Distinct phosphorylation profiles of tau in brains of patients with different tauopathies.

Tauopathies are neurodegenerative diseases that are characterized by pathological accumulation of tau protein. Tau is hyperphosphorylated in the brain of tauopathy patients, and this phosphorylation is proposed to play a role in disease development. However, it has been unclear whether phosphorylation is different among different tauopathies. Here, we investigated the phosphorylation states of tau in several tauopathies, including corticobasal degeneration, Pick's disease, progressive supranuclear palsy (PSP), argyrophilic grain dementia (AGD) and Alzheimer's disease (AD). Analysis of tau phosphorylation profiles using Phos-tag SDS-PAGE revealed distinct phosphorylation of tau in different tauopathies, whereas similar phosphorylation patterns were found within the same tauopathy. For PSP, we found 2 distinct phosphorylation patterns suggesting that PSP may consist of 2 different related diseases. Immunoblotting with anti-phospho-specific antibodies showed different site-specific phosphorylation in the temporal lobes of patients with different tauopathies. AD brains showed increased phosphorylation at Ser202, Thr231 and Ser235, Pick's disease brains showed increased phospho-Ser202, and AGD brains showed increased phospho-Ser396. The cis conformation of the peptide bond between phospho-Thr231 and Pro232 (cis ptau) was increased in AD and AGD. These results indicate that while tau is differently phosphorylated in tauopathies, a similar pathological mechanism may occur in AGD and AD patients. The present data provide useful information regarding tau pathology and diagnosis of tauopathies.

A single ultrasensitive assay for detection and discrimination of tau aggregates of Alzheimer and Pick diseases.

Multiple neurodegenerative diseases are characterized by aggregation of tau molecules. Adult humans express six isoforms of tau that contain either 3 or 4 microtubule binding repeats (3R or 4R tau). Different diseases involve preferential aggregation of 3R (e.g Pick disease), 4R (e.g. progressive supranuclear palsy), or both 3R and 4R tau molecules [e.g. Alzheimer disease and chronic traumatic encephalopathy]. Three ultrasensitive cell-free seed amplification assays [called tau real-time quaking induced conversion (tau RT-QuIC) assays] have been developed that preferentially detect 3R, 4R, or 3R/4R tau aggregates in biospecimens. In these reactions, low-fg amounts of a given self-propagating protein aggregate (the seed) are incubated with a vast excess of recombinant tau monomers (the substrate) in multi-well plates. Over time, the seeds incorporate the substrate to grow into amyloids that can then be detected using thioflavin T fluorescence. Here we describe a tau RT-QuIC assay (K12 RT-QuIC) that, using a C-terminally extended recombinant 3R tau substrate (K12CFh), enables sensitive detection of Pick disease, Alzheimer disease, and chronic traumatic encephalopathy seeds in brain homogenates. The discrimination of Pick disease from Alzheimer disease and chronic traumatic encephalopathy cases is then achieved through the quantitative differences in K12 RT-QuIC assay thioflavin T responses, which correlate with structural properties of the reaction products. In particular, Fourier transform infrared spectroscopy analysis of the respective K12CFh amyloids showed distinct ß-sheet conformations, suggesting at least partial propagation of the original seed conformations in vitro. Thus, K12 RT-QuIC provides a single assay for ultrasensitive detection and discrimination of tau aggregates comprised mainly of 3R, or both 3R and 4R, tau isoforms.

An Autopsy Case of Preclinical/Early Clinical Pick Disease.

Here, we report a 74-year-old woman with a long history of schizophrenia but no clinical manifestation of dementia. Cause of death after autopsy was atherosclerotic heart disease. Although neuropathological investigation showed no significant brain atrophy, superficial microvacuolation with neuronal loss was restrictedly detected in the right anterior cingulate gyrus by microscopic examination. Pick bodies (PBs) positive for Bodian and Bielshowsky staining and 3-repeat-tau were detected in frontal and temporal lobes and limbic regions. Prevalence of PBs was most frequent in the right anterior cingulate gyrus and lateral base, followed by other neocortical regions of the frontal lobe, amygdala, and granular layer of the hippocampus. Although the number of glial inclusions was low, ramified astrocytes and various forms of astrocytes with AT8-positive inclusions were also found. Thus, the case may reflect preclinical or very early clinical Pick disease. Distribution of PBs does not necessarily have to be consistent with previously reported preclinical/early clinical Pick disease. These results show that tau pathology in the earlier stage of Pick disease may be heterogeneous, and the anterior cingulate gyrus may be initially affected in Pick disease. Neuropathological examination, including immunohistochemistry without case selection, is useful in identifying clinical and pathological manifestations of Pick disease.

Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are nowadays recognized as spectrum disorders with a molecular link, the TAR DNA-binding protein 43 (TDP-43), rendering it a surrogate biomarker for these disorders. METHODS: We measured cerebrospinal fluid (CSF) levels of TDP-43, beta-amyloid peptide with 42 amino acids (Aß42), total tau protein (τT), and tau protein phosphorylated at threonine 181 (τP-181) in 32 patients with ALS, 51 patients with FTD, and 17 healthy controls. Double-sandwich commercial enzyme-linked immunosorbent assays were used for measurements. RESULTS: Both ALS and FTD patients presented with higher TDP-43 and τT levels compared to the control group. The combination of biomarkers in the form of the TDP-43 × τT / τP-181 formula achieved the best discrimination between ALS or FTD and controls, with sensitivities and specificities >0.8. CONCLUSION: Combined analysis of TDP-43, τT, and τP-181 in CSF may be useful for the antemortem diagnosis of ALS and FTD.

Ultrasensitive and selective detection of 3-repeat tau seeding activity in Pick disease brain and cerebrospinal fluid.

The diagnosis and treatment of diseases involving tau-based pathology such as Alzheimer disease and certain frontotemporal dementias is hampered by the inability to detect pathological forms of tau with sufficient sensitivity, specificity and practicality. In these neurodegenerative diseases, tau accumulates in self-seeding filaments. For example, Pick disease (PiD) is associated with frontotemporal degeneration and accumulation of 3-repeat (3R) tau isoforms in filaments constituting Pick bodies. Exploiting the self-seeding activity of tau deposits, and using a 3R tau fragment as a substrate, we have developed an assay (tau RT-QuIC) that can detect tau seeds in 2 µl aliquots of PiD brain dilutions down to 10-7-10-9. PiD seeding activities were 100-fold higher in frontal and temporal lobes compared to cerebellar cortex. Strikingly, this test was 103- to 105-fold less responsive when seeded with brain containing predominant 4-repeat (4R) tau aggregates from cases of corticobasal degeneration, argyrophilic grain disease, and progressive supranuclear palsy. Alzheimer disease brain, with 3R + 4R tau deposits, also gave much weaker responses than PiD brain. When applied to cerebrospinal fluid samples (5 µl), tau RT-QuIC analyses discriminated PiD from non-PiD cases. These findings demonstrate that abnormal tau aggregates can be detected with high sensitivity and disease-specificity in crude tissue and fluid samples. Accordingly, this tau RT-QuIC assay exemplifies a new approach to diagnosing tauopathies and monitoring therapeutic trials using aggregated tau itself as a biomarker.

Squaring the round: An unusual progressive graphomotor impairment with post-mortem findings.

Investigations of neurodegenerative disorders may reveal functional relationships in the cognitive system. C.S. was a 63-year-old right-handed man with post-mortem confirmed Pick's disease with a range of progressive impairments including non-fluent aphasia, speech, limb, oculomotor, and buccofacial apraxia, but mostly intact intelligence, perception, orientation, memory, semantics, and phonology. During progression, agrammatism in writing with impairments in syntactic comprehension emerged in parallel with an unusual graphomotor deficit in drawing and writing, with an increasing deterioration of graphic short-term memory. We investigated C.S.'s graphomotor deficit longitudinally using tests of writing and drawing on letters, words, and sentences and drawing to command and copying. We also tested C.S.'s short-term graphemic buffer experimentally. Analysis showed deficits on selective aspects of graphomotor implementation of writing and drawing, mainly affecting the production of circles and curves, but not short straight lines in drawing and writing, and graphomotor short-term memory, which paralleled impairments of written syntax and syntactic comprehension. We believe this to be the first detailed analysis of such an unusual progressive impairment in graphomotor production, which may be related to problems with agrammatic agraphia and impairments affecting shared components of cognition reflecting damage to shared neural networks. Alternatively, they may simply reflect the effects of coincidental damage to separate mechanisms responsible for aspects of writing, drawing, and syntactic processing. Longitudinal investigations of emerging deficits in progressive conditions like C.S.'s provides an opportunity to examine the progressive emergence of symptoms in an individual with multiple progressive impairments as they appear and examine putative relationships between them.

Behavioral variant of frontotemporal dementia: Fundamental clinical issues associated with prediction of pathological bases.

Behavioral variant of frontotemporal dementia (bvFTD) is a clinical syndrome characterized mainly by behavioral symptoms due to frontal dysfunction. Major neurodegenerative bases of bvFTD include Pick's disease, frontotemporal lobar degeneration with trans-activation response DNA protein 43-positive inclusions, corticobasal degeneration, and progressive supranuclear palsy. Early disinhibition characterized by socially inappropriate behaviors, loss of manners, and impulsive, rash and careless actions is the most important clinical feature of bvFTD. On the other hand, it was reported that clinical presentations of some Alzheimer's disease cases and patients with psychiatric disorders (e.g., addictive disorders, gambling disorder and kleptomania) often resemble that of bvFTD. Although clinical differentiation of 'true' bvFTD cases with frontotemporal lobar degeneration (FTLD) pathology from mimicking cases without it is not always easy, evaluation of the following features, which were noted in autopsy-confirmed FTLD cases and/or clinical bvFTD cases with circumscribed lobar atrophy, may often provide clues for the diagnosis. (i) The initial symptoms frequently develop at 65 years or younger, and (ii) 'socially inappropriate behaviors' can be frequently interpreted as contextually inappropriate behaviors prompted by environmental visual and auditory stimuli. Taking a detailed history usually reveals various kinds of such behaviors in various situations in everyday life rather than the repetition of a single kind of behavior (e.g., repeated shoplifting). (iii) A correlation between the distribution of cerebral atrophy and neurological and behavioral symptoms is usually observed, and the proportion of FTLD cases with right side-predominant cerebral atrophy may be higher in a psychiatric setting than a neurological setting. Finally, (iv) whether the previous course and the combination of symptoms observed at the first medical visit can be explained by major evolution patterns of clinical syndromes in pathologically confirmed FTLD cases should be considered. These views may provide clues to differentiate FTLD from Alzheimer's disease and to predict a subsequent clinical course and therapeutic interventions needed in the future.

Tauopathies as clinicopathological entities.

Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial inclusions composed of the microtubule-binding protein, tau. Several lines of evidence suggest tau aggregation is central to the neurodegenerative process in tauopathies. First, recent animal and cell model studies find abnormally-modified tau alone may be transmitted between adjacent neurons and spread to anatomically connected brain regions to recapitulate human disease. Further, staging efforts in human autopsy cases suggest a sequential distribution of tau aggregation in the central nervous system that could reflect this observed cell-to-cell transmission of pathogenic tau species in animal models. Finally, pathogenic mutations in the MAPT gene encoding tau protein cause hereditary forms of tauopathy. Clinically, tauopathies can present with a range of phenotypes that include both movement- and cognitive/behavioral-disorders (i.e. frontotemporal dementia spectrum disorders) or non-specific amnestic symptoms in advanced age. A major limitation is that current clinical diagnostic criteria for these disorders do not reliably differentiate underlying tauopathy from other neurodegenerative diseases, such as TDP-43 proteinopathies. Thus, current research efforts are focused on improving the ante mortem diagnosis of tauopathies, including pre-clinical stages of disease, as many therapeutic strategies for emerging disease-modifying therapies focus on preventing abnormal folding and spread of tau pathology.

The Tree-Drawing Test (Koch's Baum Test): A Useful Aid to Diagnose Cognitive Impairment.

OBJECTIVE: To study the Tree-Drawing Test in a group of demented patients and compare it with a group of mild cognitively impaired patients (MCI) and controls. METHODS: Consecutive outpatients were classified as affected by dementia (Alzheimer's disease (AD), frontotemporal dementia (FTD), and vascular dementia (VD)) or by MCI. Patients and controls underwent the Tree-Drawing Test and MMSE. RESULTS: 118 AD, 19 FTD, 46 VD, and 132 MCI patients and 90 controls were enrolled. AD patients draw trees globally smaller than other patients and controls. FTD patients draw trees with a wider space occupation than AD and MCI patients but smaller than controls as well as VD patients. Trees drawn by MCI patients are intermediate in size between AD patients and controls. The trunk-to-crown ratio of trees drawn by cognitive impaired patients is greater than controls while the tree size-relative-to-page space index is significantly smaller. The tree size-relative-to-page space index of trees drawn by AD patients is smaller than that of the other cognitively impaired patients. Tree height and the trunk-to-crown ratio are independent predictors of cognitive impairment. CONCLUSIONS: Trees drawn by cognitively impaired patients are different from those drawn by healthy subjects with a progressive differentiation from mild to more relevant degrees of cognitive impairment.

Clinical Subtypes of Frontotemporal Dementia.

Frontotemporal dementia (FTD) was one of the lesser known dementias until the recent advancements revealing its genetic and pathological foundation. This common neurodegenerative disorder has three clinical subtypes- behavioral, semantic and progressive non fluent aphasia. The behavioral variant mostly exhibits personality changes, while the other two encompass various language deficits. This review discusses the basic pathology, genetics, clinical and histological presentation and the diagnosis of the 3 subtypes. It also deliberates the different therapeutic modalities currently available for frontotemporal dementia and the challenges faced by the caregivers. Lastly it explores the scope of further research into the diagnosis and management of FTD.

Pick and Alzheimer diseases: a rare comorbidity presenting as corticobasal syndrome.

We describe a patient with corticobasal syndrome in whom neuropathological examination on autopsy revealed Pick and Alzheimer diseases in comorbidity. Corticobasal degeneration is a tauopathy usually associated with asymmetric parkinsonism, parietal lobe involvement, and cognitive impairment. Corticobasal syndrome is the clinical presentation of corticobasal degeneration without neuropathological confirmation. A 66-year-old right-handed man slowly developed speech difficulties, right-hand clumsiness, and forgetfulness. His speech apraxia progressed to mutism with preserved comprehension, and his clumsiness progressed to severe apraxia involving both hands. He developed behavioral changes and severe amnesia. All of these features were consistent with corticobasal syndrome. His loss of episodic, verbal, and visuospatial memory suggested Alzheimer disease; however, beyond his frontotemporal neuropsychological profile, he had few symptoms characteristic of frontal lobe dementia. Magnetic resonance imaging scans showed worsening temporal, frontal, and parietal atrophy, predominant in the left hemisphere. Neuropathological examination at autopsy revealed abundant neuritic plaques and neurofibrillary tangles consistent with fully developed Alzheimer disease, as well as numerous intraneuronal Pick bodies in the frontotemporal lobes. Our findings confirm the importance of clinical and neuropathological correlations in patients with atypical neurodegenerative dementias.

[Frontotemporal dementias]. / Frontotemporale Demenzen.

Frontotemporal dementias (FTD) account for only 5-7% of all dementia aetiologies. However, FTD is one common form of dementia in the presenile period with a symptom onset between an age of 45 and 65 years. FTD are clinically classified into a group of rare genetic variants, the behavioural variant, primary progressive aphasias and a variant including motor neuron symptoms (FTD-MNS). In recent years the pathobiological characteristics of some FTD variants was clarified, demonstrating a pathological accumulation of TAR-DNA binding protein 43 (TDP-43) as a common pathological substrate. The revised diagnostic criteria of the behavioural variant of the FTD require at least three of six clinically discriminating features (disinhibition, apathy, loss of sympathy, perseverative behaviours, hyperorality and dysexecutive neuropsychological profile). The primary progressive aphasias are classified in a nonfluent/agrammatic variant, a logopenic variant and a semantic variant according to clinical and imaging features. Movement disorders and more precisely a Parkinsonian syndrome can be part of the FTD spectrum. Some clinical features overlap the clinical diagnosis of a progressive supranuclear paralysis and the corticobasal ganglionic degeneration. A causal therapy does not exist and medical treatment is directed at the patient's key symptoms. Different agents such as serotonin reuptake inhibitors, tricyclic antidepressants, atypical neuroleptics, carbamazepine, valproate, lamotrigine and when indicated also acetylcholinesterase inhibitors are potentially helpful. All together, theses medical treatments have a low level of evidence. Non-pharmacological therapies such as physiotherapy, occupational therapy, speech therapy and disease-specific education of the patient and their relatives are important to ensure a safe residential environment and daily routine.

'Limits and current knowledge of Pick's disease: its differential diagnosis'. A translation of the 1957 Delay, Brion, Escourolle article.

This article is a translation of a French article by Delay, Brion, and Escourolle. In a seminal article published in French in 1957 these authors summarized the work of previous researchers and reviewed a wide sample of frontotemporal dementia (FTD) cases formerly referred to as Pick's disease. The authors were among the first to define the critical clinical and anatomical differences between Alzheimer's disease (AD) and FTD and they even delineated distinctive FTD subtypes making possible the advances that now constitute the base of our studies. Reviewing their work allows us to appreciate the progress research has made.

Pick's disease.

Picks disease is a major clinicopathological disease having circumscribed atrophy in the frontotemporal lobe. Demented patients with frontotemporal atrophy are now clinically diagnosed as frontotemporal lobar degeneration (FTLD). Other underlying pathologies in patients with FTLD include FTLD with TDP-43-positive inclusions, corticobasal degeneration, progressive supranuclear palsy, basophilic inclusion body disease, neuronal intermediate filament inclusion disease and argyrophilic grain disease. In this chapter, recent findings regarding the distinct clinical and histopathological features of these pathological disease entities are presented including the discussion on the possibility of future antemortem diagnosis of patients with the disease.In this chapter, recent findings regarding the distinct clinical and histopathological features of these pathological disease entities are presented including the discussion on the possibility of future antemortem diagnosis of patients with the disease.

[From Pick's disease to frontotemporal dementia]. / De la maladie de Pick aux démences fronto-temporales.

Frontotemporal dementias (FTD) are defined by a gradual change in social conduct, behavior and language, associated with frontal and anterior temporal lobe degeneration. The clinicalfeatures depend on the location of the degenerative process. In the last 20 years, increasingly specific and sensitive operational criteria have been established. Ongoing neuropathological and genetic studies have highlighted overlaps between FTD, motor neuron disease, and atypical parkinsonian syndromes (supranuclear palsy, corticobasal degeneration). They have also provided a better knowledge of the pathophysiology of FTD, and new specific therapeutic targets. These dementias, which usually occur before the age of 65 years, are now better recognized but are still underdiagnosed and often initially mistaken for psychiatric illnesses. Healthcare professionals managing these patients must therefore be better informed Serotonergic agents provide a symptomatic improvement, but environmental adaptation, prevention of language and swallowing difficulties, and information and support for the family and caregivers remain essential.

[Primary progressive apraxia].

Similar to primary progressive aphasia, primary progressive apraxia has been considered to cause slowly progressive apraxia without dementia and to be a dependent disease. Of the 3 cases reported by De Renzi in 1986, 1 case showed slowly progressive apraxia without dementia. Since then, cases of primary progressive apraxia have been reported occasionally. Studies on primary progressive apraxia indicate that not only focal lesions caused by vascular disease or brain trauma but also lesions caused by neurodegenerative disease can cause apraxia alone, thereby supporting the hypothesis that apraxia-associated neurodegeneration may develop in cases of primary progressive apraxia. The pathogenesis of primary progressive apraxia is yet to be elucidated. Clinical features of primary progressive apraxia are not precisely distinguishable from those of corticobasal degeneration (CBD); further, previous studies have indicated that the brain pathology observed in primary progressive apraxia is consistent with that in Alzheimer disease (AD) or Pick disease. "Primary" progressive apraxia may be intrinsically different from slowly progressive apraxia that is associated with CBD, AD, or Pick disease and may show specific pathological findings. On the other hand, primary progressive apraxia may not be a dependent disease but a syndrome characterized by prolonged neurodegeneration that is observed in various degenetive dementias such as CBD, AD, or Pick disease.

Clinical phenotypes in autopsy-confirmed Pick disease.

BACKGROUND: Neuropathology of frontotemporal lobar degeneration is variable and relationship between the pathology and the clinical presentation remains uncertain. Abnormal deposits of hyperphosphorylated and ubiquitinated tau protein are present in 30% of cases, which include the classic presentation of Pick disease with argyrophilic, intraneuronal inclusions known as Pick bodies. This study aimed to improve sensitivity of clinicopathologic relations in cases with neuropathologically confirmed Pick disease and to identify clinical symptoms and signs predictive of disease progression. METHODS: This was a retrospective analysis of 21 cases with a pathologic diagnosis of Pick disease and sufficient clinical information to establish early presenting clinical features from 2 specialist centers, representing 70% of all cases of Pick disease identified between 1998 and 2007 in these centers. RESULTS: At presentation, 13/21 cases (62%) were clinically diagnosed with behavioral variant frontotemporal dementia (bvFTD) and 8/21 (38%) with language variant frontotemporal dementia (lvFTD) including 2 with mixed syndromes. Patients with bvFTD died on average 5 years earlier than those with lvFTD (7 years vs 12 years after disease onset). Pathologically, fewer Pick bodies were present in the frontal and inferior temporal cortices of bvFTD than lvFTD cases. In contrast, both groups showed decreased neuronal density in the dentate gyrus with increasing disease duration. CONCLUSIONS: The pathologic course of the disease in FTLD cases with Pick bodies is not uniform and disease duration can be estimated based on early clinical features. These findings have relevance as treatment options, which are likely to be pathology specific, are developed.

Early noninvasive diagnosis of neurodegenerative diseases.

This paper reviews the contemporary trends in the pathobiochemistry of neurodegenerative disorders with respect to their early predictive diagnosis and possible treatment interventions. If we consider the current epidemiological data related to neurodegenerative disorders, medicine is going to face in the near future latent pandemic situations. The introduction puts an emphasis on the emerging importance of one major cluster of neurodegenerative disorders: diseases of the abnormal protein beta-conformation. The cluster includes such significant diseases as Alzheimer, Pick, Huntington, Parkinson disease, as well as the transmissible spongiform encephalopathies (Creuzfeldt-Jakob disease). The pathogenetic mechanisms in the determination of this group of disorders are explored with an emphasis on the impairment of post-synthetic chaperone correction. The central role of a number of such protein products is discussed. In particular the pathobiochemical mechanisms concerning the formation of beta-amyloid, alpha and beta synucleins, scrapie isoform of the prion protein are presented. A new diagnostic principle allowing the early and specific diagnosis of the conformation diseases protein via amplification techniques is presented. These methods compete in sensitivity with the PCR methods and shows promises for effective treatment. In conclusion, beta-pathies are considered a suitable example for the modern concept of cluster and prototype diagnosis in medicine and especially in clinical neurosciences.