The many faces of corticobasal degeneration

Corticobasal degeneration (CBD) has characteristic neuropathological features, but is a clinically heterogeneous disorder. It can present with various clinical syndromes. The corticobasal syndrome (CBS) is the best recognized and over the course of the illness may be the most common manifestation. Dementia, progressive non-fluent aphasia, speech apraxia, progressive supranuclear palsy (PSP)-like syndrome and posterior cortical atrophy syndrome are other presentations of CBD. The CBS is not specific for the pathology of CBD. Patients presenting as CBS have CBD as the underlying pathology in about 55% of the cases, PSP pathology in 20%, Pick's disease in 7%, and non tau pathology in the remaining. CBS is a sensitive clinical phenotype for tau pathology. Patients with CBS could potentially be candidates for therapies aiming to modify tau biochemistry.     

Behavioral Variant Frontotemporal Dementia with Corticobasal Degeneration Pathology: Phenotypic Comparison to bvFTD with Pick’s Disease

Patients with corticobasal degeneration (CBD) pathology present with diverse clinical syndromes also associated with other neuropathologies, including corticobasal syndrome, progressive nonfluent aphasia, and an Alzheimer's-type dementia. Some present with behavioral variant frontotemporal dementia (bvFTD), though this subtype still requires more detailed clinical characterization. All patients with CBD pathology and clinical assessment were reviewed (N?=?17) and selected if they initially met criteria for bvFTD [bvFTD(CBD), N?=?5]. Available bvFTD patients with Pick's [bvFTD(Pick's), N?=?5] were selected as controls. Patients were also compared to healthy older controls [N?=?53] on neuropsychological and neuroimaging measures. At initial presentation, bvFTD(CBD) showed few neuropsychological or motor differences from bvFTD(Pick's). Neuropsychiatrically, they were predominantly apathetic with less florid social disinhibition and eating disturbances, and were more anxious than bvFTD(Pick's) patients. Voxel-based morphometry revealed similar patterns of predominantly frontal atrophy between bvFTD groups, though overall degree of atrophy was less severe in bvFTD(CBD), who also showed comparative preservation of the frontoinsular rim, with dorsal?>?ventral frontal atrophy, and sparing of temporal and parietal structures relative to bvFTD(Pick's) patients. Despite a remarkable overlap between the two patient types, bvFTD patients with underlying CBD pathology show subtle clinical features that may distinguish them from patients with Pick's disease neuropathology.     

Neuropathology of Frontotemporal Lobar Degeneration-Tau (FTLD-Tau)

A clinically and pathologically heterogeneous type of frontotemporal lobar degeneration has abnormal tau pathology in neurons and glia (FTLD-tau). Familial FTLD-tau is usually due to mutations in the tau gene (MAPT). Even FTLD-tau determined by MAPT mutations has clinical and pathologic heterogeneity. Tauopathies are subclassified according to the predominant species of tau that accumulates, with respect to alternative splicing of MAPT, with tau proteins containing three (3R) or four repeats (4R) of ~32 amino acids in the microtubule binding domain. In Pick's disease (PiD), 3R tau predominates, whereas 4R tau is characteristic of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Depending upon the specific mutation in MAPT, familial FTLD-tau can have 3R, 4R or a combination of 3R and 4R tau. PiD is the least common FTLD-tau characterized by neuronal Pick bodies in a stereotypic neuroanatomical distribution. PSP and CBD are more common than PiD and have extensive clinical and pathologic overlap, with no distinctive clinical syndrome or biomarker that permits their differentiation. Diagnosis rests upon postmortem examination of the brain and demonstration of globose tangles, oligodendroglial coiled bodies and tufted astrocytes in PSP or threads, pretangles and astrocytic plaques in CBD. The anatomical distribution of tau pathology determines the clinical presentation of PSP and CBD, as well as PiD. The basis for this selective cortical vulnerability in FTLD-tau is unknown.     

Staging disease severity in movement disorder tauopathies: brain atrophy separates progressive supranuclear palsy from corticobasal degeneration.

The movement disorders progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) both deposit tau in degenerating neurons and are considered to be tauopathies. The recently developed scheme for staging tissue degeneration in another tauopathy, frontotemporal dementia [Broe et al., Neurology 2003;60:1005-1011] was applied to pathologically confirmed PSP (n = 24) and CBD (n = 9) cases and correlated with clinical indices. In contrast to frontotemporal dementia, the majority of PSP cases had limited or no visible atrophy, while the pattern of atrophy in CBD cases conformed to the existing staging scheme (all but one case exhibiting substantial visible tissue atrophy). Despite similar clinical severity and disease duration between groups, there was a marked difference between the PSP and CBD cases in pathological disease stage (chi(2) = 8.86; P = 0.03). The degree of global atrophy in PSP appears to be distinct from other tauopathies, while CBD fits the same pattern as other pathological forms of frontotemporal dementia.     

Tau-inclusion body formation in oligodendroglia: the role of stress proteins and proteasome inhibition

Filamentous tau-positive inclusions in neurons and glia are a unifying mechanism underlying a variety of late onset neurodegenerative disorders termed "tauopathies". Oligodendroglial lesions and white matter pathology have long been underestimated and are specifically prominent in frontotemporal dementias (FTDs), such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Oligodendrocytes contain an extensive microtubule network and express the microtubule-associated protein tau. Tau-positive inclusion bodies in oligodendrocytes are positively stained with antibodies against ubiquitin and heat shock proteins (HSPs). Specifically the small HSP alphaB-crystallin has been identified in oligodendroglial lesions. HSPs act as molecular chaperones and prevent the accumulation of abnormal proteins, and support proteolytic degradation by targeting non-reparable proteins to the ubiquitin proteasomal pathway. HSPs and the proteasomal system closely work together. The present report summarizes recent data on HSP induction and aggregate formation in oligodendroglia cell culture systems, indicating that posttranslational modification of tau, HSP induction and alterations of the proteasomal system, which might occur during aging and disease processes, are involved in the neuropathological events leading to aggregate formation and degeneration.     

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.     

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.     

Non-Alzheimer's disease dementias: anatomic, clinical, and molecular correlates.

OBJECTIVE: To review the clinical and molecular features of non-Alzheimer's disease (non-AD) dementias, focusing on disorders associated with tau pathology (that is, frontotemporal lobar degeneration [FTLD], corticobasal ganglionic degeneration [CBD], and progressive supranuclear palsy [PSP]) or on disorders with synuclein pathology (that is, dementia with Lewy bodies [DLB] and multisystem atrophy [MSA]). We also discuss the pharmacologic treatment of these disorders. METHODS: We report a selective review of the literature on FTLD, CBD, PSP, DLB, and MSA. RESULTS: The non-AD dementias can present with a wide variety of cognitive and behavioural symptoms. Through common clinical features and shared molecular etiologies, neurodegenerative disorders previously thought to be distinct are now classified into tauopathies and synucleinopathies. CONCLUSIONS: The unique cognitive and behavioural manifestations of the non-AD dementias can be mistaken for psychiatric disorders. Improved detection of tauopathies and synucleinopathies and their differentiation from AD is possible.     

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.

     

Dynamic neuropathology of tauopathy]

Tauopathy is defined as abnormal accumulation of aberrantly phosphorylated microtubule-associated protein tau in the central nervous system, best demonstrated by immunocytochemistry using anti-tau antibodies. The newly recognized familial tauopathy with mutation in tau gene, that is located on chromosome 17, confirms that the process directly leads to neuronal degeneration. Tau consists of six isoforms translated from alternative splicing of a single gene. They are classified into three repeat (3R) and four repeat (4R) subtypes, by the number of microtubulus-binding domain from the reading or skipping of the exon 10. In sporadic tauopathy, 3R + 4R accumulate in Alzehimer's disease (AD), 3R in Pick's disease, and 4R in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). In familial tauopathy, the mutations affecting the splicing of the exon 10 accumulate 4R and phenotypically mimick CBD/PSP, while majority of others simulate neurofibrillary tangle-predominant form of dementia (NFTD). Argyrophlic grains (AG) are tau-immunoreactive comma-shaped or filiform structure, and argyrophilic grain dementia (AGD) is a form of senile dementia carrying AG as only morphological substrate explaining dementia. In our consecutive autopsy cases from the oldest old, AGD is the second leading cause of degenerative type of dementia, highlighting the importance of tauopathy in the aging and dementia.     

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.     

Frontotemporal dementia: one disease, or many?: probably one, possibly two

Accumulating evidence suggest that frontotemporal dementia is best viewed as a clinical syndrome even though there are distinct presentations of the behavioral variety, progressive aphasia, semantic dementia, corticobasal degeneration and progressive supranuclear palsy. Similarly the pathology should be regarded as a spectrum even though histological varieties are distinguished. More than half of FTD pathology is associated with ubiquitin positive and tau negative inclusions that are common in ALS. However the majority of FTD cases do not have ALS clinically and relatively few ALS cases develop FTD. The pathological and biochemical varieties can be dichotomized as tau positive and tau negative pathology and biochemistry. The genetics of the tau positive variety is associated with tau mutations and so far the tau negative variety is not, although some are linked to chromosome-17 also. There is a corresponding clinical dichotomy combining the behavioral variety of FTD presentation with semantic dementia and usually ubiquitin positive tau negative pathology on one hand and the association of primary progressive aphasia and cortical basal degeneration/PSP syndrome with tau positive pathology on the other. The overlap between them is too great to establish two separate diseases.     

Progress in clinical neurosciences: Frontotemporal dementia-pick's disease

Frontotemporal dementia (clinical Pick's disease) is a relatively common, but underdiagnosed degenerative disease in the presenium. Estimated prevalence ranges from 6-12% of dementias. The behavioural, aphasic and extrapyramidal presentations are labeled FTD-behavioural variant, Primary Progressive Aphasia (PPA) and Corticobasal Degeneration/Progressive Supranuclear Palsy (CBD/PSP). The diagnostic features and course of each are described and their overlap in the evolution of the illness is emphasized. The neuropathology ranges from the most common tau negative ubiquitin positive amyotrophic lateral sclerosis (ALS) type inclusions to the tau positive classical Pick bodies and more or less distinct changes of PSP and CBD. The genetics of the relatively frequent tau mutations and the yet unsolved problem of tau negative families are discussed. The tau negative cases tend to be associated with the behavioural presentation and semantic dementia and the tau positive ones with PPA and the CBD/PSP syndrome. However the overlap is too great to split the disease. A glossary to navigate the proliferating terminology is included.     

Phosphorylated TDP-43 pathology and hippocampal sclerosis in progressive supranuclear palsy

TDP-43 is characteristically accumulated in TDP-43 proteinopathies such as frontotemporal lobar degeneration and motor neurone disease, but is also present in some tauopathies, including Alzheimer’s disease, argyrophilic grain disease, and corticobasal degeneration (CBD). However, several studies have suggested that cases of progressive supranuclear palsy (PSP) lack TDP-43 pathology. We have therefore examined limbic regions of the brain in 19 PSP cases, as well as in 12 CBD cases, using phosphorylation-dependent anti-TDP-43 antibodies. We observed TDP-43-positive inclusions in five PSP cases (26%), as well as in two CBD cases (17%). The amygdala and hippocampal dentate gyrus were most frequently affected in PSP. Regional tau burden tended to be higher in TDP-43-positive PSP cases, and a significant correlation between tau and TDP-43 burden was noted in the occipitotemporal gyrus. Hippocampal sclerosis (HS) was found in 3/5 TDP-43-positive PSP cases, but HS was significantly more frequent in TDP-43-positive than TDP-43 negative PSP cases. Dementia was present in 13/19 (58%) of the PSP cases, in 4/5 TDP-43-positive cases, in all 3 TDP-43-positive cases with HS, in 1/2 TDP-43-positive cases without HS, and 7/14 cases lacking both. TDP-43 and tau were frequently colocalized in the amygdala, but not in the hippocampal dentate gyrus. Immunoblotting demonstrated the characteristic (for TDP-43 proteinopathies) 45 and 25 kDa bands and high molecular weight smear in the TDP-43-positive PSP case. These findings suggest that (1) although PSP is nominally a tauopathy, pathological TDP-43 can accumulate in the limbic system in some cases, and (2) TDP-43 pathology may be concurrent with HS.     

Argyrophilic grain disease is a sporadic 4-repeat tauopathy

Argyrophilic grain disease (AGD) was first reported as an adult-onset dementia, but recent studies have emphasized personality change, emotional imbalance, and memory problems as clinical features of AGD. AGD is characterized by spindle- or comma-shaped argyrophilic grains in the neuropil of entorhinal cortex, hippocampus, and amygdala. Immunohistochemistry with monoclonal antibodies specific to tau isoforms with four (4R) or three (3R) repeats in the microtubule-binding domain showed immunostaining of grains with 4R, but not 3R, tau antibodies, suggesting that AGD was a 4R tauopathy. The tau isoform composition of AGD was confirmed with densitometric analysis of Western blots of sarkosyl-insoluble tau from the medial temporal lobe of AGD brains with a range of concurrent neurofibrillary pathology and compared with Alzheimer controls. The 4R/3R ratio was 1 or less for Alzheimer disease; the 4R/3R ratio was more than 1 for AGD, decreasing with increasing neurofibrillary pathology and demonstrating that insoluble tau in AGD was enriched in 4R tau. The frequency of the extended tau haplotype was not different in AGD compared to other sporadic 4R tauopathies, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Furthermore, AGD occurred in PSP and CBD more frequently than in dementia controls, including Alzheimer disease. These results suggest that AGD, PSP and CBD are 4R tauopathies that share common pathologic, biochemical, and genetic characteristics.     

Atypical progressive supranuclear palsy with corticospinal tract degeneration

Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), sporadic multisystem tauopathy, and some forms of frontotemporal dementia with Parkinsonism linked to chromosome 17 are characterized by neuronal and glial lesions accumulating tau protein containing 4 conserved repeats in microtubule-binding domain (4R tau). Corticospinal tract degeneration is not a common feature of 4R tauopathies. Our objective was to describe 12 cases with pathologic features similar to those of PSP but with prominent corticospinal tract degeneration. We reviewed the historical records and neuropathologic evaluation using standardized sampling, immunohistochemistry, semiquantitative analysis, image analysis, and electron microscopy. The mean age at onset and illness duration was 71 and 5.7 years, respectively. Eight cases were female. Eleven cases had clinical evidence of prominent upper motor neuron disease plus extrapyramidal features. There was focal parasagittal cortical atrophy involving motor cortex and degeneration of corticospinal tract with sparing of lower motor neurons like in primary lateral sclerosis. Prominent tau pathology was found in oligodendrocytes in motor cortex, subjacent white matter, and corticospinal tract characterized by globular cytoplasmic filamentous inclusions that were immunoreactive for 4R tau. The clinicopathologic features of these 12 cases expand the spectrum of 4R tauopathies.     

Corticobasal syndrome: recent advances and future directions

Corticobasal degeneration (CBD) is a progressive neurodegenerative disorder described by Rebeiz et al. It is characterized by progressive, asymmetric, cortical (eg, apraxia, alien limb phenomena, cortical sensory loss, and myoclonus), and extrapyramidal (eg, rigidity, bradykinesia, dystonia, and tremor) dysfunction. However, CBD has many clinical phenotypes, and the features used for predicting CBD have low sensitivity. Therefore, the term corticobasal syndrome (CBS) has been used to characterize such clinical features, whereas the term CBD is used to refer to the pathological disorder. The most frequent causes of CBS are CBD, followed by Alzheimer's disease, progressive supranuclear palsy, frontotemporal lobar degeneration with TDP-43 pathology (sporadic and familial), Pick's disease, Lewy body disease, frontotemporal lobar degeneration with fused in sarcoma-positive inclusions, Creutzfeldt-Jakob disease, and mutations in the microtubule-associated protein tau (MAPT) and progranulin (GRN) genes. The topography of neurodegeneration dictates the clinical syndrome not according to the underlying pathology. Researchers have attempted to develop fluid biomarkers or imaging analysis for diagnosing CBS. The aim of this review was to highlight recent advances in CBS diagnosis and discuss future directions.     

AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer’s disease and other tauopathies

Tauopathies represent a class of neurodegenerative disorders characterized by abnormal tau phosphorylation and aggregation into neuronal paired helical filaments (PHFs) and neurofibrillary tangles. AMP-activated protein kinase (AMPK) is a metabolic sensor expressed in most mammalian cell types. In the brain, AMPK controls neuronal maintenance and is overactivated during metabolic stress. Here, we show that activated AMPK (p-AMPK) is abnormally accumulated in cerebral neurons in 3R+4R and 3R tauopathies, such as Alzheimer’s disease (AD), tangle-predominant dementia, Guam Parkinson dementia complex, Pick’s disease, and frontotemporal dementia with parkinsonism linked to chromosome 17, and to a lesser extent in some neuronal and glial populations in the 4R tauopathies, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease. In AD brains, p-AMPK accumulation decorated neuropil threads and dystrophic neurites surrounding amyloid plaques, and appeared in more than 90% of neurons bearing pre-tangles and tangles. Granular p-AMPK immunoreactivity was also observed in several tauopathies in apparently unaffected neurons devoid of tau inclusion, suggesting that AMPK activation preceded tau accumulation. Less p-AMPK pathology was observed in PSP and CBD, where minimal p-AMPK accumulation was also found in tangle-positive glial cells. p-AMPK was not found in purified PHFs, indicating that p-AMPK did not co-aggregate with tau in tangles. Finally, in vitro assays showed that AMPK can directly phosphorylate tau at Thr-231 and Ser-396/404. Thus, activated AMPK abnormally accumulated in tangle- and pre-tangle-bearing neurons in all major tauopathies. By controlling tau phosphorylation, AMPK might regulate neurodegeneration and therefore could represent a novel common determinant in tauopathies.