Neuropathological Alzheimer’s Disease Lesions in Nasu-Hakola Disease with TREM2 Mutation: Atypical Distribution of Neurofibrillary Changes

Nasu-Hakola disease is a rare autosomal recessive disorder associated to mutations in TREM2 and DAP12 genes, neuropathologically characterized by leukoencephalopathy with axonal spheroids. We report the neuropathologic findings of a 51-year-old female with a homozygous mutation (Q33X) of TREM2 gene. Beside severe cerebral atrophy and hallmarks of Nasu-Hakola disease, significant Alzheimer’s disease lesions were present. Neurofibrillary changes showed an atypical topographic distribution being severe at spots in the neocortex while sparing the mesial temporal structures. Our finding suggests that TREM2 genetic defects may favor Alzheimer’s disease pathology with neurofibrillary changes not following the hierarchical staging of cortical involvement identified by Braak.

From the Entorhinal Region via the Prosubiculum to the Dentate Fascia: Alzheimer Disease-Related Neurofibrillary Changes in the Temporal Allocortex

The pathological process underlying Alzheimer disease (AD) unfolds predominantly in the cerebral cortex with the gradual appearance and regional progression of abnormal tau. Intraneuronal tau pathology progresses from the temporal transentorhinal and entorhinal regions into neocortical fields/areas of the temporal allocortex. Here, based on 95 cases staged for AD-related neurofibrillary changes, we propose an ordered progression of abnormal tau in the temporal allocortex. Initially, abnormal tau was limited to distal dendritic segments followed by tau in cell bodies of projection neurons of the transentorhinal/entorhinal layer pre-α. Next, abnormal distal dendrites accumulated in the prosubiculum and extended into the CA1 stratum oriens and lacunosum. Subsequently, altered dendrites developed in the CA2/CA3 stratum oriens and stratum lacunosum-moleculare, combined with tau-positive thorny excrescences of CA3/CA4 mossy cells. Finally, granule cells of the dentate fascia became involved. Such a progression might recapitulate a sequence of transsynaptic spreading of abnormal tau from 1 projection neuron to the next: From pre-α cells to distal dendrites in the prosubiculum and CA1; then, from CA1 or prosubicular pyramids to CA2 principal cells and CA3/CA4 mossy cells; finally, from CA4 mossy cells to dentate granule cells. The lesions are additive: Those from the previous steps persist.

Alois Alzheimer and vascular brain disease: Arteriosclerotic atrophy of the brain

Alois Alzheimer is best known for his description of neurofibrillary changes in brain neurons of a demented patient, identifying a novel disease, soon named after him by Kraepelin. However, the range of his studies was broad, including vascular brain diseases, published between 1894 and 1902. Alzheimer described the clinical picture of Arteriosclerotic atrophy of the brain, differentiating it from other similar disorders. He stated that autopsy allowed pathological distinction between arteriosclerosis and syphilis, thereby achieving some of his objectives of segregating disorders and separating them from syphilis. His studies contributed greatly to establishing the key information on vascular brain diseases, predating the present state of knowledge on the issue, while providing early descriptions of what would be later regarded as the dimensional presentation of the now called "Vascular cognitive impairment", constituted by a spectrum that includes a stage of "Vascular cognitive impairment not dementia" and another of "Vascular dementia".