Differences in tau and apolipoprotein E polymorphism frequencies in sporadic frontotemporal lobar degeneration syndromes

BACKGROUND: Frontotemporal lobar degeneration (FTLD) has different clinical phenotypes and is associated with several pathologic findings, most commonly dementia lacking distinctive histology or Pick disease. We know that the tau H1 haplotype is associated with some clinical and histologic phenotypes, for example, progressive supranuclear palsy and corticobasal degeneration. Furthermore, the apolipoprotein epsilon4 allele (APOE epsilon4) may be associated with Pick disease. OBJECTIVE: To determine if different clinical phenotypes of FTLD are associated with different tau haplotype and APOE allele frequencies. PATIENTS AND METHODS: All patients with FTLD with available DNA specimens (n = 63) seen at the Mayo Clinic, Jacksonville, Fla, were retrospectively classified according to the following clinical phenotypes: frontal dementia (FD); progressive, nonfluent aphasia (PA); or fluent, anomic aphasia (AA). DNA specimens were genotyped for APOEallele and tau haplotype frequencies and were compared with cognitively normal patients (n = 338) and patients with Alzheimer disease (AD) (n = 193). RESULTS: Patients with AA had increased APOE epsilon4 frequency (30.4%) compared with patients with FD (14.8%, P=.04) and cognitively normal patients (11.1%, P<.001). Patients with AA also had increased tau H2 haplotype (37.0%) frequency compared with patients with FD (11.1%,P=.002), patients with AD (21.8%, P=.02), and cognitively normal patients (19.8%, P=.004). The increase in tau H2 haplotype frequency (50.0%) is especially pronounced in patients with AA who are APOE epsilon4 positive compared with patients with FD (18.8%, P=.04), patients with AD (24.8%, P=.005), and cognitively normal patients (15.3%, P<.001).APOE epsilon4 and tau H2 haplotype frequencies are not significantly different in patients with FD and PA compared with healthy patients. CONCLUSIONS: Clinical subtypes of FTLD have different tau and APOE genotype frequencies, suggesting these genes may influence the clinical presentation. Further studies should be performed to confirm this finding and to see if the pathologic phenotypes are also associated with different tau and APOE genotype frequencies.     

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.     

Tau pathology in the olfactory bulb correlates with Braak stage, Lewy body pathology and apolipoprotein epsilon4

Olfactory dysfunction increases with disease severity in Alzheimer's disease (AD), is early and independent of disease severity in Parkinson's disease (PD), but is absent in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Previous histopathologic studies of olfactory bulbs in AD have shown neurofibrillary tangles (NFTs) and senile plaques while Lewy bodies (LBs) have been described in PD. Little is known about olfactory bulb pathology in PSP and CBD. Tau and alpha-synuclein pathology was assessed with immunohistochemistry in olfactory bulbs of AD (N=15), Lewy body disease (LBD; N=10), LBD with concurrent AD (AD/LBD; N=19), PSP (N=27), CBD (N=3) and cases with no significant neurodegenerative pathology (NSP; N=15). The Braak NFT stage, counts of senile plaques and NFT in cortical and hippocampal sections, and counts of LBs in amygdala and cortical sections were recorded for each case. Apolipoprotein E (APOE) genotypes were determined on DNA prepared from frozen brain tissue. All AD and AD/LBD cases and nine of 10 LBD cases had tau pathology in the anterior olfactory nucleus (AON), but it was uncommon in PSP (9/27), CBD (0/3) and NSP (5/15). Multiple linear regression analysis demonstrated that tau pathology in the AON correlated with Braak stage (P<0.001), cortical LB counts (P<0.001), as well as APOE epsilon4. Tau pathology is common in the olfactory bulb of AD and LBD but is minimal or absent in PSP and CBD. It correlates with APOE epsilon4, severity of tau pathology in the brain and surprisingly with cortical and amygdala LBs, suggesting a possible synergistic effect between tau and synuclein in the AON in cases with both pathologic processes.     

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.     

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.     

Multiple system atrophy/progressive supranuclear palsy: alpha-Synuclein, synphilin, tau, and APOE

Article abstract-Alpha synuclein, tau, synphilin, and APOE genotypes were analyzed in patients with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) and controls. The predisposing effect of the tau insertion polymorphism to the development of PSP is confirmed. However, no effect of alpha-synuclein, synphilin, or APOE variability on the development of PSP, or of tau, alpha-synuclein, APOE, or synphilin gene variability on the development of MSA, are demonstrated.     

Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects

OBJECTIVE: The authors conducted a prospective study of neurodegenerative and vascular dementia in Belgium. Strict diagnostic inclusion criteria were used to include well defined patients and controls. The results of apolipoprotein E (APOE) genotype effect on risk and clinical characteristics are presented. METHODS: APOE genotyping was performed in patients with probable Alzheimer's disease (AD) (n=504), frontotemporal dementia (FTD) (n=47), vascular dementia (VaD) (n=152), mixed dementia (n=132), mild cognitive impairment (MCI) (n=44), Parkinson's disease (PD) (n=30), dementia with Lewy bodies (DLB) (n=17), and multisystem atrophy (MSA)/progressive supranuclear palsy (PSP) (n=12). RESULTS: The APOE allele frequencies of this Belgian control population (epsilon 2: 6.9%; epsilon 3: 76.2%; epsilon 4: 16.9%) did not differ from those reported for other white populations. AD, MCI, and mixed dementia patients had higher APOE epsilon 4 (32.9%, 38.6%, and 28.4% respectively) and lower APOE epsilon 3 (62.2%, 53.4%, and 66.3%) frequencies compared with controls, whereas only AD and mixed dementia patients had lower APOE epsilon 2 frequencies (4.9% and 5.3%). Apart from a borderline significant different distribution of APOE allele frequencies in VaD patients compared with controls, no other differences were detected. The influence of APOE epsilon 4 on clinical features of dementia was limited to lower age at onset in AD patients and a less pronounced negative correlation between age at onset and number of epsilon 4 alleles in MCI and mixed dementia patients. CONCLUSIONS: This study confirmed the risk association between APOE epsilon 4 and AD. The observation that APOE epsilon 4 is associated with mixed dementia reflected the role of AD in the aetiopathogenesis of this condition. Although MCI is an aetiologically heterogeneous syndrome, the increased APOE epsilon 4 frequencies indicated that a large proportion of the MCI patients included in the study might be predisposed to develop AD.     

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.     

Argyrophilic grain disease: A late‐onset dementia with distinctive features among tauopathies

Argyrophilic grain disease (AgD) is a late‐onset dementia morphologically characterized by the presence of abundant spindle‐shaped argyrophilic grains (ArG) in neuronal processes and coiled bodies in oligodendrocytes. AgD changes consist of the microtubule‐associated protein tau in an abnormally and hyperphosphorylated state and are mainly found in limbic regions, for example, in the hippocampus, the entorhinal and transentorhinal cortices and the amygdala. AgD shows a significant correlation with advancing age, and it became apparent from recent clinicopathological studies that it might account for approximately 5% of all dementia cases. Further immunohistochemical and biochemical studies revealed that AgD is a four‐repeat (4R) tauopathy similar to PSP and corticobasal degeneration (CBD), but distinct from Alzheimer's disease (AD) and Pick's disease. Moreover, a common genetic background regarding the tau gene haplotype has been suggested for AgD, PSP and CBD. However, although there are currently only limited data available, AgD seems to be clinically distinct from PSP and CBD and shares rather features of (mild) AD or other forms of ‘limbic’ dementias, among them senile dementia with tangles and the localized form of AD.     

Brain Accumulation of Amyloid-beta in Non-Alzheimer Neurodegeneration

We report an unusual case of amyotrophic lateral sclerosis (ALS) marked by extensive cerebral amyloid-beta deposition in small and medium-size vessels, capillaries, and perivascular plaques in the cerebral cortex, and in most leptomeningeal vessels. Despite considerable cerebral amyloidosis, the patient remained cognitively intact until death. For comparison with other neuro-degenerative diseases and normal aging, we assessed the densities of amyloid-beta-immunoreactive cortical vessels and plaques in matched frontal and temporal lobe sections from archival uncomplicated cases of Alzheimer's disease (N=10), Pick's disease (PkD; N=4), Parkinson's disease (PD; N=6), Diffuse Lewy body disease (DLBD; N=7), progressive supranuclear palsy (PSP; N=5), multiple systems atrophy (MSA; N=4), ALS (N=7), or normal aging (N=10) by semi-quantitative grading (0 to 3+). Moderate (2+) or abundant (3+) cerebrovascular amyloid-beta immunoreactivity was detected in 8/10 AD, 3/7 DLBD, 3/6 PD, 1 each with PSP or PkD, and 2/10 controls. Moderate or abundant densities of amyloid-beta-immunoreactive diffuse plaques were detected in all cases of AD or DLBD, 4/6 with PD, 3/5 with PSP, and 2/10 controls. Moderate or abundant amyloid-beta-immunoreactive mature (dense core) plaques were present in all cases of AD or DLBD, and 3 each with PD or PSP. Importantly, amyloid-beta-immunoreactivity was not observed in the 4 MSA or 7 archival ALS cases. This study demonstrates that prominent amyloid-beta accumulation in cerebral vessels and plaques occurs frequently in AD, DLBD, PSP, and PD, but not in ALS or MSA, indicating that the case described is unique. The lack of cognitive impairment in the case presented argues against the idea that extensive amyloid-beta deposition in the brain causes dementia.     

Association between the extended tau haplotype and frontotemporal dementia

BACKGROUND: Recent studies have shown an association between an extended tau haplotype (H1) that covers the entire human tau gene and progressive supranuclear palsy or, more inconsistently, other neurodegenerative disorders, such as corticobasal degeneration, Parkinson disease, Alzheimer disease, and frontotemporal dementia (FTD). In addition, disease-causing mutations in the tau gene on chromosome 17 have been detected in some families with autosomal dominant FTD and parkinsonism. In FTD, the pathological accumulation of the microtubule-associated protein tau suggests that the tau gene may be a genetic risk factor for this disorder. OBJECTIVE: To confirm or refute the association between the H1 haplotype or the H1H1 genotype of the tau gene and FTD. DESIGN: Case-control study. SETTING: Neurology departments of 12 French university hospitals. PARTICIPANTS: One hundred unrelated patients with FTD and 79 controls. METHODS: Tau genotype (contiguous polymorphisms in exons 1, 7, and 13 and in intron 9 used to reconstruct the extended haplotypes H1 and H2). Clinical examination, psychometric testing, laboratory tests, computed tomography and magnetic resonance imaging, single-photon emission computed tomography, and electroencephalography for patients with FTD. RESULTS: The H1H1 genotype was significantly overrepresented in patients with FTD compared with controls (62% vs 46%; P=.01, 1-sided; odds ratio adjusted for age and sex, 1.95). After stratification according to apolipoprotein E (APOE) genotype, we found a significant interaction between APOE and tau genotypes (P=.03). CONCLUSIONS: This study of the largest series of patients with FTD confirms the primary role of tau in FTD and establishes that the H1 haplotype of the tau gene and the E2 allele of APOE interact by an unknown mechanism that increases the risk of FTD.     

Corticobasal degeneration with olivopontocerebellar atrophy and TDP-43 pathology: an unusual clinicopathologic variant of CBD

Corticobasal degeneration (CBD) is a disorder affecting cognition and movement due to a progressive neurodegeneration associated with distinctive neuropathologic features, including abnormal phosphorylated tau protein in neurons and glia in cortex, basal ganglia, diencephalon, and brainstem, as well as ballooned neurons and astrocytic plaques. We identified three cases of CBD with olivopontocerebellar atrophy (CBD-OPCA) that did not have α-synuclein-positive glial cytoplasmic inclusions of multiple system atrophy (MSA). Two patients had clinical features suggestive of progressive supranuclear palsy (PSP), and the third case had cerebellar ataxia thought to be due to idiopathic OPCA. Neuropathologic features of CBD-OPCA are compared to typical CBD, as well as MSA and PSP. CBD-OPCA and MSA had marked neuronal loss in pontine nuclei, inferior olivary nucleus, and Purkinje cell layer. Neuronal loss and grumose degeneration in the cerebellar dentate nucleus were comparable in CBD-OPCA and PSP. Image analysis of tau pathology showed greater infratentorial tau burden, especially in pontine base, in CBD-OPCA compared with typical CBD. In addition, CBD-OPCA had TDP-43 immunoreactive neuronal and glial cytoplasmic inclusions and threads throughout the basal ganglia and in olivopontocerebellar system. CBD-OPCA met neuropathologic research diagnostic criteria for CBD and shared tau biochemical characteristics with typical CBD. These results suggest that CBD-OPCA is a distinct clinicopathologic variant of CBD with olivopontocerebellar TDP-43 pathology.     

Clinical features differentiating patients with postmortem confirmed progressive supranuclear palsy and corticobasal degeneration

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are often clinically confused with each other because they share a rapid disease progression, parkinsonism that responds poorly or transiently to levodopa therapy, and associated signs (e.g., ocular abnormalities, pyramidal signs and cognitive involvement). To improve the accuracy in diagnosing these disorders, this study examined the clinical features of 51 patients pathologically diagnosed with PSP and CBD. Logistic regression analysis identified two sets of predictors (models) for CBD patients, one consisting of asymmetric parkinsonism, cognitive disturbances at onset and instability and falls at first clinic visit, and the other one of asymmetric parkinsonism, cognitive disturbances at symptom onset and speech disturbances. While PSP patients often had severe postural instability at onset, symmetric parkinsonism, vertical supranuclear gaze palsy, speech and frontal lobe-type features, CBD patients presented with lateralized motor (e.g., parkinsonism, dystonia or myoclonus) and cognitive signs (e.g., ideomotor apraxia, aphasia or alien limb). On the other hand, CBD patients presenting with an alternate phenotype characterized by early severe frontal dementia and bilateral parkinsonism were generally misdiagnosed. PSP patients without vertical supranuclear gaze palsy were misdiagnosed. Recognizing the features which differentiate these disorders and the less obvious disease presentations as well as developing an increased index of suspicion will improve the diagnostic accuracy of these disorders.

     

Neuropathologic, biochemical, and molecular characterization of the frontotemporal dementias

The frontotemporal dementias (FTDs) are a heterogeneous group of neurodegenerative disorders that are characterized clinically by dementia, personality changes, language impairment, and occasionally extrapyramidal movement disorders. Historically, the diagnosis and classification of FTDs has been fraught with difficulties, especially with regard to establishing a consensus on the neuropathologic diagnosis. Recently, an international group of scientists participated in a consensus conference to develop such neuropathologic criteria. They recommended a diagnostic classification scheme that incorporated a biochemical analysis of the insoluble tau isoform composition, as well as ubiquitin immunohistochemistry. The use and reliability of this classification system has yet to be examined. In this study, we evaluated 21 cases of FTD. Using traditional histochemical stains and tau protein and ubiquitin immunohistochemistry, we separated each case into one of the following categories: classic Pick disease (PiD; n = 7), corticobasal degeneration (CBD; n = 5), dementia lacking distinctive histopathologic features (DLDH; n = 4), progressive supranuclear palsy (PSP; n = 2), frontotemporal lobar degeneration with motor neuron disease or motor neuron disease-type inclusions (FTLD-MND/MNI; n = 2), and neurofibrillary tangle dementia (NFTD; n = 1). Additionally, we independently categorized each case by the insoluble tau isoform pattern, including 3R (n = 5), 4R (n = 7), 3R/4R (n = 3), and no insoluble tau (n = 6). As suggested by the proposed diagnostic scheme, we found that the insoluble tau isoform patterns correlated strongly with the independently derived histopathologic diagnoses (p < 0.001). The data show that cases containing predominantly 3R tau were classic PiD (100%). Cases with predominantly 4R tau were either CBD (71%) or PSP (29%). Cases with both 3R and 4R tau were either a combination of PiD and Alzheimer disease (67%) or NFTD (33%). Finally, cases with no insoluble tau were either DLDH (67%) or FTLD-MND/MNI (33%). To further characterize these cases, we also performed quantitative Western blots for soluble tau, APOE genotyping, and, in selected cases, tau gene sequencing. We show that soluble tau is reduced in DLDH and FTLD-MND/MNI and that APOE4 is overrepresented in PiD and DLDH. We also identified a new family with the R406W mutation and pathology consistent with NFTD. This study validates the recently proposed diagnostic criteria and forms a framework for further refinement of this classification scheme.     

Apolipoprotein epsilon4 advances appearance of psychosis in patients with Parkinson's disease

BACKGROUND: Psychosis is one of the most serious complications of advanced parkinsonism, but many patients are spared. The genetic factors predisposing to psychosis are unclear. OBJECTIVES: To assess the association between apolipoprotein E (APOE) polymorphism and the development of psychosis in patients with Parkinson's disease (PD). METHODS: Eighty-seven patients with advanced PD were assessed. Psychosis was diagnosed in 50 patients who manifested paranoid delusions, hallucinations without insight, or disorders of perception. Time of onset of psychosis was retrieved from the medical records and caregivers' recall. APOE genotype was determined by restriction enzyme digests of amplified alleles. Cox models of logistic regression and Kaplan-Meier survival curves were used to assess factors determining early development of psychosis. RESULTS: APOE epsilon3/epsilon4 allele was carried by 20 patients (14 with psychosis), epsilon2/epsilon3 by 11 patients (10 with psychosis), epsilon3/epsilon3 by 55 patients (25 with psychosis) and epsilon2/epsilon4 by one patient who had psychosis. The mean age of onset of PD symptoms was 60.0 +/- 12.5 years. The mean duration of motor symptoms at the onset of psychosis was 7.3 +/- 4.3 years for the 15 patients harboring an APOE epsilon4 allele and 10.1 +/- 6.2 years among those who did not carry APOE epsilon4 (n = 35). The APOE epsilon4 allele was significantly associated with earlier onset of psychosis (P < 0.05) when the age of onset of motor symptoms and presence of dementia were included in the Cox regression model. Carrying the APOE epsilon4 allele was a significant risk factor for earlier appearance of psychosis with a hazard ratio of 3.24 (95% CI 1.62-6.46) while dementia by itself did not increase the risk. CONCLUSION: Parkinson's disease patients who carry the APOE epsilon4 allele develop psychosis earlier.     

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.     

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.     

Analysis of tau haplotypes in Pick's disease

Pick's disease (PiD) is characterized by the deposition of tau protein as three-repeat tau Pick bodies, whereas progressive supranuclear palsy (PSP) involves the deposition of four-repeat tau neurofibrillary tangles. PSP is associated with the tau H1 haplotype. The authors investigated a possible association between PiD and the tau H1 or H2 haplotype. There was no difference between the tau H2 haplotype or H2H2 genotype frequency in PiD cases and control subjects. No tau mutations were identified in pathologically typical cases of PiD, with antibody 12-E8-negative Pick bodies.     

具有帕金森样症状患者相关疾病探讨

目的探讨具有帕金森样症状(PLS)患者的相关疾病。方法收集我院近3年来因PLS而住院的78例患者的临床资料(病史、临床表现和辅助检查结果),按中华医学会神经病学分会运动障碍及帕金森病学组制定的诊断标准确定诊断。结果本组78例患者,出院诊断分别为:帕金森病(PD)36例,继发性帕金森综合征(PS)26例(血管性16例、脑外伤后3例、CO中毒后3例、脑炎后2例,杀虫剂中毒后2例),多系统萎缩(MSA)4例,进行性核上性麻痹(PSP)4例,路易体痴呆(DLB)2例,肝豆状核变性(WD)2例,特发性震颤(ET)2例,基底节钙化症(BGC)1例,皮质基底节变性(CBD)1例。结论具备PLS的疾病谱很广,其中PD大约占60%,另有30～40%的非PD患者具有类似表现,称为非典型帕金森综合征(AP),如多系统萎缩(MSA)、进行性核上性麻痹(PSP)、Wilson病(WD)、路易体痴呆(DLB),基底节钙化症(BGC)、皮质基底节变性(CBD)等,容易误诊,应注意鉴别。     

Pathological heterogeneity in progressive supranuclear palsy and corticobasal degeneration

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are sporadic neurodegenerative disorders of late adult life. Focal asymmetric cortical atrophy with ballooned neurons, nigral degeneration, and tau‐positive neuronal and glial lesions in both the gray and white matter, especially astrocytic plaques in the affected cerebral cortex, are characteristic features of CBD. While cortical involvement may occur in PSP, ballooned neurons are sparse and limited to the limbic system, and tufted astrocytes are abundant in the precentral gyrus and striatum. The present findings suggest that PSP and CBD are distinct pathological entities. However, there exist ‘atypical’ cases of PSP and CBD. Severe cortical involvement or asymmetric cortical atrophy can be seen in PSP. Ballooned neurons are sparse or difficult to detect in some cases of CBD, in spite of typical cortical tau pathology. Cortical symptoms are absent or only mild in ‘minimal change’ CBD. Moreover, several neurodegenerative disorders can underlie CBD. This pathological heterogeneity leads to difficulty in the clinical and pathological diagnosis of both disorders.