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SHORT COMMUNICATION
Amyotrophic lateral sclerosis and Alzheimer’s disease – clinical and
neuropathological considerations in two cases
R. Rusina
a
, K. Sheardova
´
b
, I. Rektorova
´
b
, P. Ridzon
ˇ
a
, P. Kulis
ˇtÕa
´k
a
and R. Mate
ˇj
c
a
Department of Neurology Institute for Postgraduate Medical Education and Thomayer Teaching Hospital, Prague, Czech Republic;
b
First
Department of Neurology, Masaryk University, St Anne’s Hospital, Brno, Czech Republic; and
c
Department of Pathology, Institute for
Postgraduate Medical Education and Thomayer Teaching Hospital, Prague, Czech Republic
Keywords:
Alzheimer’s disease,
amyotrophic lateral
sclerosis, dementia,
senile plaques,
ubiquitin inclusions
Received 12 September 2006
Accepted 2 February 2007
Amyotrophic lateral sclerosis (ALS) may be accompanied by cognitive impairment;
when present, it is mainly in the form of frontotemporal impairment. We report on
two cases with clinically defined ALS that subsequently developed dementia. Neuro-
pathological examination showed not only the typical neuropathological hallmarks
characteristic of ALS but, surprisingly, also showed neurofibrillary tangles and
neuritic plaques in sufficient numbers to fulfill the diagnostic criteria of definite
Alzheimer’s disease.
Introduction
Amyotrophic lateral sclerosis (ALS) has long been
considered a disease of both upper and lower motor
neurons. However, there has been increased interest,
recently, in the relationship between ALS and altered
cognition [1,2]. Estimates [3] suggest that from one-
third to a half of all ALS patients have cognitive
impairment and many studies have pointed to an
overlap between ALS associated with cognitive
impairment and frontotemporal dementias [3,4]. A
nosologic entity [frontotemporal lobar degeneration
and motor neuron disease (FTLD–MND)] has been
established for ALS cases with ubiquitin positive
intraneuronal inclusions [4,5].
A recent study [6] suggests that the number of
patients with clinically defined ALS who also have
neuropathological changes indicative of Alzheimer’s
disease (AD) is much larger than previously thought.
Case report 1
A 68-year-old woman presented with progressive dys-
arthria and mild left-sided pure motor impairment
evolving over 6 months, but without noticeable cogni-
tive impairment. The dysarthria progressively worsened
and fasciculations developed, mainly in the tongue and
around the left shoulder.
On admission, slight left-sided wasting of the triceps,
deltoid, tibial and peroneal muscles was noted. Reflexes
were brisk in the upper extremities but diminished in
the lower extremities, however, there was no sensory
deficit.
Nerve conduction studies were normal, while needle
EMG studies were pathological, showing polyphasic,
high amplitude motor unit potentials, fibrillation po-
tentials, and a few fasciculations, along with reduced
EMG activity in the extremities and tongue (Fig. 1a).
magnetic resonance imagings (MRIs) showed mild
atrophy in the temporal regions (Fig. 1b) and spiro-
metry revealed a 37% reduction in vital capacity.
A neuropsychological evaluation revealed excellent
nonverbal intellectual performance (Raven’s progres-
sive matrices); attention was normal (attentiveness, risk
taking and hit reaction time were tested using the
ConnorsÕContinuous Performance Test [7]. Executive
functions were slightly impaired (Wisconsin Card
Sorting Test) and the patient had difficulties when tes-
ted using Rey’s figure.
The patient was started on riluzole, however, the
dysarthria progressed and dysphagia developed with
subsequent weight loss. Nutritional management
required a percutaneous endoscopic gastrostomy
(PEG).
During the following months, muscle strength re-
mained, essentially, unchanged, however, the patient
developed cognitive impairment which included me-
mory difficulties. A bedside assessment, conducted after
10 months revealed that the patient was oriented in
place, but disoriented in time and episodic memory was
impaired in both recall and recognition of verbal and
visual material. There was some impairment of com-
prehension, but naming skills were preserved. The Digit
Span Memory Test was normal and there was no
apraxia. However, the patient had a tendency to
Correspondence: Dr Robert Rusina, Department of Neurology,
Thomayer Teaching Hospital, Vı
´den
ˇska
´800, 140 59 Praha, Czech
Republic (tel.: + 420 261 082 479; fax +420 261 083 338; e-mail:
robert.rusina@ftn.cz).
2007 EFNS 815
European Journal of Neurology 2007, 14: 815–818 doi:10.1111/j.1468-1331.2007.01759.x
perseverate and confabulate. The patient was unaware
of her cognitive symptoms. No signs of depression or
delusion were evident on the examination none were
reported by her relatives. A more detailed neuropsy-
chological examination had been planned but because
of the patient’s and her family’s disinclination, was
never carried out. Ultimately, the patient’s dementia
prevented proper use of her PEG, leading to a pre-
dictable decrease in her quality of living.
The patient refused respiratory support, despite in-
creased dyspnea, and died from respiratory failure
14 months after initial assessment.
Case report 2
A 62-year-old man presented with memory impairment
and dysarthria, which had been progressive during the
proceeding year, but without any other motor symp-
toms. Depression with anxiety was diagnosed and he
was put on antidepressives. The MMSE at that time
was 26 and the patient was oriented to person, place
and time. Over the next half year his behavioural
symptoms worsened. The patient discontinued antide-
pressive therapy, became aggressive and proclaimed
suicidal intentions, which precipitated a psychiatric
hospitalization.
On admission to the neurological department,
2 months after his initial hospitalization, we noted
hyperreflexia and diffuse muscle wasting in the upper
and lower limbs, tongue atrophy, weakness of the soft
palate and fasciculations, predominantly in the deltoids,
quadriceps and tongue. Severe paralytic dysarthria and
dysphagia required a PEG intervention. Rapid pro-
gression to severe dementia left the patient confined to
bed, incontinent and unable to communicate. The pa-
tient was free of delusions during the course of his illness.
The patient’s dementia, speech impediment, and
physical paralysis made neuropsychological examina-
tions impossible. A routine cerebrospinal fluid exa-
mination was normal. MRI showed advanced cortical
atrophy, mainly in the medial temporal areas. Single
photon emission computed tomography (SPECT)
imaging revealed focal hypoperfusion in the left tem-
poral and parietal regions. Early stage electrophysio-
logical studies revealed subacute axonal affection of
bulbar motor neurons.
The patient deteriorated rapidly and died of terminal
bronchopneumonia 2 years from the time of the first
clinical symptoms.
Autopsy findings
Both cases shared many common features. Severe
muscle atrophy seen macroscopically, contrasted with
discrete spinal cord and frontotemporal brain atrophy.
Microscopically, we observed hallmarks of chronic
neurogenic denervation atrophy in the striated muscles
of the upper and lower extremities, diaphragm, inter-
costal respiratory muscles and tongue.
We found the severe loss of large, anterior horn cells
in the spinal cord, cranial nerve motor nuclei and, to a
lesser degree, in the motor cortex. Slight gliosis and
sclerosis were noted in the lateral columns of the spinal
(a)
(b)
Figure 1 Motor unit analysis in the tongue in case 1 (a) and
temporal atrophy on coronal FLAIR MRI scans (b).
816 R. Rusina et al.
2007 EFNS European Journal of Neurology 14, 815–818
cord and dystrophic neurons occasionally contained
intracytoplasmatic ubiquitin positive, mainly of the
skein-like, inclusions, which are pathognomonic of
ALS. These findings confirmed the diagnosis of a motor
neuron disease in both cases, however, no ubiquitin or
tau positive neuronal inclusions, considered hallmarks
of FTLD–MND, were found in the sampled cortical
regions.
Observation of the hippocampal regions and previ-
ously examined neocortical areas, using a silver stain
impregnation method, revealed an abundance of neu-
ritic plaques and neurofibrillary tangles. These diag-
nostic features are consistent with the neocortical stage
of Alzheimer’s disease, as defined by NIA-Reagan
Institute criteria, as well as Consortium to Establish a
Registry for Alzheimer’s Disease criteria. Conforma-
tion was provided through routine immunohistoche-
mical testing using specific monoclonal antibodies
against hyperphosphorylated tau protein and amyloid-
beta peptide (Fig. 2).
Discussion
The overlap between cognitive impairment and motor
neuron disease is far more extensive than previously
recognized. Cognition can be altered in 37–50% of ALS
patients, with frank dementia being found in about
20% of this subgroup [2,3]. Patients with bulbar onset
forms of ALS are more likely to develop cognitive
dysfunctions then those with limb-onset forms [8].
Cognitive changes in ALS affect the natural course of
the disease. ALS patients with dementia have signifi-
cantly shorter survival than those with classic ALS
(2.33 years vs. 3.25 years in limb-onset forms and
2.00 years vs. 2.83 years in bulbar onset forms) and are
twice as likely to be noncompliant with proven sup-
portive treatments [8]; features evident in both studied
patients.
Many cognitively impaired ALS patients meet the
criteria for frontotemporal lobar degeneration
(FTLD), however, little has been published on the
ALS and AD association other than retrospective data
analysis studies. In a study of 30 ALS patients [6],
50% had A-beta plaques; of the seven cases without
cortical motor neuron inclusions, only two had
neuritic plaques.
We described two cases of bulbar onset ALS with
dementia (with histopathologically proven MND)
which also included the neuropathological hallmarks of
AD. Neither of them had a family history of dementia
nor ALS. Both had temporal atrophy, visible on MRIs.
In the first case, late onset progressive amnestic
dementia was consistent with AD, in the second, while
early behavioural problems and depression were sug-
gestive of FTLD, when these are taken together with
the early memory impairment and the SPECT and MRI
results, FTLD had to be ruled out.
Our findings suggest a critical need for additional
studies in this area. In particular, studies providing
detailed neuropsychological follow-ups, brain MRI
studies and neuropathological verification of MND; to
reveal the true extent of AD dementia in ALS patients.
Conflict of interest
The authors have disclosed any commercial or other
associations that might pose a conflict of interest in
connection with the submitted article.
Acknowledgements
This study was supported by grants IGA NR/8491–3
and MSM 0021622404 (Ministry of Public Health and
Ministry of Education, Youth and Sports, Czech
Republic).
The authors wish to thank Dr Pohly (Hospital So-
kolov, Czech Republic), for providing MRI services,
and Thomas Secrest, for revision of the English version
of this article.
(a)
(b)
Figure 2 Different morphology of amyloid plaques, which tested
positive using an immunohistochemical reaction with monoclonal
antibodies against amyloid-ß-peptide, in case 1 (a) and neuro-
fibrillary degenerative structures, stained with monoclonal anti-
bodies against hyperphosphorylated tau protein, in case 2 (b).
Original magnification was 200·.
Amyotrophic lateral sclerosis and Alzheimer’s disease 817
2007 EFNS European Journal of Neurology 14, 815–818
References
1. Strong MJ, Grace GM, Orange JB, et al. A prospective
study of cognitive impairment in ALS. Neurology 1999;
53: 1665–1670.
2. Lomen-Hoerth C, Murphy J, Langmore S, et al. Are
amyotrophic lateral sclerosis patients cognitively nor-
mal? Neurology 2003; 60: 1094–1097.
3. Ringholz GM, Appel SH, Bradshaw M, et al. Prevalence
and patterns of cognitive impairment in sporadic ALS.
Neurology 2005; 65; 586–590.
4. Abrahams S, Leigh PN, Goldstein LH. Cognitive change
in ALS: A prospective study. Neurology 2005; 64: 1222–
1226.
5. McKhann GM, Albert MS, Grossmann M, et al. Cli-
nical and Pathological Diagnosis of Frontotemporal
Dementia. Archives of Neurology 2001; 58: 1803–1809.
6. Hamilton RL, Bowser R. Alzheimer disease pathology in
amyotrophic lateral sclerosis. Acta Neuropathologica
2004; 107: 515–522.
7. Conners CK. Continuous Performance Test (CPT).
Odessa, FL: Psychological Assessment Resources, 1996.
8. Olney RK, Murphy J, Forshew D, et al. The effects of
executive and behavioral dysfunction on the course of
ALS. Neurology 2005; 65: 1774–1777.
818 R. Rusina et al.
2007 EFNS European Journal of Neurology 14, 815–818
