Huntington s Disease COGS 172
Overview Part I: What is HD? - Clinical description and features - Genetic basis and neuropathology - Cell biology, mouse models and therapeutics Part II: HD as a model in cognitive neuroscience - Differential roles of cortical-striatal-pallidal-thalamic loops in cognition and emotion
Part I: What is HD? First described by Dr George Sumner Huntington of Long Island in 1872 in Medical and Surgical Reporter One of the most remarkable papers in the history of medicine All the cardinal features of HD were recognized: Adult onset Progressive course Choreic movements Intellectual impairment Psychiatric disturbance Hereditary nature
Symptoms and genetic basis Autosomal, dominantly inherited, neurodegenerative disorder characterized by triad of cognitive, affective and motor disturbance affective cognitive motor 5-10 cases per 100 000 Affects all ethnic groups Gene cloned in 1993 Mutant Huntingtin protein (expanded CAG repeats) Genetic test available Only ~4% of at risk individuals choose testing Raises very complex and fascinating ethical issues
How does mutant Huntingtin destroy cells? Still not clear Huntingtin expressed in all cells Massive effort underway in cell biology Aided by good transgenic mouse models R6/2 human exon 1 fragment knock-in Note: hun*ng*n is a protein. The gene coding for hun*ng*n is IT15 ("interes*ng transcript 15") gene
Finding the HD gene
Living with the burden of family HD? Would you want to know?
CAG repeats and age of onset < 36 CAG repeats for healthy people > 37 or more repeats (up to 121) will develop HD Number of repeats roughly predicts age of neurological diagnosis But other symptoms begin long before motor problems PreHD HD Birth Current Age Est. onset age Death Years to onset
Early Onset Hun.ngton s About 6% of cases start before the age of 21 Akine*c-rigid syndrome Faster progression Called juvenile, akine*c-rigid or Westphal variant HD.
Motor and other symptoms Choreic movements - classic HD symptom - involuntary writhing - saccade system - early finger tapping problems Psychiatric/affective symptoms - impulsivity/irritability/aggression - suicidality and depression - disgust recognition impairment Cognitive impairments - Executive function - Visual recognition memory - Feedback-driven learning and control
Chorea Although not completely characterised, chorea is thought to be due to imbalance in the direct and indirect pathways in the basal ganglia circuitry. It is found most commonly in HD, but can also be drug induced (toxins, B vitamin deficiencies), or related to infec*ous diseases.
Drugs for Treatment No cure but symptoms can be addressed: Physical and occupa*onal therapy Drugs Tetrabenazine, some an*psycho*cs and benzodiazepines may be used for chorea Parkinsonian drugs for the juvenile variant with rigidity Psychiatric drugs for mood and behavioral symptoms
Choreic movements: htp://www.youtube.com/watch?v=kinxijs_v3m Virginia Pilot piece on HD: htp://www.youtube.com/watch?v=hblry_nxu_u
Neuropathology in HD Classically seen as a basal ganglia disorder Striatal GABAergic medium spiny cells cells take a massive hit, but, still not known where/how HD begins Cortical functional change and atrophy evident long before manifest neurological signs ( onset ) Classic view is changing - this is not just a basal ganglia disorder, even in the earliest change Mouse studies show functional change (physiological) in cortico-striatal projection neurons even before striatal cell death
Longitudinal structural imaging of caudate in premanifest HD Caudate volume reduced even 20 years away from onset Rate of cell loss accelerates ~11 years from onset At time of onset, ~50% of striatal cells gone YTO > 8 years" YTO < 8 years" Aylward et al 2004, Neurology
How does striatal cell loss produce symptoms? Histopathology for people who died at different points in the course of the disease suggests spread of pathology in striatum is: Lateral-to-medial Dorsal-to-ventral Anterior-to-posterior To some extent, the lateral to medial spread corresponds to the lateral globus pallidus (GPe) vs. medial (GPi) This could relate to the relative staging or signs of choreic vs. rigid motor symptoms
Simplistic functional model of direct and indirect basal ganglia pathways THALAMO -CORTICAL! TARGETS! CORTICAL MOTOR PLAN! STRIATUM! GPe! GPi! THALAMUS!
Chorea relates to loss of striatal projection neurons to lateral GP (or GPe) Albin et al. visually compared the density of striatal neurons affected by choreic or rigidakinetic Huntington's disease (HD) THALAMO -CORTICAL! TARGETS! CORTICAL MOTOR PLAN! Near total loss of all striatal neurons projecting to the lateral GP, medial GP, and substantia nigra in brains affected by rigid-akinetic HD preservation of neurons projecting to the medial globus pallidus in choreic HD. STRIATUM! GPi! THALAMUS! GPe!
Part II: HD as a model in cognitive neuroscience HD impaired in a number of tasks Degree of impairment relates to degree of atrophy Tower of London task Dalento et al., 2006 Heart & Laurence et al., 1998 TICS
Part II: HD as a model in cognitive neuroscience HD affects different cortico-striatal-pallidal loops at different times May relate to dorsal-to-ventral and lateral-to-medial spread of disease through striatum Could account for different symptoms -> important insights into neural basis of cognition and emotion
Cortico-striatal loops Adapted from Alexander et al by Lawrence et al. 1998 TICS
Cortico-striatal loops verified in vivo with Diffusion Weighted Imaging Lehericy et al. 2004, Ann Neurology
Dorsal to ventral striatal spread of disease differentially a effects cognition Dorsal striatum connected with dorsolateral PFC Ventral striatum connected with orbital frontal PFC Different tasks are purported to tax dorsal vs ventral frontostriatal circuitry to different degrees
Reversal learning vs extra-dimensional shift
Dorsal vs ventral frontal cortex differentially engaged by shift vs reversal lateral orbital Dias et al. 1996 Nature
Pattern of data consistent with dorsal-toventral spread of disease Early HD has big shift problem - consistent with dorsal striatal damage Advanced HD has both shift and reversal problem - consistent with dorsalto-ventral spread of disease in striatum controls Alzheimer s early HD advanced HD Reversal ED shift Lawrence et al. 1998, TICS
HD is a neurodegenerative genetic disorder characterized by triad of symptoms Take home Basal ganglia bears brunt of pathology, but not known how/where disease starts affective cognitive motor There are functionally separate frontostriatal pathways, and HD may differentially affect these at different stages, giving fascinating insights into the nature of cognition and emotion Great progress in neurobiology/mousemodels heralds major breakthroughs in neuroprotection - but tricky to evaluate in humans