Huntington's Disease

Abstract

Huntington's disease, which MeSH indexes among the cognition disorders for its prominent cognitive decline, is an inherited neurodegenerative disorder caused by an expanded CAG repeat in a single gene, and although it is known for its involuntary movements, its cognitive and psychiatric features are just as central to the condition. The cognitive profile is that of a subcortical dementia: executive control, psychomotor speed, and the retrieval of stored information decline, while recognition memory and general knowledge are comparatively spared. Because the causative mutation can be identified before any symptom appears, the disease also offers a rare view of a dementia in its earliest, premanifest stage, where cognitive change is measurable years before a movement diagnosis. This article sets out the genetics, the cognitive signature, the prodromal trajectory, and the underlying striatal pathology, with three interactive demonstrations of memory, prodromal decline, and the repeat-length clock of onset.

Keywords: huntington disease, subcortical dementia, executive dysfunction

Huntington's disease is an autosomal-dominant neurodegenerative disorder in which an expanded trinucleotide repeat in the huntingtin gene sets off a slow loss of neurons that begins in the striatum and spreads outward (The Huntington's Disease Collaborative Research Group, 1993; Walker, 2007). Its public image is a movement disorder, the involuntary dance-like chorea that gave it its older name, but the condition is a disorder of movement and mind together: alongside the motor signs it produces a characteristic decline in thinking and a range of psychiatric change, and it is catalogued in the Medical Subject Headings vocabulary among the cognition disorders. In clinical classification the tenth revision of the International Classification of Diseases codes it as G10, and the eleventh revision places it at 8A01.10 among diseases of the nervous system. What makes it so instructive for cognitive psychology is that its dementia is subcortical in character, sparing the storage and knowledge that a cortical dementia erodes while striking executive function, speed, and retrieval, and that its genetic cause lets the decline be watched from before it begins.

A Disorder of Movement and Mind

Huntington's disease is caused by a single mutation, an expansion of a CAG trinucleotide repeated too many times near the start of the huntingtin gene on chromosome 4 (The Huntington's Disease Collaborative Research Group, 1993). Every child of an affected parent has a one-in-two chance of inheriting the expansion, and because it is fully penetrant above a threshold length, inheriting it means, in the ordinary case, developing the disease if one lives long enough. The expanded repeat is translated into a stretch of the amino acid glutamine, giving a mutant huntingtin protein that misfolds and, through a cascade still being worked out, becomes toxic to neurons (Bates et al., 2015; Tabrizi et al., 2020). The damage is not uniform: it falls first and hardest on the striatum, the input hub of the basal ganglia, and from there on the cortical circuits that loop through it. Figure 1 traces that path from gene to symptom. The result is the classic triad of Huntington's disease, motor, cognitive, and psychiatric, and it is a mistake to treat the cognitive and psychiatric strands as secondary, because they often trouble patients and families as much as the movements do (Walker, 2007).

The Cognitive Signature of a Subcortical Dementia

The dementia of Huntington's disease is the textbook example of a subcortical dementia, a pattern that differs from the cortical dementia of Alzheimer's disease not in degree but in kind (Paulsen, 2011; Snowden, 2017). Where a cortical dementia erodes the stored contents of memory and produces frank amnesia, aphasia, and agnosia, a subcortical dementia leaves the store comparatively intact and instead slows and disorganises the operations that act on it. Thinking becomes slow, a change captured by the term psychomotor slowing, and the person struggles most with tasks that demand self-direction: planning, switching between rules, holding and manipulating information, and inhibiting a prepotent response. This executive profile follows directly from the neuropathology, because the striatum sits in the circuits that the prefrontal cortex uses to control behaviour, and damaging the striatal node degrades the whole loop (Ross et al., 2014). Recognition and old knowledge, which lean less on those control operations, are relatively preserved until late. Table 1 sets out the principal cognitive domains with the pattern seen in each.

Table 1

Cognitive Domains in Huntington's Disease and the Typical Pattern

Note. The pattern is that of a subcortical dementia, in which the operations that act on memory, chiefly executive control, speed, and retrieval, decline while the stored contents are relatively spared (Paulsen, 2011; Snowden, 2017).

The most revealing single feature is what happens to memory. A person with Huntington's disease often cannot bring a word or an event to mind on demand, yet recognises it at once when it is offered, which tells us the trace was stored and the failure was in retrieval. The demonstration below makes that dissociation concrete, showing free recall fall away as the disease advances while recognition, which supplies the missing cue, holds up.

Cognitive Change Before the Diagnosis

Huntington's disease is almost unique among dementias in that its cause can be known before its effects, and this has made it a natural laboratory for studying how a neurodegenerative process begins (Ross et al., 2014). A person who carries the expansion but has no motor signs is described as premanifest, and large longitudinal studies of such carriers have shown that the disease casts a long shadow: subtle cognitive change, particularly in processing speed and executive tasks, is detectable years, sometimes more than a decade, before a movement diagnosis is made (Paulsen et al., 2008; Stout et al., 2011). The Predict-HD and TRACK-HD cohorts followed premanifest and early-stage carriers over time and found measurable decline in cognition and brain structure that tracked the estimated nearness of onset, establishing that the prodrome is real and quantifiable rather than a matter of anxious self-report (Tabrizi et al., 2013). This premanifest window matters clinically, because it is the period in which a future disease-modifying treatment would ideally act, and it matters theoretically, because it lets cognitive psychology watch the earliest erosion of executive control as it happens. The demonstration below plots that trajectory, following an illustrative measure of processing speed from the premanifest years through estimated onset.

The Genetics: CAG Repeats and the Clock of Onset

The mutation is a stretch of the DNA letters C, A, and G repeated over and over, and the number of repeats decides a great deal (Duyao et al., 1993). Fewer than about 36 repeats is a normal allele; 36 to 39 is a grey zone of reduced penetrance, where some carriers develop the disease and some do not; 40 or more is fully penetrant. Above that threshold the length of the repeat is inversely related to the age at which the disease begins, so that longer expansions bring earlier onset, and the very longest cause a juvenile form (Bates et al., 2015). This relationship is strong, and it accounts for much of the variation in onset age, but it is not the whole story: two people with the same repeat length can begin the disease years apart, so other genetic and environmental factors modify the clock (Duyao et al., 1993). The repeat is also unstable when passed on, tending to lengthen across generations, especially through the father, which is the molecular basis of the clinical phenomenon of anticipation, whereby the disease can strike earlier and harder in successive generations. The demonstration below sets the repeat length against the illustrative median onset, with the reduced- and full-penetrance ranges marked.

Neuropathology: The Striatum and Beyond

The neuropathology of Huntington's disease explains why its cognitive signature takes the form it does. The earliest and most severe loss falls on the medium spiny neurons of the striatum, the caudate nucleus and putamen, and the degree of that loss is graded in a widely used scheme that runs from a brain indistinguishable from normal on inspection to one with gross shrinkage of the striatum (Vonsattel et al., 1985). Because the striatum is the great input station of the basal ganglia, its degeneration disrupts a family of parallel loops that run from the cortex, through the striatum, and back to the cortex by way of the thalamus. One of these loops serves movement, and its disruption yields the chorea; others serve cognition and emotion, passing through the prefrontal cortex, and their disruption yields the executive slowing and the psychiatric change (Ross & Tabrizi, 2011). As the disease advances the pathology spreads beyond the striatum to the cortex and other regions, which is why the profile broadens over time. Understanding the disorder at this level has driven the search for treatments aimed at the root cause, chiefly strategies to lower the production of the mutant protein, though none has yet been shown to change the course of the disease in people (Tabrizi et al., 2020).

Worked Example

The repeat-length demonstration turns on an inverse relationship worth making concrete, because it shows how much a single number can say and how much it leaves unsaid. The illustrative model behind the demonstration sets the predicted median onset age as a baseline of 17 years plus 45 years scaled by an exponential decline in the repeat length, so that at 40 repeats the exponent is zero and the predicted onset is 17 plus 45, that is 62 years. Now lengthen the repeat to 50. The exponential term falls to e raised to the power of minus 0.10 times 10, that is e to the minus one, about 0.368, so the predicted onset is 17 plus 45 times 0.368, which is 17 plus about 16.6, close to 34 years. Ten extra repeats have advanced the predicted onset by about 28 years, from the early sixties to the mid-thirties, which is why repeat length is described as setting the clock of the disease. Yet the same reasoning shows the limit of prediction. The curve gives a median, not a date: two people at 44 repeats share the same predicted onset near 47 years, but the empirical spread around that median is wide, so one may begin in the late thirties and the other in the late fifties. Repeat length explains much of the variation in onset age but not all of it, and the residual is carried by other genes and by chance (Duyao et al., 1993). The illustrative curve is therefore a description of a population trend, not a forecast for an individual, and reading it as a personal prediction is exactly the error the wide spread warns against.

Discussion

Huntington's disease holds an unusual place in cognitive psychology because it dissociates, in a single natural experiment, things the intact mind keeps fused. It separates storage from retrieval, showing that memory can be preserved as a trace yet inaccessible on demand, which is why recognition can be near normal while free recall collapses (Snowden, 2017). It separates the contents of cognition from the operations that manage them, sparing knowledge while degrading the executive control, speed, and self-direction that put knowledge to use, and it ties that dissociation to a specific piece of neural machinery, the corticostriatal loop (Paulsen, 2011; Ross & Tabrizi, 2011). Perhaps most striking, its genetic certainty lets the decline be studied before it declares itself, turning the premanifest years into a moving picture of how executive function first frays (Paulsen et al., 2008; Tabrizi et al., 2013). For the science this is a gift, a model of subcortical cognition and of neurodegeneration caught early. For the people who carry the expansion it is a hard knowledge, and the same genetics that make the disease so tractable to study also make its prediction a weighty personal matter, which is why the science and the counselling advance together.

Common Misconceptions

Huntington's disease is only a movement disorder.

The chorea is the most visible sign, but the disease affects cognition and mood from early on, and the executive and psychiatric changes often burden patients and families as much as the movements do (Walker, 2007; Paulsen, 2011).

Its dementia is the same as Alzheimer's disease.

It is a different kind of dementia. The subcortical pattern of Huntington's disease spares stored knowledge and recognition and instead strikes retrieval, speed, and executive control, unlike the storage failure and frank amnesia of a cortical dementia (Snowden, 2017).

A genetic test tells a carrier exactly when the disease will start.

The repeat length predicts age of onset only on average. It explains much of the variation across people but leaves a wide spread, so two carriers with the same repeat length can begin the disease years apart (Duyao et al., 1993; Bates et al., 2015).

Glossary

Age of onset.

The age at which the disease first becomes clinically manifest, conventionally marked by the emergence of unequivocal motor signs.

Anticipation.

The tendency of an inherited disease to appear earlier and more severely in successive generations, here because the CAG repeat lengthens as it is passed on.

Basal ganglia.

A group of subcortical nuclei, including the striatum, that participate in movement, habit, and the control of behaviour through loops with the cortex.

CAG repeat.

A stretch of the DNA triplet cytosine-adenine-guanine repeated in tandem within the huntingtin gene; its expansion beyond a threshold causes the disease.

Caudate nucleus.

A part of the striatum whose early atrophy is a hallmark of the disease and a marker of its progression on brain imaging.

Chorea.

Involuntary, irregular, dance-like movements that flit from one part of the body to another; the classic motor sign of the disease.

Corticostriatal circuit.

A loop running from the cortex through the striatum and back, by which the basal ganglia help regulate movement, cognition, and emotion; its disruption underlies the cognitive signs.

Executive function.

The set of control processes, including planning, set-shifting, working memory, and inhibition, that direct thought and action toward a goal; impaired early in the disease.

Huntingtin.

The protein encoded by the HTT gene; in the disease the mutant form carries an expanded polyglutamine tract and becomes toxic to neurons.

Medium spiny neuron.

The principal projection neuron of the striatum and the cell type lost earliest and most severely in the disease.

Penetrance.

The probability that a person carrying a mutation will show the disease; repeats of 40 or more are fully penetrant, while 36 to 39 are reduced.

Polyglutamine tract.

The run of glutamine amino acids produced by the CAG repeat; its expanded length in mutant huntingtin drives the protein's toxicity.

Premanifest.

The stage in which a person carries the expansion but has not yet developed diagnostic motor signs, though subtle cognitive change may already be measurable.

Procedural memory.

The memory for skills and habits acquired through practice, supported by the striatum and impaired in the disease.

Psychomotor speed.

The pace at which mental and motor operations are carried out; its slowing is an early and characteristic feature of the disease.

Striatum.

The input hub of the basal ganglia, comprising the caudate nucleus and putamen; the first and hardest-hit site of degeneration in the disease.

Subcortical dementia.

A dementia in which slowing, executive impairment, and retrieval difficulty dominate while stored knowledge and recognition are relatively spared, in contrast to a cortical dementia.

Vonsattel grade.

A five-point neuropathological scale, from 0 to 4, grading the severity of striatal degeneration in the disease.

Key Researchers

Gillian P. Bates. Professor of Neurogenetics at University College London and a Fellow of the Royal Society; her work established the first mouse model of Huntington's disease and the role of huntingtin aggregation, and she led the disease primer that anchors much of this article. Faculty Page - ORCID - Google Scholar - Wikipedia

Jane S. Paulsen. Neuropsychologist and Professor of Neurology at the University of Wisconsin-Madison; she led the Predict-HD study, which established that cognitive change in Huntington's disease is measurable decades before diagnosis. Faculty Page - ORCID - Google Scholar

Christopher A. Ross. Professor of Psychiatry, Neurology, and Neuroscience at Johns Hopkins University; his work on the molecular pathogenesis of Huntington's disease and its biomarkers has shaped the modern account of how the mutant protein damages neurons. Faculty Page - ORCID

Sarah J. Tabrizi. Professor of Clinical Neurology and Director of the Huntington's Disease Centre at University College London, and a Fellow of the Royal Society; she led the TRACK-HD studies of disease progression and the first trials of huntingtin-lowering therapy. Faculty Page - ORCID - Google Scholar - Wikipedia

Nancy S. Wexler. Geneticist and Professor of Neuropsychology at Columbia University; her decades-long study of an extended Venezuelan family enabled the localisation and identification of the Huntington's disease gene, a landmark in human genetics. Faculty Page - Wikipedia

Frequently Asked Questions

What is Huntington's disease?
It is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, which slowly destroys neurons beginning in the striatum (The Huntington's Disease Collaborative Research Group, 1993). It produces a triad of movement, cognitive, and psychiatric changes, and it is classed among the cognition disorders because of its prominent effect on thinking.

Is Huntington's disease only about movement?
No. Although the involuntary chorea is its most visible sign, the disease also produces a subcortical dementia and psychiatric change, and the cognitive and mood symptoms often affect daily life as much as the movements (Walker, 2007; Paulsen, 2011).

How does its dementia differ from Alzheimer's disease?
Huntington's disease causes a subcortical dementia, which slows thinking and impairs retrieval, speed, and executive control while sparing stored knowledge and recognition, whereas Alzheimer's disease is a cortical dementia marked by loss of the memory store itself (Snowden, 2017).

Why can someone recognise what they cannot recall?
Because the memory difficulty in the disease is largely a retrieval problem rather than a storage problem. The trace is laid down, but summoning it without help fails, so a recognition test, which supplies the cue, succeeds where free recall does not (Paulsen, 2011).

Can cognitive change be detected before diagnosis?
Yes. Long-term studies of gene carriers who have no motor signs have found measurable change in processing speed and executive tasks years before a formal diagnosis, a period known as the premanifest or prodromal stage (Paulsen et al., 2008; Stout et al., 2011).

Does the CAG repeat length predict when the disease starts?
It predicts the age of onset on average: longer repeats bring earlier onset, and the relationship is strong (Duyao et al., 1993). But it leaves a wide spread, so repeat length is a population trend rather than an individual forecast, and two carriers with the same length can begin the disease years apart.

What part of the brain does it affect first?
The earliest and most severe damage falls on the medium spiny neurons of the striatum, especially the caudate nucleus, and from there it disrupts the corticostriatal circuits that serve movement, cognition, and emotion (Vonsattel et al., 1985; Ross & Tabrizi, 2011).

Is there a treatment for Huntington's disease?
Current treatment manages the symptoms, and research is pursuing therapies aimed at the root cause, chiefly lowering production of the mutant huntingtin protein, though none has yet been shown to slow the disease in people (Tabrizi et al., 2020).

Support Organizations

Organizations that provide information, support, and research funding for people affected by Huntington's disease.

References