The pace of basic science research defining the mechanisms of selective neuronal
degeneration in Huntington disease (HD) has far exceeded the pace of translation of this
information into clinically effective treatments for the disease. One reason for this
bottleneck between bench and bedside is the paucity of available surrogate markers for HD.
Identification of surrogate markers is critical for the design of future clinical trials.
Such markers could provide a reliable signal of early brain dysfunction in HD and could be
used as a biomarker in trials of agents that could prevent onset or delay progression of
Frontal-subcortical networks are known to be affected in HD and contribute to the cognitive
dysfunction characteristic of the disease. Quantitative EEG (QEEG) can be used to assess
the integrity of this circuitry; characteristic QEEG abnormalities long have been known to
be present in the early stages of the illness (Bylsma et al., 1994). More recent research
has suggested that a comprehensive topographic approach to QEEG analysis may reveal
additional changes in brain activity (Bellotti et al., 2004) that may be indicative of
subclinical disease (de Tommaso et al., 2003). This proposal aims to determine whether
quantitative EEG techniques can be used to identify HD-specific abnormalities and thus serve
as surrogate markers of disease.
The goals of this pilot project are three-fold. First, we will determine if there are QEEG
differences between normal control subjects and those with mild or moderate HD. Second, we
will examine associations between severity of HD and the QEEG differences detected and
determine if these QEEG differences are present when comparing the least affected HD
subjects and normal controls. Third, we will examine associations between QEEG variables of
interest and other clinical variables, including age of onset of symptoms, number of CAG
repeats, severity of motor and behavioral symptoms as measured by the Unified Huntington
Disease Rating Scale (UHDRS) subscores, and severity of cognitive impairment as measured by
the cognitive subscore of the UHDRS and Mini-Mental State Examination (MMSE).
We will examine three subject groups in this study: those with mild HD, those with moderate
HD, and normal controls. Fifteen subjects will be examined in each group, for an overall
total of forty-five subjects. HD subjects will be recruited from the UCLA Huntington
Disease Center of Excellence where they have been followed with serial neurologic
examinations and completion of all portions of the UHDRS every 6-12 months. Subjects that
have been given a diagnosis of HD based on appropriate motor signs and a confirmatory
genetic test or a known family history of HD will be invited to participate. Healthy
control subjects will be recruited from the clinic as well through spouses or other
unaffected relatives of patients. In addition, control subject data acquired from previous
studies will be used after matching for age. All subjects will be over the age of 21 and
free of other medical illnesses that could also affect brain function and will be able to
give informed consent. Mild HD is defined as having Total Functional Capacity [TFC] scores
on the UHDRS of 11-13, moderate is defined as TFC of 7-10, and normal control subjects will
be free of any neurologic or psychiatric illness. Subjects will be free of antipsychotic or
antidepressant medications, benzodiazepines, or other medications known to affect central
nervous system function for at least 10 days prior to QEEG examination.
All subjects will undergo QEEG recording in a manner similar to that employed clinically,
using procedures that have been approved in other protocols by the UCLA Medical IRB and that
are consistent with standard clinical EEG procedures promulgated by ABRET (American Board of
Registered Electroencephalographic Technologists). Recording electrodes are applied to the
scalp using an electrode cap (ElectroCap, Inc., Eaton OH); electrodes are arrayed to record
electrical activity from all major brain regions using a standard extension of the
International 10-20 system (figure 1). Recording electrodes are connected to an isolation
amplifier that is part of the digital EEG system (NuAmp System, NeuroScan, Inc., El Paso,
TX). Data are recorded in real-time on computer disk. During recording, subjects will be
resting in a quiet room with subdued lighting, in the eyes-closed, maximally alert state;
the EEG technologists will alert the subjects whenever drowsiness is evident on the computer
monitor. Data will be displayed in real-time on a computer monitor during recording, with
adjustable filtering and amplification to facilitate identification of EEG patterns as well
as artifact. Data will be collected using a bandpass filter of 0.3 to 70 Hz, and will be
digitized at a rate of 250 samples/channel/second. Data will be recorded with a Pz
referential montage, and the NeuroScan software then will reformat the data into bipolar
montages as needed for the cordance calculations. Three EOG leads will be used (RIO-A2,
ROC-A2, and LOC-A1) so that lateral, horizontal, or oblique eye movement artifact may be
detected easily. Data for quantitative analysis will be selected from the data recorded
according to standard procedures: each EEG will be reviewed by a technician and the first
20-32 seconds of artifact-free data will be selected to be processed to obtain absolute and
relative power in four frequency bands (0.5-4 Hz, 4-8 Hz, 8-12 Hz, and 12-20 Hz) after the
selections are confirmed by a second technician; both technicians will be blinded to
clinical status while making or reviewing the selections.
Two QEEG measures will be calculated for each subject. The first of these is cordance,
which will be calculated using an algorithm that has been detailed elsewhere (Leuchter et
al., 1999). Cordance is based upon a normalization of absolute and relative power values
across all electrode sites and all frequency bands for a given recording. Cordance values
have a stronger association with cerebral perfusion in brain tissue underlying each
electrode site than do standard QEEG power measures. The second QEEG measure to be examined
is QEEG coherence (Leuchter et al., 1992; 1994b), a measure of the shared functional
activity between brain regions. Coherence values range between 0 - 1 and are analogous to a
correlation coefficient, with values near 1 signifying highly coordinated cerebral activity.
Coherence reflects not only cortical activity, but also the function of deep gray matter
structures that coordinate cortical activity as well as white-matter tracts connecting brain
- Subjects affected by HD or those who are at risk for HD by virtue of having a
first-degree relative with the illness, methamphetamine abuse or dependence, as well
as normal controls, can participate.
- All subjects will be above the age of 21.
- Subjects will be recruited from clinical settings, and will also be self-referred.
- Individuals with pacemakers, infusion pumps, or metallic shrapnel will be excluded
from MRI assessments.
- Such implanted metals may be attracted by the MRI machine and put the individual at
- Moreover, individuals with a history of brain surgery and/or skull fracture will also