The cognitive burden in Huntington's disease: Pathology, phenotype, and mechanisms of compensation

Abstract

Huntington's disease (HD) is an inherited autosomal dominant neurodegenerative disorder. The most prominent sign of HD is the presence of involuntary motor movements. However, HD is also characterized by marked cognitive decline, which often precedes the onset of motor symptoms and is generally considered to be more debilitating to the patients and their families, compared to motor symptoms. Cognitive decline is widespread across most faculties of cognition in later stages of the disease, but seems to be selective in preclinical and early stages of the disease, with deficits in the HD patients' ability to multitask, their speed of processing, and executive function. It is now well established that preceding clinical diagnosis there is a preclinical stage, during which HD gene mutation carriers are relatively symptom free, despite disease pathological onset and the presence of neurodegeneration. Evidence from functional brain imaging studies suggests the presence of neural compensation in preclinical stages of HD, whereby the brain undergoes functional reorganization in response to neurodegeneration to preserve motor and cognitive performance. In this review, we will describe the underlying HD pathology with a focus on how it links to the cognitive phenotype. We will also present evidence regarding the presence of neural compensation in HD and the possible mechanisms supporting it. Finally, we will discuss current research in the field of cognitive interventions that aim to support and enhance neural compensation in HD. These research efforts could, one day, prolong the preclinical stage and assist with symptom management of those affected with HD.

Compromised Dopaminergic Encoding of Reward Accompanying Suppressed Willingness to Overcome High Effort Costs Is a Prominent Prodromal Characteristic of the Q175 Mouse Model of Huntington's Disease

“…These nonmotor symptoms severely impact daily functioning and quality of life for HD patients and caregivers (Hamilton et al, 2003;Papoutsi et al, 2014), but are poorly understood and insufReceived Jan. 13, 2016; revised March 10, 2016; accepted March 15, 2016. Author contributions: D.P.C.…”

“…Psychiatric deficits in Huntington's disease (HD) appear early during a prodromal stage that precedes motor deficits (eg, chorea) by a decade or more (Paulsen et al, 2008;Epping et al, 2016). These nonmotor symptoms severely impact daily functioning and quality of life for HD patients and caregivers (Hamilton et al, 2003;Papoutsi et al, 2014), but are poorly understood and insuf-ficiently treated (Frank, 2014).…”

“…These nonmotor symptoms severely impact daily functioning and quality of life for HD patients and caregivers (Hamilton et al, 2003;Papoutsi et al, 2014), but are poorly understood and insuf-ficiently treated (Frank, 2014). Whereas striatal medium spiny neuron (MSN) degeneration represents the canonical, histopathological hallmark of HD (Reiner et al, 1988;Vonsattel and DiFiglia, 1998), altered dopamine input onto striatal MSNs is also implicated (Klawans et al, 1970;Spokes, 1980) and may promote early psychiatric impairments .…”

“…However, the functional nature of dopaminergic deficits and their behavioral relevance in HD remains controversial as estimates of extracellular dopamine levels in HD patients and animal models have been inconsistent (Cepeda et al, 2014;Schwab et al, 2015). Addressing this question is particularly important because the only FDA-approved pharmaceutical treatment option for HD targets chorea and is confined to agents that inhibit the vesicular monoamine transporter-2 (VMAT-2) to disrupt extracellular dopamine release (Venuto et al, 2012).Apathy, characterized by diminished motivation to engage reinforcers, is one of the most common psychiatric symptoms in HD (Paulsen et al, 2001; Naarding et al, 2009; Tabrizi et al, 2013;van Duijn et al, 2014). Motivational deficits appear early in the prodromal stage and worsen over disease progression.…”

The neuropsychology of first impressions: Evidence from Huntington's disease

“…The neuropathology of HD is widespread and variable, affecting predominantly the basal ganglia, but other cortical regions as well, albeit to a lesser extent. The disorder is characterised by involuntary choreiform movements, cognitive deterioration (Dumas, van den Bogaard, Middelkoop, & Roos, 2013;Papoutsi, Labuschagne, Tabrizi, & Stout, 2014;Paulsen, 2011), affective disturbances Sprengelmeyer, et al, 2014), and impaired emotion processing Sprengelmeyer, Schroeder, Young, & Epplen, 2006;Sprengelmeyer, et al, 1996).…”