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Progression of hippocampal degeneration in amyotrophic lateral sclerosis with or without memory impairment: distinction from Alzheimer disease

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Abstract

The hippocampal involvement in amyotrophic lateral sclerosis (ALS) patients has been known for more than a decade, however, its relationship to clinical manifestations including memory deficits and topographical differentiation from Alzheimer disease (AD) remain unclear. In order to clarify the anatomopathological features in the hippocampus and their relevance to disease-specific memory deficits in ALS patients, topography and cytopathology of the hippocampal lesions along the perforant pathway were quantitatively and semiquantitatively surveyed in 14 ALS patients with extramotor involvement. These pathological findings were compared with clinical characteristics assessed from their clinical records. Cytoplasmic inclusions initially appear in the granular cells of the dentate gyrus (DG) and superficial small neurons of the transentorhinal cortex (TEC) with mild subicular degeneration (stage I: inclusion stage). Subsequent gliosis and neuronal loss of the TEC, concomitant with presynaptic degeneration of the outer molecular layer of the DG, suggests an extension of the degeneration through the perforant pathway (stage II: early perforant stage). In a more advanced stage, the presynaptic degeneration is more evident with moderate to severe neuronal loss in the TEC (stage III: advanced perforant stage). This advanced stage was associated with episodic memory deficits mimicking AD in some ALS patients. This ALS pathology initiated by cytoplasmic inclusions and neuronal loss in layer II–III of the TEC is different from neurofibrillary tangles of AD, dominant in layer II–III of the entorhinal cortex. Because this involvement of the TEC-molecular DG projection and subiculum is specific to ALS, it will provide a basis for clinical characterization of memory deficits of ALS, which could be distinct from those of AD.

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Abbreviations

AD:

Alzheimer disease

ALS:

Amyotrophic lateral sclerosis

ALSD:

Amyotrophic lateral sclerosis with dementia

CA:

Cornu ammonis

DG:

Dentate gyrus

EC:

Entorhinal cortex

FTD/MND:

Frontotemporal dementia with motor neuron disease

NFTs:

Neurofibrillary tangles

TEC:

Transentorhinal cortex

UTCIs:

Ubiquitin/TDP-43-positive cytoplasmic inclusions

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Acknowledgments

We thank Dr. Norio Ishizuka, Department of Brain Structure, Tokyo Metropolitan Institute for Neuroscience, Dr. Yoko Mochizuki, Department of Pathology, Tokyo Metropolitan Neurological Hospital, Dr. Naoto Uyama, Department of Neurology, Tokyo Metropolitan Neurological Hospital and Dr. Masako Yamazaki, Department of Neurology, Tokyo Women’s Medical University for their assistance and advice for clinicopathological analyses. We are also grateful to Mr. Yoshitomo Umitsu and Ms. Ayako Nakamura for their excellent technical assistance.

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Correspondence to Takahiro Takeda.

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Takeda, T., Uchihara, T., Arai, N. et al. Progression of hippocampal degeneration in amyotrophic lateral sclerosis with or without memory impairment: distinction from Alzheimer disease. Acta Neuropathol 117, 35–44 (2009). https://doi.org/10.1007/s00401-008-0447-2

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  • DOI: https://doi.org/10.1007/s00401-008-0447-2

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