Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy.

Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer's disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and divergent trajectories. To study the divergent physiological properties of tau variants on a uniform immunogenetic background, we created somatic transgenesis CNS models of tauopathy utilizing neonatal delivery of adeno-associated viruses expressing wild-type (WT) or mutant tau in non-transgenic mice. We selected four different tau variants-WT tau associated with AD, P301L mutant tau associated with frontotemporal dementia (FTD), S320F mutant tau associated with Pick's disease and a combinatorial approach using P301L/S320F mutant tau. CNS-targeted expression of WT and P301L mutant tau results in robust tau hyperphosphorylation without tangle pathology, gradually developing age-progressive memory deficits. In contrast, the S320F variant, especially in combination with P301L, produces an AD-type tangle pathology, focal neuroinflammation and memory impairment on an accelerated time scale. Using the doubly mutated P301L/S320F tau variant, we demonstrate that combining different mutations can have an additive effect on neuropathologies and associated co-morbidities, possibly hinting at involvement of unique functional pathways. Importantly, we also show that overexpression of wild-type tau as well as an FTD-associated tau variant can lead to cognitive deficits even in the absence of tangles. Together, our data highlights the synergistic neuropathologies and associated cognitive and synaptic alterations of the combinatorial tau variant leading to a robust model of tauopathy.

Clinical features of the behavioural variant of frontotemporal dementia that are useful for predicting underlying pathological subtypes of frontotemporal lobar degeneration.

BACKGROUND: The behavioural variant of frontotemporal dementia (bvFTD) is the most common phenotype of frontotemporal lobar degeneration (FTLD). FTLD is divided into three main pathological subtypes: tau-positive FTLD (FTLD-tau), FTLD-TAR DNA-binding protein (TDP), and FTLD-Fused in sarcoma (FUS). At present, it is difficult to predict the underlying pathological subtypes of sporadic bvFTD before a patient's death. METHODS: We retrospectively investigated the clinical features of 34 Japanese patients with sporadic bvFTD, with or without motor neuron disease (MND), who had been pathologically diagnosed with FTLD. We examined whether, and how, the clinical features differed among Pick's disease, FTLD-TDP, and FTLD-FUS patients. RESULTS: Six of the 34 patients developed MND during the course of bvFTD. These six bvFTD-MND patients were all pathologically diagnosed with FTLD-TDP. The other 28 patients were composed of 12 FTLD-tau patients including 11 Pick's disease patients, 8 FTLD-TDP patients, and 8 FTLD-FUS patients. A comparison of the clinical features of the three pathological subtypes of the 33 patients demonstrated that the age at onset was significantly younger in FTLD-FUS patients than in Pick's disease or FTLD-TDP patients. Furthermore, while hyperorality and dietary changes in the early stage of the disease were present in approximately 40% of Pick's disease and FTLD-FUS patients, they were absent in FTLD-TDP patients. CONCLUSION: The comorbidity of MND, a younger age at onset, and hyperorality and dietary changes in the early stage may be useful clinical features for predicting underlying pathological subtypes of sporadic bvFTD. The results of our study should be confirmed by prospective studies employing a larger number of cases.

Clinicopathological correlations in behavioural variant frontotemporal dementia.

Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.

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.

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.

[From Arnold Pick's original descriptions to frontotemporal dementia: the present enlightened by the past an historical approach]. / Des observations originales d'Arnold Pick à la démence frontotemporale : regard sur le présent à partir du passé Un aperçu historique.

Since its seminal characterization, Pick's disease (PiD), was marked by a double ambiguity. Sometimes, with reference to original Pick's descriptions, PiD was macroscopically defined by a circumscribed frontotemporal cerebral atrophy, independently of its causes. Sometimes, on the other hand, it was histologically characterized by absence of Alzheimer pathology and considered as a special form of degenerative process. However, this special degenerative process was defined either by the particular topography of neuronal loss or by specific histological changes, which were described by Alzheimer. Therefore, individualization of PiD and its relationships with Alzheimer's disease have long been controversial, particularly in the United States, despite the clarification provided by French authors in the 1960s, Swiss authors in the 1970s and Swedish and English authors in the 1980s. The term of Frontotemporal dementia (FTD) was choosed by the last authors in 1994 to avoid the debates on the definition of PiD, and to characterize a particular degenerative process without Alzheimer pathology or other diseases. However, the definition and nature of FTD currently remain ambiguous because the term FTD is applied either to clinical syndromes with different presentations according to predominant frontal or temporal atrophy, and regardless of histologic pathology, or to a particular degenerative process, hereditary or sporadic. Notwithstanding neuropathologic and genetic advances in the last decades, significant challenges remain for FTD therapeutic research as a result of the degenerative processes complexity and lack of parallelism between clinical, neuropathological, and genetic data.

The unique experience of spouses in early-onset dementia.

To date, few studies have examined the experience of spouse caregivers living with a person with early-onset dementia. Moreover, few support resources are offered to these family caregivers and fewer are still tailored to their unique trajectory. The aim of this qualitative study was to document the lived experience of spouse caregivers of young patients in order to inform the development of professional support tailored to their reality. A sample of 12 spouses of persons diagnosed with dementia before the age of 65 participated in semistructured interviews. Six themes emerged from their caregiver trajectories, namely, difficulty managing behavioral and psychological symptoms, long quest for diagnosis, nondisclosure to others and denial of diagnosis, grief for loss of spouse and midlife projects, difficulty juggling unexpected role and daily life responsibilities, and difficulty planning for future. Results open up innovative avenues for the development of interventions geared to facilitating role transition for these spouse caregivers.

Primary progressive apraxia of speech (AOS) in a patient with Pick's disease with Pick bodies: a neuropsychological and anatomical study and review of literatures.

A 56-year-old right-handed man suffered from progressive apraxia of speech (AOS), characterized by agrammatism and buccofacial apraxia. He also became mute at the later stages of the disease progression. At autopsy, the left precentral gyrus, pars opercularis, and hippocampus showed severe atrophy. Pick bodies and Pick cells were observed. In this report, we also review previous case reports of AOS. Pick's disease is among the most commonly associated of the major diseases. Brain lesions associated with AOS may be found in regions such as the precentral gyrus and the pars opercularis in the left hemisphere.

[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.

[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.

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.

The overlapping syndromes of the pick complex.

A significant expansion of knowledge in the last few years, especially in the molecular biology of frontotemporal dementia (FTD) is summarized. This condition, formerly known as Pick's disease and considered rare, is estimated to be 12-15% of all dementias and 30-50% early onset ones. The clinical picture is protean, mainly a behavioural and language impairment, but the extrapyramidal syndromes of CBD and PSP are often seen and conversely FTD and progressive aphasia often has motor symptoms, including ALS. These seemingly different presentations converge, as one or other areas in the brain are affected. Our experience with FTD in a clinical cohort, with high rate of autopsy confirmation is presented. Less than half of the cases are tauopathies, the majority has been discovered to have a TDP-43 and most recently a FUS proteinopathy, shared with ALS, opening potential opportunities for pharmacological approaches to treatment. Tau and progranulin mutations on Ch-17 and some others, point to molecular mechanisms. A glossary is provided to navigate the complex terminology.

"Fantastic thinking" in pathologically proven Pick disease.

BACKGROUND: Reports of false beliefs may be a unique feature of behavioral variant frontotemporal dementia (bvFTD) but the nature of these experiences is unclear. OBJECTIVE: To report a case of pathologically verified Pick disease in a patient presenting with prominent and recurrent fantasies. METHODS: We describe the clinical, neuroradiologic, and neuropathologic findings of a 53-year-old woman presenting with fantasies and meeting Clinical Consensus Criteria for bvFTD. RESULTS: Early in her course, she reported interactions with different actors, having torrid affairs with them, and other related fantasies. When confronted with her false beliefs, she admitted that these relationships were imaginary. Autopsy revealed Pick disease with tau-immunoreactive Pick bodies in the frontal and temporal cortices, and in the hippocampi. CONCLUSIONS: Fantastic thinking, or vividly experienced imagination, may be a manifestation of bvFTD that is distinct from delusions and confabulations and could be the source of previously reported delusions and confabulations in bvFTD.

Association between a genetic variant of the alpha-7 nicotinic acetylcholine receptor subunit and four types of dementia.

We tested the hypothesis whether the partially duplicated variant of alpha7 nicotinic acetylcholine receptor subunit gene (CHRFAM7A) 2-bp deletion (-2 bp) polymorphism and apolipoprotein E (ApoE) epsilon4 allele confer susceptibility to Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Pick's disease (PiD) and vascular dementia (VD). The study included 175 AD, 35 DLB patients, 38 PiD, 96 VD and 175 healthy control (HC) probands. The CHRFAM7A genotype without the -2 bp allele was significantly over-represented in AD (p = 0.011), DLB (p = 0.001) and PiD (p < 0.0001) compared to HC, but there were no statistical differences in VD (p = 0.407) compared to HC. We confirmed again that the ApoE epsilon4 allele is a risk factor for dementias. The -2 bp polymorphism of CHRFAM7A can be implicated in AD, DLB and PiD. However, it is unlikely that it plays an important role in the pathogenesis of VD.

[Semantic dementia. A case report in the context of an independent medical examination]. / Semantische Demenz. Ein kasuistischer Beitrag zur Differenzialdiagnostik der degenerativen Demenzen.

Semantic dementia (SD) is a relatively rare primary degenerative brain disease, often with onset before the age of 65, which belongs to the group of frontotemporal lobar degenerations. The central characteristic of SD is a progressive loss of semantic knowledge with manifestation in aphasia as well as impaired face and object recognition. A reliable discrimination of SD from other neurodegenerative conditions, in particular from Alzheimer's disease, may be a challenge for neurologists as well as neuropsychologists. In the first place, a sound knowledge base is expected from the expert in order to minimize false diagnoses. To illustrate this, a detailed case history of a 55-year old patient is presented who was referred for an independent medical and neuropsychological examination for disability benefits. The referral question was Pick's disease. However, the clinical manifestation as well as the results of a comprehensive neuropsychological evaluation clearly indicated the diagnosis of SD with neuroimaging and neuropsychological evidence of marked right temporal lobe atrophy. The case history highlights a number of problems inherent in current practice of dementia assessment. For differential diagnosis of dementing conditions, a thorough neuropsychological assessment appears to be indispensable.

"What" and "where" in word reading: ventral coding of written words revealed by parietal atrophy.

The visual system of literate adults develops a remarkable perceptual expertise for printed words. To delineate the aspects of this competence intrinsic to the occipitotemporal "what" pathway, we studied a patient with bilateral lesions of the occipitoparietal "where" pathway. Depending on critical geometric features of the display (rotation angle, letter spacing, mirror reversal, etc.), she switched from a good performance, when her intact ventral pathway was sufficient to encode words, to severely impaired reading, when her parietal lesions prevented the use of alternative reading strategies as a result of spatial and attentional impairments. In particular, reading was disrupted (a) by rotating word by more than 50 degrees , providing an approximation of the invariance range for words encoding in the ventral pathway; (b) by separating letters with double spaces, revealing the limits of letter grouping into perceptual wholes; (c) by mirror-reversing words, showing that words escape the default mirror-invariant representation of visual objects in the ventral pathway. Moreover, because of her parietal lesions, she was unable to discriminate mirror images of common objects, although she was excellent with reversible pseudowords, confirming that the breaking of mirror symmetry was intrinsic to the occipitotemporal cortex. Thus, charting the display conditions associated with preserved or impaired performance allowed us to infer properties of word coding in the normal ventral pathway and to delineate the roles of the parietal lobes in single-word recognition.

Un caso de enfermedad de Pick con síntomas catatónicos / A Pick´s disease case with catatonic symptoms

Introducción: En 1998 se estableció el último consenso para la definición de la demencia frontotemporal, prevaleciendo los síntomas neuropsiquiátricos. El caso que presentamos tuvo un inicio muy precoz, con síntomas catatoniformes. Caso clínico: Presentamos el caso de un paciente varón, de 42 años. A la edad de 30 años y progresivamente, fue desapareciendo el lenguaje dirigido, predominando el mutismo y la vociferación, con oposicionismo y estereotipias motoras. Con el tiempo se ha instaurado un déficit cognitivo generalizado, compatible con una demencia, con implicación de áreas corticales frontales. Conclusiones: La evolución del cuadro ha permitido establecer el diagnóstico codificado según la CIE-10 de demencia en la enfermedad de Pick (F.02.0). Dos aspectos del caso otorgan su interés: por una parte, el inicio temprano y por otra, su confusión diagnóstica en las fases iniciales con otras entidades psiquiátricas, en este caso una esquizofrenia catatónica

Introduction: The poor clarification of the etiology has promote a recent agreed sorting for the frontotemporal dementia diagnostic. At 1998 last consensus for TFD was created. Clinical case: We present the case of a 42 year old male patient. There were no problems during pregnancy or childbirth. Just some psychomotor slowdown during his childhood, no other alterations. With 30 years old he gave up in some usual activities he used to be envolved in; irritable, dream alterations, anxiety against neutral stimulations, self aggressions strollness. Later on, directed language disappeared, predominating mutism and screaming in different psychomotor agitation episodes. Conclusion: The schedule evolution, has allowed to stablish, the encoded diagnosis according to CIE-10. Dementia in the Pick’s disease (F.02.0). Two aspects of the case award their interest, first, the early beginning, after, its diagnosis confusion during first stages with other psychiatric organizations