Search

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 1050g 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.

Frontotemporal lobar degeneration (FTLD) with ubiquitin/TDP-43-positive inclusions (FTLD-TDP) and Pick's disease are two major pathological substrates in sporadic FTLD patients. Although identifying these underlying pathologies during the life of the patient is crucial for specific pathology-based treatment in the future, adequate clinical data to infer pathologies are not available. Several recent studies demonstrated that Pick's disease cases tend to present clinically with frontotemporal dementia (FTD) or progressive non-fluent aphasia as the first syndrome, while sporadic FTLD-TDP cases frequently show semantic dementia. Some asymmetric motor disturbances (e.g., pyramidal signs, parkinsonism, and contracture) are frequent in sporadic FTLD-TDP during the course, but rare in Pick's disease. On the other hand, several previous studies have demonstrated that the most frequent first syndrome of FTLD-TDP with progranulin gene (PGRN) mutations is FTD and that neuronal loss in the frontal cortex is more severe than that in the temporal cortex. Therefore, it is plausible that the clinicopathological features of sporadic FTLD-TDP are different from those of Pick's disease and FTLD-TDP with PGRN mutations. Given that in vivo Abeta imaging will soon be put to practical use, clinical data useful for clinical differentiation of pathological subtypes of FTLD besides AD with atypical cerebral atrophy will be essential in the future.

We report a 51-year-old female with Pick's disease with Pick bodies (PDPB) showing a brainweight of 530 g. This case was considered to be a very rare case of PDPB, in which the lesion developed in the temporal and frontal lobes and later spread to the parietal lobe, occipital lobe, brainstem, cerebellum and spinal cord. This case showed very atypical clinicopathological findings. Clinically, bulging eyes and myoclonus were observed. Neuropathologically, Pick bodies were widely distributed beyond the usual distribution areas to the parietal cortices, occipital cortices, dentate nuclei, motor neuron nuclei in the brain stem, and spinal cord. The atypical clinical symptoms and the widespread neuropathological abnormalities observed in this case seem to represent an extremely extended form of PDPB.

Frontotemporal dementia (FTD) is an uncommon but important form of degenerative disease. It may make up 50% of dementia cases presenting before age 60. The symptoms are related to the anatomic areas affected. Neary divided the clinical syndromes into "frontotemporal dementia," "progressive nonfluent aphasia," and "semantic dementia." However, the pathology may extend beyond the frontal and temporal lobes and additional symptoms may be found. Although most cases are sporadic, some cases are genetic. The best-known genetic mutation causing FTD is frontotemporal dementia with parkinsonism, linked to the microtubule-associated protein tau on chromosome 17. There are other known genes and chromosome loci related to FTD. The most common pathology found is frontotemporal degeneration with ubiquitin inclusions. In contrast, FTD with Pick bodies is rare. Although there are strategies to help patients and their families, there is no known treatment for the disease.

Background: The relation between atherosclerosis and brain atrophy remains unclear in patients with risk factors for cardiovascular diseases., Objective: This study was performed to clarify the relation between brain atrophy and carotid atherosclerosis., Methods: A total of 142 patients (78 women and 64 men, mean age 74 years) with no neurologic disturbances were studied. Brain atrophy was evaluated on the basis of the brain atrophy index (BAI, BAI = brain parenchyma/intracranial space A 100%), calculated by means of digitized computed tomographic scans obtained at the level of the basal ganglia. Carotid atherosclerosis was evaluated on the basis of the plaque score (PS), defined as the sum of all plaque heights in both carotid arteries, intima-media thickness (IMT), and vessel diameter (VD) of the common carotid artery as assessed by ultrasonography., Results: Age negatively correlated with BAI in both men (r = -0.587, p < 0.001) and women (r = -0.724, p < 0.001). PS of the carotid artery also negatively correlated with BAI in men (r = -0.502, p < 0.001) as well as women (r = -0.480, p < 0.001). VD and IMT of the right carotid artery negatively correlated with BAI in women (VD; -0.256, p < 0.05, IMT; -0.216, p < 0.05) but not in men. Other characteristics were unrelated to BAI. Multiple regression analysis showed that age and PS were independent predictors of brain atrophy in both sexes. The percentage of variance of BAI values explained by this model in women (51.9%) was much greater than that in men (35.5%)., Conclusion: Carotid atherosclerosis may be a useful morphological index of brain atrophy., (Copyright 2007 S. Karger AG, Basel.)

G-protein coupled receptor kinases (GRKs) constitute a serine/threonine kinase family playing a major role in agonist-induced phosphorylation and desensitization of G-protein coupled receptors. Recently, GRK2 and GRK5 have been demonstrated to phosphorylate alpha-synuclein (Ser129) and other synuclein isoforms. We studied colocalization of GRK2, GRK5, alpha-synuclein, and tau in neurodegenerative disorders characterized by fibrillary tau inclusions and/or alpha-synuclein-enriched Lewy bodies. We found that Lewy bodies were negative for both GRK2 and GRK5 in Lewy body disease (LBD) and LBD mixed with Alzheimer disease (AD + LBD). Instead, GRK2 but not GRK5 colocalized with 40% to 50% of neurofibrillary tangles in AD + LBD and AD brains. In disorders with less prominent alpha-synucleinopathy, neuronal and glial fibrillary tau deposits known to contain distinct subsets of tau isoforms were also positive for GRK2. These deposits included tufted astrocytes and coiled bodies in progressive supranuclear palsy, astrocytic plaques in corticobasal degeneration, and Pick bodies in Pick disease. In addition, paired helical filaments isolated from AD and AD + LBD brains were found to immunogold-label for GRK2, suggesting that GRK2 could be a potential tau kinase associated with fibrillary tau. Our studies indicate that GRK2 is a novel component of neuronal and glial fibrillary tau deposits with no preference in tau isoform binding. GRK2 may play a role in hyperphosphorylation of tau in tauopathies.

A patient with progressive anomia and alexia with agraphia for kanji (Japanese morphograms) is described. The patient showed a deficit in single-word comprehension and on-reading (a type of reading that conveys phonetic value) dominance in kanji reading, i.e. on-preceding (pronouncing first with on-reading, irrespective of its preferred reading) and kun-deletion (inability to recall and recognize kun-reading [another type of reading that conveys meaning]) when reading a single-character kanji. These features were due to loss of lexico-semantic information and thus the patient was regarded as having progressive Gogi (word-meaning) aphasia by Imura, a Japanese manifestation of semantic dementia. Macroscopically, neuropathological examination disclosed atrophy of the left frontotemporal lobe with accentuation in the anterior portion of the temporal lobe. Histologically, there was neuronal loss in the cerebral cortex, hippocampus, parahippocampal gyrus, amygdala, caudate nucleus, and putamen. Ubiquitin-immunoreactive neuronal inclusions were present in the hippocampal dentate granular cells. This case demonstrates that progressive Gogi aphasia is semiologically identical to semantic dementia, and our patient clinicopathologically resembled those of Rossor et al. [Rossor, M.N., Revesz, T., Lantos, P.L., Warrington, E.K. Semantic dementia with ubiquitin-positive tau-negative inclusion bodies. Brain 2000; 123: 267-76.] and Hodges et al. [Hodges, J.R., Davies, R.R., Xuereb, J.H., Casey, B., Broe, M., Bak, T.H., et al. Clinicopathological correlates in frontotemporal dementia. Ann Neurol 2004; 56: 399-406.].

This report concerns the upper motor neuron involvement in 16 autopsy cases of Pick disease with Pick bodies, including 11 cases reported by us previously. Prominent, circumscribed atrophy of the precentral gyrus, conspicuously in the lower portion, was noted in one case. Loss of Betz cells and astrocytosis of the precentral gyrus layer V were encountered in 15 cases (94%) and eight cases (50%), respectively. Appearance of Pick bodies and ballooned neurons in the precentral gyrus layer V was confirmed in seven cases (44%). Degeneration of the pyramidal tract in the medulla oblongata was noted in all 15 cases in which this structure was examined. Pyramidal signs were observed in four (67%) of the six cases that were neurologically sufficiently examined: hyperreflexia in four cases (67%), spasticity in one case (17%). Babinski sign was not encountered in any of the six cases. In all four cases having pyramidal signs, degeneration of the pyramidal tract was observed. In contrast, two cases having degeneration of the pyramidal tract did not develop pyramidal signs. In Pick's disease with Pick bodies, obvious involvement of the precentral gyrus and pyramidal tract was not previously noticed. Furthermore, we suggest that pyramidal signs in Pick's disease with Pick bodies have been underestimated.

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.

A number of neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by intraneuronal accumulation of the tau protein. Some forms of FTDP-17 are caused by mutations in the tau gene affecting exon 10 splicing. Therefore, dysregulation of tau pre-mRNA splicing may be a contributing factor to sporadic tauopathies. To address this question, we devised a real-time RT-PCR strategy based on the use of a single fluorogenic probe to evaluate the ratio between tau isoforms containing or lacking exon 10 (4R/3R ratio) in post-mortem brain samples. We found a two- to six-fold increase in the 4R/3R ratio in cases of FTDP-17 linked to a splice site mutation, hence confirming the validity of the strategy. The difference in the 4R/3R ratio in the superior temporal and superior frontal gyri between AD and control brains was not statistically significant. Similarly, there was no significant difference in the 4R/3R ratio between Pick's disease cases and controls, indicating that the predominance of tau3R protein in PiD reflects post-translational modifications of specific isoforms. This study indicates that post-translational events are likely to be the main factors controlling tau isoform composition in sporadic tauopathies and highlights the benefit of quantitative RT-PCR in the assessment of splicing abnormalities in tauopathies.

Sleep disturbances are found in the course of most dementing syndromes. We report a longitudinal polysomnographic and 18FDG-PET study in a 38-year-old male with FTDP17 carrying the Tau gene mutation G389R. All-night sleep EEG and wake cerebral glucose metabolism at rest (eyes/ears covered) of the preceding day were studied twice, eight months (Night 1; PET 1) and sixteen months (Night 2; PET 2) after the initial neurological evaluation. The Night 1 study showed sleep fragmentation associated to a short REM latency and a severe reduction of slow wave sleep, with relatively preserved NREM-REM sleep cycles; daytime PET 1 revealed severe cerebral glucose metabolic reductions in frontal and temporal areas, with relative preservation of remaining cortical regions and subcortical structures. On Night 2, the total sleep time was less than 5 hours, delta sleep and REM latency remained shortened and only two sleep cycles could be identified; daytime PET 2 exam revealed a greater cortical metabolic impairment and an involvement of subcortical brain regions as compared to PET 1. Post-mortem neuropathological data showed severe neuronal loss, spongiosis and gliosis that were mostly marked in cortical layers I, II, V and VI. In vivo, neurometabolic and post-mortem neuropathological data are consistent with and indicative of a severe dysfunction of intra- and trans-hemispheric regional connectivity and of cortico-thalamic circuits. These findings suggest that the decreased cortical and subcortical connectivity may have been the main pathophysiological mechanism responsible for delta sleep reduction and the cognitive decline.

Two patients fulfilling suggested clinical diagnostic criteria for corticobasal degeneration (CBD) are presented, who were found at postmortem to have alternative pathological diagnoses not suspected during life, namely, Alzheimer's disease and Pick's disease, respectively. The nosological position of these cases is considered in light of a literature review of previous reports of clinically diagnosed corticobasal degeneration with atypical (not corticobasal degeneration) pathology. Since such phenocopies may be common, we suggest that all clinically diagnosed cases of corticobasal degeneration should initially be labelled as "corticobasal degeneration syndrome" (CBDS) to emphasize that this is a diagnosis based on clinical phenotype, with the term corticobasal degeneration being reserved for the specific neuropathological phenotype, which itself may have a variety of clinical presentations.

Histamine-N-methyltransferase (HMT) inactivates the neurotransmitter histamine. Central histaminergic deficits may contribute to the cognitive impairment of neurodegenerative disorders including Alzheimer's disease (AD) and Down syndrome (DS). However, there is no evidence for histaminergic deficits in Pick's disease (PiD). HMT levels were measured in the frontal cortex and cerebellum of brains of patients with AD, DS, and PiD, and normal aged subjects using proteomics techniques. In frontal cortex, HMT was significantly decreased in DS, but significantly increased in PiD compared with controls. HMT levels were comparable in cerebellum of all groups. Elevated HMT in PiD could lead to increased histamine degradation that in turn would be in agreement with impaired cognitive functions of PiD. Decreased HMT in DS would be compatible with findings of decreased histamine synthesis, thus reflecting a compensation mechanism to antagonize reduced synthesis by decreased degradation.

This report concerns an autopsy case of argyrophilic grain disease (AGD) mimicking temporal Pick's disease. The patient was a Japanese woman without hereditary burden who was 89 years old at the time of death. She developed memory impairment and began wandering at the age of 74, followed by prominent character changes about 6 years after disease onset. A neurological examination 5 months before her death revealed poor rapport, unconcern, severe dementia, and double incontinence, without aphasia or muscle rigidity. Serial neuroradiological examination revealed progressive enlargement of the bilateral inferior horns of the lateral ventricle, reflecting progressive atrophy of the medial temporal lobes. Macroscopically, neuropathological examination showed circumscribed atrophy of the bilateral amygdalae, hippocampi, parahippocampal gyri, and lateral occipitotemporal gyri. Histologically, there was neuronal loss in the areas mentioned above, the caudate nucleus, putamen, thalamus, substantia nigra, and locus ceruleus, with ballooned neurons in the cerebral cortex and amygdala. Numerous argyrophilic grains with coiled bodies were present not only in the limbic system, but also in the affected cerebrum. Rare neurofibrillary changes were present in the limbic areas, consistent with Braak stage II, with no senile plaques. Based on these findings and a review of the literature, we note that AGD is clinicopathologically similar not only to mesolimbocortical dementia, but also to atypical senile dementia of Alzheimer type. This report may contribute to the elucidation of the clinicopathological hallmarks of AGD.

Calcium/calmodulin-dependent kinase II (alpha- and beta-CaM kinase II), and phosphorylated mitogen-activated extracellular signal-regulated protein kinase (MAPK/ERK-P), phosphorylated protein kinase of 38 kDa (p38-P) and phosphorylated stress-activated protein kinase (SAPK/JNK-P) expression have been examined in Alzheimer disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The study was carried out to increase understanding of the signals that may regulate tau phosphorylation in tauopathies. MAPK/ERK-P was found in a subset of neurons and glial cells bearing abnormal tau deposition, but rarely in neurofibrillary tangles. Strong p38-P immunoreactivity was observed in about 50-70% of neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques in AD. Strong p38-P immunoreactivity was seen in practically all Pick bodies in PiD, and in most neurons with neurofibrillary degeneration or with tau deposits (pre-tangle neurons) in PSP and CBD, as revealed with single and double-labeling immunohistochemistry to p38-P and tau. In addition, strong p38-P immunoreactivity was present in tau-positive astrocytes and in coiled bodies in PSP and CBD. Single and double-labeling immunohistochemistry to MAPK/ERK-P and p38-P disclosed that MAPK/ERK-P appeared at early stages of tau phosphorylation in neurons and glial cells in tauopathies, and that MAPK/ERK-P and p38-P co-localize only in a subset of neurons and glial cells with phosphorylated tau deposits. SAPK/JNK-P immunoreactivity was seen in a subset of neurons, including many neurons with neurofibrillary degeneration, and in glial cells accumulating abnormal tau, in AD, PiD, PSP and CBD. Double-labeling immunohistochemistry disclosed partial co-localization of SAPK/JNK-P and either MAPK/ERK-P or p-38-P immunoreactivity. These findings indicate that MAPK/ERK-P, SAPK/JNK-P and p-38-P are differentially expressed in association with tau deposits in tauopathies. Finally, CaM kinase II is present in neurons but not in glial cells, thus suggesting no role of CaM kinase II in tau phosphorylation of glial cells. These observations, together with previous results of in vitro studies, support the idea that several MAPK/ERK, SAPK/JNK, p38 and CaM kinase II may participate in tau phosphorylation in tauopathies. Lack of co-localization between MAPK/ERK-P, SAPK/JNK-P and p-38-P over-expression, and staining with the method of in situ end-labeling of nuclear DNA fragmentation in individual cells indicate that over-expression of these kinases is not linked with increased nuclear DNA vulnerability in AD, PiD, PSP and CBD.