Cognitive changes in amyotrophic lateral sclerosis

Cognitive changes in amyotrophic lateral sclerosis


1- Russian Charity ALS Foundation, Moscow, 2- Real Health clinic, Moscow, 3- Medical Preventive Ambulatory № 51, Moscow, 4- Department of Psychiatry and Suicidology, City Hospital № 20, Moscow, 5- Department of Neurology of Russian Academy of Postgraduate Education


Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with impairment of central and peripheral motoneurons, which, according to modern views, is not restricted by suffering related with the locomotor system disorder, but can be also accompanied by cognitive impairments designated as frontotemporal disfunction (FTD). FTD at ALS can be represented by a number of malfunctions from mild cognitive abnormalities or behavioral disorders to deep dementia. Executive, speech, behavioral disfunctions or mixed syndromes can be usually observed within FTD. For FTD diagnostics, tests for speech fluency, optical-spatial praxis, tests for memory, scales for depression assessment, pseudobulbar emotional lability, as well as behavioral questionnaires are used, with the questionnaires being completed by caregivers of ALS patients (3). It was demonstrated that cognitive disorders at ALS are accompanied by decrease of the quality of life in case of the lack of behavioral disorders, and decrease of the lifespan of patients at presence of behavioral disfunctions (8). The follower of Charcot, Marie, was the first who described emotional lability at ALS, and ALS patients with irritability, delirium, hallucinations were described in some works published in the beginning of the twentieth century (6.10.21). In spite of this, until the beginning of current century, lecturers on neurology described ALS as a disease with intact cognitive functions.

Executive disfunction at FTD is expressed in problems with planning, organization, generalization and placing of priorities along with disturbance of speech fluency (4). The syndrome of primarily progressing aphasia is expressed in dysnomia, phonematic paraphasia, grammatical mistakes, paragraphia, oral apraxia, stammering, dyslexia and dysgraphia (11). The syndrome of semantic dementia, more rare variant of FTD, is characterized with grammatically correct and rather fluent, but senseless speech with abnormality of the process of naming of known and famous people without disturbance of repetition and severe impairment of confrontation naming (15). The behavioral variant of FTD is characterized with changes of behavior according to the frontal type (apato-abulic syndrome or disinhibition), decrease of ability to critical analysis, impairment of expressive speech (11). A specific feature of FTD observed at magnetic-resonance imaging is primary atrophy of one of hemispheres of the brain, presence of which correlates with manifestation of one of clinical variants of FTD (13).

Molecular-genetic study in some cases can reveal hexanucleotide repetition in the gene С9orf72, the presence of which is connected with psychiatric symptoms and the behavioral variant of FTD (18).

The problem of neurophysiological examination at ALS is impossibility of performance of tests for speech fluency in case of some patients with severe bulbar impairments and unfeasibility of carrying out graphical tests by some patients at disorders of the dominant hand function. Recently, Edinburgh Cognitive and Behavioral ALS Screen has been elaborated (ECAS), which includes a non-specific scale with tests for memory and optical-spatial tests, specific scale for speech fluency and executive functions as well as a behavioral questionnaire completed by the ALS patient’s caregiver (2). It was demonstrated that at the behavioral variant of FTD, the assessment on the Frontal Systems Behavior Scale (FrSBe) does not correlate with the ALSFRS-R, a scale of ALS progression assessment, parameters of external respiration, age, gender of patients, at that predominance of bulbar debut is seen among ALS patients (19). At ALS, progressing and non-progressing forms of FTD are distinguished (23).

Based on the data of Rippon et al., the prevalence of FTD at ALS is about 31%; this being the case, 8% and 10% of patients respectively suffer from probable or possible dementia (16). Lately, the growing number of ALS patients and members of their families have been interested in the problem of cognitive disorders (22).

It is suggested that inhibitors of reverse serotonin uptake may be effective at ALS with FTD (3).

In Russia, no studies of cognitive disorders at ALS have been previously performed.

This study objective is screening assessment of cognitive functions of ALS patients along with multiparameter evaluation of the emotional status and quality of life.

Materials and methods

The study was conducted at the basis of Moscow SBIPH MH № 144 (Head Physician A.A. Gurin, Candidate of Medical Sciences) and Clinical Diagnostic Center Real Health, LLC (Head Physician R.V.Chub, Candidate of Medical Sciences) from 2009 to 2014. 116 ALS patients at the age of 26-76 years old (63 men and 53 women, mean age 57.4±11.9 years old) were examined. The diagnosis was established according to the Revised El-Escorial Criteria taking in account the results of needle and stimulation myography and magnetic-resonance imaging of the brain and spinal cord (5). Neurophsychological examination included the assessment on the Montreal Scale of cognitive functions, Hamilton Depression Scale (HDS), CNS-LS (the scale for emotional lability assessment), ALSFRS-R (the scale for ALS progression evaluation), ALS-AQ40 (the scale for the quality of life assessment), the scale of frontotemporal dementia ( The diagnosis of discirculatory encephalopathy was set for thirteen patients based on the clinical criteria and MRI data. At the moment of examination, 20 patients interrogated on the Montreal Scale were not able to speak, and 11 could not perform the graphic test. The diagnosis of frontotemporal dementia was established according to the criteria of D.Neary (15). In agreement with classification by A.Hudson in the modification by V.I.Skvortzova and G.N.Levitsky (2006), among the examined patients, 36 people had bulbar debut, 32 patients ‒ cervical debut, 8 patients ‒ thoracic and 8 patients ‒ diffuse debut with 32 patients having lumbar debut of ALS (1).

The statistical processing was performed using the software packages BIOSTAT (Hungary, 1998). Besides, U-criterion of Mann-Whitney, chi-square criterion and Spearman correlation analysis were used. Differences were considered significant at р<0.05.


Cognitive disorders (CD) were revealed in 47 ALS patients (40.5%), 27 women and 20 men at the age from 44 to 76 years old (mean age 64.5±7.7 years old). Patients with CD were reliably older than patients without CD (52.5±12.1 years old, р=0.0001). Progression of ALS in patients with CD was reliably faster (13.5±9.3 and 10.4±9.1 scores a month on the ALSFRS-R scale, р=0.033). The number of patients with bulbar debut in the group with CD was slightly more (19/28 and 16/53, х2=2.8; р=0.093), at the level of a tendency. In the group without CD, patients with lumbar debut dominated reliably (8\39 and 24\45, х2=3.94; р=0.047). Among patients with bulbar debut, the number of women was significantly higher (27\36 and 9\44, х2=7.63;р=0.005), however, the rate of progression did not differ between men and women (13.6±9.4 and 9.48±7.3 scores a month on the ALSFRS-R scale, p=0.106). The average score on the Montreal Scale in the group of patients with CD was reliably lower than in the group of patients without CD (21.7±4.4 and 28.1±1.4, р=0.0001).

The average score on the HDS in the group of patients with CD amounted to 11.4±6.5, and in the group of patients without CD to 11±6.8 (no differences were revealed). The average score on the Montreal Scale did not correlate with the mean score on the Hamilton scale either in the group as a whole (r=-0.066; p=0.5), or in the group with CD (r=-0.05; p=0.7), or in the group without CD (r=-0.2; p=0.8). The average score on the positive spectrum of the emotional lability scale amounted to 12±5.8 in the group with CD and 11±7.4 in the group without CD (no differences were revealed). The average score on the negative spectrum of the emotional lability scale was 12.9±6.6 in the group with CD and 12.8±5.5 in the group without CD (no differences were revealed). The average score on the subscale of emotional condition of the quality of life scale ALS-AQ40 in the group with CD equaled to 40.9±20.4, and in the group without CD-31.7±20.1 (no differences were revealed, р=0.204). The average total result on the scale of quality of life in the group with CD amounted to 182.6±84.2, and in the group without CD – 183.5±99.5.

Table 1 contains correlation coefficients of parameters of different scales of emotional condition and general quality of life. Table 1. Correlation of parameters of different scales of emotional condition and quality of life in ALS patients with CD and without CD

ALS patients without CD

HDS - r=0.48 p=0.02 r=0.7 p=0.0001 r=0.45 p=0.031 r=0.54 p=0.008
CNS-LS (П) - - - r=0.168 p=0.43 r=0.2 p=0.3
CNS-LS (Н) - - -- r=0.23 p=0.25 r=0.4 p=0.054
ES - - - - r=0.83 p=0.0001
GQL - - - -

ALS patients with CD

HDS - r=0.43 p=0.062 r=0.48 p=0.037 r=0.45 p=0.053 r=0.35 p=0.13
CNS-LS (П) - - - r=0.36 p=0.119 r=0.45 p=0.052
CNS-LS (Н) - - - r=0.6 p=0.008 r=0.52 p=0.022
ES - - - - r=0.78 p=0.0001
GQL - - - - -

Table 1 shows that in ALS patients without CD parameters of the Hamilton scale correlate with parameters of positive and negative spectrum of the emotional lability scale, subscale of emotional condition ALS0-AQ40 and general quality of life. The last two parameters correlate with each other. The positive spectrum of the emotional lability scale does not correlate with the general quality of life, with the negative spectrum demonstrating correlation.

In ALS patients with CD, parameters of the Hamilton scale also correlate with the positive and negative spectrum of the emotional lability scale, but do not correlate with the general quality of life, which might represent the main difference between the groups. The positive spectrum of the emotional lability scale, as in the group of patients without CD, does not correlate, and negative one correlates with the general quality of life. The emotional state correlates with the general quality of life.

In 41 patients, FTD was detected (the average log-rank 1.47 [1.92; 1.26]), reaching the level of dementia in 4.2% of cases (the average log-rank -0.4 [1.07; -3.09]).

The quality analysis of FTD assessed on the Montreal Scale demonstrated that decrease of auditory-verbal memory was documented in 34 patients (72.3%), at that, the reaction to hinting was preserved only in 23 patients (48.9%), decrease of phonetic activity was detected in 25 patients (53.1%), neurodynamic disorders occurred in 10 patients (21.2%), disorders of generalization ‒ in 4 patients (8.5%), paragraphia ‒ in 3 patients (6.3%), 2 patients failed to name the current date (4.2%).

Optical-spatial disorders (temporal) were seen in 17 patients (36%), in 15 cases they were accompanied by the decrease of auditory-verbal memory, phonetic activity or impairments of neurodynamics (frontal). Abnormalities of verbal counting were not observed in the patients. In 8 cases, disorders of repetition of sentences and numbers were revealed, false recognition / naming was registered in 1 case.

Thus, in 23 patients (48.9%), frontotemporal (mixed, executive and verbal) disorders, in 16 patients (34%) – frontal (executive), in 2 patients – temporal (isolated optical-spatial) (4.2%), and in 2 the most severe patients – isolated behavioral disorders (4.2%) were observed. No patients with isolated verbal impairments were revealed.


In this study of cognitive abnormalities at ALS, the first one in the Russian Federation, it has been established that the percentage of patients with cognitive impairments is 35.3% (at exclusion from the analysis of patients with discirculatory encephalopathy, presented in the group of ALS patients without CD in the number of 5, and in the group with CD - 8). It approximately corresponds to the international data – 31%. In the study of Van der Hulst et al., in 38 ALS patients without dementia, the executive type of the disorder was revealed in 56.8%, in 24.3 % of cases the executive-verbal variant was detected, and in 18.9% of cases ‒ the verbal variant. In one patient (2.7%), the isolated behavioral variant was registered. Differences in representation of FTD variants in the abovementioned and present studies can be explained by the significantly lesser volume and the lack of representability of the sample of patients from Scotland or population-related genetic differences; in our work, isolated speech disorders were absent (20). We have established the connection of FTD with the age and progression of ALS as well as bulbar debut (as a tendency), which correlates only partly with data of foreign experts (19, 23).

We have demonstrated that at lumbar debut of ALS, FTD are much more rarely. The comparison of parameters of different scales of emotional condition and the quality of life allows coming to the conclusion that the presence of CD did not influence the emotional state, level of emotional lability and general quality of life in the study group. The multiparameter correlation analysis performed in the current study indicates that the emotional state of ALS patients renders no influence on the revealed patterns of CD and vice versa. It makes doubtful the suggestion that inhibitors of reverse serotonin uptake may be effective at ALS with FTD (3). The lack of correlation of the mean score on the HDS with general parameter of the quality of life in patients with CD may be connected with decrease of ability to critical analysis in these patients. Figure 1 depicts similar optical-spatial disorders in ALS patients with depression and discirculatory encephalopathy or without them.

Single observations in dynamics have been performed. Figure 2 contains the Montreal test in the course of treatment with cholinolytics for correction of salivation and after their withdrawal. Improvement of drawing of the watch and elimination of mistakes in writing can be observed. During the course of treatment with galantamine, akatinol memantine and their combination, some positive dynamics was detected in ALS patients with FTD. Unfortunately, the small number of observations hampers making a statistically confirmed conclusion about the efficacy of these drugs.


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