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Cognitive Correlates in Amyotrophic Lateral Sclerosis PDF
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JNNP Online First, published on April 25, 2014 as 10.1136/jnnp-2013-307223
Neurodegeneration
RESEARCH PAPER
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Montuschi A, et al. Article author
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Neurodegeneration
were interviewed at home, at the GP ofce or at the hospital. Neurological and Communicative Disorders and Stroke
Only nine subjects asked to participate as controls denied their Alzheimers Disease and Related Disorders Association.16
participation. Most GPs were willing to collaborate (85%). D. ALS with executive cognitive impairment (ALS-ECI). Patients
When a GP did not collaborate, another GP practicing in the with ALS who did not meet criteria for FTD or other types
same area was contacted. of dementia, but who had an impairment in two tests of
executive dysfunction compared with healthy controls, that
is, had an executive dysfunction, were classied as ALS with
Neuropsychological battery
executive cognitive dysfunction. A more conservative cut-off
Patients and controls underwent a battery of neuropsychological
than that proposed by the ALS-FTD Consensus Criteria5
tests encompassing executive function, memory, visuospatial
was used (2.3rd centile).4
function and language, selected according to Clinical Diagnostic
E. ALS with non-executive cognitive impairment (ALS-NECI).
Criteria for Frontotemporal Lobar Degeneration,9 and
This group includes patients with ALS with impairment in
ALS-FTD Consensus Criteria.5 The neuropsychological battery
two non-executive domains, in particular visuopraxic abil-
included: Mini Mental State Examination; Wisconsin Card
ities, and no impairment in executive function.
Sorting Test; Trail Making A and B; Stroop Colour-Word
F. ALS with behavioural impairment (ALS-Bi). This group
Interference Test; letter and category uency test; Wechsler
includes patients with predominant behavioural disturbances
Memory Scale IIrevised (Form 2); Rey-Osterrieth Complex
and with impairment in none or only one test of executive
Figure Test; Token test; Wechsler Adult Intelligence Scale
dysfunction and no impairment in non-executive domains.
revised; Ravens Progressive Colored Matrices; Frontal
G. ALS with non-classiable cognitive impairment (ALS-NCCI).
Assessment Battery. In some cases supplementary tasks were
This group includes patients with ALS with impairment in
administered for a comprehensive evaluation of language; the
one executive and/or one non-executive test, sometimes
following tests were used: semantic systems tests (7 and 8) of
associated with smooth behavioural changes.
the Battery for the Analysis of Aphasic Decits10 and the
Silhouette trial of the Visual Object and Space Perception
battery.11 Genetic analysis
Neurobehavioral dysfunction was determined on the basis of All coding exons and 50 bp of the anking intron-exon bound-
direct observation and patients history,9 12 and with the Frontal aries of SOD1, of exon 6 of TARDBP, and of exons 14 and 15
Systems Behavior Scale,13 using the Family-form evaluated by a of FUS and exons 5, 9, 12 and 14 of OPTN and the single exon
close relative (scores: normal 59, borderline 6064; patho- of ANG have been PCR amplied, sequenced using the Big-Dye
logical 65). If a subject had scores reecting a frontal systems Terminator v3.1 sequencing kit (Applied Biosystems), and run
abnormality in the premorbid and in the postillness forms, he/ on an ABIPrism 3130 genetic analyser. In patients with positive
she was considered pathological only if there was an increase of family history for ALS or FTD all coding exons of VCP have
10 points at the T score between the two forms.14 Anxiety and also been assessed. These exons were selected as the vast major-
depression were assessed with the Hospital Anxiety and ity of known pathogenic variants are known to lie within these
Depression Scale; the item I feel slowed down was discussed mutational hot spots. A repeat-primed PCR assay was used to
with patients in order not to refer to physical disability. screen for the presence of the GGGGCC hexanucleotide expan-
Cognitive impairment was dened as impairment on two tests sion in the rst intron of C9ORF72.17 A cut-off of 30 repeats
of executive or non-executive function that was below the 5th was considered pathological.
centile of healthy controls.
The battery was administered following the same sequence in
Statistical methods
order to avoid the possible differential interference of the
Comparisons between means were made with Student t test or
answers of one test over the others. The administration of
analysis of variance; comparisons between categorical variables
the battery required 2 h, and was usually performed in the
were made with 2 test; for all comparisons, Levenes test was
morning. If the subject felt too tired, a further session was
used to conrm the equality of variances.
scheduled to complete the battery, within 2 weeks after the rst
Survival was calculated from onset to death/tracheostomy or
one. Patients and controls O2 saturation at the time of the
censoring date (30 June 2013), using the Kaplan-Meier method,
neuropsychological testing was measured with a pulse oximetry;
and compared with the log-rank test. No patients were lost to
none of the patients and controls had evidence of hypoxaemia
follow-up. Multivariable analysis was performed with Cox pro-
(oxygen saturation <92 mm Hg).
portional hazards model (stepwise backward) (for details, see
table 3). For the analysis of the relationship between cognitive
Cognitive classication status and disease progression, the progression rate for the
Clinical diagnosis and cognitive classication were performed ALSFRS-R score, its four subscores (bulbar, ne motor, gross
with the collaboration of two neurologists specialist in ALS and motor and respiratory) and forced vital capacity per cent of pre-
FTD and two neuropsychologists. Patients cognitive status was dicted (FVC%) was calculated as the mean monthly number of
classied as follows: points lost from disease onset to the time of cognitive evalu-
A. ALS with normal cognition. ation. For example, the progression rate for the ALSFRS-R
B. ALS with frontotemporal dementia (ALS-FTD). The diagno- score was calculated as follows: (48-ALSFRS-R at time of cogni-
sis of frontotemporal dementia was dened according to tive evaluation)/duration from onset to diagnosis (months). In
Clinical Diagnostic Criteria for Frontotemporal Lobar the Cox model, these variables were dichotomised on the basis
Degeneration.9 of their median value. The list of all variables included in the
C. ALS comorbid with non-FTD dementias. The diagnoses of Cox model is reported in table 3.
non-FTD dementias were based on the criteria of the A p level <0.05 was considered statistically signicant. All
Diagnostic and Statistical Manual of Mental tests were two-tailed. Statistical analyses were carried out using
Disorders-IV-TR15 and those of the National Institute of SPSS V.20.0 (SPSS, Chicago, Illinois, USA).
Neurodegeneration
Standard protocol approvals, registrations and patient Cognitive groups were clinically and demographically different
consents (table 2). Patients with ALS-FTD, ALS-ECI and ALS-Bi had a
The study design was approved by our institutional Ethical higher mean age (70 years) than those with normal cognition
Committee. Patients and controls signed a written informed and ALS-NECI. ALS-NCCI had the lowest age at onset. Patients
consent. The database was managed according to the Italian law with ALS-FTD and those with ALS-NECI had a higher frequency
for the protection of privacy. of bulbar onset than all other groups ( p=0.003). The mean
number of education years was signicantly lower in patients
with ALS-FTD than in all other groups. ALSFRS-R score and
RESULTS FVC% at the time of the cognitive examination did not show sig-
A ow chart of the sequence of participants selection is nicant differences. However, the ALSFRS-R bulbar subscore
reported in gure 1. Of the 281 patients diagnosed in the study (items 1, 2 and 3 of the ALSFRS-R scale) was signicantly lower
area in the 20092011 period, 202 (71.9%) underwent the in the group with ALS-FTD (data not shown). The rate of decline
neuropsychological battery. Of the 79 non-captured patients, 34 of ALSFRS-R, of its subscores and of FVC% was similar in the
were not able to undergo the battery of tests due to their motor various groups (see online E-table S2).
disability (7 patients were tracheostomised or used non-invasive
ventilation for more than 16 h; 18 patients had severe difcul-
ties in writing and speaking; 9 patients had a severe fatigue and,
although willing to collaborate, could not adequately perform Patients cognitive status and genetics
the whole battery), 5 were not of Italian mother tongue, 30 Of the nine cases carrying the GGGGCC hexanucleotide repeat
declined participation and 10 died before being tested. expansion in the rst intron of the C9ORF72 gene, six had
Nineteen tested patients were excluded from the analysis due to ALS-FTD, two ALS-ECI and one was cognitively normal. One
previous neurological disorders affecting cognition (seven of the ve patients with SOD1 mutations and one of the ve
patients), severe mental illness (six), drug or alcohol abuse patients with TARBDP mutation had ALS-Bi. Both patients with
(two), use of high-dose psychoactive medications (one due to FUS and OPTN mutations were cognitively normal. Genetic
bipolar disorder, one due to paranoid schizophrenia), analpha- status was signicantly correlated to the presence/absence of
betism (one) and mental retardation (one). cognitive impairment ( p=0.0001).
Non-captured patients did not differ demographically and
clinically from those who underwent the examination (table 1).
The median time from diagnosis to the neuropsychological
assessment was 1.9 months (IQR 1.23.8 months). Survival analysis
The overall median survival time was 2.7 years (95% CI 2.4 to
2.9) (gure 2). Patients with ALS-FTD had a signicantly
Cognitive classication shorter survival (1.9 years, 95% CI 1.7 to 2.2) than any other
According to the classication criteria for patients cognitive group of patients with cognitive impairment, with the only
status, 23 (12.6%) had ALS-FTD, 36 (19.7%) ALS-ECI, 10 exception of those with ALS-NECI (2.0 years, 95% CI 1.6 to
(5.5%) ALS-NECI, 11 (6.0%) ALS-Bi and 11 (6.0%) ALS-NCCI; 2.4). Patients with ALS-Bi (3.0 years, 95% CI 0.8 to 5.3) had a
91 (49.7%) patients were cognitively normal (see online survival time similar to that of cognitively normal patients (3.1
E-gure S1). One patient had comorbid Alzheimer disease (AD). years, 95% CI 2.7 to 3.4). Patients with ALS-ECI had an inter-
Twenty-two out of the 23 patients with ALS-FTD presented with mediate survival between the two groups (2.6 years, 95% CI
behavioural changes typical of behavioural variant fronto-temporal 2.0 to 3.1). Cognitive status remained signicant in Cox multi-
lobar dementia (FTLD); one patient had semantic dementia. variable analysis (table 3). The presence of FTD signicantly
Mean scores of the performed tests for each cognitive group and increased the risk of death compared with non-demented
controls are reported in online E-table 1. Box plots of selected test patients; also ALS-NECI and ALS-ECI resulted to be independ-
are reported in online E- gures S2S6. ently related to a worse outcome.
Neurodegeneration
Table 2 Demographic and clinical characteristics of patients with ALS according to cognitive status
Cognitively normal ALS-FTD ALS-ECI ALS-NECI ALS-Bi ALS-NCCI
(n=91) (n=23) (n=36) (n=10) (n=11) (n=11) p Value
Mean age at onset (years, SD) 65.9 (10.6) 69.1 (7.7) 70.0 (7.4) 64.9 (12.8) 68.1 (9.9) 61.9 (9.5) 0.04
Gender (female, %) 40 (43.5%) 11 (47.8%) 14 (38.9%) 4 (40.0%) 4 (36.8%) 4 (36.8%) 0.97
Disease duration at time of interview (years, SD) 1.23 (1.11) 1.28 (0.60) 1.18 (0.76) 1.03 (0.63) 1.19 (1.17) 1.20 (0.62) 0.99
Site of onset (bulbar, %) 28 (30.4%) 10 (60.9%) 10 (27.8%) 6 (60.0%) 2 (18.2%) 2 (18.2%) 0.015
Time lapse between diagnosis and interview (years, SD) 0.25 (0.23) 0.35 (0.31) 0.26 (0.26) 0.12 (0.05) 0.18 (0.12) 0.31 (0.32) 0.12
Mean education (years, SD) 8.6 (3.7) 4.7 (1.9) 7.8 (4.0) 9.5 (5.1) 9.9 (5.2) 12.4 (4.4) 0.0001
FALS (%) 11 (12.1%) 7 (30.4%) 2 (5.6%) 0 0 0 0.015
Mean ALSFRS-R score at time of interview (SD) 38.8 (7.6) 34.9 (7.3) 36.4 (7.6) 40.9 (6.4) 34.5 (12.8) 39.7 (6.3) 0.086
Mean FVC% at time of interview (SD) 91.2 (25.5) 80.7 (25.0) 88.4 (28.7) 83.2 (22.3) 83.7 (26.6) 92.3 (23.1) 0.181
One patient with comorbid Alzheimers disease is not included in the table.
p Value is calculated with analysis of variance (age, education, time lapse, ALSFRS-R, FVC) or 2 (gender, site of onset, FALS status).
ALS, amyotrophic lateral sclerosis; Bi, behavioural impairment; ECI, executive cognitive impairment; FALS, familial ALS; FTD, frontotemporal dementia; FVC%, forced vital capacity per
cent of predicted; NECI, non-executive cognitive impairment; NCCI, non-classifiable cognitive impairment.
Neurodegeneration
Neurodegeneration
Regione Piemonte (Ricerca Finalizzata), University of Torino, Federazione Italiana 16 McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimers
Giuoco Calcio, Fondazione Vialli e Mauro onlus, and European Commission (Health disease: report of the NINCDS-ADRDA Work Group under the auspices of
Seventh Framework Programme); he serves on scientic advisory boards for Biogen Department of Health and Human Services Task Force on Alzheimers Disease.
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17 Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in
Patient consent Obtained.
C9ORF72 is the cause of chromosome 9p21-Linked ALS-FTD. Neuron
Ethics approval Comitato Etico Ospedale San Giovanni Battista di Torino. 2011;72:25768.
Provenance and peer review Not commissioned; externally peer reviewed. 18 Banca dItalia. Indagine sui Bilanci delle Famiglie Italiane. Anno 2010
http://www.bancaditalia.it/statistiche/indcamp/bilfait
19 Stern Y. Cognitive reserve in ageing and Alzheimers disease. Lancet Neurol
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These include:
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References This article cites 27 articles, 3 of which can be accessed free at:
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