The frontotemporal syndrome in amyotrophic lateral sclerosis: screen, impact, imaging and pathology.

Amyotrophic lateral sclerosis (ALS) is a devastating disease, affecting the
central and peripheral motor neurons, rendering them to wheelchair dependence
and death due to respiratory insufficiency three years after the onset of
symptoms. Recently, focus has been shifting to involvement of frontotemporal
brain regions in up to 50% of the patients leading to a frontotemporal syndrome
(i.e. mild to moderate cognitive and behavioral changes or frontotemporal
dementia, FTD). The frontotemporal syndrome has a negative impact on survival,
on the decision to opt for life-prolonging therapies and, possibly on the
relationship between patients and carers, and is therefore an important
syndrome to recognise. In addition, the correct classification of ALS patients
(phenotyping) is essential for clinical trials and for the interpretation of
genetic and pathological findings.

The main objectives are:
1. to develop a diagnostic tool for the assessment of the frontotemporal
syndrome.
2. To investigate the structural and functional brain networks of ALS patients
with and without a frontotemporal syndrome, in order to gain understanding of
the pathophysiology of ALS.

The secondary objectives are:
1. to examine the impact of the frontotemporal syndrome of ALS on the carers.
2. to correlate clinical signs and symptoms with pathological findings.

Step 1: Development of an easy-to-administer screening instrument to detect
frontotemporal cognitive dysfunction in ALS
Step 2: Examination of the clinimetric properties of the new screen
(ALS-FTD-Cog)
Step 3: Examination of the quality of life of patients and caregivers
Step 4: Classification of patients into three groups, based on the results of
the neuropsychological examination and the score on the ALS-FTD-Q: no, moderate
or severe frontotemporal syndrome.
Step 5: In a subgroup (N=102) an MRI of the brain and an MEG recording will be
performed.
Step 6: Six months later, a repeat MRI scan, MEG recording and
neuropsychological examination will be performed in this subgroup (N=102).
Step 7: Neuropathological examination in patients who consent to autopsy

Group benefits
The aim of this study is to develop and improve diagnostic tools for the
detection of the frontotemporal syndrome of ALS. For future clinical trials and
the interpretation of basic scientific studies (genetics and pathology), it
will be beneficiary to be able to accurately phenotype patients within the
spectrum of ALS-FTD, i.e. ALS without cognitive or behavioural disturbances,
ALS with cognitive impairment, ALS with behavioural changes or ALS with
cognitive impairment and behavioural changes.
Also, we aim at clarifying the pathophysiology of ALS, by investigating the
structural and functional brain networks of ALS patients with and without a
frontotemporal syndrome. This might result in possible new drug targets.

Risks and burden
In a subgroup of patients and controls MRI scans of the brain will be
performed. There is a small chance that there will be incidental findings on
the MRI, such as old infarction, a meningeoma, a vascular anomaly or a brain
tumour. On the magnetoencephalogram epileptic activity might be observed.
Incidental findings will not be communicated to the participants, unless it
concerns a lesion for which further evaluation or treatment is warrented, e.g a
lesion suspicious for malignancy or an aneurysm. Patients will be refered to a
neurologist. All suspicious lesions will be examined by a radiologist (Prof.
Dr. C. Majoie).

ALS is a devastating disease with a median survival of 3 years after diagnosis.
A subgroup of patients will undergo 2 neuropsychological examinations, 2 MRI
scans and MEG recordings. We realize that this study will consume some of their
time. We calculated that this study will cost patients 7 hours at most, not
including travel time. We tried to limit the number of hospital visits and
related inconvenience in this study by including a home visit.