ALS-FTD Research Briefs: P62 Gene’s Role and Screening Tool for ALS-FTD

Research news items on the role of the p62 gene in ALS-FTD and the ALS-FTD-Q, a new screening tool for assessing behavioral disturbances in ALS

By Amy Madsen, originally posted at MDA/ALS NewsMagazine, September 26, 2012

Article Highlights:

  • The finding that mutations in the p62 gene can cause frontotemporal lobar degeneration, added to an earlier finding that such mutations can cause ALS, bolsters support for an underlying mechanism shared by the two conditions.
  • A new screening tool called the ALS-FTD-Q can help accurately assess behavioral disturbances that may be signs of frontotemporal dementia (FTD) in people with ALS.

The most visible symptom in amyotrophic lateral sclerosis (ALS) is progressive weakness and loss of muscle control due to the loss of nerve cells called motor neurons. But approximately half of all people with ALS also exhibit some symptoms of cognitive impairment and associated behavioral symptoms (frontotemporal dementia, or FTD) at some stage of their disease.

FTD is caused by frontotemporal lobar degeneration (FTLD), a type of progressive deterioration in the frontal and temporal lobes of the brain, which are responsible for cognitive function. The simultaneous occurrence of both ALS and FTD is called ALS-FTD. (For more, read When the Thinking Parts of the Brain Go Awry in ALS.)

Read on to learn about a new gene associated with ALS and FTD, and a new screening tool for use in assessing FTD symptoms in ALS.

P62 gene in ALS and FTLD

Mutations in the p62 gene (also known as the sequestosome 1, or SQSTM1, gene) have been found in people with FTLD, an international team of researchers has reported.

The gene is located on chromosome 5 and carries instructions for the p62 protein, which is thought to play a major role in a cellular cleanup and disposal system called autophagy.

Taken together with previous research from the laboratory of Teepu Siddique at Northwestern University in Chicago (reported in April 2011) showing that mutations in the p62 gene can cause ALS, the new findings add to a growing body of evidence suggesting that common genetic risk factors underlie both disorders.

The researchers analyzed data taken from 170 people with FTLD; 124 with sporadic ALS; 145 healthy volunteers; and 288 people with Paget disease of bone, which also is caused by mutations in the p62 gene. Seven mutations were found in people with FTLD or ALS, none of whom had mutations in other ALS- or FTLD-associated genes.

Those identified with p62-related FTLD showed aggressiveness, mood changes and social detachment. Those with p62-related ALS showed variable age of onset (78 years, 53 years and 81 years) and survival time (not deceased, two years and eight months, respectively).

Mutations in other genes including charged multivesicular body protein 2B (CHMP2B), fused in sarcoma (FUS), optineurin (OPTN), progranulin (PGRN), tar DNA binding protein 43 (TDP43), ubiquilin 2 (UBQLN2), valosin-containing protein (VCP) and chromosome 9 open reading frame 72 (C9ORF72) have been implicated in both ALS and FTLD.

Genes linked to both diseases may converge into a common pathway, “explaining the overlap of clinical symptoms,” the research team noted.

In an editorial about the new finding, Stanley H. Appel at the Methodist Neurological Institute in Houston and Lewis P. Rowland at the Columbia University College of Physicians & Surgeons in New York suggest that the key question is whether SQSTM1 is a major contributor to the disease process in the FTLD/ALS spectrum. (Appel is a longtime MDA research grantee who directs the MDA/ALS Center at Methodist Neurological Institute in Houston.)

The team reported its findings online Sept. 12, 2012, in Neurology. (See SQSTM1 Mutations in Frontotemporal Lobar Dementia and Amyotrophic Lateral Sclerosis.)

A new screening tool for behavioral disturbances in ALS

A new screening tool called the Amyotrophic Lateral Sclerosis-Frontotemporal Dementia Questionnaire (ALS-FTD-Q) can help accurately assess behavioral disturbances that may be signs of FTD in people with ALS, a Netherlands-based research team has reported.

Currently, the best way to evaluate cognitive and behavioral disturbances in people with ALS is via a detailed family or caregiver interview.

When this isn’t possible, however, various neuropsychiatric screening tests may be used. A potential problem with such tests is an inability to account for effects of ALS symptoms including muscle weakness, dysarthria (difficulty speaking) or pseudobulbar affect (uncontrollable laughing or crying).  Symptoms such as these can influence test scores, resulting in an inaccurate assessment. (For example, it may appear that someone is unable to construct a proper sentence because they are unable to write it due to arm or hand weakness.)

The ALS-FTD-Q was constructed to avoid any testing bias that could be caused by motor and speech impairment. It can be administered at a home visit or in an outpatient clinic. Phrasing of items on the 25-item questionnaire is adjusted for motor and speech dysfunction, and it’s estimated to take between five and 10 minutes to complete.

The reliability and easy way of administering the ALS-FTD-Q “make it a feasible screening instrument in clinical practice as well as for research projects,” the research team reported.

It’s important to be able to accurately assess FTD in people with ALS because it’s been shown that people with cognitive impairment are less likely to adhere to therapies and supportive measures.  (Studies show that only about one-fourth of those with a diagnosis of ALS-FTD comply with recommendations for noninvasive ventilation and feeding tubes, as compared with compliance from three-fourths of those with ALS alone.) Survival time is shorter in people with ALS-FTD than in those with only ALS, and behavioral disruptions associated with FTD often have a great impact on the patient-caregiver relationship.

The research team, which was led by Rob J. DeHaan at the University of Amsterdam, published its findings on the ALS-FTD-Q online Sept. 12, 2012, in Neurology. (The article called The ALS-FTD-Q: A New Screening Tool for Behavioral Disturbances in ALS is available for purchase.)

RASCALS Note: The abstract is below.


Objective: The assessment of behavioral disturbances in amyotrophic lateral sclerosis (ALS) is important because of the overlap with the behavioral variant of frontotemporal dementia (ALS-bvFTD). Motor symptoms and dysarthria are not taken into account in currently used behavioral questionnaires. We examined the clinimetric properties of a new behavioral questionnaire for patients with ALS (Amyotrophic Lateral Sclerosis-Frontotemporal Dementia-Questionnaire [ALS-FTD-Q]).

Methods: In addition to other clinimetric properties, we examined reliability, clinical validity, and construct validity of the ALS-FTD-Q, using data from patients with ALS (n = 103), ALS-bvFTD (n = 10), bvFTD (n = 25), muscle disease control subjects (n = 39), and control subjects (n = 31). Construct validity of the ALS-FTD-Q was assessed using the Frontal Systems Behavior scale (FrSBe), Frontal Behavioral Inventory (FBI), Hospital Anxiety and Depression Scale, ALS Functional Rating Scale?Revised, Frontal Assessment Battery, Mini-Mental State Examination, and a fluency index. In addition, the point prevalence of behavioral disturbances according to the ALS-FTD-Q was compared with those obtained with the FrSBe and FBI.

Results: The internal consistency of the ALS-FTD-Q was good (Cronbach ? = 0.92). The ALS-FTD-Q showed construct validity because it correlated highly with other behavioral measures (r = 0.80 and 0.79), moderately with measures of frontal functions and global cognitive functioning (r = 0.37; r = 0.32), and poorly with anxiety/depression and motor impairment (r = 0.18 for both). The ALS-FTD-Q discriminated between patients with ALS-bvFTD, patients with ALS, and control subjects. The point prevalence of behavioral disturbances in patients with ALS measured with the ALS-FTD-Q was lower than that for the FrSBe and FBI.

Conclusion: The ALS-FTD-Q is a feasible and clinimetrically validated instrument for the screening of behavioral disturbances in ALS.

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