Identification of amino-terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative diseases that are characterized by intracytoplasmic aggregates of hyperphosphorylated tau with four microtubule-binding repeats. Although PSP and CBD have distinctive pathological features, no biochemical difference in aggregated tau has been identified. In this study, we examined the brains of eight patients with PSP, six patients with CBD, and one atypical case with pathological features of both CBD and PSP. On immunoblots of sarkosyl-insoluble brain extracts, a 33kDa band predominated in the low molecular weight tau fragments in PSP, whereas two closely related bands of approximately 37kDa predominated in CBD. Immunoblots of the atypical case showed both the 33kDa band and the 37kDa doublet. Protein sequencing and immunochemical analyses showed that the 33kDa band and the 37kDa doublet consisted of the carboxyl half of tau with different amino termini. These results suggest that, despite the identical composition of tau isoforms, different proteolytic processing of abnormal tau takes place in these two diseases. Such a biochemical divergence may be related to the neuropathological features of these diseases.     

Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy

Distinguishing corticobasal degeneration (CBD) from progressive supranuclear palsy (PSP) is clinically and pathologically difficult, and a useful biological marker to discriminative these two diseases has been a subject of clinical interest. In the present study, we assessed tau protein levels in cerebrospinal fluids by sandwich ELISA to distinguish CBD from PSP. The subjects consisted of 27 cases of CBD, 30 cases of PSP, and 36 healthy controls (CTL). The tau values in CBD were significantly higher than those in PSP (P<0.001) and those in CTL (P<0.001). The assay of CSF tau provided diagnostic sensitivity of 81.5% and specificity of 80.0% between CBD and PSP according to receiver-operating characteristic (ROC) curve analysis. When values were compared separately with respect to stage of the disease, differences in the values for moderate CBD vs. moderate PSP had the greatest significance (P<0.001 sensitivity 92.3%, specificity 100.0%), followed by cases of mild CBD and PSP (P<0.005, sensitivity 100.0%, specificity 87.5%). The values in severe CBD and PSP were not significantly different (P=0.07, sensitivity 100%, specificity 75.0%). Using data obtained from a larger number of disease cases, we confirmed our previous findings that tau protein levels in cerebrospinal fluids in patients with CBD are significantly higher than those in patients with PSP. Because tau protein levels in cerebrospinal fluids are significantly higher in early CBD cases than in early PSP cases, measurement of tau protein levels in cerberospinal fluids may be useful for the differential diagnosis of early CBD from early PSP.     

Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are usually sporadic multisystem degenerations associated with filamentous tau inclusions in neurons and glia. As such they can be considered sporadic tauopathies in contrast to familial tauopathies linked to mutations in the tau gene. Mutations have not been found in the tau gene in either PSP or CBD. The clinical syndromes and neuroimaging of typical cases of PSP and CBD are distinct; however, atypical cases are described that have overlapping clinical and pathologic features. Both PSP and CBD have similar biochemical alterations in the tau protein, with the abnormal tau protein containing predominantly four-repeat tau. While there is overlap in the pathology in PSP and CBD, there are sufficient differences to continue the present day trend to consider these separate disorders. Several important pathologic features differentiate PSP from CBD. Ballooned neurons are frequent and nearly a sine qua non for CBD, but they are found in PSP at a frequency similar to that of other neurodegenerative diseases, such as Alzheimer’s disease. Astrocytic lesions are different, with tufted astrocytes found in motor cortex and striatum in PSP and astrocytic plaques in focal atrophic cortices in CBD. The most characteristic neuronal tau pathology in CBD is wispy, fine filamentous inclusions within neuronal cell bodies, while affected neurons in PSP have compact, dense filamentous aggregates characteristic of globose neurofibrillary tangles. Thread-like processes in gray and white matter are much more numerous and widespread in CBD than in PSP. The brunt of the pathology in CBD is in the cerebrum, while the basal ganglia, diencephalon and brainstem are the targets of PSP. Further clinicopathologic studies will refine our understanding of these disorders and open the possibility that common etiologic factors may be identified for these unusual sporadic tauopathies.

     

Astrocytic inclusions in progressive supranuclear palsy and corticobasal degeneration

Tufted astrocytes (TAs) in progressive supranuclear palsy (PSP) and astrocytic plaques (APs) in corticobasal degeneration (CBD) have been regarded as the pathological hallmarks of major sporadic 4‐repeat tauopathies. To better define the astrocytic inclusions in PSP and CBD and to outline the pathological features of each disease, we reviewed 95 PSP cases and 30 CBD cases that were confirmed at autopsy. TAs exhibit a radial arrangement of thin, long, branching accumulated tau protein from the cytoplasm to the proximal processes of astrocytes. APs show a corona‐like arrangement of tau aggregates in the distal portions of astrocytic processes and are composed of fuzzy, short processes. Immunoelectron microscopic examination using quantum dot nanocrystals revealed filamentous tau accumulation of APs located in the immediate vicinity of the synaptic structures, which suggested synaptic dysfunction by APs. The pathological subtypes of PSP and CBD have been proposed to ensure that the clinical phenotypes are in accordance with the pathological distribution and degenerative changes. The pathological features of PSP are divided into 3 representative subtypes: typical PSP type, pallido‐nigro‐luysian type (PNL type), and CBD‐like type. CBD is divided into three pathological subtypes: typical CBD type, basal ganglia‐ predominant type, and PSP‐like type. TAs are found exclusively in PSP, while APs are exclusive to CBD, regardless of the pathological subtypes, although some morphological variations exist, especially with regard to TAs. The overlap of the pathological distribution of PSP and CBD makes their clinical diagnosis complicated, although the presence of TAs and APs differentiate these two diseases. The characteristics of tau accumulation in both neurons and glia suggest a different underlying mechanism with regard to the sites of tau aggregation and fibril formation between PSP and CBD: proximal‐dominant aggregation of TAs and formation of filamentous NFTs in PSP in contrast to the distal‐dominant aggregation of APs and formation of less filamentous pretangles in CBD.     

Corticobasal degeneration and progressive supranuclear palsy--biochemical marker]

The diagnostic significance of tau proteins in cerebrospinal fluids (CSF) has been described in many cases of dementia of Alzheimer type (AD). However, in patients with other diseases showing neurofibrillary tangles (NFT) similar to those in AD, tau proteins in cerebrospinal fluids have not been rigorously investigated. In particular, differentiating corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is clinically and pathologically difficult, and a useful biochemical marker to discriminate these two diseases has been a subjects of clinical interest. Therefore, we examined the usefulness of CSF tau and amyloid beta (A beta) proteins for the differentiation between CBD and PSP. CSF total tau (t-tau) and A beta proteins were measured with the sandwich ELISA method (Innogenetics, Belgium). CSF tau protein phosphorylated at serine 199 (p-tau) was measured by a recent established sandwich ELISA (Mitsubishi Chemical Co.). In conclusion, measurement of tau protein levels in CSF may be useful for the differential diagnosis of CBD from PSP. We also suggest that CSF p-tau may be a better biochemical marker than CSF t-tau.     

Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype.

OBJECTIVE: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD). BACKGROUND: The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD. METHODS: The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls. RESULTS: Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X(2) = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X(2) = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]). CONCLUSIONS: The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.     

Substantia nigra in progressive supranuclear palsy, corticobasal degeneration, and parkinsonism-dementia complex of Guam: specific pathological features

Disease-specific findings in the substantia nigra were examined in cases of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and parkinsonism-dementia complex of Guam (PDC); diseases in which the patients exhibit dementia and parkinsonism, with neurofibrillary tangles (NFTs) and glial tangles composed of hyperphosphorylated tau. Loss of pigmented neurons was extremely severe in these 3 diseases, and decrease of the nonpigmented neurons was severe in PSP and CBD. On the other hand, in PDC the decrease of the nonpigmented neurons was different in each patient. Topographically, in PSP the nonpigmented neurons were particularly depleted in the ventral part and relative preservation of the pigmented neurons was observed in the medial part at the level examined. Many NFTs were observed in PDC. Although the number of NFTs was small, many pretangles were seen in the neurons in CBD. Granular and hazy astrocytic inclusions were identified exclusively in PDC. Numerous argyrophilic neuropile threads were identified in CBD and PSP, but these were few in PDC. Many foamy spheroid bodies as well as coiled bodies were observed in PSP and CBD, but only a few were observed in PDC. In conclusion, PDC is a disease that is distinctly different from PSP and CBD. It is possible to differentiate between PSP and CBD by the occurrence of many pretangles in CBD, but some similarities between these 2 diseases indicate the existence of common pathological mechanisms.     

Progressive supranuclear palsy: what's new?

Progressive supranuclear palsy (PSP) has been described as a clinical syndrome characterized by an impairment of voluntary control of gaze (supranuclear palsy), postural and gait instability, and behavioral and cognitive deficits including a frontal syndrome and psychic retardation. However, in the recent years, at least four other clinical forms of PSP have been recognized: PSP-Parkinsonism, "pure akinesia with gait freezing", PSP with cortico-basal syndrome, and PSP with speech apraxia. PSP-Parkinsonism mimics the signs and symptoms of idiopathic Parkinson's disease, including a significant reactivity to levodopa. "Pure akinesia with gait freezing" is characterized by a difficulty of self-initiation of motor programs, usually walking program. PSP with cortico-basal syndrome mimics cortico-basal degeneration (CBD) in that unilateral or asymmetric limb dystonia and apraxia are prominent signs. PSP with speech apraxia is an isolated syndrome of progressive anarthria. All these clinical syndromes are due to brain accumulation of phosphorylated tau protein. The differences in clinical expression within the framework of PSP can be explained by the differences in the topographical distribution of the lesions. PSP is considered as a primary tau disease ("tauopathy") such as CBD and some forms of fronto-temporal lobar degeneration. At the level of neuropathology, the pattern of tau abnormal inclusions differentiates PSP from other tau diseases, but some overlaps are reported. Moreover, several of the clinical forms of PSP partially or fully overlap with the other tauopathies. As a whole, the emergence of new clinical forms of PSP challenges the nosology of tauopathies and our understanding of these diseases.     

Selective tau tyrosine nitration in non-AD tauopathies

Previously, we reported the characterization of two novel antibodies that react with tau nitrated at tyrosine 197 (Tau-nY197) and tyrosine 394 (Tau-nY394) in Alzheimer’s disease (AD). In this report, we examined whether tau nitration at these sites also occurs in corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick’s disease (PiD), three neurodegenerative tauopathies that contain abundant tau deposits within glial and neuronal cell types but lack amyloid deposition. The reactivity of these antibodies was also compared to two previously characterized antibodies Tau-nY18 and Tau-nY29, specific for tau nitrated at tyrosine 18 and tyrosine 29, respectively. In the present experiments, Tau-nY18 did not label the classical pathological lesions of CBD or PSP but did label the neuronal lesions associated with PiD to a limited extent. In contrast, Tau-nY29 revealed some, but not all classes of tau inclusions associated with both CBD and PSP but did label numerous Pick body inclusions in PiD. Tau-nY197 was restricted to the neuropil threads in both CBD and PSP; however, similar to Tau-nY29, extensive Pick body pathology was clearly labeled. Tau-nY394 did not detect any of the lesions associated with these disorders. In contrast, extensive neuronal and glial tau pathology within these diseases was labeled by Tau-Y197, a monoclonal antibody that reacts within the Y-197-containing proline-rich region of the molecule. Based on our Western and IHC experiments, it appears that nitration of tau at tyrosine 29 is a pathological modification that might be associated with neurodegeneration. Collectively, our data suggest that site-specific tau tyrosine nitration events occur in a disease and lesion-specific manner, indicating that nitration appears to be a highly controlled modification in AD and non-AD tauopathies.     

Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration

The role of microglia in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) is unknown. To address this issue we examined 10 cases of PSP, 5 cases of CBD, and 4 normal controls. Microglial and tau burdens were determined with image analysis on brain sections that had been immunostained with monoclonal antibodies to HLA-DR and phospho-tau. We found that microglial activation was greater in PSP and CBD than normal controls, and that the microglial burden correlated with the tau burden in most areas. There were distinct patterns of microglial activation and tau pathology in PSP and CBD, with PSP showing more pathology in infratentorial structures and CBD showing more pathology in supratentorial structures. These results support the notion that PSP and CBD are distinct clinicopathologic entities. Microglial activation was not well correlated with tau pathology in the brainstem of PSP, which suggests that brainstem pathology in PSP is not exclusively due to tau pathology. While the results do not necessarily support a direct causal link between microglial activation and neurodegeneration in PSP or CBD, they nevertheless suggest that microglia play a role in disease pathogenesis.     

A proteomic study identifies different levels of light chain ferritin in corticobasal degeneration and progressive supranuclear palsy

Clinical and pathological evidence supports the notion that corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are distinct, but overlapping neurodegenerative tauopathies. Although both disorders are characterized by abnormal accumulation of 4-repeat tau, they display distinct proteolytic profiles of tau species and they have distinct astrocytic lesions, astrocytic plaques in CBD and tufted astrocytes in PSP. To investigate other differences between these two disorders at the molecular level, we compared the profiles of proteins from caudate nucleus of CBD and PSP by quantitative two-dimensional difference gel electrophoresis. Twenty-one protein spots differentially expressed in CBD and PSP were dissected for mass spectrometry (MS). One of the spots was identified by MS to contain light chain (LC) ferritin. Western blot analysis verified the presence of LC ferritin in this spot and showed that this protein was two-fold higher in caudate of CBD than that of PSP samples. These results were confirmed by LC ferritin immunohistochemistry. Co-labeling of caudate nucleus with tau and LC ferritin antibodies showed the presence of LC ferritin immunoreactivity in astrocytic plaques of CBD, but minimal labeling of tufted astrocytes in PSP. This difference did not reflect the extent of gliosis. Analysis of other brain regions in CBD and PSP showed no difference in LC ferritin levels. Together the data suggest that LC ferritin is a unique marker of astrocytic lesions in CBD, adding further support to the notion that CBD and PSP are distinct clinicopathologic entities.     

Phosphorylation and cleavage of tau in non-AD tauopathies

The tau protein, well known as the primary component of neurofibrillary tangles, also comprises the Pick bodies found in Pick’s disease (PiD) and the glial lesions associated with progressive supranuclear palsy (PSP) and cortico-basal ganglionic degeneration (CBD). Many of the tau alterations that are characteristic of Alzheimer’s disease have also been identified in PSP and CBD. In this report, we examine three non-AD tauopathies (PSP, CBD, and PiD) for the presence of two specific tau alterations, phosphorylation at Ser422 and truncation at Asp421. We find that truncation at Asp421 is an alteration that is unique to neuronal lesions, occurring in Pick bodies as well as in neurofibrillary tangles, but not in lesions associated with glia. Conversely, phosphorylation at Ser422 is not only present in all these lesions, but identifies additional glial and neuronal pathology in disease-susceptible cortical regions. These results suggest that the molecular alterations of tau that occur during the initial process of tangle formation in AD are similar in non-AD tauopathies, but the middle and later changes are not common to all diseases. This work is supported by grants AG021184 and AG09466 from the NIH.     

Epitope expression and hyperphosphorylation of tau protein in corticobasal degeneration: differentiation from progressive supranuclear palsy

Corticobasal degeneration (CBD) is a rare, progressive neurological disorder characterized by widespread neuronal and glial accumulation of abnormal tau protein. Using immunohistochemistry we analyzed tau epitope expression and phosphorylation state in CBD and compared them to cytoskeletal changes in Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Epitopes spanning the entire length of the tau protein were present in CBD inclusions. An antibody against the alternatively spliced exon 3 did not recognize cytoskeletal lesions in CBD, but did in AD and PSP. Tau epitopes from each region of the molecule were present in cytoskeletal inclusions in CBD, including gray matter astrocytic plaques, gray and white matter threads, and oligodendroglial inclusions. As in AD, tau from CBD was highly phosphorylated. Antibodies that recognized phosphorylated tau epitopes reacted with material from CBD in a highly phosphatase-dependent manner. Again, all types of inclusions contained phosphorylated epitopes. We conclude that abnormal tau protein in CBD comprises the entire tau molecule and is highly phosphorylated, but is distinguished from AD and PSP by the paucity of epitopes contained in the alternatively spliced exon 3.     

Different immunoreactivities of the microtubule-binding region of tau and its molecular basis in brains from patients with Alzheimer's disease,Pick's disease,progressive supranuclear palsy and corticobasal degeneration

The microtubule-associated protein tau accumulates as cytoplasmic inclusions in Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We investigated the immunoreactivity of tau-positive structures using a panel of antibodies to epitopes spanning the entire length of the tau molecule. In ethanol-fixed brain tissues, most antibodies to the microtubule-binding domain (MBD) required formic acid (FA) treatment to stain tau inclusions in PSP and CBD. This is in contrast with the intense labeling of neurofibrillary tangles in AD without FA treatment. Pick bodies (PiB) in PiD showed an intermediate pattern with respect to the immunoreactivity of the MBD because accumulated tau in PiB mostly lacks the insertion of exon 10, and the proportion of tau phosphorylated at Ser262 is smaller than in other abnormal tau structures. Such immunohistochemical profiles appeared to correlate with the occurrence of the smeared tau on immunoblot analysis of brain homogenate. The smeared tau was more abundant in AD and PiD than in PSP and CBD. Since the smeared tau was N-terminally truncated and was characteristic of advanced forms of modified tau, these findings suggest that tau accumulated in AD and PiD was processed more markedly than that in PSP and CBD. The MBD of tau may be masked in the presence of the intact N terminus and require FA treatment for antibody recognition in tissue sections. Advanced modification may expose the MBD in brain tissues of AD and PiD. It is suggested that the processing of abnormally accumulated tau characterizes the pathophysiology of each tauopathy.     

Relationship between frontotemporal dementia and corticobasal degeneration/progressive supranuclear palsy

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) were described as separate entities, but prior to that an extrapyramidal variety of Pick's disease was recognized. Subsequently a pathological overlap between these conditions and clinical overlap between frontotemporal dementia, primary progressive aphasia, corticobasal degeneration syndrome and more recently PSP was recognized. Initially only the movement disorder had been emphasized, but now the behavioral and language symptoms are considered common. The syndromes of frontotemporal dementia/Pick's disease can be produced by underlying CBD, PSP or Pick pathology as well as with neural inclusions of the motor neuron disease type. The concept of this overlap has been confirmed genetically finding a similar spectrum of pathology with different tau mutations and even with tau negative pathology, which could be a deficiency of normal tau. The overlap of CBD with PSP and both with PPA and FTD allows to consider these relatively rare conditions as part of a more commonly occurring degenerative disease than previously recognized.     

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.     

A variety of glial pathological structures by the modified Gallyas-Braak method

Recent knowledge on tau-positive glial abnormal structures and their clinico-pathological significance were introduced. The structures outlined here, which are strikingly visualized by the modified Gallyas-Braak method and have tauepitopes, included (i) tuft-shaped astrocytes, (ii) thorn-shaped astrocytes, (iii) glial coiled bodies, (iv) argyrophilic threads, (v) firework-like structures and (vi) argyrophilic perivascular astrocytic feet. This study concludes that the tuft-shaped astrocytes are favored in cases of progressive supranuclear palsy (PSP), and that there is a massive appearance of both the argyrophilic threads and the firework-like structures characteristic in prototype of corticobasal degeneration (CBD). Unlike these structures, glial coiled bodies were observed in a wider range of neurological diseases such as PSP, CBD and some other cases with precocious appearance of the neurofibrillary tangles, although the glial coiled bodies were rare in routine laboratory examination and were not always uniform in their configuration. Thus, the modified Gallyas-Braak method is useful for the diagnosing of some neurodegenerative diseases with tau abnormalities, especially of PSP and CBD. It must be noted, however, that this method could also impregnate tau-negative structures such as glial cytoplasmic inclusions (oligodendroglial microtubular tangles) in multiple system atrophy or grumose or foamy spheroid body in various conditions, especially in PSP and CBD.     

Corticobasal degeneration and atypical progressive supranuclear palsy: their symptomatology, laboratory examination and differential diagnosis]

Corticobasal degeneration (CBD) and atypical progressive supranuclear palsy (PSP) were reviewed with special reference to their symptomatology, laboratory examination and differential diagnosis. In our survey of the autopsy cases of CBD in Japan, only about 60% of the pathologically confirmed CBD cases were correctly diagnosed clinically, meaning that atypical (non-classical) clinical forms are common in CBD. Concerning the autopsy cases of PSP in Japan, 75% of the PSP cases had correct clinical diagnosis. In literatures, the clinically atypical CBD includes (1) frontotemporal dementia, also with primary progressive aphasia and frontal lobe dementia as subforms, (2) PSP-like form, and (3) others. The clinically atypical PSP comprises (1) pure akinesia, (2) pure easy falling syndrome (Yuasa), (3) no postural instability, (4) no gaze palsy, (5) asymmetric parkinsonism, (6) no or severe dementia, etc.. PSP with cortical manifestations such as primary progressive aphasia and CBD-like features were also reported. The atypical CBD and PSP probably reflect the distribution of tau pathology different from that in typical forms. Except for the report that phosphorylated tau is increased in CSF in CBD, but not in PSP (Urakami et al), no reliable laboratory data have been available on clinical differentiation between atypical CBD and PSP.     

4-repeat tauopathy sharing pathological and biochemical features of corticobasal degeneration and progressive supranuclear palsy

We report a 67-year-old man with 4-repeat (4R) tauopathy sharing both features of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Although CBD and PSP have a common pathological feature that 4R tau accumulates in neurons and glia, recent pathological studies have confirmed differences between the two disorders. Clinical features of the present case were asymmetrical apraxia, parkinsonism, memory disturbance, disorientation and left limb myoclonus with a 5-year history. Pathological features were the widespread occurrence of 4R tau-positive structures including pre-tangles, neurofibrillary tangles, astrocytic plaques, tufted astrocytes, coiled bodies and argyrophilic threads. Biochemically, immunoblotting of insoluble tau demonstrated the low molecular fragments of 37 kDa and 33 kDa observed in typical CBD and PSP, respectively, in addition to the presence of 4R tau isoforms. The present case shared tau-related pathological and biochemical features of CBD and PSP. These findings support that CBD and PSP are closely associated disorders having a pathogenesis common to 4R tauopathy.