Liling Dong,Caiyan Liu,Chenhui Mao,Shanshan Chu,Jie Li,Xinying Huang,Jing Gao

Department of Neurology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College,Beijing 100730,China

Key words:Huntington’s disease;Alzheimer’s disease;transcortical motor aphasia

Objective Linguistic problem is common in Huntington’s disease (HD) patients.It has been studied before in native speakers of alphabetic languages,such as English.As a hieroglyphic language,Chinese differs from alphabetic languages in terms of phonology,morphology,semantics and syntax.We aimed to investigate the linguistic characteristics of manifest HD in native speakers of Mandarin.Meanwhile,we expected to explore the linguistic differences associated with cortical or subcortical pathology.Methods Five HD patients and five Alzheimer’s disease (AD) patients matched in age,gender,disease course and educational level were enrolled.All the participants were Mandarin native speakers.All finished history inquiry,physical examination,basic test,genetic test and neuropsychological assessment.Language evaluation was performed by Aphasia Battery of Chinese.Results HD patients had a mean disease course of 5.4±2.97 (range,2-10) years.They showed a linguistic disorder close to transcortical motor aphasia.They exhibited prominent phonological impairment,as well as slight semantic and syntactic abnormality.Tonic errors were found in speech.Character structural errors and substitutions were detected in writing.In comparison,AD patients showed a more severe linguistic impairment,characterized by global aphasia with more semantic errors.Conclusion Mandarin-speaking HD patients have a transcortical motor aphasia-like disturbance with prominent phonological impairment,whereas AD patients have a more severe global aphasia with salient semantic impairment.

HUNTINGTON’S disease (HD) is an autosomal dominant neurodegenerative disorder due to an expansion of CAG repeats in the exon 1 of huntington (HTT) gene.[1]It is characterized by motor disorder,cognitive decline and psychiatric symptom.[2]

Linguistic problem is common in HD patients.It has been studied before in native speakers of alphabetic languages,such as English,French,Spanish,German,Portuguese and so on.[3]Chinese is a kind of hieroglyphic language,which is completely different from alphabetic languages in terms of phonology,morphology,semantics and syntax.In this paper,we aimed to investigate the linguistic characteristics of Mandarin-speaking HD patients.Literature review indicates a complex and bidirectional interaction between cognitive and linguistic processes.[4-7]As a result,we also illustrated their cognitive characteristics.

HD and Alzheimer’s disease (AD) are representatives of subcortical and cortical dementia,respectively.HD is generally characterized by progressive degeneration of neostriatum,including caudate nucleus and putamen.[8]However,the major pathology of AD is progressive deterioration of medial temporal,frontal and parietal cortices.[9]In order to understand the linguistic differences associated with subcortical or cortical pathology,comparisons were made between HD and AD.

PATIENTS AND METHODS

Patients and enrollment

Five HD patients,together with five AD patients matched in age,gender,disease course and educational level,were recruited from the dementia and leukoencephalopathy clinic of Peking Union Medical College Hospital (PUMCH).All the participants were Mandarin native speakers.HD patients fulfilled the diagnostic criteria for HD issued in 1986.[10]They all had an expansion of CAG repeats in HTT gene,ranging from 38 to 41.AD patients met the diagnostic criteria for probable AD dementia with evidence of AD pathophysiological process,according to the recommendations of National Institute on Aging and the Alzheimer’s Association(NIA-AA) released in 2011.[11]All the participants gave informed consent.And this study was approved by the ethical committee of PUMCH.

All the individuals finished history inquiry,physical examination,basic test,genetic test and neuropsychological assessment.

Basic and genetic tests

Basic test consisted of blood routine test,hepatic and renal function,thyroid function,homocysteine,folic acid,cobalamin,blood ammonia,rapid plasma reagin test,immune function,antibodies to Hu,Yo and Ri,electroencephalography and brain magnetic resonance imaging (MRI).In addition,five AD patients and one HD patient had cerebrospinal fluid test of Aβ1-42,t-tau and p-tau.Five HD patients received CAG repeats measurement,and five AD patients took whole genome sequencing.

Neuropsychological test

Neuropsychological test consisted of screening test,multi-domain assessment and language evaluation.The latter was performed by Aphasia Battery of Chinese (ABC).[12]

The screening test included mini-mental state exam (MMSE),Montreal cognitive assessment(Moca),[13]activities of daily living (ADLs) and hospital anxiety and depression scale (HADS).Five HD patients received extra neuropsychiatric inventory (NPI).

The multi-domain battery involved four domains,such as executive,visuospatial,memory,reasoning and calculation domains.It is comprised of the following tests:digital symbol substitution task (DSST),trail making test part A (TMT-A),clock drawing,single and serial gesture imitation,figure copying,block design,Rey complex figure,paired associative learning (PAL),episodic memory,auditory verbal learning test (AVLT),similarity test and calculation.

Statistical analysis

Statistical analysis was carried out by SPSS (version 18.0).The demographic and neuropsychological data were displayed as mean±standard deviation.A simple scatterplot was created to give an intuitive description of linguistic differences between HD and AD patients.

RESULTS

Clinical profile

HD patients had a mean disease course of 5.4±2.97(range,2-10) years and a mean educational level of 10.4±3.85 (range,6-15) years.Two patients started with choreic movement of head or limbs.The cognitive,linguistic and psychiatric symptoms occurred within 3 to 8 years afterwards.Among the other 3 patients,motor disorder and neuropsychological symptoms occurred almost simultaneously.(Tables 1,2)

AD patients had a mean disease course of 5.0±1.87 (range,3-8) years and a mean educational level of 13.4±1.95 (range,11-16) years.The initial symptom was memory loss.The linguistic symptom occurred 0 to 3 years afterwards.(Tables 1,2)

Brain MRI

As demonstrated inTable 2andFigure 1,among the five HD patients,the axial MRI revealed an prominent atrophy of the head of caudate nucleus (HCN),with an enlarged anterior horn of lateral ventricle.However,the medially convex outline of HCN remained.Atrophy of frontal,temporal,parietal and occipital cortices was also detected.Compared with HD patients,AD patients showed no HCN atrophy and less cortical atrophy.

Cognitive profile

HD patients showed low scores in DSST,TMT-A,clock drawing,gesture imitation,as well as in similarity test and calculation,which suggested impairment in executive and reasoning domains.The scores in AVLT,recall of Rey complex figure,paired associative learning and episodic memory were even lower,suggesting more severe impairment in memory domain.In visuospatial domain,although they could finish block design test,the time spent was longer than expected.Comparatively,AD patients showed a more severe cognitive impairment,involving all the four domains.(Tables 1and3)

Linguistic profile

The linguistic feature in HD patients was close to transcortical motor aphasia (TCMA),called TCMA-like disturbance.Oral comprehension and repetition was slightly affected at the level of long complex sentence.Color naming was flawless,whereas picture naming,object naming and responsive naming were a bit affected.They showed a slight deficit in verbal category fluency test of animal and vegetable.They could finish the serial speech tasks well,such as counting up to 21 and reciting 12 Chinese zodiac animals.Reading was relatively intact.However,reading comprehension paralleled oral comprehension and was slightly impaired at the level of long complex sentence.(Figure 2)

HD patients showed a non-fluent spontaneous speech with decreased verbal output and grammatical complexity.Phonological error and speech dysprosody were obvious.The former was mainly manifestedas the initial consonant substitution.YANG and DONG were pronounced as RANG and ZHONG,respectively.Pa-Ta-Ka became Ka-Ka-Ka.The latter was characterized by aperiodicity and irregular pitch fluctuation.Tonic errors also existed.The third tone was pronounced as the first tone.(Figure 2)

Table 2.Clinical data of HD and AD patients

HD patients showed a worse writing impairment than other linguistic deficits.In spontaneous writing,one wrote nothing,one wrote two phrases,and only three wrote sentences.Most sentences had an intact grammatical structure.Some were lack of subjects or objects.In addition,there were plenty of character structural errors and character substitutions.The former included stroke addition,subtraction or substitution.The latter referred to character substitution by those with similar phoneme,grapheme or semanteme.(Figures 2,3)

In comparison,AD patients showed a more severe form of global aphasia.Both oral and reading comprehension were affected at the word or phrase level (Figure 2).They showed more naming errors,as well as more verbal category fluency difficulties.They exhibited fluent aphasia,which was characterized by an effortless and empty speech.The speech prosody was almost normal (Figure 2).As shown inFigures 2and3,in spontaneous writing,two wrote nothing and one only wrote her name.The other two stacked some nouns or pronouns,with lack of verbs or functional words.Besides,they showed more character substitu-tions by those with relevant semanteme.For example,one patient wrote SLEEP when she saw a BED.Another answered SUN when asked “WHAT COLOUR IS THE SUNNY SKY”.

Table 3.Neuropsychological data and drug treatment of HD and AD patients

DISCUSSION

With regard to cognitive profile,HD patients present with executive,reasoning and memory impairment.They can finish DSST,TMT-A and block design tests with a high accuracy but a low speed.This indicates the contribution of decreased psychomotor speed in executive dysfunction.However,even if enough time is given,they all show difficulty in gesture imitation.Therefore,other executive resource should exist in addition to the decreased psychomotor speed.After removing the possible influence from decreased psychomotor speed,the visuospatial function is relatively spared.In AVLT,they do not benefit from semantic cueing.The recognition of AVLT and Rey complex figure is also poor.These indicate that besides memory retrieval deficit due to executive dysfunction,there should be an encoding or storage problem.

As for linguistic profile,HD patients suffer from phonological impairment,as well as slight semantic and syntactic abnormality.These are in accordance with the previous findings.[15,16]The speech dysprosody might be related to voluntary motor disorder in HD.They have a slight deficit in comprehension,repetition,naming and verbal category fluency.These might be related to slight semantic or syntactic impairment,or retrieval deficit due to executive dysfunction.

Compared with native speakers of alphabetic languages,Mandarin-speaking HD patients have their own linguistic features.In writing,they show character structural errors and character substitutions,instead of letter omissions.[3]In addition,Chinese is a typical tonal language with four tones.The same phoneme with different tones indicates different meanings.HD patients show tonic errors in speech.The third tone is pronounced as the first tone.

In comparison,AD patients present with a worse cognitive and linguistic impairment.The executive,visuospatial,memory and reasoning domains are all affected.They do not have phonological impairment as HD patients.However,they seem to have more loss of semantic knowledge.They show a worse performance in comprehension,naming and verbal category fluency.And they have more character substitutions of semantic category in both oral and written language.

These cognitive and linguistic differences between HD and AD patients might be related to their different pathological changes.The neurodegeneration in HD starts from caudate and putamen.Gradually,it extends to the frontostriatal connections between striatum and cingulate,precentral,prefrontal cortices.[17]The frontostriatal network is implicated in motor-language coupling,syntactic processing,executive function,working memory,emotional processing,etc.[18,19]Unlike HD,AD is generally characterized by progressive degeneration of medial temporal,frontal and parietal cortices.[9]These cerebral cortices are involved in a wide range of cognitive and linguistic activities.For example,the frontal and temporal cortices are implicated in semantic processing.[20]

Brain MRI demonstrates cortical atrophy in both HD and AD patients.However,the severity of cortical atrophy is not parallel to their cognitive and linguistic behaviors.Compared with AD patients,HD patients show more severe cortical atrophy,but less cognitive and language impairment.These might be associated with their different genetic bases.HTT CAG-repeat expansion may influence cortical neurodevelopment.However,the influence might be independent of neurodegeneration.[21]

In conclusion,Mandarin-speaking HD patients have a TCMA-like disturbance with prominent phonological impairment,whereas AD patients have a global aphasia with salient semantic impairment.The limitation of this paper is that the sample size is too small.We cannot stratify the subjects according to the disease course or drug treatment.Next,we expect to accumulate more cases and have a longitudinal follow-up.

Conflict of Interests Statement

The authors have no conflict of interests to report.