Argyrophilic Grain Disease Cases Research Articles

Argyrophilic grain disease is common in older adults and may be a risk factor for suicide: a study of Japanese forensic autopsy cases

BackgroundNeuropathological 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.MethodsIn 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.ResultsOf 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.ConclusionOur 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.

Four-repeat tauopathies and late-onset psychiatric disorders: Etiological relevance or incidental findings?

Argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP) and corticobasal degeneration are four-repeat (4R) tauopathies that develop in the presenium or later. Whether these diseases are associated with the occurrence of late-onset psychiatric disorders remains unclear. To facilitate the accumulation of clinicopathological findings regarding this issue, we here present a selected series of 11 cases that clinically developed psychotic disorder (n=7; age at onset: 41-75 years), depressive disorder (n=1; 49 years), bipolar disorder (n=2; 32 and 37 years) and somatoform disorder (n=1; 88 years), and had at least one pathological hallmark of these tauopathies. The mean age at death was 74.3 years. No case showed dementia, at least in the early stage of the course. Nine cases had AGD. Granular fuzzy astrocytes in the amygdala were noted in all AGD cases and one non-AGD case. Two AGD cases had tufted astrocytes (TAs) in the amygdala but not in the frontal cortex and striatum. Three AGD and two non-AGD cases had TAs in the frontal cortex and/or striatum but not in the amygdala. One AGD case had a small number of astrocytic plaques in the frontal cortex, striatum and globus pallidus. Only one case was diagnosed as atypical PSP according to the NINDS-PSP neuropathological criteria. No case had high-level Alzheimer's disease pathology, Lewy body disease or limbic-predominant age-related TDP-43 encephalopathy. Two cases had mild neuronal loss in the hippocampus and substantia nigra, respectively. Clinicopathological studies focusing especially on early changes of 4R tauopathies, as well as the development of surrogate markers of these diseases, may be necessary for better understanding of the pathogenic backgrounds of late-onset psychiatric disorders.

Caspase‐6‐mediated tau cleavage and pathology in Alzheimer’s disease and other tauopathies

AbstractBackgroundCaspases are being explored as targets for pharmacological treatment of tauopathies due to their role in tau cleavage, which leads to tau aggregation and neuronal loss. Tau truncated at Asp421, a residue cleaved by effector caspases, is found in four common tauopathies: Alzheimer’s disease (AD), corticobasal degeneration (CBD), Pick’s disease (PiD), and progressive supranuclear palsy (PSP) (Newman et al., 2005). We previously demonstrated that active caspase‐6 colocalizes with neurons containing phosphorylated tau during early AD stages and that the number of neurons positive for both active caspase‐6 and p‐tau increases throughout AD's progression. However, how caspase‐6 activity differs between tauopathies involving different tau isoforms is unknown. This study compares caspase‐6 activation and caspase‐6 cleavage of tau between AD, argyrophilic grain disease (AGD), CBD, PiD, and PSP using novel neoepitope antibodies against caspase‐6‐cleaved tau.MethodUsing multiplex immunofluorescence on tissue microarrays, we measured levels of neuronal active caspase‐6, tau cleaved at C‐terminal residue D402 (D402), tau cleaved at N‐terminal residue D13 (D13), and tau phosphorylated at Ser202 (p‐tau; CP13) in the middle frontal gyrus (MFG) of well‐characterized AD, AGD, CBD, PiD, and PSP cases and controls. We used semi‐automated methods to calculate the percentage of neurons positive for each marker.ResultWe found similar percentages of neuronal p‐tau in every tauopathy except AGD, as expected. Only AD and PiD showed substantial percentages of neuronal caspase‐6‐cleaved tau (Figure 1, Table 1). The mean percentages of neuronal D402 and D13 were up to 121.88‐fold higher in AD and up to 16.75‐fold higher in PiD compared to the other tauopathies (Figure 1, Table 1). In PiD, on average, 79.82‐87.61% of neurons positive for D402 or D13 were also positive for p‐tau. Interestingly, in AD, only an average of 50.70‐58.98% of neurons positive for D402 or D13 showed p‐tau positivity (Figure 2).Conclusion1) Caspase‐6‐cleavage of tau appears to be a more defining feature of tauopathies involving 3‐repeat isoforms of tau than 4‐repeat tauopathies. 2) Caspase‐6‐cleaved tau inclusions do not necessarily colocalize with p‐tau inclusions. 3) Future research on the therapeutic potential of caspase modulators should focus on AD and PiD.

Astrocytic Tau Pathologies in Argyrophilic Grain Disease and Related Four-repeat Tauopathies.

Neurodegenerative diseases in which tau accumulation plays a cardinal role in the pathogenic process are called tauopathies, and when tau isoforms having four repeats of the microtubule binding sites, four-repeat tau, are selectively accumulated as pathological hallmarks, the term four-repeat tauopathy is used. The major four-repeat tauopathies are progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD). Historically, neuronal cytopathologies, e.g., neurofibrillary tangles and ballooned neurons, were emphasized as characteristic lesions in PSP and CBD. Now, however, astrocytic tau pathologies, i.e., tufted astrocytes (TAs) and astrocytic plaques (APs), are considered to be highly disease-specific lesions. Although granular/fuzzy astrocytes (GFAs) frequently develop in the limbic system in AGD cases, the specificity is not conclusive yet. Some AGD cases have a few TAs, and to a lesser frequency, a few APs in the frontal cortex and subcortical nuclei. The number of astrocytic tau pathologies including TAs and GFAs increases with the progression of AGD. In this paper, histopathological features of astrocytic tau pathologies in PSP, CBD, and AGD are first reviewed. Then, recent findings regarding the coexistence of these tauopathies are summarized from a viewpoint of astrocytic tau pathologies. Further biochemical and pathological studies focusing tau-positive astrocytic lesions may be useful to increase understanding of the pathological process in four-repeat tauopathies and to develop novel therapeutic strategies for patients with these diseases.

Argyrophilic Grain Pathology in Frontotemporal Lobar Degeneration: Demographic, Clinical, Neuropathological, and Genetic Features.

Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically, and genetically heterogeneous group of disorders that affect the frontal and temporal lobes of the brain. FTLD classification distinguishes three main neuropathological groups: FTLD-tau, FTLD-TDP, and FTLD-FUS. As a four-repeat tauopathy, argyrophilic grain disease (AGD) is included in the FTLD-tau group. AGD may also appear in association with other neuropathological disorders. We describe the demographic, clinical, neuropathological, and genetic characteristics of a series of FTLD cases presenting with AGD. For this purpose, a clinico-pathological study of 71 autopsy-confirmed FTLD cases from different tissue banks was performed. AGD was found in 52.1% of FTLD cases. The presence of AGD increased with the increasing age (up to 88.9% in cases older than 80 years; p < 0.001) and was associated with higher ages at onset (p < 0.001) and death (p < 0.001). In AGD cases, progressive supranuclear palsy (PSP) was the most frequent clinical diagnosis (29.7%) and gait disturbance was the most common symptom (64.5%); behavioral and language symptoms were less frequent as compared with non-AGD cases (p = 0.055; p = 0.012). PSP was the most frequent neuropathological diagnosis among cases with AGD (32.4%). This group also showed less brain atrophy (p = 0.094) and higher prevalence of Alzheimer (p = 0.002) and vascular pathology (p = 0.047) as compared to the non-AGD group. We also observed that H1/H1 genotype was overrepresented in AGD cases (p = 0.018) and that there was no association with any specific APOE allele. A subanalysis of PSP cases according to the AGD status was carried out, yielding no significant differences.

Neuropathological comorbidity associated with argyrophilic grain disease.

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.

The Relationship Between Development of Neuronal and Astrocytic Tau Pathologies in Subcortical Nuclei and Progression of Argyrophilic Grain Disease.

Progressive supranuclear palsy (PSP) cases frequently have argyrophilic grain disease (AGD). However, the PSP-like tau pathology in AGD cases has not been fully clarified. To address this, we examined tau pathologies in the subcortical nuclei and frontal cortex in 19 AGD cases that did not meet the pathological criteria of PSP or corticobasal degeneration, nine PSP cases and 20 Braak NFT stage-matched controls. Of the 19 AGD cases, five (26.3%) had a few Gallyas-positive tau-positive tufted astrocytes (TAs) and Gallyas-negative tau-positive TA-like astrocytic inclusions (TAIs), and six (31.6%) had only TAIs in the striatum and/or frontal cortex. Subcortical tau pathology was sequentially and significantly greater in AGD cases lacking these tau-positive astrocytic lesions, AGD cases having them, and PSP cases than in controls. There was a significant correlation between three histologic factors, including the AGD stage and the quantities of subcortical neuronal and astrocytic tau pathologies. Tau immunoblotting demonstrated 68- and 64-kDa bands and 33-kDa low-molecular mass tau fragments in PSP cases, and although with lesser intensity, in AGD cases with and without TAs and TAIs also. Given these findings, the progression of AGD may be associated with development of the neuronal and astrocytic tau pathologies characteristic of PSP.

Argyrophilic grain disease as a neurodegenerative substrate in late-onset schizophrenia and delusional disorders

To study the relationship between neurodegenerative diseases including argyrophilic grain disease (AGD) and late-onset schizophrenia and delusional disorders (LOSD; onset ≥40 years of age), we pathologically examined 23 patients with LOSD, 71 age-matched normal controls, and 22 psychiatric disease controls (11 depression, six personality disorder, two bipolar disorders, and three neurotic disorders cases). In all LOSD cases (compared to age-matched normal controls), the frequencies of Lewy body disease (LBD), AGD, and corticobasal degeneration (CBD) were 26.1 % (11.3 %), 21.7 % (8.5 %), and 4.3 % (0.0 %), respectively. There was no case of pure Alzheimer's disease (AD). The total frequency of LBD, AGD, and CBD was significantly higher in LOSD cases than in normal controls. Argyrophilic grains were significantly more severe in LOSD than in controls, but were almost completely restricted to the limbic system and adjacent temporal cortex. In LOSD patients whose onset occurred at ≥65 years of age (versus age-matched normal controls), the frequencies of LBD and AGD were 36.4 % (19.4 %) and 36.4 % (8.3 %), respectively, and AGD was significantly more frequent in LOSD patients than in normal controls. In LOSD patients whose onset occurred at <65 years of age, the frequencies of LBD, AGD, and CBD were 16.7, 8.3, and 8.3 %, comparable to those of age-matched normal controls (10.2, 5.1, and 0.0 %). In all psychiatric cases, delusion was significantly more frequent in AGD cases than in cases bearing minimal AD pathology alone. Given these findings, LOSD patients may have heterogeneous pathological backgrounds, and AGD may be associated with the occurrence of LOSD especially after 65 years of age.

Mitochondrial Dysfunction and Oxidative and Endoplasmic Reticulum Stress in Argyrophilic Grain Disease

Argyrophilic grain disease (AGD) is characterized by the accumulation of hyperphosphorylated 4R tau in dendritic varicosities (i.e."grains") in neurons and pretangles in certain areas of the cerebral cortex and other brain regions. We investigated oxidative and endoplasmic reticulum (ER) stress and dysregulation of mitochondrialbiogenesis as potential mechanisms involved in the AGD pathogenesis. Samples from AGD patients (n = 8) and nonpathologic, age-matched controls (n = 5) were compared using biochemical and immunohistochemical techniques with a panel of antibodies to markers of ER stress responses, stress chaperones, oxidative stress and associated cellular responses, respiratory chain complexes, mitochondrial regulators, and modulators of mitochondrial biogenesis. Because AGD is often associated with other tauopathies, mainly Alzheimer disease (AD), results were also compared with those of a group of similar Braak AD stage cases without grains (n = 5). In both AD and AGD cases, we found activation of key molecules that are involved in the unfolded protein response and lead to elevated ER chaperone levels, increased oxidative stress damage, mainly related to lipoxidation and targeting glycolytic enzymes. Altered expression of components of the respiratory chain markers modulating mitochondrial biogenesis were selectively affected in AGD. The findings suggest that, despite the common pathogenic trends in AD and AGD, there is molecular specificity for AGD.

Argyrophilic grain disease: an update about a frequent cause of dementia.

Argyrophilic grain disease (AGD) is a sporadic, very late-onset tauopathy, accounting for approximately 4–13% of neurodegenerative dementias. AGD may manifest with a range of symptoms such as cognitive decline and behavioral abnormalities. To date, no study has been able to demonstrate a distinct clinical syndrome associated with AGD. The diagnosis is exclusively based on postmortem findings, the significance of which remains controversial because up to 30% of AGD cases are diagnosed in subjects without any cognitive impairment, while AGD findings often overlap with those of other neurodegenerative processes. Nevertheless, the presence of AGD is likely to have a significant effect on cognitive decline. The neuropathological hallmarks of AGD are argyrophilic grains, pre-neurofibrillary tangles in neurons and coiled bodies in oligodendrocytes found mainly in the entorhinal cortex and hippocampus. This review aims to provide an up-to-date overview of AGD, emphasizing pathological aspects. Additionally, the findings of a Brazilian case series are described.

Accumulation of phosphorylated TDP-43 in brains of patients with argyrophilic grain disease

To determine whether TAR-DNA binding protein 43 (TDP-43) immunoreactivity was present in brains of argyrophilic grain disease (AGD), we immunohistochemically examined 15 cases of AGD (mean age at death: 84 years) using a panel of anti-TDP-43 antibodies, including both phosphorylation-independent and -dependent ones. Nine AGD cases (60%) showed TDP-43 immunoreactivities mainly in the limbic regions and lateral occipitotemporal cortex. TDP-43 positive structures included neuronal cytoplasmic inclusions, dystrophic neurites, glial cytoplasmic inclusions, grain-like dot-shaped structures, and neurofibrillary tangle (NFT)-like structures. The distribution of these TDP-43 positive structures was largely consistent with that of argyrophilic grains. Double-labeling confocal microscopy revealed, however, that many of phospho-TDP-43 positive structures were not colocalized with phospho-tau staining. Colocalization of phospho-TDP-43 and phospho-tau was observed only in part of neuronal cytoplasmic inclusions, grain-like structures and NFT-like structures. There were no differences in demographics, disease duration, brain weight, NFT Braak stage, or severity of amyloid burden between AGD cases with and without TDP-43-immunoreactivity. However, cases of AGD with TDP-43-immunoreactivity were assigned to higher AGD stages than those without TDP-43-immunoreactivity (P < 0.05). Furthermore, the TDP-43 pathology tended to be prominent in cases with severe grain pathology. The results of the present study indicate for the first time a high frequency of concomitant TDP-43 pathology in AGD, and suggest that abnormal accumulation of TDP-43 may be involved in the pathological process and disease progression of AGD.

Tracing of temporo-entorhinal connections in the human brain: cognitively impaired argyrophilic grain disease cases show dendritic alterations but no axonal disconnection of temporo-entorhinal association neurons

Argyrophilic grain disease (AGD), a neurodegenerative disorder, is often associated with mild to moderate Alzheimer’s disease (AD)-related pathology. The development of dementia in AGD is associated with the extent of coexisting AD-related pathology. Therefore, the question arises whether the degenerative changes in the neuronal network of demented AGD-patients represent a distinct pattern or show similar changes of disconnection as considered for AD. We were able to apply DiI-tracing in two human autopsy cases with mild AD-related pathology (controls), in one AD-patient, in one non-demented patient with advanced AD-related pathology, and in three cognitively impaired AGD-patients. DiI-crystals were injected into the entorhinal cortex. Pyramidal neurons of layers III and V of the adjacent temporal neocortex (area 35) were retrogradely marked with the tracer and analyzed. The AD case did not exhibit any retrogradely labeled neurons in the temporal neocortex. In the non-demented case with advanced AD-related pathology, the number of traced neurons was reduced as compared to that in the two controls and in the three AGD cases. In contrast, all three cognitively impaired AGD cases exhibited labeled pyramidal neurons in area 35 in an almost similar number as in the controls. However, alterations in the dendritic tree were observed in the AGD cases. These results show the existence of temporo-entorhinal connections in the adult human brain similar to those reported in animal models. Furthermore, the present study based on seven cases is the first attempt to study changes in the neuronal network in a human tauopathy with targeted axonal tracing techniques. Our findings in three cognitively impaired AGD cases suggest that AGD-related dementia constitutes a distinct disorder with a characteristic pattern of degeneration in the neuronal network.

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.

The ubiquitin-binding protein p62 identifies argyrophilic grain pathology with greater sensitivity than conventional silver stains

The routine diagnosis of argyrophilic grain disease is fraught by the lack of availability of an easily applied reproducible stain that can highlight the grain pathology with sensitivity and with minimal background. The Gallyas silver iodide technique is not widely used and, even in experienced hands, is difficult to perform due to inconsistencies inherent in silver-based techniques on thin sections. Grain pathology can be detected using immunohistochemistry for phosphorylated tau protein, but the grain pathology is most often masked by background tau-positive material; leading to problems with interpretation, especially for practitioners seeing small numbers of cases. There is a need for a reliable immunohistochemical stain that can detect grain pathology and provide a clear contrast between grains and other tau-positive neurodegenerative pathologies. We have investigated the novel ubiquitin-binding protein p62 as a potential biomarker for grain pathology in argyrophilic grain disease. Four cases of argyrophilic grain disease, in which the pathology was determined using the Gallyas silver iodide technique, were re-assessed using paraffin-embedded sections immunostained with antibodies specific for p62. We found that the detection of grain pathology was more sensitive than with silver-based techniques and that the resolution of the pathology was significantly improved. We suggest that p62 could be used to replace the Gallyas technique in the routine diagnosis of argyrophilic grain disease.

Argyrophilic grain disease presenting with frontotemporal dementia: A neuropsychological and pathological study of an autopsied case with presenile onset

A right-handed Japanese man with no consanguinity exhibited personality changes, speech disorder and abnormal behaviors, such as stereotypical, running-away, environment-dependent, and going-my-way behaviors, since the age of 49 years. At age 52 years, neuropsychological examination revealed frontal lobe dysfunctions, mild memory impairment, and transcortical sensory aphasia. MRI showed symmetrical severe atrophy of the anterior part of the temporal and frontal lobes. The clinical diagnosis was FTD. He died at age 54 years after a clinical illness of approximately 5 years. Numerous argyrophilic grains were observed throughout the limbic system, temporal lobe, frontal lobe and brainstem. In addition, there were many tau-positive neurons and glial cells. These findings are all compatible with argyrophilic grain disease (AGD). Our case, however, is atypical AGD because of the young age of onset of the disease and sharply circumscribed cortical atrophy exhibiting severe neuronal loss and gliosis. Our case, together with some other similar cases of atypical AGD, gives rise to the possibility that this type of AGD would constitute a part of pathological background of FTD.

The impact of argyrophilic grain disease on the development of dementia and its relationship to concurrent Alzheimer's disease‐related pathology

Argyrophilic grain disease (AGD) constitutes a neurodegenerative disorder that occurs in the brains of the elderly and affects 5% of all patients with dementia. Tau protein-containing lesions known as argyrophilic grains and located predominantly in limbic regions of the brain characterize this disease. Dementia is encountered in only a subset of cases that display the morphological pattern of AGD. The aim of this study is to determine the role of concurrent Alzheimer's disease (AD)-related pathology for the development of dementia in AGD patients. A total of 204 post-mortem brains from 30 demented and 49 nondemented AGD patients, 39 AD patients, and from 86 nondemented controls without AGD were staged for AD-related neurofibrillary tangles (NFTs) as well as amyloid beta-protein (Abeta) deposition. To identify differences in AD-related pathology between demented and nondemented AGD cases, and to differentiate the pattern of AD-related changes in demented and nondemented AGD cases from that seen in AD and nondemented controls, we statistically compared the stages of Abeta and NFT distribution among these groups. Using a logistic regression model, we showed that AGD has a significant effect on the development of dementia beyond that attributable to AD-related pathology (P < 0.005). Demented AGD cases showed lower stages of AD-related pathology than did pure AD cases but higher stages than nondemented AGD patients. AGD associated dementia was seen in the presence of NFT (Braak)-stages II-IV and Abeta-phases 2-3, whereas those stages were not associated with dementia in the absence of AGD. In conclusion, AGD is a clinically relevant neurodegenerative entity that significantly contributes to the development of dementia by lowering the threshold for cognitive deficits in the presence of moderate amounts of AD-related pathology.

P3-186 Concurrent Alzheimer's disease-related pathology lowers the threshold for developing dementia in argyrophilic grain disease

Background: Argyrophilic grain disease (AGD) constitutes a neurodegenerative disorder that occurs in the brains of the elderly and affects 5% of all patients with dementia, tan-protein-containing lesions known as argyrophilic grains in neuronal processes and coiled bodies in oligodendrocytes characterize this disease. Dementia is encountered in only a subset of cases that display the morphological pattern of AGD at autopsy. Objective: To determine the role of concurrent Alzheimer's disease (AD)-related pathology for the development of dementia in AGD patients. Methods: Autopsy brains from 30 demented and 49 non-demented AGD patients, from 46 AD patients and from 86 non-demented controls without AGD were staged for the distribution of AD-related neurofibrillary changes and amyloid 13-protein (AI3) deposits. To identify differences in the distribution of AD-related pathology between demented and non-demented AGD cases, and to differentiate the pattern of AD-related changes in AGD cases from that seen in AD and non-demented controls, we compared the distribution of AI3-deposits and neurofibrillary changes among these groups of cases. Differences in the stages of the distribution of neurofibrillary changes and A[3-deposits among these groups were analyzed statistically. Conclusions: Demented AGD patients exhibited significantly higher stages of AD-related AI3-deposition and neurnfibrillary tangle pathology as compared to non-demented AGD cases, but significantly lower stages of both lesions compared to AD without AGD. In conclusion, AGD is a clinically relevant neurodegenerative entity that significantly lowers the threshold for developing dementia when it is associated with AD-related pathology.

Selective neurofibrillary degeneration of the hippocampal CA2 sector is associated with four-repeat tauopathies.

The CA2 sector of the hippocampus is relatively resistant to neurofibrillary tangles in aging and Alzheimer disease; however, some cases have selective neurofibrillary degeneration in CA2 with sparing of the more vulnerable CA1 sector. Cases such as this do not fit in the Braak and Braak staging scheme and can be considered to have an atypical pattern of neurofibrillary degeneration. We identified 24 atypical cases with an average age at death of 78.6 +/- 1.4 yr and average Braak stage of 3.2 +/- 0.4 and describe their pathologic and genetic characteristics with Gallyas silver staining, immunohistochemistry for tau and alphaB-crystallin, as well as apolipoprotein-E (ApoE) and tau genotyping. Three cases were excluded from further analysis due to presence of hippocampal sclerosis. All but 1 of the remaining 21 atypical cases were four-repeat (4R) tauopathies, including progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease (AGD). Remarkably, 19 of the 21 atypical cases were pure or mixed cases of AGD. The ApoE epsilon4 allele frequency was similar to normal controls, while there was a trend for an increased frequency of the extended tau H1 haplotype in atypical cases. Selective neurofibrillary degeneration in CA2 sector of the hippocampus is not widely recognized, but when detected should suggest the possibility of a 4R-tauopathy, particularly AGD.

Genetic association of argyrophilic grain disease with polymorphisms in alpha-2 macroglobulin and low-density lipoprotein receptor-related protein genes.

Argyrophilic grain disease (AGD) is a neurodegenerative disorder of the aged human brain associated with the formation of abnormal tau protein in specific neurones and macroglial cells. Previously, we reported the association between AGD and the epsilon2 allele of apolipoprotein E (ApoE). Here, the polymorphisms of the alpha-2 macroglobulin gene (A2M) and those of the low-density lipoprotein receptor-related protein gene (LRP) were assessed in 115 AGD cases and compared with 170 controls. The results reveal an association between AGD and the C766T polymorphism of LRP (P=0.001). In addition, the present study shows that the valine to isoleucine (Val1000Ile) polymorphism of A2M is linked with AGD (P=0.03). By comparison, no relationship between AGD and the intronic 5-bp deletion/insertion polymorphism of A2M is demonstrable (P=0.8). Finally, this report corroborates and extends our earlier finding in that the frequency of the epsilon2 allele of ApoE is higher in AGD cases than in controls (17.4% vs. 8.5%, P=0.003), whereas the epsilon4 allele frequency approximates that in control cases (13.9% vs. 13.2%, P=0.93). This association, however, is only apparent in the presence of the LRP CC genotype. In conclusion, the present study shows that AGD is associated with the LRP, A2M and ApoE genes.

The subthalamic nucleus has neurofibrillary tangles in argyrophilic grain disease and advanced Alzheimer's disease

Neurofibrillary tangles (NFT) are present in the subthalamic nucleus (STN) of progressive supranuclear palsy and corticobasal degeneration, two sporadic tauopathies with preferential accumulation of tau with four repeats in the microtubule binding domain (4R tau). Since recent evidence suggests that argyrophilic grain disease (AGD) is also a 4R tauopathy, we hypothesized that the STN may also be affected in AGD. Tau immunostaining was used to evaluate NFT in the STN in 18 cases of AGD compared with 18 non-AGD cases matched for age, sex and Braak stage. AGD cases had significantly more NFT in the STN than non-AGD cases ( P=0.008) with no relationship between NFT score and Braak stage. Surprisingly, NFT were also found in the STN of some non-AGD cases, notably in cases with advanced Braak stage (i.e. Alzheimer's disease). When AGD and non-AGD were considered as a whole there was a correlation between neurofibrillary degeneration in the STN and Braak stage. This study demonstrates that neurofibrillary degeneration is frequent in the STN in AGD, but also detected in non-AGD cases with advanced Braak stage.