# Consolidation deficits in episodic memory define distinct clinical and neurodegenerative profiles in Huntington’s disease

## TL;DR

This study shows that memory problems in Huntington’s disease can be categorized into different types, each linked to specific brain changes and cognitive issues.

## Contribution

The paper identifies distinct memory profiles in HD, revealing divergent neurodegenerative patterns and cognitive subtypes.

## Key findings

- HD patients show predominant retrieval deficits, but a subgroup has severe consolidation failure linked to medial temporal atrophy.
- Consolidation deficits correlate with hippocampal, entorhinal, and parahippocampal atrophy and worse cognitive outcomes.
- Plasma NfL does not reflect regional brain degeneration related to memory impairment in HD.

## Abstract

•Distinct memory profiles in HD reflect divergent trajectories of brain atrophy.•Retrieval deficits predominate but a subgroup shows marked consolidation failure.•Medial temporal atrophy underlies severe consolidation deficits.•Plasma NfL fails to reflect regional memory-related brain degeneration.•Neuroimaging uncovers non-frontostriatal trajectories in HD cognitive impairment.

Distinct memory profiles in HD reflect divergent trajectories of brain atrophy.

Retrieval deficits predominate but a subgroup shows marked consolidation failure.

Medial temporal atrophy underlies severe consolidation deficits.

Plasma NfL fails to reflect regional memory-related brain degeneration.

Neuroimaging uncovers non-frontostriatal trajectories in HD cognitive impairment.

Huntington’s disease (HD) is primarily associated with executive dysfunction, but episodic memory impairment is also present. Traditionally, these memory deficits have been attributed to retrieval difficulties linked to fronto-striatal dysfunction, rather than to disruptions in encoding or consolidation processes. However, the specific nature and diversity of memory impairments in HD remain underexplored.

To characterize the profile of episodic memory impairment in HD, identify distinct cognitive phenotypes, and examine their clinical, neuroanatomical, and biomarker correlates.

We assessed episodic memory in HD patients and healthy controls using the Free and Cued Selective Reminding Test (FCSRT), complemented by Item-Specific Deficit Approach (ISDA) indices to quantify encoding, consolidation, and retrieval deficits. Structural MRI was used to identify gray matter volume correlates, and plasma neurofilament light chain (NfL) was measured as a marker of neuroaxonal injury.

Compared to controls, HD patients showed marked impairments in free recall with preserved cued recall, suggesting predominant retrieval deficits. However, nearly one-third of patients exhibited global impairments across all FCSRT components, mainly driven by consolidation deficits consistent with medial temporal lobe dysfunction. This subgroup also showed worse cognitive and functional performance and significant atrophy in the hippocampus, entorhinal cortex, and parahippocampal gyrus.

Episodic memory dysfunction in HD is heterogeneous and includes both retrieval-related and consolidation-driven profiles. These profiles reflect distinct neurodegenerative patterns, emphasizing the importance of cognitive subtyping for improving clinical characterization and biomarker development in HD.