Association of an extended haplotype in the tau gene with progressive supranuclear palsy

We describe two extended haplotypes that cover the human tau gene. In a total of approximately 200 unrelated caucasian individuals there is complete disequilibrium between polymorphisms which span the gene (which covers approximately 100 kb of DNA). This suggests that the establishment of the two haplotypes was an ancient event and either that recombination is suppressed in this region, or that recombinant genes are selected against. Furthermore, we show that the more common haplotype (H1) is significantly over-represented in patients with progressive supranuclear palsy (PSP), extending earlier reports of an association between an intronic dinucleotide polymorphism and PSP.     

The structure of the tau haplotype in controls and in progressive supranuclear palsy

The group of neurodegenerative diseases collectively known as tauopathies are characterized by hallmark lesions consisting of fibrillar aggregates of the microtubule-associated protein, tau (MAPT). Mutations of the tau gene (MAPT) are the cause of frontotemporal dementia with parkinsonism linked to chromosome 17, giving tau a central role in the pathogenic process. The chromosomal region containing MAPT has been shown to evolve into two major haplotypes, H1 and H2, which are defined by linkage disequilibrium (LD) between several polymorphisms over the entire MAPT gene. Studies to date suggest a complete absence of recombination between these two haplotypes. The more common haplotype H1 is over-represented in patients with progressive supranuclear palsy (PSP) and corticobasal degeneration. Using single nucleotide polymorphisms, we mapped LD in the regions flanking MAPT and have established the maximum extent of the haplotype block on chromosome 17q21.31 as a region covering approximately 2 Mb. This gene-rich region extends centromerically beyond the corticotrophin releasing hormone receptor 1 gene (CRHR1) to a region of approximately 400 kb, where there is a complete loss of LD. The telomeric end is defined by an approximately 150 kb region just beyond the WNT3 gene. We show that the entire, fully extended H1 haplotype is associated with PSP, which implicates several other genes in addition to MAPT, as candidate pathogenic loci.     

Pattern of Tau forms in CSF is altered in progressive supranuclear palsy

Cerebrospinal fluid (CSF) total Tau levels vary widely in neurodegenerative disorders, thus being not useful in their discrimination over Alzheimer disease. No CSF marker for progressive supranuclear palsy (PSP) is currently available. The aim of this study was to characterise and measure Tau forms in order to verify the differential patterns among neurodegenerative disorders. Seventy-eight patients with neurodegenerative disorders and 26 controls were included in the study. Each patient underwent a standardised clinical and neuropsychological evaluation, MRI, and CSF total-Tau and phospho-Tau dosage. In CSF and cerebral cortex, a quantitative immunoprecipitation was developed. An extended (55 kDa), and a truncated (33 kDa) forms of Tau were recognised. CSF samples were assayed, the optical density of the two Tau forms was measured, and the ratio calculated (Tau ratio, 33 kDa/55 kDa forms). Tau ratio 33 kDa/55 kDa was significantly decreased in patients with PSP (0.46+/-0.16) when compared to controls, including healthy subjects (1.16+/-0.46, P=0.002) and Alzheimer disease (1.38+/-0.68, P<0.001), and when compared to frontotemporal dementia (0.98+/-0.30, P=0.008) or corticobasal degeneration syndrome (0.98+/-0.48, P=0.02). Moreover, in PSP patients Tau form ratio was lower than in other neurodegenerative extrapyramidal disorders, such as Parkinson disease (1.16+/-0.26, P=0.002) and dementia with lewy bodies (1.44+/-0.48, P<0.001). Tau ratio 33 kDa/55 kDa did not correlate either with demographic characteristics, cognitive performances or with motor impairment severity. Truncated Tau production shows a different pattern in PSP compared to other neurodegenerative disorders, supporting the view of disease-specific pathological pathways. These findings are promising in suggesting the identification of a marker for PSP diagnosis in clinical practice.     

Ferritin is associated with the aberrant tau filaments present in progressive supranuclear palsy.

Tau-containing filaments purified from the brain of progressive supranuclear palsy (PSP) patients were isolated and characterized. These filaments co-purify with regular particles that biophysical and biochemical methods identified as ferritin shells. In vivo, brain tau accumulation in PSP co-localized with ferritin. These results suggest that ferritin/iron could modulate the formation of tau aggregates in PSP.     

Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration

Background: The haplotype H1 of the tau gene, MAPT, is highly associated with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Objective: To investigate the pathogenic basis of this association. Methods: Detailed linkage disequilibrium and common haplotype structure of MAPT were examined in 27 CEPH trios using validated HapMap genotype data for 24 single nucleotide polymorphisms (SNPs) spanning MAPT. Results: Multiple variants of the H1 haplotype were resolved, reflecting a far greater diversity of MAPT than can be explained by the H1 and H2 clades alone. Based on this, six haplotype tagging SNPs (htSNPs) that capture 95% of the common haplotype diversity were used to genotype well characterised PSP and CBD case–control cohorts. In addition to strong association with PSP and CBD of individual SNPs, two common haplotypes derived from these htSNPs were identified that are highly associated with PSP: the sole H2 derived haplotype was underrepresented and one of the common H1 derived haplotypes was highly associated, with a similar trend observed in CBD. There were powerful and highly significant associations with PSP and CBD of haplotypes formed by three H1 specific SNPs. This made it possible to define a candidate region of at least ∼56 kb, spanning sequences from upstream of MAPT exon 1 to intron 9. On the H1 haplotype background, these could harbour the pathogenic variants. Conclusions: The findings support the pathological evidence that underlying variations in MAPT could contribute to disease pathogenesis by subtle effects on gene expression and/or splicing. They also form the basis for the investigation of the possible genetic role of MAPT in Parkinson''s disease and other tauopathies, including Alzheimer''s disease.     

No evidence of CRHR1 gene involvement in progressive supranuclear palsy

Several genes have been located in the chromosomal region 17q21 genetically associated with progressive supranuclear palsy (PSP). Corticotropin releasing hormone receptor 1 (CRHR1) is a gene included in this region. In order to investigate the possible involvement of CRHR1 in PSP pathogenesis, we measured the globus pallidus mRNA expression of this gene using real-time PCR in 12 PSP comparing with several control groups composed by 10 Alzheimer's disease, 5 cerebrovascular disease and 6 healthy controls subjects. We furthermore sequenced directly the entire coding region of CRHR1 of two histopathologically confirmed PSP patients. Expression pattern of CRHR1 in globus pallidus was similar in all groups. We did not find any coding non-synonymous mutation in the patients analysed. Our results do not support an involvement of CRHR1 gene in PSP pathogenesis.     

A comparison of tau protein in cerebrospinal fluid between corticobasal degeneration and progressive supranuclear palsy

Many clinical and pathological discussions have been focused on the difficulty of differential diagnosis between corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) in recent years. This study was conducted to evaluate the usefulness of tau proteins in cerebrospinal fluid (CSF) for the differentiation of these two diseases. Subjects consisted of 10 patients with CBD (four males and six females with a mean age of 67.9+/-5.8 years), 12 patients with PSP (eight males and four females with a mean age of 62.6+/-5.8 years) and 36 control subjects (CTL) (16 males and 20 females with a mean age of 65.8+/-9.9 years). The CBD group included patients with probable CBD, while all the patients in the PSP group satisfied the diagnostic criteria developed by the National Institute of Neurological Disorders and Stroke and Society for PSP (NINDS-SPSP). CSF tau proteins were measured with the sandwich ELISA method (Innogenetics, Belgium). The CSF tau protein level was 320.1+/-86.5 pg/ml in the CBD group, 151.5+/-52.7 pg/ml in the PSP group and 128.7+/-91.7 pg/ml in the CTL group. Significant differences were noted in tau protein levels between the CBD group and both the PSP group (P<0.001) and the CTL group (P<0.005). We suggested that the measurement of CSF tau proteins may be useful for the differentiation between CBD and PSP.     

Contribution of the astrocytic tau pathology to synapse loss in progressive supranuclear palsy and corticobasal degeneration

Primary 4‐repeat tauopathies with frontotemporal lobar degeneration (FTLD) like Progressive Supranuclear Palsy (PSP) or Corticobasal Degeneration (CBD) show diverse cellular pathology in various brain regions. Besides shared characteristics of neuronal and oligodendroglial cytoplasmic inclusions of accumulated hyperphosphorylated tau protein (pTau), astrocytes in PSP and CBD contain pathognomonic pTau aggregates — hence, lending the designation tufted astrocytes (TA) or astrocytic plaques (AP), respectively. pTau toxicity is most commonly assigned to neurons, whereas the implications of astrocytic pTau for maintaining neurotransmission within the tripartite synapse of human brains is not well understood. We performed immunofluorescent synapse labeling and automated puncta quantification in the medial frontal gyrus (MFG) and striatal regions from PSP and CBD postmortem samples to capture morphometric synaptic alterations. This approach indicated general synaptic losses of both, excitatory and inhibitory bipartite synapses in the frontal cortex of PSP cases, whereas in CBD lower synapse densities were only related to astrocytic plaques. In contrast to tufted astrocytes in PSP, affected astrocytes in CBD could not preserve synaptic integrity within their spatial domains, when compared to non‐affected internal astrocytes or astrocytes in healthy controls. These findings suggest a pTau pathology‐associated role of astrocytes in maintaining connections within neuronal circuits, considered as the microscopic substrate of cognitive dysfunction in CBD. By contrasting astrocytic‐synaptic associations in both diseases, we hereby highlight astrocytic pTau as an important subject of prospective research and as a potential cellular target for therapeutic approaches in the primary tauopathies PSP and CBD.     

Distinct subcortical tau burden: The tau pallido‐claustral ratio separates progressive supranuclear palsy and corticobasal degeneration

Neuropathological diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) requires interpretation of tau morphology based on extensive brain sampling. Here we report subcortical tau burden is sufficient to distinguish PSP and CBD, regardless of the tau morphology. The tau pallido‐claustral ratio is a promising diagnostic indicator for PSP and CBD.     

Central conduction time in progressive supranuclear palsy.

Progressive nuclear palsy (PSP) is a parkinson-like extrapyramidal disorder with pathological evidence of brain stem demyelination. We studied brain stem auditory (BAEP) and somatosensory (SSEP) evoked potentials in 8 patients with progressive supra-nuclear palsy to look for evidence of such central demyelination. We found minor alterations in BAEPs and frequently abnormal SSEPs, suggestive of brain stem white matter involvement in this disorder. Evoked potentials may assist in the differentiation of PSP from other parkinsonian conditions.     

Effect of ApoE and tau on age of onset of progressive supranuclear palsy and multiple system atrophy

In addition to allelic association between genetic polymorphisms and diseases, modulation of age of onset is a well recognised effect of disease susceptibility genes. The ApoE epsilon4 allele is associated with an earlier age of onset of sporadic and familial Alzheimer's disease. It has been suggested that the tau genotype influences the age of onset of progressive supranuclear palsy (PSP), a form of atypical parkinsonism caused by tau neurofibrillary tangle deposition. We have therefore analysed the relationship between tau and ApoE genotypes and the age of onset of PSP and another form of atypical parkinsonism, multiple system atrophy (MSA). We have not found any effect of possession of the tau H1 haplotype or the ApoE epsilon4 allele on the age of onset of MSA or PSP.     

Disease specificity and pathologic progression of tau pathology in brainstem nuclei of Alzheimer's disease and progressive supranuclear palsy

Previous studies have shown tau pathology in the inferior colliculus (IC) and superior colliculus (SC) in Alzheimer's disease (AD); however, it has not been compared to other tauopathies, such as progressive supranuclear palsy (PSP), or characterized with respect to progression of tau pathology in AD. The main purpose of this study was to investigate frequency, neuroanatomical selectivity and disease specificity of tau pathology in visual and auditory nuclei (SC and lateral geniculate body (LGB); IC and medial geniculate body (MGB), respectively). We measured phospho-tau burden with immunohistochemistry and image analysis in 26 cases of AD, 37 PSP and 11 normal controls. Tau burden was also assessed in two unrelated brainstem nuclei (substantia nigra (SN) and pedunculopontine nucleus (PPN)) of the same cases. We found tau burden to be greater in the SC of PSP compared to AD and controls. Conversely, tau burden was greater in the IC of AD compared to PSP and controls. The MGB and LGB had sparse tau pathology in both AD and PSP. This disease selectivity parallels known deficits in visual reflexes in PSP and auditory reflexes in AD. Tau burden was greater in the SC, IC, and PPN in both PSP and AD compared to controls, and greater in the SN in PSP compared to AD and controls. Although present at early Braak neurofibrillary tangle stages, the SC, IC, PPN and SN did not accumulate tau consistently until later stages. These findings support a concept of tau pathology affecting the brainstem at mid-to-late stage AD.     

Antigenic characteristics of neurofibrillary tangles in progressive supranuclear palsy

The antigenic components of neurofibrillary tangles in the basal forebrain and brainstem were studied in 4 cases of progressive supranuclear palsy (PSP) at the light and electron microscopic levels, using antibodies to neurofilaments (in the phosphorylated and non-phosphorylated forms); the high, middle and low molecular weight neurofilament subunits; ubiquitin; the microtubule associated proteins MAP1, MAP2 and tau; isolated Alzheimer paired helical filaments and to tubulin, in the tyrosinated and detyrosinated forms. Although PSP neurofibrillary tangles appear to have most antigenic sites in common with those of Alzheimer disease, PSP tangles share epitopes with tyrosinated and detyrosinated tubulin, which has not been demonstrated in Alzheimer neurofibrillary tangles.     

Clinical correlations of microstructural changes in progressive supranuclear palsy

In patients with progressive supranuclear palsy (PSP), previous reports have shown a severe white matter (WM) damage involving supra and infratentorial regions including cerebellum. In the present study, we investigated potential correlations between WM integrity loss and clinical-cognitive features of patients with PSP. By using magnetic resonance imaging and diffusion tensor imaging with tract based spatial statistic analysis, we analyzed WM volume in 18 patients with PSP and 18 healthy controls (HCs). All patients and HCs underwent a detailed clinical and neuropsychological evaluation. Relative to HCs, patients with PSP showed WM changes encompassing supra and infratentorial areas such as corpus callosum, fornix, midbrain, inferior fronto-occipital fasciculus, anterior thalamic radiation, superior cerebellar peduncle, superior longitudinal fasciculus, uncinate fasciculus, cingulate gyrus, and cortico-spinal tract bilaterally. Among different correlations between motor-cognitive features and WM structural abnormalities, we detected a significant association between fronto-cerebellar WM loss and executive cognitive impairment in patients with PSP. Our findings, therefore, corroborate the hypothesis that cognitive impairment in PSP may result from both “intrinsic” and “extrinsic” frontal lobe dysfunction, likely related to cerebellar disconnection.     

Gaze-shift strategies during functional activity in progressive supranuclear palsy

The relative sparing of visual fixation in parallel with disruption of saccade function in progressive supranuclear palsy (PSP) creates a unique human model for the study of gaze-shift strategies which are adopted when vertical gaze palsy impairs primarily the eye-movement component of gaze control. It was hypothesized that people with PSP would rely on head pitch as a primary component of gaze shift during a platform stepping task and that there would be a predominance of fixation behavior (counter rotation of the eyes during head pitch) while attempting a down-gaze shift. Fourteen subjects with probable and 5 subjects with possible PSP participated in two experiments to measure visual fixation and gaze shift on the same continuum (using a derived vertical gaze fixation score, vGFS). Experiment #1 required gaze fixation during passive head pitch at 0.1–0.2 Hz, whereas experiment #2 required gaze shifts during a continuous platform step on, over, and off task. The primary gaze-shift strategy involved pitching the head downward to compensate for a loss in vertical saccade function. This strategy produced head pitch velocity that leads vertical eye velocity on the order of 200–500 ms. Gaze shifts during platform stepping showed greater fixation suppression (e.g., lower vGFS) in both groups of PSP compared to the visual stabilization task, but some subjects showed “fixation intrusion” during attempted gaze shift. The amount of eye movement was relatively constant when corrected for orbit height, whereas the extent of head pitch varied in proportion to the task demands. The mechanism controlling gaze in PSP, therefore appears to modulate head pitch independently of eye movement, but the gaze strategy seems dependent upon the extent of gaze dysfunction. These findings support the view that the desired gaze signal is parsed into separate eye and head pathways upstream from the burst neurons.     

进行性核上性麻痹和皮质基底节变性的胶质细胞病变的观察

目的 观察进行性核上性麻痹和皮质基底节变性胶质细胞变性特征,探讨不同类型胶质细胞变性的病理意义。方法 对具有详细临床资料和病理确诊的2例进行性核上性麻痹和3例皮质基底节变性的脑标本进行了Gallyas—Braak银染色和tau蛋白免疫组织化学链霉素抗生物素蛋白-过氧化物酶法染色,并以5例阿尔茨海默病,4例帕金森病和6例无神经疾病史的同龄老年人脑标本作对照。结果 Gallyas-Braak银染色显示进行性核上性麻痹和皮质基底节变性的脑组织内存在广泛分布的两种形态胶质细胞变性,即呈菊花团或蜘蛛网样形态的葱状星形细胞和位于核周线圈样或逗点样形状的线团样少突胶质细胞变性。葱状星形细胞主要见于额顶叶皮层,基底节和脑干灰质区,而线团样少突胶质细胞则主要分布于基底节,脑干和小脑白质束内。星形细胞斑是由粗短的突起样结构呈放射状排列形成,仅见于皮质基底节变性的额、顶叶皮层和纹状体区。这3种类型胶质细胞变性的tau蛋白免疫组织化学染色均为阳性。所有对照病例脑组织内未见上述形态的胶质细胞变性改变。结论 葱状星形细胞和线团样少突胶质细胞变性是进行性核上性麻痹和皮质基底节变性的共同的组织学改变特征之一;星形细胞斑是皮质基底节变性相对特异性的病理标志。     

Tau epitope display in progressive supranuclear palsy and corticobasal degeneration

Filamentous aggregates of the protein tau are a prominent feature of Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). However, the extent to which the molecular structure of the tau in these aggregates is similar or differs between these diseases is unclear. We approached this question by examining these disorders with a panel of antibodies that represent different structural, conformational, and cleavage-specific tau epitopes. Although each of these antibodies reveals AD pathology, they resolved into three classes with respect to PSP and CBD: AD2 and Tau-46.1 stained the most tau pathology in all cases; Tau-1, 2, 5, and 12 exhibited variable reactivity; and Tau-66 and MN423 did not reveal any tau pathology. In addition, hippocampal neurofibrillary tangles in these cases showed a predominantly PSP/CBD-like, rather than AD-like, staining pattern. These results indicate that the patterns of the tau epitopes represented by this panel that reside in the pathological aggregates of PSP and CBD are similar to each other but distinct from that of AD.     

The basal nucleus of Meynert in patients with progressive supranuclear palsy

Unilateral inoculation of hamster substantia nigra (SN) with scrapie agent led to an early decrease in tyrosine hydroxylase (TH) activity in the corresponding striatum, which was detectable by the 5th day. This decrease was accompanied by an increase in glutamate decarboxylase (GAD) observed on the 20th day. Local phenomena related to administration of the agent were investigated by intrastriatal inoculation followed by local measurement of TH, GAD and choline acetyltransferase (ChAT) activities. A rise in GAD activity was observed 20 days later. The decrease in TH activity which occurred 5 days after inoculation of the substantia nigra with scrapie agent constitutes an extremely early indication in hamsters of the slow pathological processes at work: at clinical and behavioural levels, these can be detected at best only 80 days after the intracerebral inoculation.