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Cognitive impairment frontotemporal dementia and the motor neuron diseases.

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Cognitive Impairment, Frontotemporal
Dementia, and the Motor Neuron Diseases
Michael J. Strong, MD,1 Catherine Lomen-Hoerth, MD, PhD,2 Richard J. Caselli, MD,3
Eileen H. Bigio, MD,4 and Wencheng Yang, MD1
Cognitive Impairment in Amyotrophic
Lateral Sclerosis
Traditionally, amyotrophic lateral sclerosis (ALS) has
been considered to be a disorder in which the primary
pathology resides in the degeneration of motor neurons, giving rise to progressive, diffuse muscle wasting,
weakness, and spasticity. This view is rapidly being
challenged to include a more widespread disease process in which motor system degeneration remains the
core feature but not the sole system affected.1
Although its incidence remains to be determined,
the evidence of cognitive impairment in ALS is overwhelming.2– 6 However, it is important to recognize
that there is likely to exist a continuum of cognitive
dysfunction in ALS, ranging from mild cognitive impairment (ALSci) to a more fulminant progressive dementia of the frontotemporal type (FTD) with a small
subset with an aphasic pattern. Most commonly, ALSci
is reported as a subtle neurological presentation marked
by deficits primarily in frontal and temporal functions.7–9 Although in the Japanese population, alterations in cognition have been reported to precede the
motor system manifestations, typically the cognitive
dysfunction follows the onset of neuromuscular deficits.10 Individuals with bulbar-onset disease appear to
be at greater risk for the development of cognitive impairment, although these deficits are found to a lesser
degree in limb-onset patients.5,6 Typical impairments
include alterations in mental flexibility, verbal and
nonverbal fluency, abstract reasoning, and memory, for
both verbal and visual material.3,4,6,11 Less often, there
is a rapidly progressive aphasic dementia.7 ALSci language characteristics include word-finding difficulty,
lexical disorganization, and reliance on stereotypical
sentences. Anterior-based language functions (eg, fluency, syntax, and grammar) are compromised.12,13
The relationship between FTD, FTD with ALS, and
FTD with the neuropathological features of ALS in the
absence of clinical findings remains to be clarified.
There is likely to be significant overlap among these
entities, as illustrated in a study of 36 FTD patients
with no known diagnosis of ALS, 5 of whom met clinical and electrophysiological criteria for a definite diagnosis of ALS and an additional 13 who met criteria for
possible ALS, of whom 1 subsequently developed
ALS.14 The converse is also true. A study of word generation tests in 100 consecutive ALS patients identified
a subset of 44 patients with impairments.5 Of these,
diminished word generation was found in one third.
Of this latter group, nearly all were shown to meet
research criteria for FTD. In addition, one quarter of
the patients with normal word generation who agreed
to further evaluation met research criteria for FTD;
these patients had new-onset personality changes.
In addition to the precentral gyrus atrophy that is
well recognized in ALS, neuroimaging in ALSci demonstrates a more widespread frontal and temporal cortical atrophy, with variable involvement of the precentral and postcentral gyrus, the anterior cingulate gyrus,
corpus callosum, and brainstem tegmentum. Functional
neuroimaging techniques, including single-positron
emission tomography studies with either 123 I-Nisopropyl-p-iodoamphetamine12,15 or 99mTc-d,l-hexamethylproplene–amine oxime (HM-PAO), 16,17 and
positron emission tomography, are sensitive to reduced
frontal and temporal cortical blood flow in ALSci.18 Reductions in the N-acetylaspartase to creatine ratio of
anterior cingulate gyrus neurons with the use of proton
magnetic resonance spectroscopy has been shown to be
a sensitive marker of ALSci.6
The typical neuropathological features of ALS include degeneration of the descending supraspinal motor pathways and their neurons of origin, and of brainstem and spinal motor neurons in addition to
From the 1Department of Clinical Neurological Sciences and the
Robarts Research Institute, London, Ontario, Canada; 2Department
of Neurology, University of California, San Francisco, CA; 3Department of Neurology, Mayo Clinic, Scottsdale, AZ; 4Department of
Pathology, Northwestern University Feinberg School of Medicine,
Chicago, IL.
Address correspondence to Dr Strong, Department of Clinical Neurological Sciences and the Robarts Research Institute, Room 70F10,
UC-CHSC 339 Windermere Rd, London, Ontario, Canada N6A
5A5. E-mail: mstrong@uwo.ca
Published online Jun 23, 2003, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.10574
S20
© 2003 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
intraneuronal inclusions. The latter include aggregates
with immunoreactivity to phosphorylated neurofilament, peripherin and ␣-internexin, and discrete skeins
or homogenous aggregates of ubiquitin-immunoreactive
material.19 –21 The finding of motor neuron ubiquitinimmunoreactive aggregates in the presence of the pathological features of a FTD but in the absence of overt
clinical features of motor neuron disease has led to the
concept of a unique FTD called motor neuron disease
inclusion dementia (MNDID).22
In addition to these features, the neuropathology of
ALSci includes spongiform degeneration in frontal and
precentral gyrus cortical layers II and III.23 Neuronal
density is reduced in the anterior cingulate gyrus. Although ubiquitin-immunoreactive intraneuronal inclusions are often observed within the dentate granule
cells, the superficial frontal and temporal cortical layers, and in the entorhinal cortex, these are not specific
to ALSci and can be observed in other forms of
neurodegeneration.24 –26 However, ALSci ubiquitinimmunoreactive inclusions are unique in lacking immunoreactivity to either microtubule-associated protein
tau or ␣-synuclein.10,24,25,27,28 This is not to say that
tau-immunoreactive structures are absent in ALS or
ALSci. Noda and colleagues first described 3 cases of
late adult–onset ALS in which tau-immunoreactive
thread-like structures were observed in the neuropil
and in glial cells (as coiled bodies) in the hippocampus,
parahippocampal gyrus, and amygdala.29 In two of the
three cases, the neuropil and glial tau-immunoreactive
structures occurred in the absence of pathology typical
of Alzheimer’s disease.
Of interest has been the observation of ubiquitinated
intranuclear inclusions in the striatum of patients with
familial MNDID only. Ubiquitinated intranuclear inclusions had previously been described in 9 patients
with MNDID, none of whom had ALS.30 Six were
reported by E. H. Bigio at the September FTD–Pick’s
disease conference, and one of whom, for the first
time, had clinical ALS.
Yang and Strong have recently reported the presence
of neuronal, extraneuronal, and glial tau aggregates in
both ALSci and ALS subjects that are readily observed
using either Gallyas silver staining or immunostaining
with monoclonal antibodies directed against tau (tau-1
following dephosphorylation or AT 8).31 Although
tau-immunoreactive neuronal inclusions were observed
in ALSci patients, it was also observed in cognitively
intact ALS patients. However, in ALSci, dense tau-1
immunoreactive neuronal inclusions in frontal cortical
layer II and layer III were characteristic. Astrocytic tauimmunoreactive inclusions were also characteristic of
ALSci, as was extraneuronal tau aggregates deposition.
The latter assumed a number of morphologies, including curvilinear neuropil threads, rare argyrophilic gran-
ules, and dense rounded aggregates with irregular fibrillary margins.
Cognitive Dysfunction in Other Degenerative
Motor Neuron Diseases
Western Pacific Variant of Amyotrophic
Lateral Sclerosis
Although the western Pacific variant of ALS is clinically indistinguishable from the sporadic variant of
ALS, both ALS and parkinsonism/dementia can coexist
in the same individual, leading to the diagnosis of the
ALS/parkinsonism-dementia complex.32,33 An intriguing aspect of this variant of ALS is the co-occurrence of
the neurofilamentous pathology of ALS with severe
cortical atrophy and neurofibrillary tangles that are
morphologically identical to those observed in Alzheimer’s disease.34,35 In contrast to Alzheimer’s disease,
the hyperphosphorylated, highly insoluble, tau triplet
protein (the fundamental constituent of the neurofibrillary tangles) is more widely distributed in both cortical and subcortical structures in the western Pacific
variant of ALS.36 Lewy-like bodies, containing accumulations of ␣-synuclein and typical of those observed
in Parkinson’s disease, are also observed predominantly
within neurons of the amygdala.37
Familial Amyotrophic Lateral Sclerosis and Dementia
Familial ALS, parkinsonism, and dementia also occur
outside of the western Pacific variant of ALS. More
than 70 kindreds of families with familial ALS and dementia, and linkage to chromosome 17, have now been
described, with more than 30 pathogenic tau mutations.38 At the core of the chromosome 17–linked dementia (or FTDP-17) syndrome are behavioral
changes, psychosis, loss of executive functioning, and,
for the majority of variants, a lack of motor phenomenon with the exception of a progressive loss of speech
output. Corticospinal disturbances, muscle wasting,
and fasciculations were found in 4 of these families,
however, and there were occasional patients with dysphagia and dysarthria. Although mutations in the tau
gene were found in many of these families, particularly
those with extrapyramidal disturbances, few FTD-ALS
cases are caused by known tau mutations.39
Motor Neuron Disease Inclusion Dementia
Jackson and colleagues highlighted the existence of the
disorder MNDID in a cohort of 9 patients identified
from a larger pool of FTD patients and in whom no
clinical evidence of either upper or lower motor neuron
dysfunction was evident.22 Neuropathologically, there
was microvacuolization in cortical layer II of the frontotemporal lobes, subcortical gliosis, and ubiquitinimmunoreactive inclusions in the hippocampal dentate
granule cells and remaining neurons of layer II of the
Strong et al: MND Cognitive Impairment
S21
frontotemporal cortex. Brain stem motor nuclei were
normal. Subsequent reports have highlighted the loss of
anterior horn cells in the absence of pyramidal tract
degeneration or ubiquitinated motor neuronal inclusions.40
Primary Lateral Sclerosis
The appearance of progressive spasticity alone, in the
absence of either clinical or laboratory evidence of
lower motor neuron dysfunction, is a rare variant of
motor neuron disease termed primary lateral sclerosis.41,42 In an analysis of 9 patients with primary lateral
sclerosis, Caselli and colleagues observed mild cognitive
dysfunction consistent with frontal lobe dysfunction in
8.43 Six patients underwent HM-PAO single-positron
emission tomography studies of regional cerebral blood
flow, with evidence of bilateral posterior hypoperfusion.
Conclusions
Cognitive dysfunction occurs more frequently than traditionally expected among patients with motor neuron
diseases and may even approach 50% of patients with
the most common motor neuron disease, ALS. Consistent with the frontotemporal predominance of this
process, deficits include alterations in executive function, verbal and nonverbal fluency, abstract reasoning,
verbal and visual memory, and behavioral and personality changes. The neuroradiological characteristics include frontotemporal atrophy with reduced frontotemporal blood flow and metabolism. Neuropathological
analysis shows severe frontotemporal atrophy with superficial linear spongiosis and ubiquitinated neuronal
inclusions in hippocampal dentate gyrus and superficial
cortex. Tau-immunoreactive inclusions are observed in
patients with ALSci, including not only intraneuronal
and extraneuronal aggregates but also astrocytic tauimmunoreactive aggregates. These findings suggest a
continuum between ALS, ALS-FTD, and FTD. The
critical point, however, remains to determine the extent
to which mild cognitive deficits exist within the ALS
population, and moreover, the extent to which these
deficits actually herald the development of a more fulminant dementia typical of the progressive ALSdementia complex. To this end, two prospective studies (by M.J.S. and C.L.-H.) addressing this issue will
provide valuable insight into the natural history of
ALSci. Understanding this process will have a major
impact on our understanding of the pathogenesis of
these disorders.
This work was supported by grants from the Canadian Institutes of
Health Research (M.J.S.); Amyotrophic Lateral Sclerosis Association
(ALSA; C.L.-H.); the Scottish Rite Heritage Foundation; (P30
AG19610-01, RO1 MH57899-01A1, R.J.C.); and the Arizona Alzheimer’s Research Consortium.
S22
Annals of Neurology
Vol 54 (suppl 5)
2003
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Strong et al: MND Cognitive Impairment
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