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Mild cognitive impairment in Huntington’s disease: challenges and outlooks

  • Neurology and Preclinical Neurological Studies - Review Article
  • Published:
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Abstract

Although Huntington's disease (HD) has classically been viewed as an autosomal-dominant inherited neurodegenerative motor disorder, cognitive and/or behavioral changes are predominant and often an early manifestation of disease. About 40% of individuals in the presymptomatic period of HD meet the criteria for mild cognitive impairment, later progressing to dementia. The heterogenous spectrum of cognitive decline is characterized by deficits across multiple domains, particularly executive dysfunctions, but the underlying pathogenic mechanisms are still poorly understood. Investigating the pathophysiology of cognitive changes may give insight into important and early neurodegenerative events. Multimodal imaging revealed circuit-wide gray and white matter degenerative processes in several key brain regions, affecting prefronto-striatal/cortico-basal ganglia circuits and many other functional brain networks. Studies in transgenic animal models indicated early synaptic dysfunction, deficient neurotrophic transport and other molecular changes contributing to neuronal death. Synaptopathy within the cerebral cortex, striatum and hippocampus may be particularly important in mediating cognitive and neuropsychiatric manifestations of HD, although many other neuronal systems are involved. The interaction of mutant huntingtin protein (mHTT) with tau and its implication for cognitive impairment in HD is a matter of discussion. Further neuroimaging and neuropathological studies are warranted to better elucidate early pathophysiological mechanisms and to develop validated biomarkers to detect patients' cognitive status during the early stages of the condition significantly to implement effective preventing or management strategies.

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Abbreviations

CAG:

Cytosine-adenine-guanine

CI:

Cognitive impairment

DMN:

Default mode network

EF:

Executive function

ER:

Endoplasmic reticulum

FC:

Functional connectivity

Glu:

Glutamine

GM:

Gray matter

HCs:

Healthy controls

HD:

Huntington’s disease

HTT:

Huntingtin

MCI:

Mild cognitive impairment

mHTT:

Mutant huntingtin

PFC:

Prefrontal cortex

pre-HD:

Presymptomatic period of Huntington's disease

sdMCI:

Single domain mild cognitive impairment

tg:

Transgenic

WM:

White matter

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Acknowledgements

The author thanks Mr. E. Mitter-Ferstl for secretarial and editorial work.

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The study was funded by the Society for the Promotion of Research in Experimental Neurology, Vienna, Austria.

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    Kurt A. Jellinger

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Jellinger, K.A. Mild cognitive impairment in Huntington’s disease: challenges and outlooks. J Neural Transm 131, 289–304 (2024). https://doi.org/10.1007/s00702-024-02744-8

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