Front temporal lobar degeneration with ALS

Sunday, June 10th – Wednesday, June 13th, 2007

It was thought that ALS was a disease that was limited to the motor neurons. Now we think more and more that ALS is associated with a type of front temporal syndromes.

These syndromes also include cognitive and behavioral- symptoms, a dysexecutive syndrome and in exceptional cases a blooming front temporal dementia. At the second international research workshop, the overlapping between the front temporal degeneration and ALS is being discussed. At the first workshop they mainly dealt with the basic anatomy, bio-chemistry and pathology of these two diseases. In this workshop they want to further investigate on the clinical and the phenomenological, genetic and neuropathological overlapping between both.

New in the 2007 research workshop is a session where they will focus on the research of treatments for FTLDs, and how these can be a source of information for a better treatment of similar symptoms with ALS.

Although ALS is traditionally considered as a progressive neuro degenerative disease with which the motor system is the selective target, the finding of dementia or cognitive interferences with a significant group of ALS patients has challenged this concept.

A shorter survival time has been observed with ALS patients with a front temporal dysfunction syndrome. Maybe this is due to the lack of being faithful or interested in invasive therapies such as enteral food or in the use of non-invasive positive pressure ventilation.

The presence of FTLD (front temporal lobar disease) is important from a biological standpoint. In a number of cases, inclusive the western pacific variant of ALS and a number of sporadic forms of ALS, pathological findings typical for FTLD can be observed. This suggests, on a certain level, an overlap of ALS with other degenerative diseases. This assumption is being stressed by the finding of ubiquitin immunoreactive intraneural aggregates in both bulbar and spinal motor neurons in a population of FTLD autopsies with whom there is no clear ante mortem evidence of a motor neuron disease.

 

The core diagnostic criteria for ALS

The El Escorial criteria for the diagnosis of ALS are internationally accepted and have to be the nucleus of each diagnosis of ALS in the context of a front temporal syndrome. The criteria use clinical, electro physical, genetic and some neuro-imaging modalities for a level of certainty for the diagnosis of ALS.

The diagnosis of ALS has to include the presence of lower motor neurons degeneration (clinical, electro physical or neuro pathological criteria), and an evidence of higher motor neurons degeneration (through clinical research) with evidence of progression of the symptoms or signs in a certain region or other regions.

 

Front temporal lobar syndrome in ALS

There is substantial evidence of the existence of cognitive and behavior dysfunctions in ALS, inclusive a spectrum of front temporal syndromes and more classically defined dementias. These include pure ALS with which only motor neuron degeneration occurs, ALS in association with cognitive disorders, ALS with behavior disorders, ALS with dementia according to the Neary criteria for FTLD. Added a more florid dementia can occur with ALS that is described under the Japanese population. A frontal predominant variant of Alzheimer can also occur with ALS but it is not clear if this is a coincidental association or not. Estimation of the occurrence of cognitive disorders in ALS is 10% to 75% with the appearance of dementia 15 % to 41 %.

Front temporal lobar degeneration exists out of three clinically recognized subtypes. The most common one is a behavior symptom observed in changing social behavior, disturbed regulation of inter-personal behavior, emotional deterioration and a loss of understanding.

Added, both are a progressive non fluent aphasia (characterized by progressive non fluent agrammatism, paraphasia or anomie) and semantic dementia (characterized by a fluent speech with loss of word meaning).

Although the classification of patients with front temporal syndromes in FTLD, progressive non fluent aphasia and semantic dementia has proved very useful in general, this approach cannot be used to adequately describe the spectrum of cognitive and behavior syndromes associated with ALS. For example a frontal dysexecutive syndrome can occur in ALS in the absence of typical behavioral traits associated with FTLD in the Neary criteria. None of the standard criteria for FTLD talk directly to the topic of executive dysfunction in ALS, defects that have a direct impact on the ability to organize information mentally, or divide attention or inhibitory behavior. Added, the most common frontal lob disorder in ALS shows a combination of both cognitive and behavioral disorders. Detailed neuro physiological tests, show that the prevail of cognitive disorders in the ALS population is about 50%. Defining a minimum set of criteria that both are sensitive and specific to these different diseases is important. The neurolo physiological disorders in ALS are most of the time subtle, with the commonly observed weaknesses in the area of problem solving, concentration and mental control, continuous visual recognition memory, word generation and verbal free recall. The interpretation of weaknesses can potentially be entangled by a number of variables, standing out of the case and can disrupt the interpretation of neuro physiological studies. These variables need to be controlled (table 1). While running tests on the most important cognitive domains, neuro physiological studies have to include tests that assess executive functioning, inclusive the measurement of the verbal fluency, but also emotional and behavioral functioning measured by healthcare people. Tests that minimize the impact of speech and motor dysfunction are also critical to use, especially with longitudinal research. In the end all patients should be tested according to the Neary criteria for FTLD. While the development of a concise screening agent for a front temporal lobar syndrome with ALS should be a high means when full neuro physiological research is not available, no such means has been validated within this population (Table 2).

 

Neuro imaging

Although both right hemispheric atrophy and a loss of neurons in the anterior cingulate gyrus are associated with ALS with cognitive disorders, it is less clear that these resources are robust enough to be used as diagnostic means in the evaluation paradigm for cognitive dysfunction with ALS. The existence of front temporal atrophy, whether defined by CT scan or by MR, can be a sensitive early indicator of front temporal lobar degeneration with ALS. More dynamic tests of the metabolic function, cerebral perfusion, astrocytic proliferation, or microglial activation remain means that have to be examined at this moment but are promising.

 

Molecular and genetic diagnosis

The western pacific variant of ALS may be the prototype example of the occurrence of ALS with significant non-motor symptoms. First reported after World War II in Guam under the native Chamorro and called the amyotrophic lateral sclerosis-Parkinson dementia complex of Guam, about 50% of the sons of these patients developed Parkinson and dementia, 25% developed ALS, and 5% of the sons developed Parkinson, Dementia and ALS.

The co-occurrence of ALS and FTLD has also been described in families outside Guam as the desinhibition-dementia-Parkinson-amyotrophic complex. In the most extensive studied family (Mo family), personality and behavioral changes were the first symptoms with twelve of the thirteen affected patients. The first symptoms occurred at the average age of 45 years and the mean time to death was thirteen years. There was early amnesia, anomy, and poor construction with afterwards complications in terms of orientation, speech and calculations.

All members affected had rigidity, bradykinesia and instability of the position. On a neuro pathological level, there was atrophy and spongiform change in the front temporal cortex, and neuron loss and gliosis in the substantia nigra and the amygdala. Two individuals had anterior hoorncel loss and one subject had fasciculation and loss of muscles. There were no Lewy bodies, neurofibrillar tangles or amyloid plaques. The genetic locus was linked to chromosome 17Q21-22 and the mutation took place in the intron adjacent to exon 10 in the tau gen.

A large number of patients with FTLD and links with chromosome 17 are described. In a small proportion of these patients corticospinal disorders, loss of muscles and fasciculations have been observed. Mutations in the tau gen, localized on chromosome 17, have been found in a lot of these families, especially those with extra pyramidal disorders, although only a few FTLD-ALS cases were caused by the known tau mutations. The relation between chromosome 17 linkage and FTLD is complex, and more than 25 different mutations have been identified in the tau gen that are suspected of causing FTLD symptoms, non tau linked chromosome 17 linked FTLD with ALS is obvious. Added, another FTLD-ALS family is localized on chromosome 9q21-q22.

 

Neuro pathological correlates

There have been significant improvements in the neuro pathological characterization of the FTLD’s, inclusive the development of a classification based on the presence or absence of taupathy. The identification that a subgroup of FTLD patients will have proof of a motor neuron degeneration at the time of autopsy, based on a variety of immunohistochemical markers, had lead to the overlapping of the origin of neuro pathological terminologies which are usually created to indicate the presence of a clinical syndrome. However, the neuro pathological characterization of the FTLD’s associated with ALS remains completely clear. The core component of the neuro pathological diagnosis of the ALS-FTLD has to be the presence or absence of neuro pathological symptoms of ALS. The problem then becomes the classification of the patients where there is no ante mortem evidence of ALS, but where the symptoms of FTLD are found at the same time of one or more aspects of the neuro pathology of ALS. This dilemma has been emphasized by the recent discovery that abnormal intraneuronal accumulations of TDP-43 have been found in both ALS and FTLD with ubiquitin inclusions.

As with the clinical criteria for the diagnosis of ALS, there are minimum criteria for the neuro pathological diagnosis of ALS. There has to be proof of degeneration of the motor system inclusive the loss of anterior hoorncells (AHC), brainstem motor nuclei, and the descending supraspinal pathways involved in the motor function. This degenerative process is being accompanied by a large range of neuro pathological symptoms where both cortical (upper motor neurons) and brainstem motor neurons or lower motor neurons are involved. Under the neuro pathological hallmarks of ALS are a variety of intracellular inclusions, inclusive Bunina bodies, ubiquitinated inclusions or skein-like structures, and hyaline conglomerates. Although none of these findings are pathognomic, a lot are unique enough to ALS to be able to make the diagnosis of ALS.

The full extent of the neuro pathological basis of the front temporal dysfunction syndromes of ALS still has to be described. For the individuals with ALS and cognitive symptoms, the neuro pathological symptoms are typical for FTLD, inclusive spongiform degeneration in the frontal and the precentral gyrus cortical layers 2 and 3 with diffuse sub cortical gliosis. There is a loss of neurons in the anterior cingulate gyrus, substantia nigra and amygdale. The finding of microglia activation and proliferation by the affected neocortex is a reminder of the PET-imaging studies used markers of the microglia activation.

The neuro pathological hallmark of FTLD in ALS is the presence of ubiquitin immunoreactive intraneuronal inclusions in the dentate granule cells, the superficial frontal and temporal cortical layers, and the entorhinal cortex.

It is useful to know although these are not specific to cognitive-limited ALS cases and that they can be observed in other forms of neuro degeneration. The fact is that these ubiquitin immunoreactive inclusions lack immunoreactivity by both microtubule associated protein tau or alfa-synuclien that lead to, considered unique for ALS. However there is the evidence to suggest that interruptions in the tau metabolism also can be associated with ALS with cognitive deficiencies, inclusive aberrant tau phosphorylation at the threonine 175 site. In addition to these findings, ubiquitin immunoreactive dystrophic neuritis in the extramotor cortices with a predominance or involvement in the frontal, temporal and hippocampal corext has been observed.

 

FTLD with ALS-like pathology

There remains a group of FTLD’s with whom motor neuron degeneration can only be observed by neuro pathological examination. The FTLD’s are a heterogeneous group of diseases that share the same phenomena in the field of front temporal lobar degeneration but where there is also a substantial overlap in neurological phenomena. As an addition to this, the classification of FTLD’s is a process in evolution, adapted or changed by newer neuro chemical studies, and by new immunohistochemical markers. To emphasize this, there has been a recent analysis of 29 cases deduced from a brain bank that were prior neuro pathological classified as FTLD. The majority of the cases were non-taupathy, with the most common diagnosis of front temporal lobar degeneration (FTLD) with ubiquitin-only immunoreactive neuron changes. Other diagnoses, inclusive the disease of Pick, FTLD with Parkinson linked to chromosome 17 (FTLDP-17), FTLD (also known as dementia with lack of distinctive histopathology – DLDH), FTLD with motor neuron disease (FTLD-MND) and neurofilament inclusion body disease (NIBD).

The finding of motor neuron ubiquitin-immunoreactive aggregates in the presence of the pathological phenomena of an FTLD but in absence of openly clinical phenomena of motor neuron disease, lead to a concept of a unique FTLD called “motor neuron disease inclusion dementia” (MNDID). Of interest was the observation of ubiquitinated intranuclear inclusions (Ub-INI) in the striatum of patients with only family MNDID. Ub-INI has been described prior in 9 cases of MNDID, none of them had ALS. From these, only one developed ALS afterwards. It is not clear that this is the same entity as described by MacKenzie en Feldman (2004) in which intranuclear ubiquitin immunoreactive inclusions were observed in the majority of family FTLD MND-like cases. It is probable although these inclusions can be seen in both ALS-D and FTLD’s with motor neuron degeneration not typical to ALS (referred to FTLD-MND-like). An FTLD with neurofilament inclusion bodies (NIBD) has also been described in which tau-negative neurofilament immunoreactive inclusions have been observed.

 

Conclusion

The non motor cognitive manifestation of ALS can increasingly be considered as a heterogeneous group of ‘front temporal dysfunction syndromes’ that include cognitive dysfunction (inclusive the dysexecutive syndrome), behavioral disorders and in proportion a floride FTLD consistency with the Neary criteria. But the disorders in a vast majority of these syndromes are relatively subtle and do not have the character of a fulminant dementia.

As a consequence the cognitive and behavioral disorders are generally overlooked at the moment of the neurological examination of an ALS patient. The day-to-day variation in decision making, impulsiveness and emotional lability are less critical findings for an individual for whom the debilitating disease requires a multi-system and a multi disciplinary approach. The concept that ALS is a pure motor system disease needs a radical revision.

 

Table 1:

Outside variables that have to be taken into account in the neuropsychological evaluation of ALS:

Depression

Pseudo bulbar affect

Education level, intellectual functioning

The presence of bulbar dysfunction (e.g. Dysartrie)

Level of disease progression

Pulmonal status

Pain

Fatigue

Medication (especially psychotropic and pain medication)

Level of motor attenuation

 

Table 2:

Diagnostic classification for ALS cognitive and behavioral dysfunction

Title ALS

Subtitle ALS

Existing synonyms in the literature

Characteristics A pure motor system disease defined by the El Escorial criteria; no clinical evidence for front temporal dysfunction

 

Front temporal lobar degeneration with ALS

	ALSci		Defects in the frontal cognitive function but insufficient in order to meet the Neary criteria for FTLD
	ALSbi		Beahvioral dysfunction but insufficient in order to meet the Neary criteria.
	ALS-FTLD ALS-PA ALS-SD	ALS-dementia (ALS-D), FTLD-MND	If patient meets the Neary criteria for FTLD
	FTLD-MND-like		Cases of FTLD where there is neuro pathological evidence of motor neuron degeneration, but insufficient to be classified as ALS
	ALS-dementia		ALS with dementia, not typical for FTLD
	ALS-parkinson-dementia complex	Western Pacific variant of ALS	ALS concurrent with dementia and/or presence of parkinson in hyper endemic foci of the western pacific.

 

Source: Strong et al. ALS FTD consensus criteria

Translation: Vinci Van Roost / Tina