A Systematic Review of Neuropsychological Tests for the Assessment of Dementia in Non-Western, Low-Educated or Illiterate Populations.

OBJECTIVE: Neuropsychological tests are important instruments to determine a cognitive profile, giving insight into the etiology of dementia; however, these tests cannot readily be used in culturally diverse, low-educated populations, due to their dependence upon (Western) culture, education, and literacy. In this review we aim to give an overview of studies investigating domain-specific cognitive tests used to assess dementia in non-Western, low-educated populations. The second aim was to examine the quality of these studies and of the adaptations for culturally, linguistically, and educationally diverse populations. METHOD: A systematic review was performed using six databases, without restrictions on the year or language of publication. RESULTS: Forty-four studies were included, stemming mainly from Brazil, Hong Kong, Korea, and considering Hispanics/Latinos residing in the USA. Most studies focused on Alzheimer's disease (n = 17) or unspecified dementia (n = 16). Memory (n = 18) was studied most often, using 14 different tests. The traditional Western tests in the domains of attention (n = 8) and construction (n = 15), were unsuitable for low-educated patients. There was little variety in instruments measuring executive functioning (two tests, n = 13), and language (n = 12, of which 10 were naming tests). Many studies did not report a thorough adaptation procedure (n = 39) or blinding procedures (n = 29). CONCLUSIONS: Various formats of memory tests seem suitable for low-educated, non-Western populations. Promising tasks in other cognitive domains are the Stick Design Test, Five Digit Test, and verbal fluency test. Further research is needed regarding cross-cultural instruments measuring executive functioning and language in low-educated people.

Longitudinal pilot-study of Sustained Attention to Response Task and P300 in manifest and pre-manifest Huntington's disease.

BACKGROUND: Earlier research has found cross-sectional attentional control deficits in manifest Huntington's disease (HD) using neuropsychological testing combined with simultaneous P300 registration. In the current pilot-study, we investigate attentional control in pre-manifest and manifest HD over a 3-year follow-up period. METHOD: Five manifest HD (MHD), 9 pre-manifest HD (PMHD), and 12 control subjects were included. Sustained Attention to Response task (SART) and P300 registration resulted in number of errors, reaction time (RT), and P300 amplitude and latency. RT change patterns surrounding No-go trials were also investigated. Within-subject differences were tested using paired-samples t-tests and between-group results with ANCOVA on delta scores (follow-up--baseline scores). RESULTS: Manifest HD made more errors and were slower than controls and PMHD. Longitudinally, MHD showed an overall RT increase and a specific slowing on trials preceding a correct No-go trial (within-group effects). The latter was also seen in PMHD. P300 latency prolongation was found for controls on No-go and for MHD on Go trials. On specific trials surrounding both correct and incorrect No-go trials, MHD became significantly slower over time than controls and PMHD (between-group effects). CONCLUSIONS: Over 3-years, MHD subjects became slower on the SART and showed a prolongation of P300 latency on specific SART trials. Specific slowing of performance over time was also seen in PMHD, suggestive of compensatory mechanisms in this group.

Striatal metabolism and psychomotor speed as predictors of motor onset in Huntington's disease.

The clinical diagnosis of Huntington's disease (HD) is based on the motor symptoms, although these can be preceded by cognitive and behavioral changes. Biomarker studies have shown that structural imaging modalities are useful biomarkers of HD onset, while functional imaging measures have been studied less often for this purpose. Our aim was to investigate the combined value of 18-fluorodesoxyglucose (FDG)-PET and cognitive measures as biomarkers of HD onset. Twenty-two premanifest mutation carriers of HD (PMCs) and 11 healthy controls were assessed twice with FDG-PET scan, neurological and neuropsychological assessments over a 2-year interval. Seventeen PMCs had an additional third neurological evaluation, 10 years after baseline. Disease load was defined as the probability of motor onset within 5 years. Metabolism in putamen, caudate and pallidum of PMCs was significantly lower than that of controls, at both assessments. Almost half of the PMCs had converted to manifest HD 10 years later and all converters had low average or abnormal putaminal metabolism at 2 year follow-up. In contrast, all PMCs with normal putaminal metabolism at 2 year follow-up remained premanifest during the following 8 years. Furthermore, glucose metabolism of putamen explained a substantial part of the variance in disease load. A composite score of psychomotor tests contributed significantly to the prediction model as well, while cognitive performance was comparable for PMCs and controls. We conclude that in future clinical trials a combination of psychomotor tests and putaminal glucose metabolism may be used to identify PMCs close to motor onset of HD.

Seven-year clinical follow-up of premanifest carriers of Huntington's disease.

Detecting subtle clinical abnormalities in the 'premanifest' phase of Huntington's disease (HD) is of importance in the development of instruments to monitor early therapeutic intervention trials. The current study examined changes in motor function, cognition and behaviour over a period of seven years in premanifest carriers of the HD gene mutation. Twenty-nine carriers without unequivocal motor signs of HD and 43 non-carrier controls were prospectively examined four times. The assessments consisted of the Unified Huntington's Disease Rating Scale (UHDRS) and an extensive neuropsychological test battery addressing global cognitive function, memory, language and executive function. Rate of Change (RoC) analysis was performed to measure longitudinal differences between carriers and non-carriers. Carriers performed consistently worse on executive function (Symbol Digit Modalities Test (SDMT), Stroop, Trail Making Test (TMT) and WAIS-R arithmetic). Over the years, carriers showed a decline in memory and concentration function (Wechsler Memory Scale (WMS)) and in motor function (UHDRS motor scale). Changes over time could be particularly ascribed to carriers converting to manifest HD. These results demonstrate that standardized motor assessments and objective memory and concentration tasks are sensitive to change over a period of 7 years, specifically in carriers converting to manifest HD. Executive tasks also showed subtle cognitive abnormalities in premanifest HD, but a decline over time could not be demonstrated.

What is the impact of education on Huntington's disease?

Huntington's disease (HD) is a neurodegenerative disease caused by a cytosine adenosine guanine (CAG) expansion in the huntingtin gene. The length of the triplet repeat is the most important factor in determining age of onset and the severity of the disease, but substantial variability of these parameters is attributed to other factors. To investigate the relationship between the years of education and the age at onset and the severity of the phenotype in patients with HD, we applied multiple linear regression analysis to examine the impact of education on the age at onset and the severity of the clinical scores assessed by the Unified Huntington's Disease Rating Scale (UHDRS) of 891 patients with HD from the multinational observational study "Registry" conducted by the European Huntintgton's Disease Network. The model was adjusted for CAG repeat length and age at the time of assessment. Patients with lengthier education exhibited earlier estimated age at onset but less severe clinical scores (motor = -3.6, P = 0.006; cognitive = 27.0, P < 0.001; behavioral = -3.0, P < 0.001; and functional capacity = 1.1 points, P < 0.001) than those with shorter education, after controlling for age and number of CAG repeats. These differences persisted throughout all quartiles of disease severity. An earlier recognition of symptoms and manifestations among the more educated patients could explain the earlier estimated age at onset in this group. The link between better clinical UHDRS scores and higher education might reflect a beneficial effect of education or its covariates on the course of HD.

MRI T2 Hypointensities in basal ganglia of premanifest Huntington's disease.

Increased iron levels have been demonstrated in the basal ganglia of manifest Huntington's disease (HD). An excess in iron accumulation correlates with MRI T2-weighted hypointensity. Determination of the amount of hypointensities in the basal ganglia in the premanifest phase of HD may give more insight in the role of iron in the pathogenesis of HD. Therefore, the present study assessed whether the degree of hypointensities on T2-w MRI in the basal ganglia of premanifest gene carriers differs from non-carriers. Seventeen HD gene carriers without clinical motor signs and 15 non-carriers underwent clinical evaluation and MRI scanning. The amount of T2-w hypointensities was determined using a computer-assisted quantitative method that classified each pixel in the basal ganglia as hypointense or not, resulting in a total of hypointense pixels for each individual. Carriers showed an increased amount of hypointensities in the basal ganglia compared to non-carriers. More hypointensities were furthermore associated with a higher UHDRS total motor score, a longer CAG repeat length and a greater probability of developing symptoms within 5 years. We concluded that the increased amount of hypointensities in the basal ganglia of premanifest carriers of the HD gene may reflect excessive iron deposition and a role for iron in the neuropathology of HD. Furthermore, this phenomenon is associated with clinical and biological disease characteristics. An increased amount of hypointensities on T2-w MRI in the basal ganglia may be considered a biomarker for HD.

Magnetization transfer imaging in 'premanifest' Huntington's disease.

To investigate whether magnetization transfer imaging (MTI) is a useful detector of diffuse brain abnormalities in 'premanifest' carriers of the Huntington's disease (HD) gene mutation. Furthermore we examined the relations between MTI, clinical measures and CAG repeat length. Sixteen premanifest carriers of the HD gene without motor manifestation and 14 non-carriers underwent a clinical evaluation and a MRI scan. MTI analysis of whole brain, grey matter and white matter was performed producing magnetization transfer ratio (MTR) histograms. A lower peak height of the grey matter MTR histogram in carriers was significantly associated with more UHDRS motor abnormalities. Furthermore, a lower peak height of the whole brain, grey and white matter was strongly associated with a longer CAG repeat length. MTI measures themselves did not differ significantly between carriers and non-carriers. In premanifest HD mutation carriers, a lower MTR peak height, reflecting worse histological brain composition, was related to subtle motor abnormalities and higher CAG repeat length. Although we could not detect altered MTI characteristics in carriers of the HD gene mutation without clinical manifestations, we did provide evidence that the MTR peak height might reflect genetic and subclinical disease burden and may be of value in monitoring further disease progression and provide insight in clinical heterogeneity.

Basal ganglia volume and clinical correlates in 'preclinical' Huntington's disease.

OBJECTIVE: To establish differences in basal ganglia and thalamic volume between preclinical carriers and non-carriers of the Huntington's disease (HD) gene and to link the volume to motor, cognitive and behavioural characteristics in carriers. METHODS: Sixteen HD gene carriers without overt clinical motor signs and 14 non-gene carriers underwent clinical evaluation and a MRI scan. Volumes of the caudate nucleus, putamen, gobus pallidus and thalamus were measured using T1-weighted MR images. Motor, cognitive and behavioural functioning was assessed using the Unified Huntington's Disease Rating Scale (UHDRS), cognitive testing and the Beck Depression Inventory (BDI-II). RESULTS: Volumes of the caudate nucleus, putamen and globus pallidus were significantly smaller in carriers than in non-carriers while no differences between groups were found on clinical evaluation. In gene carriers smaller globus pallidus volume was associated with more motor abnormalities. A smaller putamen volume correlated significantly with worse psychomotor function on the Symbol Digit Modalities Task and the Trail Making Test B. CONCLUSIONS: In line with previous research we demonstrated that basal ganglia abnormalities precede overt disease manifestation of HD. Besides we showed that smaller basal ganglia volumes are related to subtle motor abnormalities and worse psychomotor performance in gene carriers without clinical diagnosis. Motor and psychomotor measures may be suitable clinical markers in future neuroprotective trials when combined with volumetric imaging.

Memory activation reveals abnormal EEG in preclinical Huntington's disease.

The EEG is potentially useful as a marker of early Huntington's disease (HD). In dementia, the EEG during a memory activation challenge showed abnormalities where the resting EEG did not. We investigated whether memory activation also reveals EEG abnormalities in preclinical HD. Sixteen mutation carriers for HD and 13 nonmutation carriers underwent neurological, neuropsychological, MRI and EEG investigations. The EEG was registered during a rest condition, i.e. eyes closed, and a working memory task. In each condition we determined absolute power in the theta (4-8 Hz) and alpha (8-13 Hz) bands and subsequently calculated relative alpha power. The EEG during eyes closed did not differ between groups. The EEG during memory activation showed less relative alpha power in mutation carriers as compared to nonmutation carriers, even though memory performance was similar [F (1,27) = 10.87; P = 0.003]. Absolute powers also showed less alpha power [F (1,27) = 7.02; P = 0.013] but similar theta power. No correlations were found between absolute and relative alpha power on the one hand and neuropsychological scores, motor scores or number of CAG repeats on the other. In conclusion, memory activation reveals functional brain changes in Huntington's disease before clinical signs become overt.