Figure 1 (Ruocco et al., 2006). Samples of coronal and sagittal magnetic resonance imaging from a patient with Huntington's disease (top row) and a normal control (bottom row) showing the outlines of caudate and putamen (left), cerebral (center) and cerebellar volumes (right).
Huntington's disease is an inherited, autosomal dominant, neurodegenerative disorder. Although primarily viewed as a movement disorder characterized by uncontrollable body movements (chorea), there is also a marked decline in cognitive abilities, often accompanied by psychiatric issues as well.
It's a terrible disease that typically onsets in middle age. A heartbreaking New York Times article, Facing Life With a Lethal Gene, follows a 23 year old woman who decides to get tested and finds out she carries the gene. Her grandfather had the disease, meaning that her mother, who did not know her own genetic status, was doomed to develop HD.
As stated in this Lancet review article (Walker, 2007),
The mutant protein in Huntington’s disease—huntingtin—results from an expanded CAG repeat leading to a polyglutamine strand of variable length at the N-terminus. Evidence suggests that this tail confers a toxic gain of function.The defective protein causes cell death in various brain regions, particularly in the striatum (caudate and putamen), perhaps due to an excitotoxic mechanism (Sánchez et al., 2008). As Beste et al. (2008) explain in their new J Neurosci paper,
Excitotoxicity describes cell death that results from the activation of excitatory amino acid receptors. In HD, voltage-dependent NMDA receptors are assumed to be more receptive to endogenous levels of glutamate; thus glutamatergic neurotransmission is increased, leading to excitotoxic cell death.The medium spiny neurons in the striatum are especially affected. Given all this neurodegeneration and the concomitant decline in motor function and cognition, it was surprising to see a paper reporting an enhanced perceptual/cognitive ability. But that's what Beste et al. (2008) observed. In their study, patients with HD, pre-symptomatic carriers, and controls participated in an auditory processing experiment while EEG data were recorded. The task consisted of categorizing the duration of pure tones as either long (400 ms) or short (200 ms). The tones were of different frequencies and different probabilities, but this was irrelevant to the task. This difference in probability, however, results in different patterns of brain waves to the common ("standard") and rare ("deviant") tones. Specifically, the authors looked at the mismatch negativity (MMN) component associated with auditory sensory memory, and the P3a component associated with attention. These waves were derived by averaging together many trials of the task, which produces event-related potentials (ERPs).
Behaviorally speaking, the participants with HD were faster and more accurate on the auditory task.
Figure 1 (Beste et al., 2008). Behavioral data. A, Mean reaction time (error bars indicate SEM) of the control, the presymptomatic (pHD), and the symptomatic (HD) group for the standard and deviant stimuli. B, Mean error rates (error bars indicate SEM) of the control, the presymptomatic (pHD), and the symptomatic (HD) group for the standard and deviant stimuli.
For the ERPs, responses to the standard tones were subtracted from responses to the deviant tones, producing a so-called "difference wave." The MMN can be seen between 100-250 ms after stimulus presentation and the P3a can be seen between 300 and 500 ms post-stimulus. A later wave (the reorienting negativity, or "RON") was seen between 400 and 600 ms.
adapted from Figure 2 (Beste et al., 2008). Neurophysiological data (difference waves). For all electrodes shown, the time course from 200 ms before tone onset until 1100 ms beyond tone presentation is given. Red lines denote the ERP time course of the HD group, orange lines of the pHD group, and green lines of the control group.
The HD group showed a significant increase in MMN compared to the pHD and control groups. On the other hand, although the P3a looked smaller in HD participants, the difference was not significant. The later RON wave was enhanced in the HD group, however. The authors suggest:
The results show that specific cognitive functions, namely auditory sensory memory (reflected by the MMN) and reorientation of attention (reflected by the RON) are not deteriorated and can even be enhanced in late stage HD. Moreover, the results suggest that superiority in these functions emerge primal in the late stage of this disease, because pHDs performed worse.I should point out that on nearly every other neuropsychological test (i.e., word fluency, digit span, Stroop interference, immediate and delayed memory), the subjects with HD were extremely impaired. Then what is the mechanism for the enhancement of auditory abilities?
...the specific dependence of the MMN on the corticostriatal NMDA system underlies this dissociation of performance in HD as well as the enhancement and acceleration of the MMN. The NMDA-receptor system has been found to modulate the MMN (Javitt et al., 1996).What is the clinical relevance of this finding? It's not clear. But the results revealed an unexpected and striking dissociation of cognitive abilities in patients with Huntington's disease.
. . .
The observation that the reorientation of attention (reflected by the RON) was also increased in the HD group accords with the enhanced behavioral performance in the relevant task...
Although the primary effects of neurodegenerative diseases like HD might be largely confined to certain cell populations in restricted areas of the brain, these changes can affect cognitive and motor systems at multiple levels of the brain. In most cases, the pathological alterations of neural systems result in a deterioration of cognitive functions. However, as shown in the present study, a pathogenic increase in responsiveness of a transmitter system can increase cognitive functions if these functions selectively depend on this neural system, whereas other cognitive functions are deteriorated.
C. Beste, C. Saft, O. Gunturkun, M. Falkenstein (2008). Increased Cognitive Functioning in Symptomatic Huntington's Disease As Revealed by Behavioral and Event-Related Potential Indices of Auditory Sensory Memory and Attention. Journal of Neuroscience, 28 (45), 11695-11702 DOI: 10.1523/JNEUROSCI.2659-08.2008
Estrada Sánchez AM, Mejía-Toiber J, Massieu L. (2008). Excitotoxic neuronal death and the pathogenesis of Huntington's disease. Arch Med Res. 39:265-76.
Javitt DC, Steinschneider M, Schroeder CE, Arezzo JC. (1996). Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: Implications for schizophrenia. Proc Natl Acad Sci. 93:11962–11967.
H.H. Ruocco, I. Lopes-Cendes, L.M. Li, M. Santos-Silva, F. Cendes. (2006). Striatal and extrastriatal atrophy in Huntington’s disease and its relationship with length of the CAG repeat. Braz J Med Biol Res. 39: 1129-1136.
Walker FO. (2007). Huntington's disease. Lancet 369:218-28.
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