Impact of Language

A new finding of this normative study is the influence of the language in which the tests are administered on the cognitive performance of healthy control subjects. However, the same observation has been already described in several, showing the essential impact of language on performance in neuropsychological tests (Bezdicek et al., 2015, Ardila, 2020) and the cultural background (Fernández and Marcopulos, 2008). This study emphasizes the need to address cultural and language biases on cognitive testing (Statucka and Cohn, 2019). The strategies for developing culture - and language-independent cognitive tests that avoid verbal tasks have proven unsuccessful in clinical practice and research (Marcinkowska, 2017, Fernández and Abe, 2018). In the old fashion, it was mostly TMT, and SDMT was considered language-independent, but there is clear evidence that avoiding the verbal task is insufficient. Numerous studies, mostly from Asian regions, evaluated the TMT- part A using other languages than English (Stanczak et al., 2001, Bhatia et al., 2007, Kim et al., 2014), reported that healthy Asians performed worse than English native controls. Such factors could lead to diagnostic errors while evaluating cognitively impaired individuals in different cultural and language contexts. The TMT-B is even more restrained to be used in the different language contexts.

Although the TMT may be measuring visual scanning, psychomotor speed and mental flexibility, that are not defined primarily by language, normative data comparison study from ten different countries such as Argentinian, Belgium, Canada, China, Denmark, Italy, New Zealand, Sweden, UK and USA showed that the normative data is not equivalent which might lead to serious diagnostic errors (Fernández and Marcopulos, 2008), although matched for the age and education. In addition, we obtained the same results as the study of Bezdicek et al. showing, TMT-A and TMT-B performance may be significantly faster in Czech and English populations than in Spaniards, demonstrating a lack of sociocultural equivalence on TMT-A and B, suggesting the need for adjustment of available TMT norms for use in different cultures (Bezdicek et al., 2016).

Language and cultural differences have also influenced SDMT performance, even involving adjustment to the basic sociodemographic factors (González et al., 2007, Agranovich et al., 2011, Cores et al., 2015). Different hypotheses are trying to explain the differences in the performance of these tests. For example, a matched sample of Russian and American adults found that cultural differences in time

133 attitudes were associated with differences in performance on timed neuropsychological tests, including the SDMT (Agranovich et al., 2011). Not all studies comparing different language groups and backgrounds may explain the apparent differences in SDMT by sociodemographic factors (Cores et al., 2015). Indeed, it is now well recognized that ethnicity and, more broadly, culture influence neuropsychological test performance, including psychomotor speed (Fernández and Marcopulos, 2008, Ojeda et al., 2016a, Fernández and Abe, 2018).

Even the Stroop Tests are dependent on the language, as shown in the several studies that established their specific normative values to evaluate Stroop tests appropriately in different languages (Van der Elst et al., 2006).

It is an open question how language influences neuropsychological tests and our performance.

Recently, Amici et al. observed that even language syntax might influence verbal working memory.

Moreover, speakers of right-branching languages such as Italian (the head of the sentence usually comes first, followed by information modifiers) could process information incrementally (Amici et al., 2019). Another example is the study by Steenhuis and Ostbye, reporting a significant difference in verbal fluency between French and English for the letters F, A and S and Animal Naming (Steenhuis and Østbye, 1995, Ardila, 2020). The language was found to affect verbal working memory, thus potentially explaining an impact on neuropsychological test performance (Amici et al., 2019). There is an obvious need to provide language-specific normative data for appropriate test interpretation from a clinical and research perspective. There is clear evidence for the language-specific norms, as presented in several studies of the Hispanic population living in the English-speaking environment (Ardila et al., 1999, Fortuny et al., 2005, Gasquoine et al., 2007). The strategies to develop culturally and linguistically independent cognitive tests that avoid verbal tasks have proven unsuccessful (Marcinkowska, 2017, Fernández and Abe, 2018).

Although the demographic variables impact neuropsychological scores, few studies examine the relationship between language and cultural background and cognitive scores in patient populations.

However, this information is critical because it is vital to consider language when interpreting patient scores (Boone et al., 2007), (Marcopulos et al., 1997, Manly et al., 1998, Manly et al., 2002, Lucas et al., 2005, Ojeda et al., 2016b). These findings are also relevant for multi-centre studies when the same neuropsychological tests are applied in different countries and languages (Katz, 2020). It is also essential to look at the impact of language when considering the generalizability of normative values derived from datasets originating from different countries or cultures (Marcopulos et al., 1997, Manly et al., 1998, Manly et al., 2002, Lucas et al., 2005, Ojeda et al., 2016b, Agelink Van Rentergem et al., 2020).

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Application to Huntington Disease

Although in HD, the clinical diagnosis of HD is typically based on the onset of characteristic motor signs combined with a positive family history, the cognitive impairments stay a key symptom occurring at very early, even premanifest diseases stage (Paulsen and Long, 2014, Paulsen et al., 2017). There is strong evidence from the numerous studies referring to the subtle cognitive deficits in attention, working memory, processing speed, psychomotor functions, episodic memory, emotion processing, perception and executive functions occurring before the diagnostic motor signs, therefore assessing cognitive performance continuously is of high importance for monitoring disease progression (Kirkwood et al., 2000, Paulsen et al., 2008, Snowden, 2017). Several studies have highlighted the importance of monitoring the longitudinally cognitive decline in carriers of the htt-expansion mutation at early stages of the disease process (clinically ‘premanifest HD’) in determining the progression of the disease (Tabrizi et al., 2013b, Paulsen et al., 2014a, Julayanont et al., 2020). As mild cognitive impairment (MCI) is thought to be common in early motor-manifest HD and likely to be a feature even in premanifest HD, normative values will assist in the clinical interpretation of cognitive deterioration, defining cut-off values for MCI (Julayanont et al., 2020).

To track the disease progression longitudinally, a reliable progression marker is needed. Numerous studies established (1) that performance decline in tests assessing psychomotor speed is an early, well- reproduced feature of HD (Stout et al., 2012, Tabrizi et al., 2012, Paulsen et al., 2014a) and (2) that performance decline in the neuropsychological tests in general is – along with an increased motor impairment - a consistent, quantifiable hallmark of disease progression in HD (Roos, 2010, Snowden, 2017). Therefore, performance in SDMT was incorporated – along with the Total Motor Score (TMS) of the UHDRS (Huntington Study Group, 1996) and the Total Functional Capacity (TFC) (Huntington Study Group, 1996) – as a component into a composite score of the UHDRS (cUHDRS) proposed as a potential indicator of the rate of progression in HD (Schobel et al., 2017). However, several confounding factors complicate the interpretation of a decline in cognitive performance score in HD patients, the most important being a decline in performance resulting from normal ageing. Therefore, this study plans to examine the cUHDRS score under consideration of the specific norms established by using the normative calculator.

Strengths and Limitations

This study was performed on the overall large sample of control subjects with a methodologically beneficial design prospectively and systematically. The cognitive assessments were obtained from bona fide ‘healthy’ subjects. The participants were prospectively screened for comorbid conditions; the

135 medical history was annually updated data on the neurological and psychopathological phenotype and ongoing pharmacotherapy and nonpharmacological approaches.

Potential limitations of this study might be that the cohort of controls represents a convenience sample of subjects recruited from families affected by HD, recruited through Enroll-HD study centres.

Thus, the sample might not represent the diversity of a population. In addition, the burden of living in households impacted by HD may have some bearing on performance in cognitive tests. The sample size for some languages was insufficient to provide language-specific normative values. From our perspective, it would be desirable to substantially expand the normative data collection, as our results show that the language used during the examination influences cognitive performance.

5. Conclusions

In conclusion, this study established normative data for the cognitive battery consisting of SDMT, Stroop tests (SWRT, SCNT, SIT), TMT-A and TMT-B, Letter and Category Fluency tests from an international, sizeable sample of healthy controls, stratified by age, gender, education and language. In addition, this work resulted in the implementation of an easy-to-use, web-based normative calculator freely accessible to clinicians and researchers worldwide. A range of CNS disorders similar to HD is characterized by executive function impairments and reflects the dysfunction of pre-frontal-striatal thalamic circuits (Mega and Cummings, 1994). However, the anatomical sites responsible for the pathological alterations differ between distinct disease entities, e.g. cortex in frontotemporal dementia (FTD) (Burrell et al., 2016) (Plutino et al., 2020), white matter in multiple sclerosis (MS) (Chiaravalloti and Deluca, 2008, Zhang et al., 2016), basal ganglia in HD (Graybiel et al., 1994, Parent et al., 1995, Blumenstock and Dudanova, 2020) and Parkinsonian disorders (PD), e.g. progressive supranuclear palsy (PSP) (Aarsland et al., 2017, Plutino et al., 2020), thalamus in Creutzfeld-Jakob disease (CJD) (Gibson et al., 2018), the alteration of this circuitry and anatomical structures typically results in similar cognitive impairments.

Based on this fact, the cognitive battery examined in this study may be applied on the principle of the generality to assess the cognitive disruptions referring to the pre-frontal-striatal-thalamic circuits (Albin et al., 1989, Parent et al., 1995, Peters et al., 2016) altered in disorders mentioned above. In particular, it is important to develop an appropriate tool for tracking disease progression; a battery of cognitive tests is well suited for repeated, longitudinal application (Molinuevo et al., 2017) is commonly used.

Aside from first exposure and practice effects (Bartels et al., 2010, Calamia et al., 2012), isolating the impact of disease progression on cognitive performance is of high importance for clinical practice and

136 research. In line with this approach is minimizing of the key confounding factors, such as age (Alenius et al., 2019), gender (Weber et al., 2014), an education level (Harrison et al., 2015), language and cultural background (Boone et al., 2007) at a single subject level. However, no comprehensive normative data for the mode of application of these commonly employed cognitive tests are available, primarily because of a lack of data from a large cohort of control subjects. In the context of large, international observational studies on the natural history of HD, data were prospectively collected from a sizable cohort of control subjects not carrying the htt-expansion mutation.

Outlook

The neuropsychological assessment itself reflects a culturally embedded process. Culture permeates all aspects of neuropsychological assessment, from the identification and definition of relevant constructs, the development and construction of tests, the clinical interview and observations, the process of test administration and the interpretation of performance (Ardila 2007a, b). Thus, a central question concerns how we can recognize the influence of culture and language on neuropsychological assessment to address such highly varied issues meaningfully. In this way, it is important to continuously develop the appropriate neuropsychological tests considering the key sociodemographic variables, including language and cultural background, or to provide the specific normative values considering the basic sociodemographic. In addition, there is an urgent need to expand the collection of normative data from healthy controls to increase sample size and to cover additional languages missing in the sampling efforts as currently conducted in the context of the Enroll-HD study.

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