Alzheimer’s disease (AD) is a progressive neurodegenerative disease of the brain and the most common cause of dementia among elderly people worldwide, accounting for at least two-thirds of all dementia cases. Macroscopically, a general cerebral atrophy is a hallmark of AD. Microscopically, prone features include diffuse and neuritic extracellular plaques composed of amyloid beta (Aβ) peptides frequently surrounded by dystrophic neurites, and intraneuronal neurofibrillary tangles (NFT) composed of paired helical filaments of phosphorylated tau proteins. These hallmark pathologies are often accompanied by reactive microgliosis and synapse loss. The neuropathological staging of AD in research centers may be performed using the Braak and Braak (1991) staging, where NFT and neuritic plaques exhibit a distribution pattern used to classify the degree of pathology into six stages. Frontotemporal dementia is a lesser known but equally devastating condition. Frontotemporal lobar degeneration (FTLD) represents a group of disorders that is considered to be clinically and pathologically distinct from AD. Macroscopically, there may be focal atrophy of the frontal and temporal lobes with variable involvement of the striatum. FTLD is genetically, neuropathologically, and clinically heterogeneous and may present as a dementia with three major clinical syndromes dominated by behavioral, language, and motor disorders, respectively. Most of these diseases are characterized by the pathological aggregation of misfolded proteins, either in neurons or glial cells, or both. About half of these cases have abnormal intracellular cytoplasmic accumulations of the microtubule-associated protein tau (MAPT). The characteristic aggregate-forming protein in non-tau FTLD is either TAR DNA-binding protein 43 (TDP-43), the most frequent protein or RNA-binding Fused in Sarcoma (FUS) protein or FUS. Additionally, inflammation mediated by activated microglia is an important component of AD pathophysiology, and neuritic plaques and neurofibrillary tangles are foci of a local inflammatory response. The pathogenic mechanisms implicated in neurodegenerative disorders are not linked to individual clinical entities. Neuroinflammation is probably a common cause across the disease spectrum. In contrast, neurodegenerative pathogenesis shows a considerable overlap in protein misfolding and aggregation. The overlapping proteinopathies /comorbidities exist throughout the entire spectrum of most neurodegenerative disorders. Notably, these comorbidities may often influence the main pathology and affect both disease progression, cognitive decline and duration of the disease.

Neuropathological Diagnoses of Dementia

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发表日期：

2026年

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Rajka M. Liscic

摘要

Alzheimer’s disease (AD) is a progressive neurodegenerative disease of the brain and the most common cause of dementia among elderly people worldwide, accounting for at least two-thirds of all dementia cases. Macroscopically, a general cerebral atrophy is a hallmark of AD. Microscopically, prone features include diffuse and neuritic extracellular plaques composed of amyloid beta (Aβ) peptides frequently surrounded by dystrophic neurites, and intraneuronal neurofibrillary tangles (NFT) composed of paired helical filaments of phosphorylated tau proteins. These hallmark pathologies are often accompanied by reactive microgliosis and synapse loss. The neuropathological staging of AD in research centers may be performed using the Braak and Braak (1991) staging, where NFT and neuritic plaques exhibit a distribution pattern used to classify the degree of pathology into six stages. Frontotemporal dementia is a lesser known but equally devastating condition. Frontotemporal lobar degeneration (FTLD) represents a group of disorders that is considered to be clinically and pathologically distinct from AD. Macroscopically, there may be focal atrophy of the frontal and temporal lobes with variable involvement of the striatum. FTLD is genetically, neuropathologically, and clinically heterogeneous and may present as a dementia with three major clinical syndromes dominated by behavioral, language, and motor disorders, respectively. Most of these diseases are characterized by the pathological aggregation of misfolded proteins, either in neurons or glial cells, or both. About half of these cases have abnormal intracellular cytoplasmic accumulations of the microtubule-associated protein tau (MAPT). The characteristic aggregate-forming protein in non-tau FTLD is either TAR DNA-binding protein 43 (TDP-43), the most frequent protein or RNA-binding Fused in Sarcoma (FUS) protein or FUS. Additionally, inflammation mediated by activated microglia is an important component of AD pathophysiology, and neuritic plaques and neurofibrillary tangles are foci of a local inflammatory response. The pathogenic mechanisms implicated in neurodegenerative disorders are not linked to individual clinical entities. Neuroinflammation is probably a common cause across the disease spectrum. In contrast, neurodegenerative pathogenesis shows a considerable overlap in protein misfolding and aggregation. The overlapping proteinopathies /comorbidities exist throughout the entire spectrum of most neurodegenerative disorders. Notably, these comorbidities may often influence the main pathology and affect both disease progression, cognitive decline and duration of the disease.