Metabolic state and survival in patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease
without a cure. Besides solely focusing on a cure, it is important to develop
strategies that alleviate or slow the progression of the disease. ALS is
considered as a purely neurological disease, however a metabolic component
seems to underpin disease progression and prognosis: an increased metabolism,
reduced body mass index (BMI) and malnutrition contribute to earlier death
(Kasarskis, Berryman et al. 1996, Desport, Preux et al. 1999). Along the course
of ALS, the metabolic balance is distorted and hyperbolism is observed in both
familial as sporadic ALS patients (Desport, Torny et al. 2005, Funalot, Desport
et al. 2009). This in combination with the fact that ALS patients only consume
84% of the recommended daily calorie intake, disease progression will
eventually lead to weight loss (Funalot, Desport et al. 2009). The weight loss
and accompanying decline in BMI is of clinical importance due to its influence
on clinical outcomes (Kasarskis, Berryman et al. 1996, Shimizu, Nagaoka et al.
2012, Gallo, Wark et al. 2013, Reich-Slotky, Andrews et al. 2013, Ahmed, Mioshi
et al. 2014). First, a lower BMI in early life has an increased risk of ALS
mortality (Gallo, Wark et al. 2013). Second, patients with a higher BMI prior
to diagnosis have better scores on the ALS functional rating scale (ALSFRS-R)
(Reich-Slotky, Andrews et al. 2013). Moreover, a fast decline in BMI throughout
the course of disease is highly correlated with a shortened disease duration
and overall survival (Shimizu, Nagaoka et al. 2012). While BMI depends on both
muscle and fat mass, a significant relationship has been found between patient
survival and their subcutaneous fat mass (Lindauer, Dupuis et al. 2013).
Additionally, a positive correlation was found between increased survival and
elevated serum triglyceride and cholesterol in ALS patients (Dupuis, Corcia et
al. 2008, Dorst, Kühnlein et al. 2010). The loss of total fat mass and
hypermetabolism were confirmed in the SOD1G86R mice model (Dupuis, Oudart et
al. 2004). These findings suggest that the body fat mass and an altered
metabolic profile are factors that influence disease progression and thus the
prognosis of ALS patients. Recent results from our workgroup reveal that
patients with the C9orf72 mutation have a lower BMI during life and during the
course of disease compared to ALS patients without the mutation. Moreover,
asymptomatic carriers of the C9orf72 mutation have a lower BMI during life
compared to non-carriers (Westeneng, van den Berg, unpublished data). These
results may be indicative that a genetic background correlates the metabolic
function and ALS symptomology.
Metabolic profile and body composition are heavily influenced by food intake
and therefore dietary intervention might have therapeutic potential in ALS
patients. In animal studies, a high-fat diet improved symptoms and extended the
survival of SOD1G93A and SOD1G86R mice (Dupuis, Oudart et al. 2004, Mattson,
Cutler et al. 2007). Moreover, by reversing the metabolic imbalance, metabolic
function was improved and delayed the onset of neuromuscular denervation
(Palamiuc, Schlagowski et al. 2015). Recent studies in ALS patients report that
supplementation with protein, carbohydrates, fats and nutriceuticals have some
benefit on body weight, clinical outcomes and survival (Veldink, Kalmijn et al.
2006, Silva, Mourão et al. 2010, Dorst, Cypionka et al. 2013, Wills, Hubbard et
al. 2014). A recent phase 2 placebo-controlled clinical trial assessed
nutritional intervention in ALS patients and found favorable results in the
hypercaloric intake groups. The authors recommend that dietary approaches
should be studied in larger trials at an earlier disease stage (Wills, Hubbard
et al. 2014).
Unfortunately, not all patients will tolerate dietary intervention (Dorst,
Cypionka et al. 2013, Wills, Hubbard et al. 2014). Relatively high drop-out
rates have been reported which indicate that dietary regimens might be
unpleasant or unsustainable (Dorst, Cypionka et al. 2013). Sustaining adequate
dietary supplementation in ALS becomes a greater challenge as disease
progresses. Eventually, ALS will lead to the patients* inability to control
their diet (i.e. by loss of fine motor control and weakness of the hand
musculature) and patients are at increasing risk to develop complications due
to dysphagia. Moreover, it remains unknown if the improved outcomes in response
to dietary intervention are due to the surplus of calories or due to
availability of specific dietary substrates. Therefore there is a need to
comprehensively assess the metabolic needs in ALS patients and their dietary
intake. Identifying dietary components that are associated with an improved
ability to sustain energy requirements provides vital information about the
mechanisms that underlie the increased energy needs in ALS. Moreover, the
association between metabolic balance, dietary intake and disease progression
can be used in future, more efficient and tolerable strategies. These
strategies can in turn assist the body with providing optimal energy needs and
potentially improve the prognosis of ALS patients.

The UMC Utrecht and the Royal Brisbane and Women*s Hospital in Brisbane,
Australia, initiated a close collaboration in 2015. In June 2017, we jointly
analysed preliminary data of the Australian group who initiated a similar study
two years earlier. Data of 58 patients with ALS were matched with 58 controls
on BMI, gender and age and is currently not yet published. Hypermetabolism,
defined as a metabolic rate of 120% or higher of the predicted metabolic rate,
was present in 41% of the ALS patients and in 12% of the healthy controls
(adjusted odd ratio of 5.4, p < 0.001). Subsequently, we compared ALS patients
with and without hypermetabolism. We looked at preliminary survival data of the
hyper- and normometabolic patients (figure), which showed a remarkable
difference in overall survival (p = 0.0006). 18-month survival after assessment
was 94.4% in normometabolic patients (CI: 84.4% - 100.0%) vs 32.6% in
hypermetabolic patients (CI: 11.4% - 93.1%). These results indicate that
hypermetabolism is a strong prognostic factor and may help in guiding medical
decision making and counseling.

Interestingly, hypermetabolic patients showed a faster rate of functional
decline (p = 0.028) and had more lower motor neuron involvement (p = 0.030).
Moreover, 29% of the hypermetabolic patients had a familial form of ALS,
whereas this was only 3% in normometabolic ALS patients (p = 0.013). Of the
familial patients (N = 8), 7 were hypermetabolic (88%). This indicates a strong
genetic link with the presence of hypermetabolism. At the moment, genetic
information (C9orf72 repeat expansion) of these patients are analysed in the
UMC Utrecht and are not yet available. Combined with our presymptomatic weight
loss and alteration in body composition for C9orf72-cases, it would be
worthwhile to assess asymptomatic C9orf72 carriers and determine whether
hypermetabolism is related to C9orf72 mutation. It would be worthwhile to
assess other genes related to ALS as well, to compare the different genetic
links with the presence of hypermetabolism.

Primary Objective:
To study alterations in metabolic balance in ALS patients and their impact on
disease progression and survival.

Secondary Objective(s):
1. To evaluate and compare the metabolic balance in patients with ALS and
neurological control subjects
2. To evaluate and compare the metabolic balance in asymptomatic
C9orf72-carriers and neurological control subjects
3. To evaluate and compare the metabolic balance in family members of familial
ALS (fALS) patients (carriers and non-carriers)
4. To study the association between alterations in metabolic balance and the
rate of disease progression and total survival time
5. To identify dietary components associated with the ability to sustain energy
requirements
6. To study the change in body composition and metabolic state over time as ALS
progresses
7. To study the relationship between dietary components and metabolic balance,
body composition, clinical parameters and disease progression
8. To determine if the improved outcomes in response to dietary intervention
are due to the surplus of calories or due to the availability of specific
dietary substrates
9. To improve and optimize future dietary interventions in ALS patients
10. To study if single or a combination of metabolic blood products, muscle
proteins and/or cholesterol products can serve as an prognostic or surrogate
biomarker for disease progression in ALS
11. To study the change in nutritional status, indicated by PG-SGA, over time
in patients with ALS
12. To study the relationship between nutritional status, indicated by PG-SGA,
and disease progression and overall survival

Design: cross-sectional case-control and prospective cohort study. The first
part of the study consists of a cross-sectional case-control study with ALS
patients, and neurological controls and asymptomatic carriers of ALS related
genes matched on gender, age and BMI. The ALS patients of the first part will
be followed up longitudinally.
Duration: follow-up period of two years
Setting: The study will be carried out at the premises of the University
Medical Center Utrecht (UMCU) the Netherlands. The sample size calculated for
this study is 234 subjects, of which 78 ALS patients and 78 neurological
age-gender-BMI matched controls. Additionally, we will include 39 asymptomatic
carriers and 39 families of ALS patients (carriers and non-carriers).
Procedures: baseline measurements for both control and ALS-patients consisting
of evaluation of dietary intake, clinical progression, energy expenditure,
metabolic state and body composition. Survival data will be gathered for all
patients. ALS patients are (optionally) followed-up at 3-monthly intervals
(window of four weeks) and evaluated at the clinic for energy expenditure,
metabolic state, body composition, dietary intake and clinical progression.
Daily activity will be measured using the ActiGraph, an accelerometer to
estimate the Metabolic Equivalent of Task (MET) scores in kcal/kg x hour. The
ActiGraph GT9X Link (ActiGraph LLC, Pensacola, FL), is a small (.5 × 3.5 × 1
cm), lightweight (14 g) tri-axial accelerometer. The ActiGraph will be worn on
the right hip in the anterior axillary line using a belt clip during waking
hours for 7 days. The ActiGraph reduces the burden for patients by removing the
need to keep an activity diary. We validated the ActiGraph in 42 patients with
ALS (unpublished) in a recent study.
The ActiGraph will be handed over after completing the study visit.
Participants will be asked to return the ActiGraph by mail.

The energy metabolism and body composition are assessed using non-invasive
methods such as respiratory calorimetry and air-displacement plethysmography.
Metabolic blood products can be determined by venous blood tests with a minimal
risk of complications. Patients (controls once) are required to visit the
hospital nine times in two years, each visit lasting one morning. But it is
possible for patients as well to visit the hospital only once. Furthermore,
patients and controls are asked to register their daily food intake. Collation
of data between patient and neurological controls will provide essential
knowledge to help characterise the altered metabolic profile in ALS and
ascertain associated changes in energy intake, storage and metabolism.