Pick Bodies Research Articles

An autopsied case of senile onset frontotemporal lobar degeneration

A Japanese male with no family history of neurological disease or dementia showed behavioral abnormalities including egocentric and antisocial behavior at the age of 80. Over the next few years, other psychiatric symptoms such as allotriophagy and stereotypical behavior were also observed and his abnormal behavior became a social problem. Neurological examination revealed no apparent motor abnormalities, pyramidal and extrapyramidal signs, or ataxia. Aphasia, including semantic dementia was not apparent. The severity of memory disturbance was relatively milder than his psychiatric symptoms. Daily living activities and conversational ability were relatively maintained until shortly before his death at the age of 86. The clinical diagnosis was Alzheimer disease. Autopsy revealed that the brain weighed 950 g; frontotemporal atrophy with lateral ventricular dilatation was apparent. Neuron loss, gliosis, and tissue rarefaction were recognized in the frontotemporal cortex, subiculum, transentorhinal cortex, amygdala, and insular cortex and were particularly noticeable in the superficial layer of the cortex. Many ubiquitin-positive/TDP-43 positive but tau-negative dystrophic neurites with a few neuronal cytoplasmic inclusions were widely observed. Neuronal cytoplasmic inclusions were also observed in the dentate gyrus of the hippocampus. Although the spinal cord was not investigated, there was no apparent involvement of the motor neuron system. Small numbers of neurofibrillary tangles and senile plaques were observed, corresponding to Braak stage II and CERAD stage B, respectively. Argyrophilic grains, Lewy bodies and Pick bodies were not observed. The patient was pathologically diagnosed with frontotemporal lobar degeneration with ubiquitin-positive/TDP-43-positive inclusions (FTLD-TDP) and without motor neuron disease. No mutation was found in the TDP-43 gene. We considered the psychiatric symptoms and head CT findings of the present patient to be important observations for helping to discriminate between Alzheimer disease or other neurodegenerative diseases with dementia, and FTLD-TDP.

Functional Implications of Glycogen Synthase Kinase‐3‐Mediated Tau Phosphorylation

Tau is primarily a neuronal microtubule-associated protein that has functions related to the stabilisation of microtubules. Phosphorylation of tau is an important dynamic and regulatory element involved in the binding of tau to tubulin. Thus, highly phosphorylated tau is more likely to be present in the cytosolic compartment of neurons, whereas reduced phosphate burden allows tau to bind to and stabilise the microtubule cytoskeleton. Highly phosphorylated forms of tau are deposited in the brain in a range of neurodegenerative disorders including Alzheimer's disease, progressive supranuclear palsy, and frontotemporal lobar degeneration associated with Pick bodies. A key candidate kinase for both physiological and pathological tau phosphorylation is glycogen synthase kinase-3 (GSK-3). Multiple phosphorylation sites have been identified on tau exposed to GSK-3 in vitro and in cells. In this review, we highlight recent data suggesting a role for GSK-3 activity on physiological tau function and on tau dysfunction in neurodegenerative disease.

Posterior cortical atrophy: an exemplar for renovating diagnostic formulation in neuropsychiatry

Neurodegenerative dementias represent among the most clinically and pathologically complex syndromes in neuropsychiatry. Phenomenologically protean, and often initially presenting with subtle subsyndromal characteristics, neurodegenerative behavioral syndromes can manifest with an assortment of cognitive, mood, personality, and comportmental changes, often alloyed with elementary neurologic (eg, motor) signs. A range of pathogenic mechanisms (eg, amyloid plaques, Pick bodies, etc) typically underlie corresponding clinical syndromes. However, overlap in both clinical expression and histopathologic comorbidities frequently exist among cortical and subcortical neurodegenerative disorders. Moreover, secondary central nervous system pathologies (eg, cerebrovascular disease) commonly coexist with neurodegenerative processes, further complicating clinical phenomenology-based nosologic categorization. Evolving insight into the etiologic mechanisms of neurodegenerative dementias, and correspondingly improving potential for intervention, require more precise differentiation among dementia subtypes and comprehensive identification of contemporaneous neurodegenerative processes. Increasing appreciation of this diagnostic complexity is prompting the need for renovation of existing diagnostic schemas. We address these issues by reviewing the atypical dementia type known as posterior cortical atrophy. We then use posterior cortical atrophy as an exemplar for renovating neuropsychiatric diagnostic classification to better account for the layered complexity of clinical and pathologic domains needing to be characterized to accurately and completely diagnose neuropsychiatric disturbances.

First report of frontotemporal dementia-like phenotype in an argentine family with presenilin-1 M146V Alzheimer's disease with Pick Bodies.

First report of frontotemporal dementia-like phenotype in an argentine family with presenilin-1 M146V Alzheimer's disease with Pick Bodies.

“Fantastic Thinking” in Pathologically Proven Pick Disease

Reports of false beliefs may be a unique feature of behavioral variant frontotemporal dementia (bvFTD) but the nature of these experiences is unclear. To report a case of pathologically verified Pick disease in a patient presenting with prominent and recurrent fantasies. We describe the clinical, neuroradiologic, and neuropathologic findings of a 53-year-old woman presenting with fantasies and meeting Clinical Consensus Criteria for bvFTD. 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. 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.

New Insights into Biological Markers of Frontotemporal Lobar Degeneration Spectrum

In the last decade, there has been enormous progress in our understanding of Frontotemporal Lobar Degeneration (FTLD). Published clinicopathological series have clearly demonstrated an overlap between the clinical syndromes subsumed under the term frontotemporal dementia and the Progressive Supranuclear Palsy (PSP), and the Corticobasal Degeneration (CBD) syndrome. From a neuropathological point of view, two broad pathological subdivisions of FTLD are currently recognized: a) tau-positive pathology due to the accumulation of various forms of the microtubule-associated protein tau, that encompasses FTLD with Pick bodies, PSP and CBD, and b) tau-negative pathology, mainly characterized by ubiquitin/TDP-43-immunoreactive inclusions and in some cases due to Progranulin mutations. Several biological markers in cerebrospinal fluid and in blood have been evaluated to identify monogenic forms of FTLD and to differentiate either FTLD spectrum disorders or FTLD from other neurodegenerative disorders. The proposed biomarkers are primarily related to the mechanisms underlying the accumulation of the abnormal proteins in FTLD such as Tau, TDP-43 and Progranulin. These biomarkers may support the accurate diagnosis of the specific diseases causing FTLD, can be useful in assessing efficacy during pharmacological trials, and may help in identifying new molecular targets for treatment approaches. In this review, we summarise the most recent findings on biological markers and their usefulness in clinical practice for the diagnosis and management of FTLD.

The journey through Pick's Disease with a loved one: a personal account

The aim of this short communication is to share my personal experience of caring for a terminally ill family member who was afflicted with Pick's disease. I tell my story in the hope of increasing society's awareness on this little known but devastating disease and assisting those who might be facing a similar situation. Pick's disease is a rare and incurable type of dementia that is associated with atrophy of the frontal and temporal lobes of the brain over time as a result of accumulation of tau protein fibres known as Pick's bodies. The exact cause is not known, but genetic predisposition is implicated in some disease cases. Pick's disease tends to affect men and women alike. It affects thinking, language and problem solving. Data supporting this document were obtained from a thorough review of the literature and Internet search on Pick's disease, as well as from a personal experience with Pick's disease as it was unfolding. Clinical features, diagnosis and treatment, and stages of the disease are presented. Very little is known about Pick's disease. Additional research is needed to inform practice about tau protein dementias.

Primary progressive aphasia: clinicopathological correlations

Primary progressive aphasia (PPA) is a disorder of declining language that is a frequent presentation of neurodegenerative diseases such as frontotemporal lobar degeneration. Three variants of PPA are recognized: progressive nonfluent aphasia, semantic dementia, and logopenic progressive aphasia. In an era of etiology-specific treatments for neurodegenerative conditions, determining the histopathological basis of PPA is crucial. Clinicopathological correlations in PPA emphasize the contributory role of dementia with Pick bodies and other tauopathies, TDP-43 proteinopathies, and Alzheimer disease. These data suggest an association between a specific PPA variant and an underlying pathology, although many cases of PPA are associated with an unexpected pathology. Neuroimaging and biofluid biomarkers are now emerging as important adjuncts to clinical diagnosis. There is great hope that the addition of biomarker assessments to careful clinical examination will enable accurate diagnosis of the pathology associated with PPA during a patient's life, and that such findings will serve as the basis for clinical trials in this spectrum of disease.

Neuronal and glial tau pathology in early frontotemporal lobar degeneration-tau, Pick's disease subtype

Frontotemporal lobar degeneration-tau, Pick's disease subtype (PiD) is one of the major types of frontotemporal dementia, but its pathogenesis and disease mechanisms remain unclear. Here, we report a case of very early PiD. The patient was a 63-year-old healthy woman without dementia or any apparent psychosis. She was admitted to the hospital with multiple organ failure, and died three days later. The brain weighed 1050 g and showed focal atrophy of the parahippocampal gyrus and right medial temporal lobe. Microscopically, neuronal loss and gliosis were limited to the atrophic areas. Surprisingly, Pick bodies (PiBs) and ballooned neurons were abundant throughout the bilateral temporal cortices, including the dentate gyrus. Cortical lamination of PiBs was predominant in the upper layer (layer II > VI), and the size of early PiBs tended to be smaller than that in severely affected areas. Numerous glial tau-positive inclusions (astrocytic inclusions, oligodendroglial coiled bodies, and threads) were found not only in the cerebral cortex but also in the temporal white matter. The neuropathological findings in this case suggest that PiB formation started long before the appearance of clinical symptoms and that PiB formation originating from small neurons may differ from other tau aggregations such as neurofibrillary tangles.

Clinical entity of frontotemporal dementia with motor neuron disease

Non-Alzheimer-type dementias occur in association with a variety of pathological conditions that include a group of diseases characterized by atrophy of the frontal and temporal lobes. Frontotemporal dementia (FTD) is a clinical entity that comprises at least two distinct diseases: Pick's disease with Pick bodies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). The vast majority of FTLD-U is now referred to as FTLD-TDP, following the recent discovery of TAR DNA-binding protein of 43 kDa (TDP-43) as the major constituent of the ubiquitin-positive inclusions. FTLD-TDP, but not Pick's disease with Pick bodies, is often associated with motor neuron disease (MND). MND is a group of diseases in which the central nervous system lesions were long believed to be confined to the motor neuron system. In other words, MND was not considered to be associated with other neurological symptoms such as dementia. Nevertheless, more than 200 FTD cases associated with clinical MND have been reported in Japan since 1964. Neuropathologically, MND in such FTD cases was essentially similar to MND in cases without dementia. The combination of FTD and MND was so characteristic that we considered these cases comprise a unique clinicopathological subgroup of FTD. FTD with MND and the classical MND without dementia share the occurrence of ubiquitinated TDP-43-positive inclusions, a finding that could be a key to unlock the pathological backgrounds of both diseases.

Semantic dementia: demography, familial factors and survival in a consecutive series of 100 cases

A great deal has been written about cognitive aspects of semantic dementia but little is known about the demography or prognosis. We describe these features in a consecutive series of 100 patients seen over a 17-year period; all cases were assessed and followed up in a specialist clinic. The mean age at diagnosis was 64.2 (+/-7.1) range 40-79 years, but 46 presented after age 65 and 7 after 75; a higher proportion than the existing literature might predict. Fifteen had a first-degree relative with dementia, but in seven this was almost certainly unrelated. Only two had relatives with young-onset dementia. There were no families with more than two affected members. The familial rate was estimated at between 2% and 7% (95% confidence interval 0-12%). Kaplan-Meier analyses indicated a 50% survival of 12.8 years (95% confidence interval 11.9-13.7); a more benign course than suggested by neuropathologically based studies. We were unable to identify any factors influencing survival. Of the 100, 34 have died, with pathological confirmation in 24; 18 had frontotemporal lobar degeneration with ubiquitin-positive inclusions (13 of 13 confirmed TAR DNA binding protein-43 positive), and 3 had classic tau-positive Pick bodies and 3 had Alzheimer's pathology. The age at diagnosis or death across the pathological subgroups was equivalent. Although semantic dementia has a strong statistical association with ubiquitin-positive pathology, it does not have the signature of familial frontotemporal lobar degeneration with ubiquitin-positive inclusions, notably the presence of intranuclear lentiform TAR DNA binding protein-43 inclusions. The age of onset is older than predicted and the course more slowly progressive than suggested by earlier studies of small groups of subjects.

Hippocampal sclerosis with four-repeat tau-positive round inclusions in the dentate gyrus: a new type of four-repeat tauopathy

Hippocampal sclerosis is defined as selective neuronal loss and gliosis of the hippocampus with heterogeneous etiologies, including neurodegenerative tauopathies. We report a 78-year-old woman who presented with depression, in whom postmortem examination revealed almost complete loss of neurons with gliosis in the subiculum and CA1-3 regions of the hippocampus and abundant neuronal cytoplasmic inclusions in the dentate gyrus. The inclusions were round, slightly basophilic and argyrophilic, resembling Pick bodies. However, they were Gallyas- and 4-repeat tau-positive, and 3-repeat tau- and ubiquitin-negative. To our knowledge, the histopathological features in this case were different from those in hippocampal sclerosis or 4-repeat tauopathies reported previously. It is likely that this case is a new variant of 4-repeat tauopathy presenting with hippocampal sclerosis.

Rivastigmina en un caso de demencia frontotemporal, enfermedad de Pick verificada por autopsia

Cholinesterase inhibitors are useful in the treatment of behavioural and psychological symptoms in Alzheimer's disease. Their effectiveness in frontotemporal dementia has not been proved, since such a claim has only been backed by the publication of one open-label trial in which the behavioural and psychological symptoms of the patients treated with rivastigmine over a 12-month period improved significantly with respect to those belonging to a group that were given a placebo. We report a case of frontotemporal dementia, Pick's disease, which improved with rivastigmine treatment.A 61-year-old male who presented a progressive clinical picture of behavioural disorders and executive-cognitive impairment that had begun two years earlier. Magnetic resonance imaging of the head revealed severe frontotemporal atrophy. Neuropsychological Inventory (NPI). Overall score 36/144 (6/12: anxiety, disinhibition and aberrant motor behaviour, 4/12: agitation, irritability and apathy; 3/12: sleep and eating disorders. After three months' treatment with rivastigmine, the overall score on the NPI was 10/144. This improvement remained stable over the months that followed. The patient died eight months later after developing liver cancer with metastasis. The microscopic study of the brain showed tau-positive neuronal inclusions, gliosis and neuronal loss. The inclusions were well-circumscribed Pick bodies, which were present in the frontal and temporal cortices and in the dentate gyrus of the hippocampus.This case confirms the idea that treatment with cholinesterase inhibitors can be effective in the behavioural and psychological symptoms of frontotemporal dementia.

Ultrastructural localization of TDP-43 in filamentous neuronal inclusions in various neurodegenerative diseases

Using post-embedding immunogold electron microscopy, TAR DNA-binding protein of 43 kDa (TDP-43) was localized to neuronal cytoplasmic (NCI) and intranuclear (NII) inclusions, as well as unmyelinated neurites, in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), amyotrophic lateral sclerosis (ALS), Alzheimer's (AD), Pick's disease (PiD) and Lewy body disease (LBD). The TDP-43 immunoreactive structures were morphologically heterogeneous. The most common was characterized by bundles of 10-20 nm diameter straight filaments with electron dense granular material within NCI, NII and neurites. This type of pathology was found in FTLD-U, ALS and some cases of AD. Less often, inclusions in neuritic processes of FTLD-U and some cases of AD contained 10-17 nm diameter straight filaments without granular material. A final type of TDP-43 immunoreactivity was labeling of filaments and granular material associated with tau filaments in neurofibrillary tangles of AD and Pick bodies of PiD or alpha-synuclein filaments in Lewy bodies of LBD. The results suggest that TDP-43 is the primary component of the granulofilamentous inclusions in FTLD-U and ALS. Similar inclusions sometimes accompany filamentous aggregates composed of other abnormal proteins in AD, PiD and LBD.

Neuropathology of frontotemporal dementia

Frontotemporal dementia (FTD) is a clinical phenotype of dementia, characterized by complex of clinical symptoms, including disinhibition, character change, increased appetite, sexual misconduct and language problems. Frontotemporal lobar degeneration (FTLD) is a pathological classification of neurodegenerative disorder and its core consists of Pick's disease (PiD). Historically, PiD was morphologically subclassified into three types, but recent immunocytochemical investigations defined type I as PiD with Pick bodies (three repeat tauopathy), type II as corticobasal degeneration (CBD, four repeat tauopathy) and type III as FTLD with ubiquitinated inclusions (FTLD-U). The recent progress provided an evidence that the majority of FTLD-U represented primary TDP 43 proteionopathy. Three major clinical phenotypes of FTLD consist of FTD, semantic dementia (SD) and progressive non-fluent aphasia (PNFA). Clinical and pathological correlative studies demonstrated that majority of the background pathology of FTD is PiD with Pick bodies, that of SD is FTLD-U and that of PNFA is CBD, although there are too many exceptions. Although FTD is one of the major clinical manifestations of FTLD, the most frequent pathological background of FTD is Alzheimer disease (AD). The degenerative processes causing FTD symptoms include dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and argyrophilic grain disease. Moreover, vascular process such as Binswanger disease and inflammatory process such as neurosyphilis could also present with FTD symptoms. Since FTD requires special clinical care distinct from AD, clinical diagnosis of FTD is quite important. But for the fundamental treatment based on background pathological processes, surrogate biomarkers, including structural and functional neuroimages and findings of cerebrospinal fluid, blood and urine, should be pursued for future progress in FTD research.

TAR-DNA Binding Protein 43 in Pick Disease

Pick disease (PiD) is a frontotemporal dementia characterized by frontal and temporal atrophy, neuronal loss, gliosis, ballooned neurons that are positive for alpha-B crystallin and neurofilament, and the presence of tau- and ubiquitin-positive Pick bodies. TAR-DNA binding protein 43 (TDP-43) has been found to be a component of ubiquitinated inclusions in other neurodegenerative diseases, including frontotemporal lobar degeneration with ubiquitinated inclusions and amyotrophic lateral sclerosis. Fifteen cases of PiD were examined using immunohistochemical methods, and 5 cases with both Pick bodies and smaller intracytoplasmic inclusions that showed staining for ubiquitin, tau, and TDP-43 were observed. The presence of TDP-43 inclusions in PiD suggests that TDP-43 accumulation may be an important component of many neurodegenerative diseases, and that its presence in only some cases of PiD may indicate different pathways of disease development.

MAPT S305I mutation: implications for argyrophilic grain disease

Frontotemporal lobar degeneration (FTLD) with mutations in the tau gene (MAPT) causes familial frontotemporal dementia with tau pathology. Many of these mutations result in morphological phenotypes resembling sporadic tauopathies, although, to date, no such cases mimicking argyrophilic grain disease (AgD) have been documented. We now present a case with a novel S305I MAPT mutation and a morphological phenotype showing resemblance to AgD. At the age of 39, the patient developed behavioural and personality changes and lack of verbal fluency with later poor performance on naming tasks and rigidity in the extremities. After a short disease course of 1.5 years, the patient died. A unique neuropathological phenotype with neuronal diffuse cytoplasmic tau immunoreactivity, oligodendroglial-coiled bodies, argyrophilic grains, and non-argyrophilic, but tau-immunopositive and ubiquitin-immunonegative pre-grains were observed, whereas classical neurofibrillary tangles, Pick bodies, and neuritic plaques were absent. The tau-positive abnormal structures were composed only of 4R-tau isoforms and, ultrastructurally, straight filaments. Neuronal loss was greatest in the medial temporal cortex, hippocampus, and amygdala. These pathological features resemble AgD. The novel S305I substitution has a strong effect on MAPT exon 10 splicing, thereby causing a striking increase in 4R-tau isoforms. Our observation not only widens the phenotypic spectrum of FTLD with MAPT mutation but also underpins the notion that the predominance of similar neuropathological findings in sporadic AgD cases may be viewed as features of a distinct disease entity.

La démence frontotemporale : revue de la littérature

Frontotemporal dementia (FTD) is a neurological disorder characterised by the progressive degeneration of the frontal and anterior temporal cortex. FTD, as well as nonfluent progressive aphasia and semantic dementia, belongs to the more generic entity of frontotemporal lobe degeneration. Considering the involvement of the frontal lobe, the initial clinical presentation of FTD may be psychiatric, such as changes in personality or behavioural disorders. Psychiatrists, therefore, have to establish the differential diagnosis with late-onset schizophrenia or affective disorders. An accurate history of the onset of symptoms, thanks to the patient and especially to his/her family, is essential to recognize this dementia. In addition to behavioural changes, memory impairment, and speech disturbances are often present from the beginning. Consensus criteria have been proposed in 1998 that help to bring this diagnosis to mind in clinical practice. The progressive occurrence of personality changes or inappropriate social conducts in the fifth or sixth decade must prompt cognitive evaluation. NEUROCOGNITIVE AND BRAIN IMAGING DATA: A brief cognitive evaluation, such as the frontal assessment battery (FAB) may help to identify a dysexecutive syndrome and to prompt a thorough neuropsychological evaluation. The pattern of neuropsychological impairment reflects the involvement of the frontal lobe and appears different from that of other degenerative diseases, such as Alzheimer's dementia, which involves hippocampal damage. Additional investigations should however be made to detect a potentially curable dementia. Cerebral imaging is essential to the differential diagnosis and also shows evidence for the positive diagnosis of FTD. Structural MRI may initially not show the bilateral atrophy of the frontal lobe, but functional imaging may be helpful in the early stages of the illness by showing evidence of abnormalities in the anterior cerebral hemisphere. PATHOPHYSIOLOGICAL FINDINGS: In recent years, significant advances in the understanding of the pathological characteristics of FTD were made with genetic contribution, especially the discovery of the tau protein involvement. In fact, neuropathological examination with immunohistochemical analysis defines Pick's disease with Pick bodies that belong to tauopathies. Ubiquitinated intraneuronal inclusions may also be found, and some types of FTD have no distinctive pathological feature. However, although a definite diagnosis would only be established after postmortem pathological examination, the clinical, neuropsychological and imaging data enable the early identification of patients with FTD and, subsequently, the appropriate management. Although the prevalence of FTD reaches 1 Alzheimer's disease (AD) to 1.6 FTD in the general population between 45- and 64-year old, only few studies have focused on the treatment of FTD. Some evidence supports the positive effect of serotonergic agents, especially with regard to behavioural symptoms. Selective serotonin reuptake inhibitors or trazodone should therefore be prescribed in preference to acetylcholinesterase medications as in AD. However, no drug yet has the ability to stop or slow down the degenerative process. The management of daily life also bears specificities related to the younger age of these patients and to their behavioural disorders. Caregivers should receive some education about the characteristics of this dementia and should be helped in social management. As concerns aggressive behaviour, neuroleptics should generally be avoided because of poor tolerance. Finally, the outcome is characterized by a rapid loss of autonomy and sometimes by a premature institutionalisation.

Preferential involvement of the basolateral limbic circuit in an amyotrophic lateral sclerosis patient

Sirs, In this report, we describe a patient of amyotrophic lateral sclerosis (ALS) with dementia (ALSD) unusually presenting with personality changes or social misconduct which led to an initial diagnosis of Pick’s disease (PiD) 5 years prior to the appearance of motor neuron signs. Accentuated degeneration in the basolateral limbic circuit plausibly explains these initial manifestations [1]. A 46-year-old woman presented with progressive social misconduct, auditory and persecutory hallucination and abnormal sexual behaviors, which led to an initial clinical diagnosis of PiD or schizophrenia by a group of psychiatrists several years later. After progressive worsening of these symptoms, she became mute. She then gradually exhibited weakness and atrophy of the upper limbs after age 51. Needle electromyography showed lower motor neuron involvement and she was diagnosed as suspected ALS. Computed tomography of the brain demonstrated moderate atrophy in the fronto-temporal lobes. Single photon emission computed tomography showed a decreased uptake of the tracer not only in these atrophic areas but also in the bilateral basalganglia and thalami. She died of respiratory failure at age 53. The brain weighed 1160 g and macroscopically showed moderate atrophy of the fronto-temporal cortices, hypopigmentation of the substantia nigra and mild atrophy of the spinal cord and anterior roots. Microscopic investigation demonstrated degeneration of lower motor neurons with Bunina bodies. Upper motor neurons were mostly preserved. Spongiotic changes in layers II-III of the fronto-temporal cortices was accentuated in the orbital gyrus, mediodorsal-ventral temporal tip, and entorhinal region (Fig. 1a and b). Neuronal loss and gliosis were mild to moderate in the medio-dorsal (MD) nucleus of the thalamus (Fig. 1c), caudate nucleus and accumbens. Involvement of the amygdala was moderate to severe. Cytoplasmic inclusions (CI) in neurons immunopositive for ubiquitin and TDP-43 were present in the dentate granular cells, superficial small neurons in the fronto-temporal cortices, striatum, amygdala, and MD nucleus of the thalamus (Fig. 1d). The ubiquitin-positive CI in the striatum exhibited eosinophilia with H&E staining which had been thought to be invisible by H&E. There were few neurofibrillary tangles and amyloid senile plaques. Pick bodies were absent. Presence of Bunina bodies and cortical lesions with the CI confirmed ALSD. Although extramotor involvement in ALSD could be variable, this case is characterized by a unique distribution of the lesions, found in the orbital gyrus, temporal pole, amygdala, and MD nucleus of the thalamus. These structures are collectively grouped as basolateral limbic circuit [1] based on their anatomical

Conformational changes and cleavage of tau in Pick bodies parallel the early processing of tau found in Alzheimer pathology

Neuronal protein inclusions are a common feature in Alzheimer disease (AD) and Pick disease. Even though the inclusions are morphologically different, flame-shape structure for AD vs. spherical structure for Pick disease, both have filaments mainly composed of tau protein. In AD, a well-defined pattern of conformational changes and truncation has been described. In this study, we used laser scanning confocal microscopy to characterize and compare the processing of tau protein during Pick disease with that found in AD. We found that tau protein of Pick disease preserves most of the relevant epitopes found in AD, the conformational foldings labelled by Alz-50 and Tau-66, the cleavage sites D(421) and E(391), as well as many phosphorylated sites, such as Ser(199/202), Thr(205) and Ser(396/404). We found a strong pattern of association between phosphorylation and cleavage at site D(421), as well as the phosphorylation and the conformational Alz-50 epitope. When we used late AD markers such as the conformational Tau-66 epitope and MN423 (cleavage at site E(391)) in Pick bodies (PBs), the overlap was significantly less. Furthermore, following morphological quantification, we found significantly higher numbers of phosphorylated tau in PBs. Overall, our findings suggest that phosphorylation is an early event, likely preceding the cleavage of tau at D(421). Despite this consistency with AD, we found a major distinction, namely that PBs lack beta-sheet conformation. We propose a scheme of early tau processing in these structures, similar to neurofibrillary tangles of AD.