Argyrophilic grain disease in individuals younger than 75 years: clinical variability in an under‐recognized limbic tauopathy

Abstract

Background and purpose Argyrophilic grain disease (AGD) is a limbic‐predominant 4R‐tauopathy. AGD is thought to be an age‐related disorder and is frequently detected as a concomitant pathology with other neurodegenerative conditions. There is a paucity of data on the clinical phenotype of pure AGD. In elderly patients, however, AGD pathology frequently associates with cognitive decline, personality changes, urine incontinence and cachexia. In this study, clinicopathological findings were analysed in individuals younger than 75. Methods Patients were identified retrospectively based on neuropathological examinations during 2006–2017 and selected when AGD was the primary and dominant pathological finding. Clinical data were obtained retrospectively through medical records. Results In all, 55 patients (2% of all examinations performed during that period) with AGD were identified. In seven cases (13%) AGD was the primary neuropathological diagnosis without significant concomitant pathologies. Two patients were female, median age at the time of death was 64 years (range 51–74) and the median duration of disease was 3 months (range 0.5–36). The most frequent symptoms were progressive cognitive decline, urinary incontinence, seizures and psychiatric symptoms. Brain magnetic resonance imaging revealed mild temporal atrophy. Conclusions Argyrophilic grain disease is a rarely recognized limbic tauopathy in younger individuals. Widening the clinicopathological spectrum of tauopathies may allow identification of further patients who could benefit from tau‐based therapeutic strategies.

Tauopathies: new perspectives and challenges

“…However, imbalance in the ratio of the 3R and 4R isoforms can give rise to the pathogenesis of tauopathies, as the 4R tau is more efficient in promoting microtubule assembly with an extra repeat domain R2 which hyper-stabilize MT and more free-floating tau leads to aggregates formation [3,6,7] identified 7 patients via postmortem examination, only 2 were female. Most patients died at 64 years old with median survival time being 3 months (0.5-36) [28].…”

“…Clinicopathological correlations are not specific, which is confounded by normal ageing and concurrence of pathologies, resulting in difficulties of reaching antemortem diagnosis [52]. A retrospective study on 55 patients aged under 75 with relatively pure AGD pathology (low concurrence) concluded common symptoms for AGD patients: progressive cognitive impairment akin to the onset stage of AD, urinary incontinence, seizures, and psychological disorders [28].…”

Impact of Amyloid Pathology in Mild Cognitive Impairment Subjects: The Longitudinal Cognition and Surface Morphometry Data

“…For the Aβ− group, the pathological substrates that contributed to their cognitive impairment or cortical thinning should be determined. This category comprises several different types of amyloid-unrelated pathologies such as primary age–related tauopathy (PART) [ 26 ], hippocampal sclerosis [ 27 , 28 , 29 ], TAR DNA binding protein (TDP)-43 pathology [ 30 , 31 ], argyrophilic grain disease (AGD) [ 32 , 33 ], and accelerated aging [ 34 ]. The clinical features of the Aβ− group corresponded to the finding of another study that a nonnegligible proportion of patients clinically diagnosed as having MCI due to AD did not have amyloid deposition in their histopathology [ 4 ].…”

“…Medial temporal atrophy was reported in patients with PART [ 26 ], hippocampal sclerosis [ 27 , 28 , 29 ], and AGD [ 32 , 33 ]. In our study, the patients with Aβ− status did not exhibit any atrophy in the medial temporal lobe, suggesting a low proportion of patients within this category.…”

Recent update on the heterogeneity of the Alzheimer’s disease spectrum

“…AGD, a limbic predominant 4R tauopathy, with grain-like deposits in neuritic dendrites, oligodendroglial inclusions ("coiled bodies"), ramified astrocytes, and ballooned neurons in the amygdala, hippocampus and medial temporal lobes (Togo et al 2002), has been reported in up to 25% of AD cases (Togo et al 2002). It rarely occurs before the age of 75 years (Wurm et al 2020). Granulovacuolar degeneration (GVD), characterized as 3-5 γm vesicles, occurs in the pyramidal neurons of the hippocampus, usually in association with NFTs.…”