increased odds of PD (P = 0.013) and genetic variation in D4S3481 (Rep1) was associated with age of disease onset (P = 0.007). There was a trend toward association between variation at rs2583988 and rapid PD progression. © 2009 Movement Disorder Society     

Globular glial tauopathy Type II: Clinicopathological study of two autopsy cases

Globular glial tauopathies (GGTs) are four‐repeat tauopathies characterized by the presence of two types of tau‐positive globular glial inclusions (GGIs): globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). GGTs are classified into three different neuropathological subtypes: Types I, II and III. We report two patients with GGTs – a 76‐year‐old woman and a 70‐year‐old man – in whom the disease duration was 5 and 6 years, respectively. Both patients exhibited upper and lower motor neuron signs and involuntary movements, and the latter also had dementia with frontotemporal cerebral atrophy evident on magnetic resonance imaging. Neuropathologically, in both cases, the precentral gyrus was most severely affected, and at the gray‐white matter junction there was almost complete loss of Betz cells and occurrence of GOIs and coiled bodies with numerous neuropil threads. Both patients also showed neuronal loss and GGIs (mostly GOIs) in many other central nervous system regions, including the basal ganglia. Apart from the degree of regional severity, the distribution pattern was essentially the same in both cases. However, GAIs were not conspicuous in any of the affected regions. Based on the morphology and distribution pattern of the GGIs, we diagnosed the present two patients as having GGT Type II. Electron microscopic and biochemical findings in the former were consistent with the diagnosis. Type II cases are reported to be characterized by pyramidal features reflecting predominant motor cortex and corticospinal tract degeneration. The present observations suggest that a variety of neurological features, including dementia, can occur in GGT Type II reflecting widespread degeneration beyond the motor neuron system.     

An autopsied case of unclassifiable sporadic four‐repeat tauopathy presenting with parkinsonism and speech disturbances

A 48‐year‐old Japanese woman experienced slow‐onset parkinsonism and speech disturbances. Neurological examinations revealed rigidity in the trunk and extremities, bradykinesia and postural instability, although cognitive impairments and psychiatric symptoms were not apparent in the early disease stage. Neuroimaging revealed progressive bilateral frontotemporal lobe atrophy with cerebral blood flow hypoperfusion. No apparent signs of lower motor neuron involvement were observed, such as fasciculation or electromyogram findings. She eventually reached the akinetic mutism state, and gastrostomy and tracheotomy were performed at 4 years after onset. A clinical diagnosis of progressive supranuclear palsy was made prior to her death, which occurred 6 years after onset. Post mortem examinations revealed that the brain weighed 1200 g and showed atrophy of the frontotemporal lobe and brainstem. Severe neuron loss and gliosis were observed in the frontotemporal lobe. The superior and middle frontal gyri were the most severely affected and showed spongiform changes in the superficial layer. The globus pallidus, subthalamic nucleus, cerebellar dentate nucleus, substantia nigra and inferior olivary nucleus also showed neuronal loss with gliosis. Using hyperphosphorylated tau (AT‐8) immunostaining, pretangle‐like neurons, numerous short threads and glial tau pathology were extensively observed. Using Gallyas?Braak silver staining, thin and short threads were also extensively observed, but considerably fewer than those observed by AT‐8 immunostaining. Neither astrocytic plaques nor tuft‐shaped astrocytes were observed. Examination by immunoelectron microscopy showed straight fibrils approximately 15 nm in diameter in the neuronal cytoplasmic inclusions in the cerebral cortex and in the fibrillary structures in the cerebral white matter. Western blot analysis of sarkosyl‐insoluble tau revealed predominantly four‐repeat tau and a banding pattern similar to that seen in progressive supranuclear palsy. No pathogenic mutations were found during the gene analysis of microtubule‐associated protein tau. After completing our comprehensive investigation, we diagnosed this patient with unclassifiable four‐repeat tauopathy.