Pick body disease and Pick syndrome*

Diagnostic criteria for Pick's disease have been criticized from many different viewpoints. This confusion is mainly derived from the ambiguity of this term ‘Pick's disease’ (PD), which may imply either purely histological findings, such as Pick body (PB), or a characteristic clinical syndrome that could occur even in the absence of PB. This taxonomic confusion will be circumvented by introducing the diagnostic term ‘Pick body disease’ to designate patients with the characteristic argyrophilic inclusions purely on histological grounds. In parallel, employment of ‘Pick syndrome’ to describe the time‐honored clinical features may be more convenient and less confusing than PD because PD implies either the presence of PB or the clinical features, two aspects not necessarily linked to each other. Three‐dimensional reconstruction of PB confirmed that tau‐like immunoreactivity was accentuated at their periphery, as was recognized with the Bodian method. Preferential affinity of three‐repeat tau pathology, as seen in Pick body disease, to the Bodian over the Gallyas method is distinct from the reversed affinity (the Gallyas over the Bodian method) of four‐repeat tau pathology, as seen in corticobasal degeneration and in argyrophilic grains. This preference of silver staining is compatible with the mixed three‐ and four‐repeat tau pathology, as seen in NFT of the Alzheimer's type, which are stained with both the Bodian and Gallyas staining. This will provide a practical basis on which to differentiate these disorders based on their distinctive tau species and possible relation of tau species to staining profile on these silver methods.     

Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies

Pathological inclusions containing fibrillar aggregates of hyperphosphorylated tau protein are a characteristic feature in the tauopathies, which include Alzheimer's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Tau isoform composition and cellular and regional distribution as well as morphology of these inclusions vary in each disorder. Recently, several pathological missense and exon 10 splice-donor site mutations of the tau gene were identified in FTDP-17. Exon 10 codes for the second of four microtubule-binding repeat domains. The splice-site mutations result in increased inclusion of exon 10 which causes a relative increase in tau isoforms containing four microtubule-binding repeat domains over those containing three repeat domains. This could be a central aetiological mechanism in FTDP-17 and, perhaps, other related tauopathies. We have investigated changes in the ratio and distribution of three-repeat and four-repeat tau in the different tauopathies as a basis of the phenotypic range of these disorders and the selective vulnerability of different subsets of neurones. In this study, we have developed two monoclonal antibodies, RD3 and RD4 that effectively distinguish these closely related tau isoforms. These new isoform-specific antibodies are useful tools for analysing tau isoform expression and distribution as well as pathological changes in the human brain.     

Sporadic Pick's disease: a tauopathy characterized by a spectrum of pathological tau isoforms in gray and white matter

Pick's disease is characterized neuropathologically by distinct tau-immunoreactive intraneuronal inclusions known as Pick bodies and by insoluble tau proteins with predominantly three microtubule-binding repeat tau isoforms. However, recent immunohistochemical studies showed that the antibody specific for exon 10, which encodes the fourth microtubule-binding repeat, detected other tau lesions in Pick's disease. To better define the spectrum of tau pathology in Pick's disease, we used biochemical, immunohistochemical, and ultrastructural techniques to analyze the tau isoform composition in 14 Pick's disease brains. Western blot analysis showed that both three and four microtubule-binding repeat pathological tau isoforms are present in gray and white matter of various brain regions. Using phosphorylation-dependent anti-tau antibodies, we show that major tau phosphoepitopes are present in sarcosyl-insoluble gray and white matter regions of Pick's disease brains. Also, for the first time to our knowledge, we demonstrated that isoforms with four microtubule-binding repeat tau isoforms are present in Pick bodies from selected brains. Isolated tau filaments were straight or twisted and formed by three microtubule-binding repeat or four microtubule-binding repeat tau isoforms. Major tau phosphorylation-dependent and exon 10-specific epitopes were present in filaments. Therefore, Pick's disease is characterized by an accumulations of Pick bodies in the hippocampal region and cortex as well as the presence of three and four microtubule-binding repeat tau pathology in both cortical gray and white matter that distinguish this tauopathy from other neurodegenerative disorders.     

Cellular tau pathology and immunohistochemical study of tau isoforms in sporadic tauopathies

Pathological inclusions in neurons and glial cells containing fibrillary aggregates of abnormally hyperphosphorylated tau protein are characteristic features in sporadic tauopathies. In the first part of this paper we outline the morphological features of some major sporadic tauopathies. In the second part, to better define the tau isoform composition, we report on the immunohistochemistry of tau isoforms in autopsied brains, including two cases with AD, two with diffuse neurofibrillary tangles with calcification, four with Pick’s disease with Pick bodies (PiD), seven with progressive supranuclear palsy (PSP), six with corticobasal degeneration (CBD) and seven cases with argyrophilic grain disease. We used two monoclonal antibodies, RD3 and RD4, and a polyclonal antibody for exon 10 that effectively distinguish between three‐repeat (3R) tau and four‐repeat (4R) tau. Neuronal neurofibrillary tangles (NFT) in AD and diffuse neurofibrillary tangles with calcification contained both 3R‐tau and 4R‐tau. The Pick bodies were immunopositive for 3R‐tau in two cases; however, in two other cases they were mainly immunopositive for 4R‐tau. Thus, Pick bodies demonstrated heterogeneity. 3R‐tau PiD contained 3R‐tau glial inclusions, and 4R‐tau PiD contained mainly 4R‐tau glial inclusions. Glial inclusions were more abundant in 4R‐tau PiD cases. In progressive supranuclear palsy and CBD, both neuronal and glial tau accumulation forming NFT, pretangles, tuft‐shaped astrocytes, astrocytic plaques, coiled bodies and threads demonstrated 4R‐tau in the cerebral cortices, although in the basal ganglia and brainstem neuronal and glial inclusions were occasionally immunopositive for 3R‐tau in addition to 4R‐tau. Argyrophilic grains (AG) were immunopositive for 4R‐tau, although pretangles were weakly stained for 4R‐tau. Thus the immunoreactivity for 4R‐tau was different between AG and pretangles. Therefore, the isoform composition on immunohistochemical study showed heterogeneity in PiD, and was not uniform in the basal ganglia and brain stem in PSP and CBD. It is suggested that the isoform composition of sporadic tauopathies may have a spectrum in individual cases, and cellular isoform composition may differ in various brain regions.     

Progressive ataxia and palatal tremor: Two autopsy cases of a novel tauopathy

Background: Sporadic progressive ataxia and palatal tremor is a rare syndrome characterized by mid‐ to late‐adult‐onset symptomatic palatal tremor and slowly progressive cerebellar ataxia. To date, there has been only one autopsy report, which described a novel 4‐repeat tauopathy with hypertrophic olivary degeneration and tau‐positive inclusions in olivary neurons and dystrophic neuritic processes termed glomeruloid bodies. We report on 2 additional autopsy cases. Methods: Sections from selected paraffin‐embedded brain regions were stained with hematoxylin and eosin/Luxol fast blue and processed for phosphorylated tau, 3‐repeat tau, 4‐repeat tau, neurofilament, glial fibrillary acid protein, phosphorylated α‐synuclein, phosphorylated TAR DNA‐binding protein 43, beta‐amyloid, and p62 immunohistochemistry. Results: Two male patients were aged 74 and 64 years at onset. Both had clinical findings consistent with progressive ataxia and palatal tremor and T2 hyperintensity in the bilateral olives on MRI. Pathological findings included bilateral hypertrophic olivary degeneration accompanied by glomeruloid bodies, 3‐repeat and 4‐repeat tau‐positive neuronal inclusions in the olive, and additional tauopathy in the midbrain, pons, and thalamus. Cerebellar cortical degeneration was extensive, but involvement of the dentate was minimal. P62‐positive, but tau‐ and TAR DNA‐binding protein 43–negative, inclusions in the cerebellum of 1 case was also a feature. Conclusions: Whereas our findings are largely in keeping with the previously published case report, we found a more extensive and mixed 3/4‐repeat tauopathy and additional cerebellar p62 pathology, highlighting our incomplete understanding of the pathogenesis of this disease. © 2017 International Parkinson and Movement Disorder Society     

A comparative study on pathological features of transgenic rat lines expressing either three or four repeat misfolded tau

Human tauopathies represent a heterogeneous group of neurodegenerative disorders characterized by distinct clinical features, typical histopathological structures, and defined ratio(s) of three‐repeat and four‐repeat tau isoforms within pathological aggregates. How the optional microtubule‐binding repeat of tau influences this differentiation of pathologies is understudied. We have previously generated and characterized transgenic rodent models expressing human truncated tau aa151–391 with either three (SHR24) or four microtubule‐binding repeats (SHR72). Here, we compare the behavioral and neuropathological hallmarks of these two transgenic lines using a battery of tests for sensorimotor, cognitive, and neurological functions over the age range of 3.5–15 months. Progression of sensorimotor and neurological deficits was similar in both transgenic lines; however, the lifespan of transgenic line SHR72 expressing truncated four‐repeat tau was markedly shorter than SHR24. Moreover, the expression of three or four‐repeat tau induced distinct neurofibrillary pathology in these lines. Transgenic lines displayed different distribution of tau pathology and different type of neurofibrillary tangles. Our results suggest that three‐ and four‐repeat isoforms of tau may display different modes of action in the diseased brain.     

Ultrastructural characteristics of tau filaments in tauopathies: Immuno‐electron microscopic demonstration of tau filaments in tauopathies

The microtubule‐associated protein tau aggregates into filaments in the form of neurofibrillary tangles, neuropil threads and argyrophilic grains in neurons, in the form of variable astrocytic tangles in astrocytes and in the form of coiled bodies and argyrophilic threads in oligodendrocytes. These tau filaments may be classified into two types, straight filaments or tubules with 9–18 nm diameters and “twisted ribbons” composed of two parallel aligned components. In the same disease, the fine structure of tau filaments in glial cells roughly resembles that in neurons. In sporadic tauopathies, individual tau filaments show characteristic sizes, shapes and arrangements, and therefore contribute to neuropathologic differential diagnosis. In frontotemporal dementias caused by tau gene mutations, variable filamentous profiles were observed in association with mutation sites and insoluble tau isoforms, including straight filaments or tubules, paired helical filament‐like filaments, and twisted ribbons. Pre‐embedding immunoelectron microscopic studies were carried out using anti‐3‐repeat tau and anti‐4‐repeat tau specific antibodies, RD3 and RD4. Straight tubules in neuronal and astrocytic Pick bodies were immunolabeled by the anti‐3‐repeat tau antibody. The anti‐4‐repeat tau antibody recognized abnormal tubules comprising neurofibrillary tangles, coiled bodies and argyrophilic threads in progressive supranuclear palsy (PSP) and corticobasal degeneration. In the pre‐embedding immunoelectron microscopic study using the phosphorylated tau AT8 antibody, tuft‐shaped astrocytes of PSP were found to be composed of bundles of abnormal tubules in processes and perikarya of protoplasmic astrocytes. In this study, the 3‐repeat tau or 4‐repeat tau epitope was detected in situ at the ultrastructural level in abnormal tubules in representative pathological lesions in Pick’s disease, PSP and corticobasal degeneration.     

Pretangles and neurofibrillary changes: Similarities and differences between AD and CBD based on molecular and morphological evolution

Pretangles are cytoplasmic tau immunoreactivity in neurons without apparent formation of fibrillary structures. In Alzheimer disease, such tau deposition is considered to represent a premature state prior to fibril formation (AD‐pretangles), later to form neurofibrillary tangles and finally ghost tangles. This morphological evolution from pretangles to ghost tangles is in parallel with their profile shift from four repeat (4R) tau‐positive pretangles to three repeat (3R) tau‐positive ghost tangles with both positive neurofibrillary tangles in between. This complementary shift of tau profile from 4R to 3R suggests that these tau epitopes are represented interchangeably along tangle evolution. Similar tau immunoreactivity without fibril formation is also observed in corticobasal degeneration (CBD‐pretangles). CBD‐pretangles and AD‐pretangles share: (i) selective 4R tau immunoreactivity without involvement of 3R tau; and (ii) argyrophilia with Gallyas silver impregnation. However, CBD‐pretangles neither evolve into ghost tangles nor exhibit 3R tau immunoreactivity even at the advanced stage. Because electron microscopic studies on these pretangles are quite limited, it remains to be clarified whether such differences in later evolution are related to their primary ultrastructures, potentially distinct between AD and CBD. As double staining for 3R and 4R tau clarified complementary shift from 4R to 3R tau along evolution from pretangles to ghost tangles, double immunoelectron microscopy, if possible, may clarify similar profile shifts in relation to each tau fibril at the ultrastructural dimension. This will provide a unique viewpoint on how molecular (epitope) representations are related to pathogenesis of fibrillary components.     

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.     

Pick's disease with neuronal four‐repeat tau accumulation in the basal ganglia,brain stem nuclei and cerebellum

It is very rare that cases of Pick's disease, a representative three‐repeat (3R) tauopathy, also have significant four‐repeat (4R) tau accumulation. Here, we report a Pick's disease case that clinically showed behavioral variant frontotemporal dementia without motor disturbance during the course, and pathologically had 3R tau‐positive Pick bodies as well as numerous 4R tau‐positive neuronal cytoplasmic inclusions (NCIs). Abundant 3R tau‐positive 4R tau‐negative spherical or horseshoe‐shaped Pick bodies were found in the frontotemporal cortex, limbic region, striatum and pontine nucleus. On the other hand, many 4R tau‐positive, 3R tau‐negative, Gallyas‐negative dot‐, rod‐ or intertwined skein‐like NCIs were found mainly in the subthalamic nucleus, pontine nucleus, inferior olivary nucleus and cerebellar dentate nucleus. Tufted astrocytes, astrocytic plaques, argyrophilic grains or globular glial inclusions were absent. Double‐labeling immunofluorescence demonstrated that 3R tau was hardly accumulated in 4R tau‐positive inclusions. On tau immunoblotting, while 60 and 64 kDa bands were demonstrated in the frontal cortex, 60, 64 and 68 kDa bands, as well as the 33 kDa tau fragments that are reported to be characteristic of progressive supranuclear palsy brains, were found in the basal ganglia and cerebellum. No mutation was identified in the tau gene. The present case suggests that, although probably rare, some Pick's disease cases have non‐negligible 4R tau pathology in the subcortical nuclei, and that such 4R tau pathology can affect the evaluation of the distribution of AT8‐positive tau pathology in Pick's disease cases.     

The new neuropathology of degenerative frontotemporal dementias

The clinical features and recent developments in the neuropathology of frontotemporal dementia are reviewed. The five main neurodegenerative disorders that underlie the clinical syndrome of frontotemporal dementia are distinguished using immunohistochemistry with antisera to ubiquitin and tau proteins. Motor neuron disease-type dementia is characterised by ubiquitin-immunoreactive intraneuronal inclusions in cortical layer II and the hippocampal dentate granule cells. A diagnosis of Alzheimer's disease changes is based upon the presence of neurofibrillary tangles, which immunostain with antibodies to tau and ubiquitin, and many associated neuritic plaques. Corticobasal degeneration is diagnosed by the presence of tau-immunoreactive, but ubiquitin-non-reactive intraneuronal inclusions in cortical layer II and the substantia nigra. Pick's disease is restricted to cases with tau- and ubiquitin-immunoreactive spherical cortical intraneuronal inclusions (Pick bodies), best seen in the hippocampal dentate gyrus and frontotemporal cortex. Dementia of frontal type is the preferred term for cases in which no intraneuronal inclusions are seen with antisera to tau and ubiquitin. A practical approach to the pathological diagnosis of frontotemporal dementia and the differential diagnosis of the five disorders using immunohistochemical studies is provided. Received: 7 August 1995 / Revised, accepted: 10 October 1995     

Lrrk2 and chronic inflammation are linked to pallido-ponto-nigral degeneration caused by the <Emphasis Type="Italic">N279K</Emphasis> tau mutation

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been identified in families with autosomal dominant late-onset Parkinson disease (PD). Lrrk2 is a phylogenetically conserved, ubiquitous protein, which is constitutively expressed in various cells including neurons and glial cells of human brain. We recently reported that Lrrk2 is identified in Lewy bodies in PD as well as in neuronal and glial inclusions in several other neurodegenerative disorders. Here we show that Lrrk2 is closely associated with the tau-positive inclusions in eight members of a family with frontotemporal dementia of the pallido-ponto-nigral degeneration type linked to the chromosome 17 N279K tau mutation (N279K/FTDP-17/PPND). Lrrk2 is colocalized with tau in oligodendroglial coiled bodies and intracytoplasmic neuronal inclusions. HLA-DR positive reactive microglia and ICAM-1 positive reactive astrocytes accumulated in affected areas demonstrating that inflammatory processes are also involved in the disease pathogenesis. Western blot analysis of soluble extracts of N279K/FTDP-17/PPND brain tissue suggests that C-terminal fragment(s) of apparent 64–75 kDa molecular weight may be the major Lrrk2 species in pathological deposits. The possibility that Lrrk2 is linked with various neurodegenerative disorders through the ubiquitin proteosome pathway is discussed. The results indicate that Lrrk2 is linked to frontotemporal atrophy of PPND type caused by N279K tau mutation. They also show that chronic inflammation is involved in the pathogenesis of N279K/FTDP-17/PPND.     

The tau gene A0 allele and progressive supranuclear palsy.

BACKGROUND: Recent studies have shown an association between a polymorphic tandem repeat allele, located in intron 9, of the tau gene and progressive supranuclear palsy (PSP). OBJECTIVE: To investigate this tau polymorphism in individuals with a clinical diagnosis of sporadic or familial PSP as well as in cases confirmed by pathology. METHODS: We analyzed the frequency of tau intronic polymorphism, the presence of linkage in two families with multiple cases of PSP, the splicing of exon 10, and direct sequence of the tau gene. RESULTS: We found that patients with a clinical diagnosis of sporadic or familial PSP and individuals with PSP confirmed by neuropathology have greater prevalence of the A0 allele and A0/A0 genotype than controls. This finding, however, was also true for asymptomatic relatives of individuals with PSP. Linkage analysis in familial PSP excluded the location of the gene in the region 17q21. Furthermore, no significant differences were found in the level of expression of exon 10 in PSP, A0/A0 brain with respect to Alzheimer A3/A3 brain. We found no mutations in the tau gene in individuals with familial PSP. CONCLUSIONS: A mutation in the tau gene was not the primary cause of familial PSP. The role of tau and the tau A0 allele in white PSP patients remains unknown, although it may represent a genetic risk factor for several neurodegenerative disorders.     

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.     

Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick's disease, corticobasal degeneration and progressive supranuclear palsy

We investigated isoform composition of aggregated tau protein in brains with Pick's disease (PiD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) by immunoblot analysis of sarkosyl-insoluble fractions of brain homogenates. We also examined the adjacent brain tissues immunohistochemically with a rabbit antibody, Ex10, which specifically recognizes exon 10 of tau. The Ex10 recognizes tau isoforms with four microtubule-binding repeats (4Rtau) but not those with three microtubule-binding repeats (3Rtau). Sarkosyl-insoluble tau from the brains of patients with CBD and PSP consisted of 4Rtau. Insoluble tau from the PiD brains contained both 3Rtau and 4Rtau, where 3Rtau predominated over 4Rtau. In brain tissues of CBD and PSP, Ex10 immunostained all neuronal and glial tau-positive structures. They included pre-tangles, astrocytic plaques, tuft-shaped astrocytes, and oligodendroglial coiled bodies. In PiD brains, astrocytic inclusions were also positive for 4Rtau. However, the majority of, if not all, Pick bodies and oligodendroglial tau inclusions were negative for 4Rtau. Such results suggest that, in neurons and oligodendroglia, tau isoforms involved in the pathological processes differ between CBD/PSP and PiD, and are thus disease specific. This contrasts with the astrocytic tau isoforms that accumulate similarly in all three disorders.     

Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam

Intracytoplasmic filamentous tau inclusions are neuropathological hallmarks of amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam and the defining lesions of other neurodegenerative disorders known as tauopathies. Here we review current insights into the cell and molecular neuropathology of ALS/PDC, a common tauopathy in the Chamorro population on Guam. We also summarize recent advances in understanding this disorder through studies of transgenic (Tg) mouse models of this tauopathy. Briefly, overexpression of human tau isoforms in the central nervous system of Tg mice resulted in a neurodegenerative tauopathy with a phenotype similar to ALS/PDC. Specifically, argyrophilic, congophilic, and tau immunoreactive inclusions accumulated with age in cortical and brainstem neurons of these mice, but they were most abundant in spinal cord neurons, and the inclusions contained 10- to 20-nm tau-positive straight filaments. There also was extensive gliosis in spinal cord associated with axonal degeneration in the ventral roots, while remaining axons in spinal nerves showed a loss of microtubules and reduced fast axonal transport. With advancing age, these Tg mice showed increasing motor weakness, and this was accompanied by a progressive increase in the phosphorylation and insolubility of brain and spinal cord tau proteins. Thus, tau Tg mice recapitulate key phenotypic features of ALS/PDC neuropathology in an ethnic minority on Guam, and these animal models provide new opportunities to discover novel therapies for this and related tauopathies.     

Recent developments in the neuropathological diagnosis of Parkinson's disease and parkinsonism

The diagnosis of Parkinson's disease (PD) is based mainly on clinical criteria. Large clinicopathological studies reveal however a different diagnosis in up to 25% of the cases (Hughes et al., 1992). Recent advances in molecular biology have shown that some proteins, especially tau and alpha-synuclein, play an essential role in the pathogenesis of parkinsonian and dementing disorders. Such diseases are now classified as tauopathies and synucleinopathies. Progressive supranuclear palsy and corticobasal degeneration are the major tauopathies. To the synucleinopathies belong PD, Lewy body dementia and multiple system atrophy. In pathological conditions abnormal proteins will aggregate in neurons and glial cells and form inclusion bodies. Lewy bodies are the hallmark of Parkinson's disease and Lewy body dementia. Identification of these inclusions and other specific lesions in parkinsonian disorders is facilitated by the routine application on formalin fixed brain of immunohistochemistry for alpha-synuclein, tau and ubiquitin. The purpose of this paper is to briefly review and illustrate the value of these new techniques in the postmortem diagnosis of parkinsonian disorders. Neuropathological examination of the brain is however time consuming and immunohistochemistry represents additional costs. As the selection of brain samples for microscopical examination and antibodies for immunohistochemistry depends on the underlying pathology, some clinical information should be provided to the pathologist such as the clinical diagnosis and when indicated the results of brain imaging studies. A close co-operation between the neurologist and neuropathologist is thus essential to select the most appropriate brains for complete neuropathological investigation.     

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.     

Familial tauopathy with P364S MAPT mutation: clinical course,neuropathology and ultrastructure of neuronal tau inclusions

Aims

This report presents the clinical course, neuropathology and ultrastructure of neuronal tau inclusions of four Slovene relatives with P364S MAPT mutation.

Methods

The clinical history of three out of four P364S MAPT mutation carriers was taken. After formalin fixation, thorough sampling of the central nervous system was followed by paraffin embedding, H&E, Gallyas, Bielschowsky and immunostaining with AT8, anti‐3R, anti‐4R tau, anti‐amyloid‐β, anti‐TDP43 and anti‐alpha‐synuclein antibodies. The distribution and density of different types of neuronal tau inclusions were semiquantitatively assessed. In addition, the ultrastructure of neuronal tau inclusions was analysed.

Results

Macroscopic examination of the brains was unremarkable. Microscopically, neuronal tau inclusions of almost all known types were widespread and distributed fairly uniformly in all cases. Pick bodies and swollen neurones were found in only one family member. Mutant tau was composed of 3R and 4R isoforms, with a slight predominance of 3R tau. Composite neuronal tau inclusion (CNTI), found in all four relatives, was a hallmark of the P364S MAPT mutation. CNTI showed compartmental differences in H&E and Gallyas staining, tau isoforms immunolabelling and ultrastructure, displaying fuzzy fibrils in the core and paired twisted tubules at the periphery.

Conclusions

P364S MAPT mutation is characterized clinically by a variable combination of frontotemporal dementia, parkinsonism and motor neurone disease of short duration, and neuropathologically by a widespread uniform distribution of all known neuronal tau inclusions in one family member. Two‐compartment CNTI is a unique characteristic of the P364S MAPT mutation.