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Abstract Background Neuropathological diagnosis of argyrophilic grain disease (AGD) is currently based primarily on the combination of argyrophilic grain (AG) visualized using Gallyas–Braak silver staining, phosphorylated tau-positive pretangles, coiled bodies, and ballooned neuron detection. Although AGD is common in patients with dementia and/or prominent psychiatric symptoms, whether it is a distinct neurological disease entity or a by-product of the aging process remains unclear. Methods In 1449 serial forensic autopsy cases > 40 years old (823 males and 525 females, aged 40–101 years, mean age 70.0 ± 14.1 years), we examined the frequency and comorbid pathology of AGD cases and investigated the clinical appearance by comparing those with non-AGD cases using the propensity score. Results Of the 1449 cases, we detected 342 AGD cases (23.6%; mean age 79.7 years; 177 males and 165 females). The AGD frequency and stage increased with age (P

Background: Neuropathological diagnosis of argyrophilic grain disease (AGD) is currently based primarily on the combination of argyrophilic grain (AG) visualized using Gallyas–Braak silver staining, phosphorylated tau-positive pretangles, coiled bodies, and ballooned neuron detection. Although AGD is common in patients with dementia and/or prominent psychiatric symptoms, whether it is a distinct neurological disease entity or a by-product of the aging process remains unclear. Methods: In 1449 serial forensic autopsy cases > 40 years old (823 males and 525 females, aged 40–101 years, mean age 70.0 ± 14.1 years), we examined the frequency and comorbid pathology of AGD cases and investigated the clinical appearance by comparing those with non-AGD cases using the propensity score. Results: Of the 1449 cases, we detected 342 AGD cases (23.6%; mean age 79.7 years; 177 males and 165 females). The AGD frequency and stage increased with age (P < 0.001). Among AGD cases, 80 (23.4%) patients had dementia, and 51 (15.2%) had a history of psychiatric hospital visits. The frequency of suicide and history of psychiatric disorders were significantly higher in AGD cases than in AGD-negative cases, matched for age, sex, and comorbidity pathology, with a relative risk of suicide of 1.72 (1.30–2.26). The frequency of suicide was significantly higher in AGD cases than in non-AGD cases in female but not male cases. The relative risk of suicide increased to 2.27 (1.20–4.30) and 6.50 (1.58–26.76) in AGD patients with Lewy and progressive supranuclear palsy pathology, respectively, and decreased to 0.88 (0.38–2.10) in those with advanced AD pathology. In AGD cases, 23.4% had dementia; however, the difference was not significant after controlling for age, sex, and comorbid pathology. Conclusion: Our study demonstrated that AGD is a significant and isolated risk factor for psychiatric hospital visits and suicide completion. In older adults, AGs may contribute to the progression of functional impairment of the limbic system, which leads to psychiatric disorders and suicide attempts. [ABSTRACT FROM AUTHOR]

Pallido‐nigro‐luysian atrophy (PNLA) is a variant of progressive supranuclear palsy (PSP). Patients with PSP sometimes show psychiatric signs, but there are few reports about such signs being associated with PSP‐PNLA. Here, we report a case of PSP‐PNLA with argyrophilic grains (AGs) in a patient clinically diagnosed as having PSP‐frontotemporal dementia (PSP‐F). A 74‐year‐old man described as "kind" presented with impaired memory, irritability, and apathy. He showed levodopa‐resistant parkinsonism and postural instability. Brain magnetic resonance imaging revealed mild atrophy of the midbrain and right‐side‐dominant atrophy of the hippocampus and temporal lobe. The patient was diagnosed as having PSP with frontal lobe cognitive or behavioral presentations (PSP‐F). He died of aspiration pneumonia at age 81. At autopsy, macroscopic examination revealed depigmentation of the substantia nigra and grayish discoloration of the dentate nucleus, globus pallidus, and subthalamic nucleus. Severe gliosis was observed in the same regions. There were many phosphorylated tau‐immunoreactive equivocal tufted astrocytes in the globus pallidus. Many neurofibrillary tangles and neuropil threads were observed in the substantia nigra and subthalamic nucleus, and few tau aggregates were observed in the frontal cortex. In contrast, AGs were abundant in the amygdala, entorhinal cortex, and anterior cingulate gyrus, with an asymmetric distribution. The pathological observations led us to change the diagnosis to PSP‐PNLA with AGs. Although most cases of PSP‐F derive from tau pathology in the frontal cortex, this patient did not have phosphorylated tau‐immunoreactive aggregates in that location. Our observations suggest that the psychiatric signs of PSP‐F should be considered as being due to the presence of limbic AGs, not frontal tau pathology. [ABSTRACT FROM AUTHOR]

IntroductionMany clinicopathological studies do not specify the presence of other pathologies located within the brain, so disease heterogeneity may be under appreciated.ObjectiveThe purpose of this study was to determine the frequencies of concomitant pathologies among parkinsonian disorders.MethodsData from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), an ongoing longitudinal clinical-neuropathological study, was used to analyze concomitant pathologies, including Alzheimer's disease (AD), argyrophilic grains (Arg), cerebral amyloid angiopathy (CAA), cerebral white matter rarefaction (CWMR) and overlap of each parkinsonian disorder in clinico-pathologically defined Parkinson's disease (PD; N = 140), dementia with Lewy bodies (DLB; N = 90), progressive supranuclear palsy (PSP; N = 64), multiple system atrophy (MSA; N = 6), corticobasal degeneration (CBD; N = 7); and normal elderly (controls; N = 166).ResultsOf the neuropathologically-confirmed PD cases, 38% had a concomitant diagnosis of AD, 9% PSP, 25% Arg, 44% CWMR, and 24% CAA. For DLB, 89% had AD, 1% PSP, 21% Arg, 51% CWMR, and 50% CAA. For PSP cases, 36% had AD, 20% PD, 1% DLB, 44% Arg, 52% CWMR and 25% CAA. Similar heterogeneity was seen for MSA and CBD cases. Many cases had more than one of the above additional diagnoses.ConclusionsThese data demonstrate a great deal of concomitant pathologies among different types of parkinsonian disorders; this may help explain the heterogeneity of clinical findings.

Neuropathologic heterogeneity is often present among Alzheimer disease (AD) patients. We sought to determine whether amyloid imaging measures of AD are affected by concurrent pathologies. Thirty-eight clinically and pathologically defined AD and 17 nondemented patients with quantitative florbetapir F-18 (F-AV-45) positron emission tomography (PET) imaging during life and postmortem histological β-amyloid quantification and neuropathologic examination were assessed. AD patients were divided on the basis of concurrent pathologies, including those with Lewy bodies (LBs) (n = 21), white matter rarefaction (n = 27), severe cerebral amyloid angiopathy (n = 11), argyrophilic grains (n = 5), and TAR DNA binding protein-43 inclusions (n = 18). Many patients exhibited more than 1 type of concurrent pathology. The ratio of cortical to cerebellar amyloid imaging signal (SUVr) and immunohistochemical β-amyloid load were analyzed in 6 cortical regions of interest. All AD subgroups had strong and significant correlations between SUVr and histological β-amyloid measures (p μ 0.001). All AD subgroups had significantly greater amyloid measures versus nondemented patients, and mean amyloid measures did not significantly differ between AD subgroups. When comparing AD cases with and without each pathology, AD cases with LBs had significantly lower SUVr measures versus AD cases without LBs (p = 0.002); there were no other paired comparison differences. These findings indicate that florbetapir-PET imaging is not confounded by neuropathological heterogeneity within AD.

Argyrophilic grain disease (AGD) is a common four‐repeat tauopathy in elderly people. While dementia is a major clinical picture of AGD, recent studies support the possibility that AGD may be a pathological base in some patients with mild cognitive impairment, late‐onset psychosis, bipolar disorder and depression. AGD often coexists with various other degenerative changes. The frequency of AGD in progressive supranuclear palsy (PSP) cases was reported to range from 18.8% to 80%. The frequency of AGD in corticobasal degeneration (CBD) cases tends to be higher than that in PSP cases, ranging from 41.2% to 100%. Conversely, in our previous study of the frequencies of mild PSP and CBD pathologies in AGD cases, five of 20 AGD cases (25%) had a few Gallyas‐positive tufted astrocytes, six cases (30%) had a few granular/fuzzy astrocytes, and one case (5.0%) had a few Gallyas‐positive astrocytic plaques in the putamen, caudate nucleus and/or superior frontal gyrus. Both Gallyas‐positive tufted astrocytes and Gallyas‐negative tau‐positive granular/fuzzy astrocytes preferentially developed in the putamen, caudate nucleus and superior frontal cortex in AGD cases, being consistent with the predilection sites of Gallyas‐positive tufted astrocytes in PSP cases. Further, in AGD cases, the quantities of Gallyas‐positive tufted astrocytes, overall tau‐positive astrocytes, and tau‐positive neurons in the subcortical nuclei and superior frontal cortex were significantly correlated with Saito AGD stage, respectively. The frequency of AGD in AD cases was reported to reach up to 25% when using four‐repeat tau immunohistochemistry. Pretangles are essential pathologies in AGD; however, the Braak stage of three‐repeat tau‐positive NFTs, which may indicate mild AD pathology or primary age‐related tauopathy, was not correlated with Saito AGD stage. Clinicians should be aware of the possibility that coexisting AGD may impact clinical and radiological features in cases of other degenerative diseases. [ABSTRACT FROM AUTHOR]

Introduction Neurofibrillary pathology of abnormally hyperphosphorylated tau (P-tau) is a hallmark of Alzheimer's disease (AD) and other tauopathies. Tau pathology can be experimentally induced and propagated. However, what induces the prion-like transmission character to tau and produces morphologically distinct tau lesions remains elusive. Methods We investigated the role of hyperphosphorylation in the spread of tau pathology in hTau transgenic mice. Results We found that intrahippocampal injection with AD P-tau, but not nonphosphorylated tau, produced numerous P-tau tangles and neuropil threads locally and in neocortex lateral to injection and upstream to the hippocampus. Dephosphorylation of AD P-tau with protein phosphatase-2A dramatically reduced and switched tau pathology from neurofibrillary tangles to argyrophilic grain-like morphology. Conclusions Our findings show that abnormal hyperphosphorylation of tau determines the spread and morphology of tau lesions and that the propagation of tau pathology takes place both locally and in axonally connected areas and highlight tau hyperphosphorylation as a potential drug target. [ABSTRACT FROM AUTHOR]

Aclinicopathological investigationwas conducted on a case of an 89-year-old man with a 10-year history of progressive dementia who also suffered strokes, apathy, aphasia, dysarthria, weakness of both legs, and walking difficulties. At autopsy, we found an obvious atrophy of the frontal and temporal cortex. Lewy bodies (LBs) could be seen in brain stem, amygdala, and neocortex. Argyrophilic grains were observed in hippocampus, entorhinal cortex, neocortex, amygdala, and pons, as well as neurofibrillary tangles in the entorhinal cortex and hippocampus. The case presented here is a rare case of frontotemporal lobar degeneration with accumulation of argyrophilic grains and Lewy bodies. [ABSTRACT FROM AUTHOR]

The Gallyas method is a silver impregnation technique that is essential in the field of neuropathology because of its high sensitivity for the detection of argentophilic inclusion bodies in the central nervous system. In Japan, the Gallyas method has improved and is widely used as the 'modified Gallyas method'. However, this method is not popularly used in general pathology laboratories because of the need for special reagents, several staining processes, and skilled techniques. The objective of the current study was to provide a simplified Gallyas method. We omitted the lanthanum nitrate step from the staining process and verified the adequacy in comparison with the original method as well as immunohistochemistry, using specimens from patients of Alzheimer's disease, argyrophilic grain disease, multiple system atrophy, Pick's disease, and Lewy body disease. The simplified method provided good staining to all the structures in archival tissues, compared with the modified Gallyas method in a significantly shorter staining time. The lanthanum nitrate step can be omitted from the modified Gallyas method, resulting in reduction in the number of reagents required and shortening of the staining time. [ABSTRACT FROM AUTHOR]

TAR DNA-binding protein 43 (TDP-43) has been heavily researched in recent years due to its involvement in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Several studies have also sought to investigate the frequency of TDP-43 deposition in other neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, but there has been relatively little work focused on the prevalence, distribution and histopathological associations of abnormal TDP-43 deposits in the brains of cognitively normal elderly subjects. We screened thick, free-floating coronal sections of mesial temporal lobe from 110 prospectively followed and autopsied cognitively normal subjects (age range 71-100 years) using an immunohistochemical method for phosphorylated TDP-43. We found a 36.4 % prevalence of pathologic TDP-43, mostly in the form of neurites while perikaryal cytoplasmic neuronal inclusions were uncommon and intranuclear inclusions were rare. With respect to other concomitant pathologies commonly found in elderly individuals, cases with TDP-43 had a greater prevalence of argyrophilic grains (ARG) (40 vs. 18.6 %) and overall ARG density (moderate vs. sparse). There were no additional associations with other concomitant pathologies, including cerebral white matter rarefaction, incidental Lewy bodies, neurofibrillary tangles or amyloid plaques. These results indicate deposition of TDP-43 occurs in a substantial subset of cognitively normal elderly subjects and is more common in those with ARG, supporting some previous studies linking pathological TDP-43 deposition with ARG and other pathological tau protein deposits. [ABSTRACT FROM AUTHOR]

TDP-43 is characteristically accumulated in TDP-43 proteinopathies such as frontotemporal lobar degeneration and motor neurone disease, but is also present in some tauopathies, including Alzheimer’s disease, argyrophilic grain disease, and corticobasal degeneration (CBD). However, several studies have suggested that cases of progressive supranuclear palsy (PSP) lack TDP-43 pathology. We have therefore examined limbic regions of the brain in 19 PSP cases, as well as in 12 CBD cases, using phosphorylation-dependent anti-TDP-43 antibodies. We observed TDP-43-positive inclusions in five PSP cases (26%), as well as in two CBD cases (17%). The amygdala and hippocampal dentate gyrus were most frequently affected in PSP. Regional tau burden tended to be higher in TDP-43-positive PSP cases, and a significant correlation between tau and TDP-43 burden was noted in the occipitotemporal gyrus. Hippocampal sclerosis (HS) was found in 3/5 TDP-43-positive PSP cases, but HS was significantly more frequent in TDP-43-positive than TDP-43 negative PSP cases. Dementia was present in 13/19 (58%) of the PSP cases, in 4/5 TDP-43-positive cases, in all 3 TDP-43-positive cases with HS, in 1/2 TDP-43-positive cases without HS, and 7/14 cases lacking both. TDP-43 and tau were frequently colocalized in the amygdala, but not in the hippocampal dentate gyrus. Immunoblotting demonstrated the characteristic (for TDP-43 proteinopathies) 45 and 25 kDa bands and high molecular weight smear in the TDP-43-positive PSP case. These findings suggest that (1) although PSP is nominally a tauopathy, pathological TDP-43 can accumulate in the limbic system in some cases, and (2) TDP-43 pathology may be concurrent with HS. [ABSTRACT FROM AUTHOR]

Argyrophilic grains (AGs) are a pathologic feature found in association with neurodegenerative disease. Some have suggested that these features may occur as a distinctive condition. We reviewed 80 subjects from our tissue bank with pathologically confirmed AGs and identified their clinical features. We compared these subjects' features to the features of subjects with matched clinical diagnoses but without AGs. Subjects with AGs represented 2 1.7% of the entire autopsy sample from 1999 to 2005 (80 out of 367). Of Alzheimer disease (AD) subjects, 43 out of 233 had AGs (18.4% of AD subjects); 11 out of 42 Parkinson disease with dementia subjects had AGs (26.1% of Parkinson disease with dementia subjects); 2 out of 9 dementia with Lewy bodies subjects had AGs (22.2% of dementia with Lewy bodies subjects); 4 out of 15 mild cognitive impairment subjects had AGs (26.7% of mild cognitive impairment subjects); and 20 out of 68 cognitively normal subjects had AGs (29.4% of cognitively normal). Subjects with AGs tended to be older but only significantly so in AD. Many comorbid non-neurologic health conditions were seen in cases of AGs without any single predilection emerging. AGs occur in approximately 22% of the entire autopsy cohort and are likely associated with advanced age. No distinctive antemortem clinical features were over represented in the AG cases. AGs can occur with or without neurodegenerative conditions and can occur in the absence of significant cognitive decline. AGs are not clearly associated with any single comorbid health condition. [ABSTRACT FROM AUTHOR]

Abstract: The risk for Alzheimer''s disease (AD) is influenced by both age and ApoE status. The present study addresses the associations of age and ApoE status on complex pathologic features in AD (n =81) including coexistent cerebrovascular disease (CVD), argyrophilic grain disease (AGD), and Lewy body disease (LBD). The frequency of coexistent cerebrovascular disease increased with increasing age. Age and ApoE status were differentially associated with atherosclerosis, lacunar infarctions, and microvascular pathology. Coexistent Lewy body pathology was negatively associated with age, dropping off abruptly after age 90. The presence of an ApoE ε4 allele was associated with an increased frequency of coexistent LBD. Logistic regression analyses demonstrated both dependent and independent effects of age and ApoE status on the presence of coexistent Lewy body pathology in AD. While the decreasing frequency of LBD in AD after age 90 could be partly accounted for by a lower probability of an ApoE ε4 allele, the independent association with age suggests either 1) a survival effect, 2) decreased incidence with advancing age, or 3) both. [Copyright &y& Elsevier]

Abstract: A case of familial frontotemporal dementia with parkinsonism (FTDP) similar to progressive supranuclear palsy (PSP) was reported. A 58-year-old man developed personality change followed by parkinsonism and dementia. Three family members showed similar symptoms. Cerebral atrophy was marked on the anterior frontotemporal lobes. The substantia nigra, hippocampus, peri-aqueductal gray matter and pontine nucleus were affected with globose neurofibrillary tangles (NFT) and glial tangles. Argyrophilic grains were distributed in the CA1–CA2. NFT, glial tangles and argyrophilic grains expressed four-repeat microtubule-associated protein tau (MAPT). MAPT gene had no mutation. Familial occurrence of FTDP with PSP-like tauopathy is rare. [Copyright &y& Elsevier]

We aim to investigate the pathological background of mild cognitive impairment (MCI). The most recent 545 cases from the Brain Bank for Aging Research (BBAR) were studied, with a mean age of 80.7 years and male : female ratio of 324 : 221. Cases with clinical dementia rating scale (CDR) 0.5 were retrieved as the best substitute of MCI. CDR was retrospectively determined from clinical charts. Pathological examinations followed the BBAR protocol (JNEN 2004). Post mortem assessment of CDR was possible for 486 cases, and was 0 in 201 cases, 0.5 in 57 cases and 1–3 in 228 cases. CDR 0.5 group was clinicopathologically classified into 33 cases with degenerative changes, nine cases with vascular changes, four cases with combined degenerative and vascular changes, two with hippocampal sclerosis, two with trauma, one with metabolic disease and six with unremarkable changes. The degenerative group was further subclassified into groups with pure and combined pathology. The former consisted of six cases each with Alzheimer change (AC), argyrophilic grain change (AGC) and neurofibrillary tangle predominant change (NFTC), three each with Lewy body disease change without parkinsonism (DLBC) or Parkinson's disease (PDMCI) and one case with progressive supranuclear palsy. The latter consisted of three cases with AC plus AGC, two with AGC plus NFTC and one each with AC plus DLBC, DLBC plus amyotrophic lateral sclerosis and AGC plus DLBC. The pathological backgrounds of patients of class CDR 0.5 were varied and not restricted to AC. [ABSTRACT FROM AUTHOR]

The somatodendritic accumulation of hyperphosphorylated tau proteins is an early event preceding the appearance of neurofibrillary tangles (NFT) in Alzheimer’s disease (AD) and might be necessary for their formation. Glycogen synthase kinase-3β (GSK-3β) is a physiological kinase for tau that generates many tau phosphorylation sites identified in NFT and in other tau-positive inclusions. We have studied the cellular distribution and the expression of the active form of GSK-3β (GSK-3 pTyr216) in AD patients, in argyrophilic grain disease and in diffuse Lewy body disease. By Western blotting analysis, a significant increase in the level of GSK-3 (pTyr216) was observed in the frontal cortex of AD patients. A population of neurones showed a somatodendritic accumulation of GSK-3 (pTyr216) but not of the inactive form of GSK-3β (GSK-3 pSer9). Most of these GSK-3 (pTyr216)-positive cells were positive for six different phosphotau epitopes known to be generated by GSK-3β. By using a quadruple labelling method using GSK-3 (pTyr216) and phosphotau immunolabelling combined with Gallyas and DAPI staining, we examined neurones containing a somatodendritic GSK-3 (pTyr216) immunoreactivity at different stages of neurodegeneration. A majority of neurones at the pretangle stage without Gallyas-positive inclusions were GSK-3 (pTyr216) positive and this GSK-3 (pTyr216) immunoreactivity remained in most cells containing Gallyas and phosphotau-positive inclusions excepted in extracellular NFT. A GSK-3 (pTyr216) immunoreactivity was present in argyrophilic grains but not in cortical Lewy bodies. These results directly suggest that the activity of GSK-3β is increased in AD and that somatodendritic accumulation and activation of GSK-3β is an early event preceding and accompanying the formation of NFT and of other tau-positive inclusions. [ABSTRACT FROM AUTHOR]

We immunohistochemically investigated the prevalence and pattern of phosphorylated tau accumulation in neurons and glia in 46 cases of dementia with Lewy bodies (DLB). Tau-positive neurons composed of neurofibrillary tangles (NFT) and pretangle neurons were found in the hippocampal area in all 46 cases, although the ratio of pretangle neurons in tau-positive neurons was higher in the cases showing low NFT stages. Tau-positive astrocytes were found in the periventricular area in 18 of 46 cases, and partly represented argyrophilic thorn-shaped astrocytes. In contrast, tau-positive oligodendroglia were found in the subcortical white matter in 9 of 46 cases, and represented argyrophilic coiled bodies. Tau-positive argyrophilic grains were found in the hippocampal area in the same cases as those with coiled bodies. The 9 cases with tau-positive coiled bodies and grains were included in the 18 cases with tau-positive astrocytes, and showed larger proportions in the low NFT stages than the 46 cases with tau-positive neurons. Tau-positive neurons were positive both to anti-three-repeat (3R) and -4R tau-specific antibodies, while tau-positive astrocytes, coiled bodies and grains were predominantly positive to anti-4R tau-specific antibody. These tau-positive structures were negative to anti-α-synuclein antibody. These findings suggest that the tau accumulation in DLB represents both tau-positive neurons with all six tau isoforms and tau-positive astrocytes, coiled bodies and grains with the 4R tau isoform, and that the different cytoskeletal abnormalities form a link between some neurodegenerative dementing disorders including DLB. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

M. Tolnay, C. Mistl, S. Ipsen and A. Probst (1998) Neuropathology and Applied Neurobiology 24,53–59 Argyrophilic grains of Braak: occurrence in dendrites of neurons containing hyperphosphorylated tau protein Braak's argyrophilic grains (ArGs) are spindle-shaped neuropil structures originally found in patients afflicted with adult onset dementia. We recently observed that tau protein is hyperphosphorylated in most nerve cells in areas rich in ArGs, suggesting that these grains may be a morphological expression of tau protein pathology in local neurons. The aim of this study was therefore to determine in three cases with ArGs whether grains are associated with individual neurons containing hyperphosphorylated tau. A combination of Gallyas silver staining and AT8 immunocytochemistry was used. AT8 is a monoclonal antibody that recognizes tau in a phosphorylation-dependent manner. Up to 80% of pyramidal cells of sector CA1 showed diffuse AT8 staining of their cell bodies and dendrites. Most grains were freely scattered throughout the neuropil. However, some were clearly located in side-branches of apical dendrites of AT8 immunoreactive pyramidal neurons. Dendritic branches often formed bush-like ramifications containing clusters of ArGs. Other dendrites consisted of a single stump containing one or two large grains at their tips. Spheroidal enlargements of dendritic branches, with a size corresponding to ArGs, were also found in Golgi Cox preparations of cases with ArGs but not in Alzheimer's disease cases or in controls. Our results show that some ArGs are formed within dendrites of neurons whose most obvious pathology is a diffuse hyperphosphorylation of the tau protein. Furthermore, morphology of dendrites containing grains suggests that a process of progressive shrinkage of dendrites is taking place in neurons bearing ArGs. [ABSTRACT FROM AUTHOR]

Argyrophilic grain disease is a progressive degenerative disorder of the human brain which becomes increasingly prevalent with advancing age. The disease entails multiple neuronal systems and results from cytoskeletal degeneration in only a few neuronal types and in oligodendrocytes. Immunoreactions for abnormally phosphorylated tau protein permit identification of the changes. Only a fraction of the emerging abnormal fibrillary material shows a pronounced argyrophilia. Essential for neuropathological diagnosis is assessment of the presence of small spindle-shaped argyrophilic grains in neuronal processes. The anteromedial portion of the temporal lobe bears the brunt of the lesions. Grains generally can be found in abundance in the entorhinal region, the first Ammon's horn sector, the subcortical nuclear complex of the amygdala, and the hypothalamic lateral tuberal nucleus. Frequently, the lesions co-exist with those typically found in Alzheimer's disease or other tauopathies. Owing to the characteristic grains, the disorder easily can be differentiated from other tauopathies. 2661 non-selected brains obtained at autopsy included 125 cases of argyrophilic grain disease (5%) from individuals between 51 and 96 years of age (mean 79 years) . The fact that the same material contained 146 cases of fully developed Alzheimer's disease (6%) supports the view that argyrophilic grain disease is not a rare disorder. Its prevalence with and without concomitant neurofibrillary changes of the Alzheimer type grows with increasing age. Argyrophilic grain disease merits attention because of its frequent occurrence and its potential to cause severe brain dysfunction. [ABSTRACT FROM AUTHOR]

Introduction: Neurofibrillary pathology of abnormally hyperphosphorylated tau (P-tau) is a hallmark of Alzheimer's disease (AD) and other tauopathies. Tau pathology can be experimentally induced and propagated. However, what induces the prion-like transmission character to tau and produces morphologically distinct tau lesions remains elusive., Methods: We investigated the role of hyperphosphorylation in the spread of tau pathology in hTau transgenic mice., Results: We found that intrahippocampal injection with AD P-tau, but not nonphosphorylated tau, produced numerous P-tau tangles and neuropil threads locally and in neocortex lateral to injection and upstream to the hippocampus. Dephosphorylation of AD P-tau with protein phosphatase-2A dramatically reduced and switched tau pathology from neurofibrillary tangles to argyrophilic grain-like morphology., Conclusions: Our findings show that abnormal hyperphosphorylation of tau determines the spread and morphology of tau lesions and that the propagation of tau pathology takes place both locally and in axonally connected areas and highlight tau hyperphosphorylation as a potential drug target., (Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)