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3) Preservation and Decline of Specific Cognitive Functions:

4) Neuropathology and Cognitive Impairment in AGD:

Verbal & Problem-Solving Abilities: Preserved longer than in AD, showing delayed cognitive decline.

Amygdala Involvement: Altered by argyrophilic grain accumulation, disrupting emotional processing.

Tauopathy Classification: Phospho-tau grains, affecting memory and executive function.

Typically presents with mild and non-progressive amnestic cognitive impairment,

6) Diagnostic Challenges in Identifying AGD’s Cognitive Profile

5) Cognitive and Psychiatric Implications

Judgment problems declines later, impacting decision-making over time.

IMMUNOHISTOCHEMISTRY

Diagnostic Challenge: AGD and Alzheimer's show similar neuroimaging features like lobar atrophy, complicating differentiation.

MACROSCOPIC FINDINGS

23.4% of patients were reported to have dementia, and 15.2% had a history of psychiatric visits.

Suicide Rate: Significantly higher in AGD cases than in AGD-negative groups across ages.

  • ArG and coiled bodies in AgD cases primarily consist of the abnormally and hyperphosphorylated tau protein.

  • Pathological tau aggregates mainly made of four-repeat tau isoforms

  • Amygdala and layers V and VI show ballooned neurons (Gallyas-negative, Tau- and B-crystallin-positive) with glial tau pathology in astrocytes, alongside coiled bodies.

Object recognition and attention may remain relatively unaffected in the early stages of AGD.

Diagnostic Limitations: Lack of specific biological assays or clinical tests for AGD

Macroscopic findings reveal cortical atrophy in the frontal, temporal, parietal and occipital lobes, The medial temporal lobe also had mild atrophy. (Koga et al., 2023)

Cortical Changes:

- Thinning of the cortical gray mantle, particularly in the medial temporal lobe.

Subcortical Structures:

- Marked atrophy observed in the hippocampal formation and amygdala.

- Gray discoloration noted in the subjacent white matter.

- Macroscopic examination revealed no remarkable changes in the basal ganglia and thalamus.

Constant presence of nonargyrophilic astrocytes expressing hyperphosphorylated tau epitopes in AgD cases, notably in anterior limbic structures and basal temporal neocortical areas (Tolnay & Clavaguera, 2004).

Associated with late-onset psychiatric conditions like bipolar disorder and schizophrenia in middle-aged or olders.

Amygdala Link: Initial argyrophilic grain buildup contributes to psychiatric symptoms.

Symptom Variability: Diverse cognitive symptoms, from memory loss to decision-making difficulties

Representative macroscopic images. (A) Mild cortical atrophy is observed in the inferior frontal and superior temporal lobes (dotted circle). (B and C) The anterior and temporal horns are markedly dilated (asterisks), but the caudate nucleus is free of atrophy. The atrophy of the hippocampus (B) is observed, while the subthalamic nucleus (B, arrows) is preserved. (D) The locus coeruleus (arrow) and substantia nigra (dotted circle) show decreased pigmentation. Scale bars = 1 cm

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Further Questions

  • What is the origin of the grains?
  • Is AGD a distinct clinical syndrome?
  • How can neurofibrillary tangles of Alzheimer disease be differentiated from those found in AGD?
  • Is there any hallmark clinical symptom suggestive of the presence of AGs in the brain?

***Additional comprehensive, prospective clinicopathological correlation studies are required to answer many of these questions.

Tau Gene Mutations:

Certain tauopathies are linked to mutations in the tau gene (MAPT).

-contributes to the diversity

Isoforms of Tau:

Six isoforms of tau exist.

Different tauopathies have unique signatures, and not all tau isoforms co-aggregate in each tauopathy.

Neuropathological Progression:

- archetypal pattern of progression

-Stages include involvement of various brain regions, from the entorhinal cortex to neocortex and brainstem.

Tau Propagation Model:

-has been considered as a natural model of tau propagation.

-Tau deposits are observed in neurons, threads, oligodendrocytes, and astrocytes following injection of AGD homogenates.

Prion-Like Tau Strains:

Brain extracts from AGD patients have the capacity to transmit tau to cultured cells expressing 4Rtau.

This suggests that prion-like tau strains can also propagate in cultured cells.

HISTOPATHOLOGICAL FINDINGS

Argyrophilic Grains (ArG) in AgD:

  • Primary histopathological hallmark of AgD is Oval, spindle-shaped, or comma-like lesions.

  • Best detected with silver staining methods (e.g., Bielschowsky or Bodian), especially Gallyas silver iodide technique.

  • However, only a fraction of abnormal intracellular deposits are argyrophilic fibrils, so silver staining is mainly for diagnostic purposes.

Distribution of ArG:

  • Found in both cortical and subcortical structures.
  • Highest susceptibility in the transentorhinal and entorhinal cortices in the anteromedial temporal lobe.
  • Mainly concentrated in the upper layer of the entorhinal and transentorhinal cortex.

E Tau progression (argyrophilic grains (AGs)) in AGD has four stages, shown in view same as D. Stage I is characterized by AGs in ambient gyrus, hippocampus (CA1), entorhinal and amygdala. Stage II shows involvement of medial temporal lobe and subiculum. Stage III, AGs reaches anterior temporal, cingulate gyrus, rectus gyrus, septum, accumbens nucleus, insular and orbitofrontal cortices, and hypothalamus (CA2 CA3). Stage IV involves neocortex and brainstem (not shown in figures).

ARGYROPHILIC

GRAIN DISEASE

Tau pathological features in an AGD case immunostained with PHF-1 antibody. [A] Grains in the CA1 subfield of the hippocampus; [B] Pretangles with perinuclear halo in the CA2 subfield of the hippocampus; [C] Coiled-body in the CA1 subfield of the hippocampus; [D] Balloon neuron in amygdala (arrow); [E] Bush-like astrocyte in amygdala; [F] Prominent involvement of CA2 subfield of the hippocampus with sparing of the CA1 subfield. Scale bars represent 50 µm in A, D, E; 20 µm in B,C and 200 µm in F.

Nonargyrophilic astrocytes expressing hyperphosphorylated tau epitopes are consistently found in anterior limbic structures, such as the amygdala and anterior entorhinal cortex, in AgD cases.

References

Argyrophilic Grain Disease

Dujardin, S., Bégard, S., Caillierez, R. et al. Different tau species lead to heterogeneous tau pathology propagation and misfolding. acta neuropathol commun 6, 132 (2018). https://doi.org/10.1186/s40478-018-0637-7

Tolnay, M., & Clavaguera, F. (2004). Argyrophilic grain disease: A late‐onset dementia with distinctive features among tauopathies. Neuropathology, 24(4), 269–283. https://doi.org/10.1111/j.1440-1789.2004.00591.x

-Very late-onset tauopathy.

-Accounts for 4–13% of neurodegenerative dementias.

-First described in 1987 by Braak and colleagues.

-characterized by argyrophilic grains in limbic structures.

Yoshida, K., Hata, Y., Ichimata, S. et al. Argyrophilic grain disease is common in older adults and may be a risk factor for suicide: a study of Japanese forensic autopsy cases. Transl Neurodegener 12, 16 (2023). https://doi.org/10.1186/s40035-023-00352-2

Koga, S., Murakami, A., Soto-Beasley, A. I., Walton, R. L., Baker, M., Castanedes‐Casey, M., Josephs, K. A., Ross, O. A., & Dickson, D. W. (2023). Diffuse argyrophilic grain disease with TDP-43 proteinopathy and neuronal intermediate filament inclusion disease: FTLD with mixed tau, TDP-43 and FUS pathologies. Acta Neuropathologica Communications, 11(1). https://doi.org/10.1186/s40478-023-01611-z

Diagram of a normal microtubule and one affected by tauopathy

  • Dilara Ahman
  • Beyza Yasak
  • Pooja Matada

Clinical Features:

-No distinct clinical syndrome associated...

-Limited studies describe clinical features correlating with AGD.

Diagnosis:

-based solely on postmortem findings.

-grains identified through microscopic examination of brain tissue.

Prevalence and Cognitive Impact:

-Highly prevalent, but up to 30% of cases diagnosed without cognitive impairment.

Overlap with Other Pathologies:

-often overlap with other neurodegenerative findings, particularly neurofibrillary tangles (NFT) seen in Alzheimer’s disease.

Zhang, Y., Wu, KM., Yang, L. et al. Tauopathies: new perspectives and challenges. Mol Neurodegeneration 17, 28 (2022). https://doi.org/10.1186/s13024-022-00533-z

Grinberg LT, Heinsen H. Argyrophilic grain disease: an update about a frequent cause of dementia. Dement Neuropsychol. 2009 Jan-Mar;3(1):2-7. doi: 10.1590/S1980-57642009DN30100002. PMID: 29213602; PMCID: PMC5619024.

What is known about how the disease progresses in the brain?

Nature of Tauopathies:

-diverse group of pathologies characterized by tau aggregation within neurons.

- sporadic, but some are associated with mutations in the tau gene (MAPT).

Heterogeneity:

-exhibit heterogeneity in terms of neuropathological signatures.

Differences include lesion shapes, affected brain regions, and the molecular composition of tau aggregates.

COGNITIVE PROFILE OF ARGYROPHILIC GRAIN DISEASE

Pathological appearance of argyrophilic grain disease.

Photomicrograph of Gallyas–Braak (a, c), AT8 (b, e, f), and luxol fast blue-hematoxylin and eosin (d).

a Argyrophilic grains.

b AT8-positive pretangle in the amygdaloid body.

c Oligodendroglial coiled body.

d, e Achromasic ballooned neuron.

f Granular astrocyte. Scale bars, 50 µm (a, b, f) and 20 µm (c–e)

1)Cognitive Impairment and Progression in AGD:

  • AGD and Alzheimer's pathology combined intensify cognitive decline.
  • Begins with subtle memory impairments.
  • Displays non-progressive memory deficits, unlike other neurodegenerative conditions.
  • Concurrent AD presence hastens cognitive deterioration beyond AGD alone.

2)Behavioral and Emotional Manifestations in AGD:

  • Behavioral Symptoms: Personality changes, mood imbalances with cognitive decline
  • Emotional Disturbances: Emotional instability, irritability, agitation; Dysphoria and apathy as progression markers
  • Psychiatric Prevalence: High psychiatric symptom prevalence, depression and aggression common before dementia, inverse to AD pattern

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