Conceptual and perceptual implicit memory in Huntington's disease.

The aims of this study were to examine and compare perceptual and conceptual implicit memory (CIM) in Huntington's disease (HD) and to characterize the relationship between tests of frontal lobe functioning and CIM. Sixteen HD patients and 16 normal controls completed structurally parallel tests of perceptual implicit memory and CIM (i.e., rhyme and category exemplar generation), tests of explicit memory, and verbal fluency. HD patients showed intact implicit memory for both rhyme and category exemplars, despite evidence of frontal dysfunction on other tests. An unexpected finding was that patients showed a deficit in cued rhyme generation that correlated with severity of neurological impairment. The authors replicated findings in controls of a correlation between letter fluency and CIM but found no relationship in patients. Frontal dysfunction in HD may lessen the influence of generative strategies on tests of CIM without compromising performance.

Longitudinal analysis of phonemic clustering and switching during word-list generation in Huntington's disease.

Two characteristics of word-list generation performance are forming clusters (i.e., contiguous words from the same subcategory) and switching among them. Patients with frontal lobe pathology show reduced switching on letter-cued word generation tasks, and clustering has been associated with temporal lobe functioning. Letter-cued word generation was examined in 72 patients with Huntington's disease (HD) and 41 healthy participants of equivalent age and education. As predicted, the patients showed reduced switching but normal clustering. In addition, switching but not clustering correlated inversely with disease severity, as measured by both movement and mental status scales. Furthermore, 5-year longitudinal analysis revealed a monotonic decrease in switching over time, whereas clustering performance remained stable. Control participants performed uniformly over time on both measures. These results are consistent with a progressive reduction in cognitive flexibility attributed to disruption of frontal-subcortical circuits secondary to neostriatal pathology in HD.

Frontal lobe volume in patients with Huntington's disease.

Neuropathologic and neuroimaging studies have suggested that frontal lobes are affected in Huntington's disease (HD), and that atrophy in this region may be associated with some of the cognitive impairment and clinical decline observed in patients with HD. We measured gray and white matter volumes within the frontal lobes on MRI for 20 patients with HD (10 mildly affected and 10 moderately affected) and 20 age- and sex-matched control subjects. We also correlated frontal lobe measurements with measures of symptom severity and cognitive function. Patients who were mildly affected had frontal lobe volumes (both gray and white matter) essentially identical to those of control subjects, despite clearly abnormal basal ganglia. Patients who were moderately affected demonstrated significant reductions in total frontal lobe volume (17%) and frontal white matter volume (28%). Frontal lobe white matter volume reductions, but not total frontal lobe volume reductions, were disproportionately greater than overall brain volume reductions (17%). Frontal lobe volume correlated with symptom severity and general cognitive function, but these correlations did not remain significant after taking into account total brain volume. We conclude that cognitive impairment and symptom severity are associated with frontal lobe atrophy, but this association is not specific to the frontal lobes. Frontal lobe atrophy (like total brain atrophy) occurs in later stages of increasing HD symptom severity and this atrophy primarily involves white matter.

Simulators for assessing driving skills in demented patients.

This paper reviews the appropriate use of simulators to assess driving abilities in individuals with dementing illnesses. Several points are addressed: What is a driving simulator? What are the characteristics of a simulator? What are the strengths and weaknesses of various types of simulators? The potential role of driving simulators for predicting future driving safety is discussed.

Perseverations during paired-associate learning in Huntington's disease.

Verbal (word) and nonverbal (design) paired-associate tasks were administered to Huntington's disease (HD) patients and healthy control subjects. An AB-AC paradigm, in which the cue stimuli were paired with different responses on the learning (e.g., BED-REST) and test trials (e.g., BED-SHEET), was used. It was hypothesized that HD patients would continue to respond with AB associations on the AC trials. The results were contrary to expectations: Patients showed impaired learning of both verbal and nonverbal associations but did not display a perseverative response style, even when the associative strength between word pairs was manipulated to elicit perseverations. Patients made more nonperseverative than perseverative errors in all conditions, an error pattern similar to that of control subjects. HD patients did not demonstrate increased susceptibility to proactive interference on these associative learning tasks.

Lewy bodies and progressive dementia: a critical review and meta-analysis.

Researchers disagree as to whether Lewy body disease (LBD) constitutes a variant of Alzheimer's (AD) or Parkinson's disease (PD), or alternatively, whether it is an independent disease process. The neuropathological, genetic, and clinical characteristics of LBD are reviewed and compared to those of AD and PD. Data for 150 cases of LBD reported in the literature were compiled and grouped according to neuropathological status. Patients with pure LBD (with limited or no concurrent AD pathology) tend to present at a younger age with extrapyramidal signs followed by dementia, whereas patients with mixed LBD-AD (concurrent LB and AD pathology) are somewhat older and tend to present with dementia. The cognitive profile of LBD patients, and the relationships among LBD, AD, and PD remain unclear due to methodological limitations and the paucity of studies comparing the groups directly.

Dementia and driving: an attempt at consensus.

The number of older drivers in Sweden will be rapidly increasing during the next decades. A possible relationship exists between the increased relative crash risk of older drivers and the prevalence of age-related diseases such as dementia. However, a clear-cut policy for evaluating driving competence in demented persons is still lacking. In recognition of this fact, the Swedish National Road Administration invited a group of researchers to formulate a consensus on the issue of driving and dementia. This consensus document is aimed at providing primary care physicians with practical advice concerning the assessment of cognitive status in relation to driving. Suggestions are based on a review of existing research and discuss the use of general and driving-specific sources of information available to the physician. Consensus was reached on the statement that a diagnosis of moderate to severe dementia precludes driving and that certain individuals with mild dementia should be considered for a specialized assessment of their driving competence.

The course of psychopathologic features in mild to moderate Alzheimer disease.

BACKGROUND: The onset and course of the psychopathologic features of Alzheimer disease have not been established in prospective, longitudinal studies. METHODS: Two hundred thirty-five patients with early, probable Alzheimer disease were recruited at 3 sites and observed naturalistically for up to 5 years. At 6-month intervals, the Columbia University Scale for Psychopathology in Alzheimer's Disease was administered. Markov analyses were used to predict the probability of a specific symptom developing or being maintained at the next visit. For each symptom category, the maximum frequency of occurrence at 4 consecutive points (duration, 2 years) was calculated. RESULTS: Misidentification, wandering or agitation, and physical aggression increased during follow-up. At any visit, the likelihood of a new symptom developing was greatest for behavioral disturbance, intermediate for paranoid delusions and hallucinations, and least for depressed mood with vegetative features. Wandering or agitation occurred at 3 or more of 4 consecutive visits (duration, 2 years) in the majority of patients, paranoid delusions and hallucinations were intermediate in their degree of persistence, and depressed mood with vegetative signs rarely persisted. CONCLUSIONS: Behavioral disturbance, particularly agitation, is common and persistent in patients with Alzheimer disease. Psychotic symptoms are less common and show moderate persistence over time. Depressed mood with vegetative signs is uncommon and rarely persists. These findings suggest leads about the optimal treatment duration for specific subtypes of psychopathologic features.

Longitudinal change in basal ganglia volume in patients with Huntington's disease.

Cross-sectional MRI studies demonstrating an association between caudate atrophy and symptom severity and duration of symptoms in patients with Huntington's disease (HD) have been assumed to reflect longitudinal changes in basal ganglia, but such neuropathologic progression has never been directly demonstrated. Subjects in the current study were 23 HD patients at various stages of the disorder who had two MRI images at least 10 months apart (mean interimage interval = 20.8 months). We measured volumes of caudate, putamen, and globus pallidus blind to the order of the images. For each structure, we calculated a change score by subtracting the volume obtained on the follow-up imaging from that obtained on the initial imaging. Results indicated significant decreases over time in caudate, putamen, and total basal ganglia volume. Age at onset and length of trinucleotide repeat correlated significantly with amount of volume change in caudate and total basal ganglia, even after controlling for length of interimage interval, duration of disease, and measures of symptom severity. Amount of change in basal ganglia structures was not significantly correlated with neurologic symptom severity at the time of the initial imaging or duration of symptoms. This is the first longitudinal MRI study to document progressive basal ganglia atrophy in HD, and suggests that quantitative neuroimaging with serial MRI may be useful in monitoring effectiveness of potential treatments. In addition, demonstration of greater rate of basal ganglia atrophy in patients with earlier symptom onset suggests that treatment effects may be more quickly observed in this subgroup of patients than in the general HD population.

Odor identification in Huntington's disease patients and asymptomatic gene carriers.

Odor identification was assessed in 20 Huntington's disease (HD) patients, 20 normal adults with the genetic mutation that causes HD, and 20 mutation-negative adults. The University of Pennsylvania Smell Identification Test (UPSIT) revealed substantial odor identification deficits only in HD patients.

A controlled trial of idebenone in Huntington's disease.

One hundred patients with clinically diagnosed Huntington's disease (HD) were randomized to either idebenone, an antioxidant and enhancer of oxidative metabolism, or placebo, in a 1-year, double-blind, parallel-group study aimed at slowing the rate of progression of the disease. Ninety-one patients completed the study. There were no significant differences between groups on the primary outcome measures of the Huntington's Disease Activities of Daily Living Scale (ADL-an index of functional status) and the Quantified Neurologic Examination (QNE). Sample size calculations based on progression of the ADL and QNE in this study group revealed that a larger study group is necessary to detect any differences less than an almost complete halting of the disease. This argues for multicenter efforts for future therapeutic trials in HD.

Item priming and skill learning in amnesia.

This study employed a semantic decision-making task to examine both item priming and skill learning in amnesia, which traditionally have been demonstrated with separate tasks. Fourteen amnesic patients of mixed etiologies and 14 normal control subjects judged whether words represented animate or inanimate objects. One list was presented repeatedly on four continuous blocks of trials, and a new list was presented on the fifth block. For both groups, decision times decreased significantly from Block 1 to Block 5 (indicating skill acquisition) and increased significantly from Block 4 to Block 5 (indicating item-specific learning). The amnesic patients demonstrated a normal rate of skill learning, but a reduced magnitude of item priming. As expected, the amnesics had significantly impaired explicit memory of the implicitly learned items, as measured by recognition accuracy. The results suggest that both implicit and explicit learning of individual items is impaired in amnesia, despite normal semantic skill learning.

Trinucleotide repeat length and clinical progression in Huntington's disease.

We examined the relationship between length of the trinucleotide (CAG) repeat at IT-15 and clinical progression of Huntington's disease in 46 mildly to moderately affected patients over a 2-year interval. Patients were divided into those with short mutations (37 to 46 repeats; n = 25) and those with long mutations (> or = 47 repeats; n = 21). Patients with long repeat lengths had earlier age at onset and were younger and less functionally impaired than those with short repeats at the initial visit, but the groups did not differ in severity of neurologic or cognitive impairment. However, the long-repeat group displayed significantly greater decline in both neurologic and cognitive functioning over the 2-year follow-up period. The length of the CAG repeat correlated highly with age at onset (r = -0.72, p < 0.001) and was a strong predictor of decline in both neurologic and cognitive function. The mechanism of gene action, and the means by which longer expansions result in a more malignant disease process, remain to be elucidated.

Impaired source memory in Huntington's disease and its relation to basal ganglia atrophy.

Memory for contrived facts and the source of those facts was assessed in a group of early-stage HD patients and an age- and education-equated group of healthy control subjects. Fact recall did not differ significantly between the groups, but erroneous source attributions were more common among the HD patients. Like individuals with frontal lobe damage, HD patients have impaired memory for the source of learned information. Volume of the left caudate nucleus on MRI scans correlated with fact recall and source memory measures. These results suggest that this nucleus, or its neocortical projections, play an important role in the coding of context.

Automobile driving in Huntington's disease.

We assessed the influence of the neurological and cognitive impairments of Huntington's disease (HD) on automobile driving. In a group of 73 HD outpatients, 53 (72%) continued to drive after illness onset. Those no longer driving had more severe symptoms than those still driving. Twenty-nine HD patients who were still driving and 16 healthy control subjects underwent a clinical examination, a cognitive examination, a driving-simulator assessment, and completed questionnaires about driving history and habits. HD patients performed significantly worse than control subjects on the driving-simulator tasks and were more likely to have been involved in a collision in the preceding 2 years (58% of HD vs. 11% of control subjects). Patients with collisions were less functionally impaired but had slower simple reaction time scores than did those without collisions. HD patients are at increased risk for accidents, but patients who have accidents are not easily distinguished from those who do not.

A standardized technique for establishing onset and duration of symptoms of Alzheimer's disease.

OBJECTIVES: To develop an informant-based semistructured interview to determine the onset and duration of symptoms of Alzheimer's disease, and to use this instrument with informants to characterize a cohort of mildly impaired patients with Alzheimer's disease. DESIGN: In study 1, interrater and interinformant reliability was examined for the date of onset and the order of appearance for specific symptoms that were elicited by the semistructured onset interview. In study 2, the instrument was used to characterize disease onset in a cohort of patients with Alzheimer's disease who were participating in a large multicenter study. SUBJECTS: Informants of patients with Alzheimer's disease. RESULTS: In study 1, interrater reliability for duration of illness was excellent (intraclass correlation coefficient = .99, P < .001), and interinformant reliability was good (intraclass correlation coefficient = .86, P < .001). Agreement for the presence of a given symptom was highest for those that were most commonly reported (eg, memory and performance difficulty). In study 2, 89% of the cohort had memory problems, and 63.9% had performance difficulties as the first or second symptom. Depression and language problems were less commonly reported. Psychosis and behavioral disturbances were rarely reported as the first problem. CONCLUSION: This instrument provides a reliable procedure for standardizing the estimation of duration of illness based on retrospective report.

Changes in visual fixation and saccadic eye movements in Alzheimer's disease.

Visual fixation and saccadic eye movements were assessed in 31 mild to moderately demented patients with probable Alzheimer's disease (AD) and 31 age- and education-matched nondemented elderly control subjects. Seventeen AD and 17 matched control subjects were reassessed after a 9-month interval. On a fixation task, duration of fixation and number of intrusive saccades were not different between groups at baseline or follow-up. Both AD patients and control subjects showed more intrusive saccades at follow-up than at baseline. AD patients showed increased latency to initiation of saccades at baseline and on follow-up. Amplitude and velocity of saccades were not different between groups at any visit. Changes in measures of fixation, but no saccade measure, correlated with changes in MMSE scores over testing sessions. These data suggest that fixation is more sensitive than are saccades to the progession of AD.

Stability of performance on the Hopkins Verbal Learning Test.

Stability of performance on the Hopkins Verbal Learning Test (HVLT) was assessed in 45 healthy elderly subjects over a 9-month period. Stability coefficients were moderate but statistically significant for total recall (r = 0.50), true-positive recognitions (r = 0.66), and false-positive errors (r = 0.42). These correlations are comparable to test-retest correlations reported for other clinical tests of verbal memory (e.g., Logical Memory subtest of the Wechsler Memory Scale-Revised, California Verbal Learning Test) and are sufficient for its clinical use.

Assessing patient dependence in Alzheimer's disease.

BACKGROUND: While cognitive and functional deficits are the hallmark of Alzheimer's disease (AD), loss of social function (and the dependence this implies) is also critical, especially in early stages of disease. Little attention has been directed to this facet of dementing disease. We describe a scale for assessing dependency in AD and present a baseline profile of dependency in a cohort of AD patients. METHODS: In a study of the predictors of the course of AD, 233 patients in early stages of disease (modified MMS > or = 30) were assessed. Psychometric properties of the dependence scale were established. To validate the scale, dependence scores at baseline were correlated with a series of measures assessing cognition and function. The course of dependency over 18 months of follow-up was also analyzed. RESULTS: The scale shows adequate reliability (test-retest, intraclass correlation). Dependence stage was related to other measures of disease severity. Scalogram analysis shows that the dependence scale is consistent with the course of functional loss established for dementing disease. Prospective data indicate sensitivity of the scale to disease progression. CONCLUSION: Dependency is a distinct, measurable component of dementing disease and should be considered an important outcome in studies of AD.

EEG power spectra in Huntington's disease: clinical and neuropsychological correlates.

Quantitative power spectral analysis (PSA) was applied to frontal (F3, F4, F7, F8), temporal (T5, T6), and occipital (O1, O2) EEGs of 16 Huntington's disease (HD) patients and eight healthy control subjects. PSA revealed HD patients' EEGs to be abnormal: (i) raw and percent Alpha power were reduced; (ii) raw and percent Theta power were reduced at F3 and F4; (iii) percent Delta and percent Beta power were increased; (iii) Theta frequency was reduced by approximately 1.0 Hz. Frontal and temporal EEG power measures and decreased EEG amplitude correlated with severity of neurological and cognitive impairment.