Understanding patient-reported outcome measures in Huntington disease: at what point is cognitive impairment related to poor measurement reliability?

PURPOSE: Symptom progression in Huntington disease (HD) is associated with cognitive decline which may interfere with the self-report of symptoms. Unfortunately, data to support or refute the psychometric reliability of patient-reported outcomes (PROs) as HD progresses are limited. This is problematic given that PROs are increasingly recognized as important measures of efficacy for new treatments. METHODS: We examined PRO data from the HDQLIFE Measurement System (Speech Difficulties; Swallowing Difficulties; Chorea) in 509 individuals with premanifest, early-stage, or late-stage HD. Clinician-administered assessments of motor functioning (items from the UHDRS) and standardized objective assessments of cognition (Stroop, Symbol Digit Modalities) were also collected. We examined item bias using differential item functioning (DIF) across HD stage (premanifest, early-, late-) and relative to cognitive performance. We also examined the correlations between self-report and clinician ratings. Regression models that considered total cognitive ability were utilized to determine psychometric reliability of the PROs. RESULTS: Most PRO items were free from DIF for both staging and cognition. There were modest correlations between PROs and clinician report (ranged from - 0.40 to - 0.60). Modeling analyses indicated that psychometric reliability breaks down with poorer cognition and more progressed disease stage; split-half reliability was compromised (i.e., split-half reliability < 0.80) when scores were < 136 for Chorea, < 109 for Speech Difficulties, and < 179 for Swallowing Difficulties. CONCLUSIONS: Results indicate that the psychometric reliability of PROs can be compromised as HD symptoms progress and cognition declines. Clinicians should consider PROs in conjunction with other types of assessments when total cognition scores exceed critical thresholds.

Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin.

Huntington's disease (HD), a progressive neurodegenerative disease, is caused by an expanded CAG triplet repeat producing a mutant huntingtin protein (mHTT) with a polyglutamine-repeat expansion. Onset of symptoms in mutant huntingtin gene-carrying individuals remains unpredictable. We report that synthetic polyglutamine oligomers and cerebrospinal fluid (CSF) from BACHD transgenic rats and from human HD subjects can seed mutant huntingtin aggregation in a cell model and its cell lysate. Our studies demonstrate that seeding requires the mutant huntingtin template and may reflect an underlying prion-like protein propagation mechanism. Light and cryo-electron microscopy show that synthetic seeds nucleate and enhance mutant huntingtin aggregation. This seeding assay distinguishes HD subjects from healthy and non-HD dementia controls without overlap (blinded samples). Ultimately, this seeding property in HD patient CSF may form the basis of a molecular biomarker assay to monitor HD and evaluate therapies that target mHTT.

New measures to capture end of life concerns in Huntington disease: Meaning and Purpose and Concern with Death and Dying from HDQLIFE (a patient-reported outcomes measurement system).

PURPOSE: Huntington disease (HD) is an incurable terminal disease. Thus, end of life (EOL) concerns are common in these individuals. A quantitative measure of EOL concerns in HD would enable a better understanding of how these concerns impact health-related quality of life. Therefore, we developed new measures of EOL for use in HD. METHODS: An EOL item pool of 45 items was field tested in 507 individuals with prodromal or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to establish unidimensional item pools. Item response theory (IRT) and differential item functioning analyses were applied to the identified unidimensional item pools to select the final items. RESULTS: EFA and CFA supported two separate unidimensional sets of items: Concern with Death and Dying (16 items), and Meaning and Purpose (14 items). IRT and DIF supported the retention of 12 Concern with Death and Dying items and 4 Meaning and Purpose items. IRT data supported the development of both a computer adaptive test (CAT) and a 6-item, static short form for Concern with Death and Dying. CONCLUSION: The HDQLIFE Concern with Death and Dying CAT and corresponding 6-item short form, and the 4-item calibrated HDQLIFE Meaning and Purpose scale demonstrate excellent psychometric properties. These new measures have the potential to provide clinically meaningful information about end-of-life preferences and concerns to clinicians and researchers working with individuals with HD. In addition, these measures may also be relevant and useful for other terminal conditions.

HDQLIFE: development and assessment of health-related quality of life in Huntington disease (HD).

PURPOSE: Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL-Quality of Life in Neurological Disorders and PROMIS-Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content. METHODS: New item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD. RESULTS: Moderate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose. CONCLUSIONS: HDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.

Detection of Huntington's disease decades before diagnosis: the Predict-HD study.

OBJECTIVE: The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington's disease (HD), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis. METHODS: We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non-linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor. RESULTS: Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies. CONCLUSIONS: These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.

Thalamic metabolism and symptom onset in preclinical Huntington's disease.

The neural basis for the transition from preclinical to symptomatic Huntington's disease (HD) is unknown. We used serial positron emission tomography (PET) imaging in preclinical HD gene carriers (p-HD) to assess the metabolic changes that occur during this period. Twelve p-HD subjects were followed longitudinally with [11C]-raclopride and [18F]-fluorodeoxyglucose PET imaging, with scans at baseline, 18 and 44 months. Progressive declines in striatal D2-receptor binding were correlated with concurrent changes in regional metabolism and in the activity of an HD-related metabolic network. We found that striatal D2 binding declined over time (P < 0.005). The activity of a reproducible HD-related metabolic covariance pattern increased between baseline and 18 months (P < 0.003) but declined at 44 months (P < 0.04). These network changes coincided with progressive declines in striatal and thalamic metabolic activity (P < 0.01). Striatal metabolism was abnormally low at all time points (P < 0.005). By contrast, thalamic metabolism was elevated at baseline (P < 0.01), but fell to subnormal levels in the p-HD subjects who developed symptoms. These findings were confirmed with an MRI-based atrophy correction for each individual PET scan. Increases in network expression and thalamic glucose metabolism may be compensatory for early neuronal losses in p-HD. Declines in these measures may herald the onset of symptoms in gene carriers.

Generalized cognitive deficits in schizophrenia: a study of first-episode patients.

BACKGROUND: Cognitive impairment is recognized as a core characteristic of schizophrenia. There has always been a debate about the nature, selectivity, and time of onset of these deficits in relationship to the onset of illness and treatment factors. To our knowledge, the present study represents the largest sample of mostly neuroleptic-naive patients with first-episode schizophrenia that has been reported to date. METHODS: A group of 94 patients experiencing their first episode of schizophrenic illness and 305 normal comparison subjects were administered a comprehensive clinical and neuropsychological evaluation. Seventy-three patients were neuroleptic naive, 14 had received treatment for less than 1 week, and the remaining 7 had been medicated for less than 2 weeks. RESULTS: Patients performed significantly worse than the comparison subjects on every neuropsychological variable except those assessing savings scores (ie, forgetting over time). Twenty-five of 30 tests had an effect size (ES) greater than 0.75 when the 2 groups were compared. An ES analysis within the schizophrenia group revealed that the greatest relative impairments were on the Wechsler Adult Intelligence Scale-Revised digit symbol (ES, -0.52) and comprehension (ES, -0.42) subscales. CONCLUSIONS: Our findings are in concert with others demonstrating that significant cognitive impairment across multiple ability domains is a core characteristic of schizophrenia and is not caused by chronic illness, treatment, or institutionalization. The ES analysis emphasizes that patients with schizophrenia have a generalized deficit that is not easily explained by a single anatomical region or ability area.

Neuropsychological deficits in schizophrenics. Relationship to age, chronicity, and dementia.

BACKGROUND: We sought to determine whether neuropsychological impairment in schizophrenia is related to current age, age at onset, or duration of illness, and whether the pattern of such impairment can be distinguished from that caused by progressive dementias of Alzheimer's type. We administered a comprehensive neuropsychological test battery to a normal control group (n = 38), a group of ambulatory patients with Alzheimer's disease (n = 42), and three ambulatory schizophrenic groups: early onset-young (n = 85), early onset-old (n = 35), and late onset (n = 22). Tests were grouped and analyzed according to eight major ability areas, and published procedures were used to remove the expected effects of normal aging. RESULTS: The three schizophrenic groups were found to be neuropsychologically similar to one another and different from normal controls and patients with Alzheimer's disease. There were no significant differences among the schizophrenic groups in level or pattern of neuropsychological functioning. Patients with Alzheimer's disease demonstrated less efficient learning and particularly more rapid forgetting than did the other groups. CONCLUSIONS: These findings suggest that neuropsychological impairment in schizophrenia is unrelated to current age, age at onset, or duration of illness. The study further suggests that the encephalopathy associated with schizophrenia is essentially nonprogressive and produces a pattern of deficits that is different from that seen in progressive cortical dementias.

Risk of tardive dyskinesia in older patients. A prospective longitudinal study of 266 outpatients.

BACKGROUND: Neuroleptic-induced tardive dyskinesia (TD) is a major iatrogenic disorder that is more prevalent among older patients. The objective of this study was to determine the incidence of and risk factors for TD in neuroleptic-treated patients over age 45 years. METHODS: We studied 266 middle-aged and elderly outpatients with a median duration of 21 days of total lifetime neuroleptic exposure at study entry. Most patients were treated throughout the study with either a high-potency or a low-potency neuroleptic and maintained on relatively low doses. The patients were followed up at 1- to 3-month intervals with "blind" assessment of psychopathologic condition, clinically as well as instrumentally (ie, using electromechanical sensors with computerized data reduction, including spectral analysis) evaluated movement disorder, and global cognitive function. RESULTS: Cumulative incidence of TD was 26%, 52%, and 60% after 1, 2, and 3 years, respectively. The principal risk factors for TD were duration of prior neuroleptic use at baseline, cumulative amount of high-potency neuroleptics, history of alcohol abuse/dependence, borderline or minimal dyskinesia, and tremor on instrumental assessment. CONCLUSION: Use of higher amounts of neuroleptics, particularly high-potency ones, should be avoided in older patients, patients with alcohol abuse/dependence, or patients with a subtle movement disorder at baseline; these patients are at a higher risk of developing TD.

Clinical and neuropsychological comparison of psychotic depression with nonpsychotic depression and schizophrenia.

OBJECTIVE: This study compared the clinical and neuropsychological characteristics of patients with psychotic depression to those of patients with nonpsychotic depression and patients with schizophrenia. METHOD: Two hundred eighteen patients over the age of 45, including 30 who met the DSM-III-R criteria for unipolar major depression with psychotic features, 28 with nonpsychotic unipolar major depression, and 160 with schizophrenia, were examined. Subjects were evaluated on several clinical measures as well as on neuropsychological tests of attention, learning, memory (retention), psychomotor speed, and motor skills. RESULTS: The three groups were comparable in age and education. The severity of depressive symptoms in the depressed patients with and without psychosis was similar. The patients with psychotic depression were comparable to those with schizophrenia on the neuropsychological measures; they were more impaired than the patients with nonpsychotic depression on the measures of psychomotor speed, motor skills, attention, and learning. The cognitive deficits seemed to be trait-related. CONCLUSIONS: The findings provide additional support for the validity of psychotic depression as a diagnostic category distinct from nonpsychotic depression.

Neuropsychiatric assessment of patients with hyperkinetic and hypokinetic movement disorders.

BACKGROUND: The role of the basal ganglia in neuropsychiatric behaviors is not well known. Anatomical, neurophysiological, and neurochemical evidence supports the notion of parallel direct and indirect basal ganglia thalamocortical motor systems, the differential involvement of which accounts for the hypokinesia or hyperkinesia observed in basal ganglia disorders. OBJECTIVES: To evaluate the neuropsychiatric manifestations of patients with a hyperkinetic movement disorder, such as Huntington disease (HD), vs a hypokinetic disease, such as progressive supranuclear palsy (PSP). To verify if patients with HD show a greater frequency of hyperactive behaviors (eg, agitation, irritation, euphoria, or anxiety), while those with PSP exhibit hypoactive behaviors (eg, apathy). PATIENTS AND METHODS: The Neuropsychiatric Inventory, a tool with established validity and reliability, was administered to 29 patients with HD (mean +/- SD age, 43.8 +/- 2 years) and 34 with PSP (mean +/- SD age, 66.6 +/- 1.2 years), matched for education, symptom duration, and overall degree of dementia. RESULTS: There was no difference between the groups in the total Neuropsychiatric Inventory scores. However, there was a double dissociation in behaviors: patients with HD exhibited significantly more agitation (45%), irritability (38%), and anxiety (34%), whereas patients with PSP exhibited more apathy (82%) (P < .01). Euphoria was present only in patients with HD. CONCLUSIONS: We found that patients with HD manifested predominantly hyperactive behaviors, while those with PSP manifested hypoactive behaviors. Based on our findings and the anatomical lesions known to occur in these disorders, we suggest that the hyperactive behaviors in HD are secondary to an excitatory subcortical output through the medial and orbitofrontal cortical circuits, while in PSP the hypoactive behaviors are secondary to hypostimulation.

Clinical markers of early disease in persons near onset of Huntington's disease.

OBJECTIVE: There is increasing evidence that neuron loss precedes the phenotypic expression of Huntington's disease (HD). As genes for late-onset neurodegenerative diseases are identified, the need for accurate assessment of phenoconversion (i.e., the transition from health to the disease phenotype) will be important. METHODS: Prospective longitudinal evaluation using the Unified Huntington's Disease Rating Scale (UHDRS) was conducted by Huntington Study Group members from 36 sites. There were 260 persons considered "at risk" for HD who initially did not have manifest disease and had at least one subsequent evaluation. Repeat UHDRS data, obtained an average of 2 years later, showed that 70 persons were given a diagnosis of definite HD based on the quantified neurologic examination. RESULTS: Baseline cognitive performances were consistently worse for the at-risk group who demonstrated conversion to a definitive diagnosis compared with those who did not. Longitudinal change scores showed that the at-risk group who did not demonstrate manifest disease during the follow-up study period demonstrated improvements in all cognitive tests, whereas performances in the at-risk group demonstrating conversion to disease during the study declined across cognitive domains. CONCLUSIONS: Neuropsychological measures show impairment 2 years before the development of more manifest motor disease. Findings suggest that these brief cognitive measures administered over time may capture early striatal neural loss in HD.

Distinct cognitive profiles of cortical and subcortical dementia in advanced illness.

We administered the Mattis Dementia Rating Scale (DRS) to 120 patients to evaluate the effect of dementia severity on distinct cognitive profiles. Sixty patients with Huntington's disease (HD) and 60 patients with Alzheimer's disease (AD) were separated by dementia severity into three groups: mildly demented (DRS mean total = 129), moderately demented (DRS mean total = 117), and severely demented (DRS mean total = 102). At all levels of dementia severity, HD patients demonstrated greater impairment than AD patients on the Initiation/Perseveration subscale, whereas AD patients demonstrated greater impairment than HD patients on the Memory subscale. At moderate and severe levels of dementia, HD patients demonstrated an additional impairment in constructional praxis. These profile differences were independent of dementia severity and continued to differentiate between so-called cortical and subcortical dementias in later stages of dementia severity.

Incidence of and risk factors for hallucinations and delusions in patients with probable AD.

OBJECTIVE: To examine the incidence of and risk factors for hallucinations and delusions associated with patients clinically diagnosed with probable AD. BACKGROUND: Estimates of the incidence of psychosis in AD range widely from 10% to 75%. The risk factors for psychosis of AD are not known, although multiple studies indicate that AD patients with psychosis demonstrate greater cognitive and functional impairment. METHODS: The authors conducted psychiatric evaluations of 329 patients with probable AD from the University of California at San Diego Alzheimer's Disease Research Center to determine the incidence of hallucinations and delusions. They examined data from annual clinical and neuropsychological evaluations to determine whether there were specific risk factors for the development of hallucinations and delusions. RESULTS: Using Cox survival analyses, the cumulative incidence of hallucinations and delusions was 20.1% at 1 year, 36.1% at 2, 49.5% at 3, and 51.3% at 4 years. Parkinsonian gait, bradyphrenia, exaggerated general cognitive decline, and exaggerated semantic memory decline were significant predictors. Age, education, and gender were not significant predictors. CONCLUSIONS: The authors found a relatively high incidence of hallucinations and delusions in patients diagnosed with probable AD and suggest that specific neurologic signs, cognitive abilities, and accelerated decline may be predictive markers for their occurrence.

Electrophysiological insights into the nature of the semantic deficit in Alzheimer's disease.

Event-related brain potential (ERP) and reaction-time measures were used to determine if the specificity of a category prime differentially affects the amount of semantic priming seen in patients with dementia of the Alzheimer type (DAT) compared with normal elderly and young controls. Subjects were primed with an auditory category name followed by the visually presented name of an imageable object and indicated whether the object was a category member; the category was either superordinate to, at, or subordinate to the basic level. All groups showed similar priming effects in response to the category manipulation, as evidenced in both reaction time and the amplitude of the N400 component of the ERP. Overall, DAT subjects showed the smallest ERP priming effects and young controls the largest. The present study did not provide evidence for a strong version of a strictly "bottom-up" breakdown of the semantic networks in subjects with DAT, suggesting a role for factors such as task difficulty and memory search strategies in online categorization tasks of this type.

Schizoaffective disorder: a form of schizophrenia or affective disorder?

BACKGROUND: The diagnostic status of schizoaffective disorder continues to be controversial. Researchers have proposed that schizoaffective disorder represents a variant of schizophrenia or affective disorder, a combination of the 2, or an intermediate condition along a continuum between schizophrenia and affective disorder. METHOD: We compared outpatients aged 45 to 77 years with DSM-III-R diagnosis of schizoaffective disorder (N = 29), schizophrenia (N = 154), or nonpsychotic mood disorder (N = 27) on standardized rating scales of psychopathology and a comprehensive neuropsychological test battery. A discriminant function analysis was used to classify the schizoaffective patients based on their neuropsychological profiles as being similar either to schizophrenia patients or to those with nonpsychotic mood disorder. RESULTS: The schizoaffective and schizophrenia patients had more severe dyskinesia, had a weaker family history of mood disorder, had been hospitalized for psychiatric reasons more frequently, were more likely to be prescribed neuroleptic and anticholinergic medication, and had somewhat less severe depressive symptoms than the mood disorder patients. The schizophrenia patients had more severe positive symptoms than the schizoaffective and mood disorder patients. The neuropsychological performances of the 2 psychosis groups were more impaired than those of the nonpsychotic mood disorder patients. Finally, on the basis of a discriminant function analysis, the schizoaffective patients were more likely to be classified as having schizophrenia than a mood disorder. CONCLUSION: These findings suggest that schizoaffective disorder may represent a variant of schizophrenia in clinical symptom profiles and cognitive impairment.

Risk factors for orofacial and limbtruncal tardive dyskinesia in older patients: a prospective longitudinal study.

Although there is a consensus that orofacial and limbtruncal subtypes of tardive dyskinesia (TD) exist and may represent distinct pathophysiologic entities, few studies have examined the incidence of and risk factors associated with the development of these TD subtypes. Two hundred and sixty-six middle-aged and elderly outpatients with a median duration of 21 days of total lifetime neuroleptic exposure at study entry were evaluated at 1- to 3-month intervals. Using "mild" dyskinesia in any part of the body for diagnosis of TD, the cumulative incidence of orofacial TD was 38.5 and 65.7% after 1 and 2 years, respectively, whereas that of limbtruncal TD was 18.6 and 32.6% after 1 and 2 years. Preclinical dyskinesia was predictive of both orofacial and limbtruncal TD. History of alcohol abuse or dependence was a significant predictor of orofacial TD only whereas tremor was a significant predictor of limbtruncal TD only. Findings support suggestions that orofacial and limbtruncal TD may represent specific subsyndromes with different risk factors.

The disparate effects of Alzheimer's disease and Huntington's disease on semantic memory.

Alzheimer's disease (AD) and Huntington's disease (HD) impair performance on semantic memory tasks, but researchers disagree on whether AD and HD cause these impairments in the same manner. According to one view, AD disrupts the storage of semantic memories, whereas HD disrupts the retrieval of semantic memories. Dissenters argue that AD, like HD, disrupts retrieval. In this study, participants generated category exemplars (e.g., kinds of fruits) for 1 min, and response latencies were examined. Relative to healthy controls, the 12 AD patients produced a larger proportion of responses earlier in the recall period, consistent with the view that AD patients quickly exhaust their limited supply of items in storage. By contrast, the 12 HD patients produced a larger proportion of their responses late in the recall period, consistent with the view that HD slows retrieval.

Is it possible to be schizophrenic yet neuropsychologically normal?

This study identified and characterized a group of schizophrenic patients without neuropsychological (NP) impairment. A comprehensive NP battery was administered to 171 schizophrenic outpatients and 63 normal comparison participants. Each participant's NP status was classified through blind clinical ratings by 2 experienced neuropsychologists; 27% of the schizophrenics were classified as NP normal. The NP-normal and NP-impaired schizophrenics were similar in terms of most demographic, psychiatric, and functional characteristics, except that NP-normal patients had less negative and extrapyramidal symptoms, were on less anticholinergic medication, socialized more frequently, and were less likely to have had a recent psychiatric hospitalization. The existence of NP-normal schizophrenics suggests that the pathophysiology underlying the cognitive deficits often associated with schizophrenia may be distinct from that causing some of its core psychiatric features.

Cognitive deficits and psychopathology in institutionalized versus community-dwelling elderly schizophrenia patients.

We evaluated psychiatric symptoms and neurocognitive functioning among 25 institutionalized and 25 outpatient DSM-IV-diagnosed schizophrenia patients, as well as 25 middle-aged and elderly normal comparison subjects. All subjects were assessed with the Positive and Negative Syndrome Scale, Hamilton Rating Scale for Depression, modified Simpson-Angus Extrapyramidal Symptom Scale, the Abnormal Involuntary Movement Scale, and the Mattis Dementia Rating Scale (DRS). The two patient groups had similar levels of depressive symptoms, but the institutionalized patients had more severe positive and negative symptoms and were on higher doses of neuroleptic medication. The institutionalized patients had significantly more cognitive impairment on the DRS than outpatients and normal comparison subjects, particularly on the subscales of initiation/perseveration, conceptualization, and memory. Results are discussed in terms of the possible neuropathology associated with cognitive impairment in chronic schizophrenia.