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The distribution of basal ganglia lesions, including the amygdala, striatum (caudate nucleus, putamen), pallidum, and substantia nigra, were reinvestigated in 19 Japanese autopsy cases of 'Pick complex', consisting of five patients with corticobasal degeneration (CBD), 10 patients with Pick's disease with Pick bodies (PDPB), and four patients with generalized variant of Pick's disease (gvPD). The lesions in the amygdala, striatum, and pallidum were classified into three categories (severe, moderate, and slight). The lesions in the substantia nigra were qualitatively judged, compared with normal controls. In CBD, basal ganglia lesions in all five cases were uniform: the pallidum showed severe lesions, the striatum moderate lesions, the amygdala slight lesions, and obvious neuronal loss of the substantia nigra was verified in all five cases. Basal ganglia lesions in 10 cases of PDPB were also uniform: the amygdala disclosed severe to moderate lesions, the striatum moderate to slight lesions, the pallidum slight lesions, while obvious neuronal loss of the substantia nigra was found in only two of nine cases in which this structure was examined. Furthermore, basal ganglia lesions in all four cases of gvPD were uniform: the caudate nucleus showed severe lesions, the putamen and amygdala severe to moderate lesions, the pallidum moderate to slight lesions, and obvious neuronal loss of the substantia nigra was confirmed in all four cases. This study, using conventional staining such as hematoxylin-eosin and Holzer, clarified that there were prominent lesions in the pallidum in CBD, in the amygdala in PDPB, and in the caudate nucleus in gvPD, respectively. In addition, nigral involvement was usually found in CBD and gvPD, but was rarely seen in PDPB. These neuropathological findings may help to elucidate the pathological heterogeneity of basal ganglia lesions in 'Pick complex'.

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.

Primary progressive aphasia (PPA) is an identifiable and distinct form of clinical presentation of focal degenerative disease. The underlying pathology is often considered heterogeneous, but we propose that, in fact, this syndrome has a characteristic underlying neurobiology related to Pick's disease and frontotemporal dementia. The authors reviewed the literature of PPA andfound 58 cases with autopsy. The majority of the cases had related underlying pathology, termed "Pick complex," a form of non-Alzheimer's dementia. This includes Pick's disease, corticobasal degeneration, dementia lacking distinctive histology, and motor neuron disease inclusions. Several of the cases described with focal Alzheimer's pathology do not fulfill the criteria of PPA, but have Alzheimer's disease with a major aphasic component.

A number of pathological changes have been reported in relation to CA1 pyramidal cells in Alzheimer's disease (AD), among them hyperphosphorylation of tau protein followed by the formation of filamentous tau lesions, granulovacuolar degeneration (GVD), Hirano bodies and spindle-shaped dilatations of distal apical dendrites. Juxtacellular clusters of glutamate receptor (GluR)-positive granules around pyramidal cells of the CA1 sector have been recently reported under the term "non-plaque dystrophic dendrites". We independently found that CA1 pyramidal cells in AD patients are regularly surrounded by ubiquitin-positive granules measuring 1-4 microns in diameter, which we have termed perisomatic granules (PSG). Using confocal microscopy, ubiquitin- and GluR-reactive granules were found to largely coincide and to correspond to the same structure. By immunoelectron microscopy PSG were found to consist of GluR1-2-reactive enlarged synaptic boutons containing tubulo-filamentous or floccular material. PSG were found to be consistently associated with pyramidal (principal) cells but not with interneurons of the CA1 sector. Dual-labeling experiments have shown that PSG are preferentially associated with tau-immunoreactive "pretangle" neurons but not with cells containing filamentous tau inclusions or with tau-negative nerve cell bodies. The number of PSG was found to increase with the severity of AD changes with almost no PSG found in Braak stages I and II and few in stage III. Furthermore, PSG were not AD specific, as shown by their presence around CA1 pyramidal cells in Pick's disease. The reasons for GluR reactivity and ubiquitin complex formation in enlarged perisomatic boutons are unclear. Marked changes in GluR subunits have been observed in association with even moderate AD pathology in hippocampal pyramidal cells in AD and our findings suggest a pathogenic link between PSG and early tau pathology in CA1 neurons. PSG might represent residual and abnormally clustered GluR subunits in degenerating perisomatic neurites. Our work confirms and extend previous study on perisomatic "non-plaque dystrophic dendrites" in AD and establish PSG as a pathological entity distinct from GVD. In addition PSG should be acknowledged among main histological changes associated with hippocampal neurons in AD and Pick's disease.

We investigated six Japanese autopsy cases of Pick's disease with Pick bodies (PDPB) both clinically and pathologically, and examined the distribution of their cerebral cortical lesions using hemisphere and/or bisphere specimens. The lesions were classified into three categories (slight, moderate, and severe). Two patients with a clinical diagnosis of primary progressive apraxia and of slowly progressive aphasia had speech apraxia as their initial signs, and the other two patients were suspected as having Alzheimer's disease, with the clinical diagnosis of the remainder two patients being presenile dementia and depression, respectively. Extrapyramidal signs, believed to be rare in PDPB, were present in four patients. Severe lesions were multicentrically present in the cerebral cortices of all six cases. In two patients with speech apraxia, severe lesions were seen in the primary motor area, which generally has not been regarded as an "atrophic center" in Pick's disease. Furthermore, in a patient with depression, severe lesions were more widespread in the convexity than in the orbital region of the frontal lobe. The parietal lobes, including the postcentral gyrus usually believed to be spared in Pick's disease, were severely involved in three patients. We postulate that the clinical features of PDPB have a much wider spectrum than previously believed. In addition, we believe that the distribution of the cerebral cortical lesions in PDPB is more widespread than previously assumed, and that clinical manifestations of PDPB depend to some extent on the topographic distribution of the cerebral cortical lesions.

An international group of clinical and basic scientists participated in the Frontotemporal Dementia and Pick's Disease Criteria Conference at the National Institutes of Health in Bethesda, Md, on July 7, 2000, to reassess clinical and neuropathological criteria for the diagnosis of frontotemporal dementia (FTD). Previous criteria for FTD have primarily been designed for research purposes. The goal of this meeting was to propose guidelines that would enable clinicians (particularly neurologists, psychiatrists, and neuropsychologists) to recognize patients with FTD and, if appropriate, to expedite their referral to a diagnostic center. In addition, recommendations for the neuropathological criteria of FTD were reviewed, relative to classical neuropathology and modern molecular biology.

The microtubule-associated tau proteins are abnormally aggregated in many tauopathies. Phosphorylation modulates the functions of tau. The serine 199 residue of tau is abnormally phosphorylated at early and late stages of Alzheimer's disease. The presence of the phosphorylated Ser199 was investigated in autopsy-derived and biopsy-derived brain tissue samples from non-demented individuals. A paradoxical expression was found in the hippocampus of the youngest ones, in granule cells of the dentate gyrus and in pyramidal cells of the Ammon's horn, which are particularly prone to neurodegeneration in several tauopathies. The rate of positive cells decreased with age. These data emphasize the importance of the phosphorylation of the Ser199 residue of tau in ageing and susceptibility to neurodegeneration.

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.

Neurofibrillary tangles (NFT), one of the histopathological hallmarks of Alzheimer's disease (AD) and progressive supranuclear palsy (PSP), and Pick bodies in Pick's disease (PiD) are composed of microtubule-associated protein tau, which is the product of alternative splicing of a gene on chromosome 17. Alternative expression of exon 10 leads to formation of three- or four-repeat tau isoforms. To study the differential expression of exon 10, we performed double-labeling immunohistochemistry of the hippocampal formation in nine AD, four PSP and three PiD cases. Cryostat sections were processed with and without formic acid (FA) treatment, and double-stained with anti-tau (Alz-50 or PHF-1) or anti-amyloid P component antibodies and one of two specific anti-exon 10 antibodies (E-10). The effect of proteinase-K treatment was also evaluated. The results suggest the following. First, in AD, E-10 immunoreactivity is present in most intracellular NFT, but not in most dystrophic neurites and neuropil threads, suggesting differential expression of tau isoforms in specific cellular domains. Second, in AD, E-10 immunoreactivity is lost or blocked in most extracellular NFT, possibly due to proteolysis. Third, in PSP, E-10 immunoreactivity is hidden or blocked in NFT and tau-positive glial inclusions, but FA treatment exposes the epitope consistent with the hypothesis that PSP inclusions contain four-repeat tau. Fourth, E-10 immunoreactivity is present in dentate fascia NFT in AD and PSP, but not in Pick bodies in the dentate fascia or other areas. The results suggest that expression of exon 10 in tau is specific for cellular domains in a disease-specific manner.

In patients with Pick's disease (PD), high densities of tau positive Pick bodies (PB) have been observed within the granule cell layer of the dentate gyrus. This study investigated the spatial patterns of PB along the granule cell layer in coronal sections of the hippocampus in eight patients with PD. In all patients, there was evidence of clustering of PB within the granule cell layer; however, there was considerable variation in the pattern of clustering. In five patients, the clusters of PB were regularly distributed along the dentate gyrus, and in two of these patients, the smaller clusters were aggregated into larger superclusters. In three patients, a single large cluster of PB, more than 1200 microm in diameter, was present. Clustering of PB may reflect a primary degenerative process within the granule cells or the degeneration of pathways that project to the dentate gyrus.

We examined the presence of ubiquitin-immunoreactive skein-like inclusions (SLI) in the neostriatum and spinal cord in normal individuals and patients with different neurodegenerative diseases. Ubiquitin-immunoreactive SLI in the neostriatum were observed both in the normal individuals and in the patients with a variety of neurodegenerative diseases. In particular, SLI were frequently seen in normal aged subjects and certain neurodegenerative diseases, such as progressive supranuclear palsy and myotonic dystrophy. In contrast, the occurrence rate of SLI in cases with Pick's disease and multiple system atrophy tended to decrease. On the other hand, SLI in the spinal anterior horn were detected in cases of amyotrophic lateral sclerosis, but not in any cases with other neurodegenerative diseases. SLI in the neostriatum were also identifiable using phosphotungstic acid-hematoxylin and Gomori trichrome staining. Ubiquitin immunoelectron microscopy demonstrated that the SLI in the neostriatum corresponded to bundles of filaments. These features of SLI in the neostriatum were quite similar to those of intracytoplasmic rod-like inclusions (RLI) in the large neurons of caudate nucleus, which were first described by Kojima and Ogawa in 1974. Our findings indicate that SLI in the neostriatum are ubiquitin-related structures whose occurrence increases by aging, and less frequently accompany several neurodegenerative diseases, and are identical to at least some RLI.

Historical bases for the special role of the prefrontal cortex are outlined and the case of a 27-year-old woman with massive bilateral prefrontal damage of unknown etiology is then described. Frontal lobe degeneration was repeatedly examined with magnetic resonance imaging and fluoro-deoxy-D-glucose-positron emission tomography and was found to include both orbital and dorsolateral aspects of the frontal lobes. While the degeneration initially measured was limited to portions of the orbital, medial and dorsolateral parts of both frontal lobes, with right-sided predominance, a second brain scan 15 months later revealed massive shrinkage of both frontal lobes, together with additional involvement of the posterior association cortices. The patient had completed her high-school education and had superior verbal long-term memory, normal short-term memory, and normal priming, but manifested grossly deficient scores in various frontal lobe-sensitive tests. Though a number of neurological examinations were performed, no plausible cause for the damage was established.

We have reported the family line with frontotemporal dementia (FTD) in Japan. This family line has so far included four patients. Patient II-1 (man) had a 10 year history of slowly progressive personality and behavioral changes and died at the age of 56. His neuropathological examination showed severe atrophy of the bilateral frontal and temporal cortices with neuronal loss, gliosis and superficial spongiosis. Pick bodies were not found. The neuropathological diagnosis was atypical Pick's disease without Pick bodies or Pick-type in FTD. Patient III-2 is patient II-1's oldest daughter and was taken ill with personality change at the age of 52. She died at the age of 68. Patient III-4 is patient II-1's second daughter. Her onset with strange speech and behavior was at the age of 59. Patient III-5 is patient II-1's oldest son. He also had onset with personality change at the age of 54 and had the P301L mutation in tau. In all III generation cases CT/MRI revealed circumscribed frontotemporal atrophy. Patient III-5's PET/SPECT showed signs of hypoperfusion or hypometabolism in the bilateral frontotemporal areas. This is the first report of familial FTD with the P301L mutation in Japan.

Frontotemporal dementias are the second largest degenerative dementia group after Alzheimer's disease. It is a clinical syndrome corresponding to at least three histological entities: Pick's disease, non-specific frontotemporal degeneration, frontal lobe abnormalities associated with motor neuron disease. There are four group of symptoms in the clinical description of FTD: behavioural disorder, affective symptoms, speech disorders, neurological signs. FTD is associated with primary degeneration of the frontal and temporal lobes. Histologically there was neuronal loss, microvacuolation, tau- and ubiquitin-immunoreactive inclusions. The ballooned cortical neurons and tau- and ubiquitin-immunoreactive, argyrophilic inclusions have been called Pick-type histology. There are many descriptions of association of FTD and Pick's disease with motor neuron disease and amyotrophic lateral sclerosis. Histological changes were similar to cortical ones. In this study, we described clinical characteristic features of frontotemporal dementia and difficulties in its identification. The distinctive histopathological pattern in the FTD patients and its value to differentiate frontotemporal degeneration from other degenerative dementias is discussed.

Three cases are reported with dementia and ubiquitin-positive but tau-negative inclusion bodies. All patients had a semantic dementia and the clinical details of two of these have been published as the first description of a selective semantic memory impairment. The original diagnosis had been of Pick's disease based on frontotemporal atrophy, but re-examination has revealed ubiquitin-positive but tau-negative inclusions as well as neurites in the frontotemporal cortices and ubiquitin-positive, intracytoplasmic inclusions in the granule cells of the dentate fascia. These inclusions are identical to those reported in association with amyotrophic lateral sclerosis (motor neuron disease), but none were seen in brainstem or spinal cord motor neurons.

This study documents a patient, SA, with an impairment of semantic memory arising as a result of Semantic Dementia (Pick's disease). The patient is impaired at deriving semantic knowledge from both words and pictures. However, his ability to derive semantic knowledge of countries is relatively spared compared to concrete nouns and famous people. The presence of a semantic deficit was used to investigate the role of semantics in reading and spelling. Several novel cueing/priming paradigms are reported which suggest that SA is able to use partial semantic knowledge to constrain his reading and spelling. These results are broadly consistent with the 'summation hypothesis' [27] and suggest that normal reading and spelling may take place by integrating both semantic information and knowledge of direct orthography-phonology correspondences.

The term frontotemporal dementia is used to describe a primary degenerative form of dementia, which is characterized by typical clinical, neuropsychological, radiological and neuropathological features. Its onset is usually before the age of 65 years; manifestations before the age of 30 years have rarely been described. We report the case of a 22-year old man, who showed symptoms of behavioural disorder such as social retreat, lack of initiative, mental rigidity, progressive reduction of speech, and stereotyped behaviour. The neuropsychological examination revealed disorders of the executive functions. The cerebral MRI investigations showed bifrontal atrophies corresponding with hypoperfusion areas on the SPECT. Other investigations including EEG, evoked potentials, duplex ultrasonography, cerebral angiography, laboratory tests and cerebrospinal fluid were normal. In the present case report we discuss the clinical presentation of frontotemporal dementia with early onset.

Neurofibrillary tangles, Pick bodies and Lewy bodies are considered quantitatively in relation to neuron loss. It would seem that the inclusions are not themselves the cause of neuron death.

To better understand the nature of the symptoms of depression in the early stages of Pick's disease, we performed a retrospective study of the medical records of eight patients who were originally treated for major depressive disorders before being clinically diagnosed with Pick's disease. Six of the eight manifested psychomotor retardation and social withdrawal, seven of the eight were agitated and five of the eight showed hyperbulia too. However, only two of the eight showed melancholia or physical symptoms such as insomnia or loss of appetite. All patients were treated with antidepressants but these were not effective in relieving the symptoms of depression. The data we gathered in this study will be useful in the future for distinguishing between Pick's disease-related depression (in the early stages of the disease) and major depression.

The tropicamide test was applied to 30 patients with probable Alzheimer's disease (pAD), 12 with frontotemporal dementia (FTD) and 46 healthy subjects. One drop of 0.01% tropicamide was instilled in one eye and one drop of saline solution in the other. The pupil diameter was measured with a Goldmann pupillometer in its basal condition and 10, 15, 20, 25, 30, 35, 45 and 55 minutes afterwards. The results do not show differences between pupil dilation observed in pAD and in FTD; in both groups, from the beginning of the test, the pupil dilated more than in healthy people. A high interindividual variability was observed. The best cutoff point is 38% of interpupillary difference at minute 25 (sensitivity = 63%, specificity = 80%). If we consider the prevalence of AD in a population over 40 years old to be 1.4%, the adjusted positive predictive value of the test would be 4.2%. According to these results, the test is not a true diagnostic marker of AD.