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

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.

How predictive are temporal lobe changes of underlying TDP-43 pathology in the ALS-FTD continuum?

“…80 Investigations of cognitive deficits in ALS, FTD and ALS-FTD patients have been found to covary with reduction of GM in several regions of the temporal lobes, including the hippocampal formation and amygdala as well as a loss of integrity of the WM networks connecting frontotemporal areas to parietal and occipital areas, including uncinate and longitudinal fasciculus. 9,54,[81][82][83][84][85][86][87][88][89][90][91][92][93] Episodic memory Amnesia, in particular, is problematic as a symptom in ALS and FTD, as it is currently considered as the diagnosis gold standard for underlying Alzheimer's disease pathophysiology. By contrast, episodic memory is considered to be preserved in the ALS-FTD spectrum and therefore, severe amnesia is even stated as a diagnostic exclusion criterion for the behavioural variant of FTD.…”

“…81,98,99 However, recent studies report authentic episodic memory deficits and implicate MTL structures, showing that memory impairment in non-demented ALS patients is not exclusively a disturbance of the executive functioning. 52,82,83,88,[100][101][102][103] Semantic memory Semantic memory is the knowledge of everyday objects and events and its loss is attributed to the deterioration of the ATL. 61,104 In particular, the temporal poles, the most anterior part of the ATL, are proposed to have a general function to form the basis of semantic memory and is also linked to face recognition, processing of auditory, olfactory and visual stimuli and ToM processing.…”

Macroscopic Localized Subicular Thinning as a Potential Indicator of Amyotrophic Lateral Sclerosis

“…However, it is not yet clear as to which systems in the hippocampus are affected in ALS and how they are related to clinical manifestations including dementia. Microscopically, in ALS brain cytoplasmic inclusions positive for transactive-response DNA-binding protein 43 kDa (TDP-43) sometimes present in the hippocampal complex along the perforant pathway, connect the entorhinal (EC) and transentorhinal cortices (TEC) to the dentate gyrus [3]. Localized neuronal loss and gliosis in the subiculum have also been reported [1, 3].…”

“…Hippocampal degeneration occurs in amyotrophic lateral sclerosis (ALS) patients with or without dementia [1-3]. Reductions in the volume of the hippocampus have been detected by MRI of brains from some ALS patients [4], and these reductions are reported to correlate with psychiatric severity [5].…”

“…Microscopically, in ALS brain cytoplasmic inclusions positive for transactive-response DNA-binding protein 43 kDa (TDP-43) sometimes present in the hippocampal complex along the perforant pathway, connect the entorhinal (EC) and transentorhinal cortices (TEC) to the dentate gyrus [3]. Localized neuronal loss and gliosis in the subiculum have also been reported [1, 3]. These histological changes are distinct from those of Alzheimer disease (AD), which exhibit more extended degeneration to yield more generalized macroscopic atrophy of the hippocampus not restricted to the subiculum [6].…”