Incidence and predictors of seizures in patients with Alzheimer's disease.
ABSTRACT To determine cumulative incidence and predictors of new-onset seizures in mild Alzheimer's disease (AD) with a cohort followed prospectively. Limited information is available on the incidence of seizures, and no reports exist of seizure predictors in AD patients.
Mild AD patients were prospectively followed at 6-month intervals to estimate incidence of unprovoked seizures, compare age-specific risk of unprovoked seizures with population norms, and identify characteristics at baseline (demographics, duration and severity of AD, physical and diagnostic test findings, and comorbid medical and psychiatric conditions) influencing unprovoked seizure risk. Review of study charts and medical records supplemented coded end-point data.
The cumulative incidence of unprovoked seizures at 7 years was nearly 8%. In all age groups, risk was increased compared with a standard population, with an 87-fold increase in the youngest group (age 50-59 years) and more than a threefold increase in the oldest group (age 85+ years). In multivariate modeling, independent predictors of unprovoked seizures were younger age [relative risk (RR), 0.89 per year increase in age; 95% confidence interval (CI), 0.82-0.97], African-American ethnic background (RR, 7.35; 95% CI, 1.42-37.98), more-severe dementia (RR, 4.15; 95% CI, 1.06-16.27), and focal epileptiform findings on electroencephalogram (EEG) (RR, 73.36; 95% CI, 1.75-3075.25).
Seizure incidence is increased in people starting with mild-to-moderate AD. Younger individuals, African Americans, and those with more-severe disease or focal epileptiform findings on EEG were more likely to have unprovoked seizures.
- SourceAvailable from: Patricio Castro[Show abstract] [Hide abstract]
ABSTRACT: Extracellular and intracellular copper and zinc regulate synaptic activity and plasticity, which may impact brain functionality and human behavior. We have found that a metal coordinating molecule, Neocuproine, transiently increases free intracellular copper and zinc levels (i.e., min) in hippocampal neurons as monitored by Phen Green and FluoZin-3 fluorescence, respectively. The changes in free intracellular zinc induced by Neocuproine were abolished by the presence of a non-permeant copper chelator, Bathocuproine (BC), indicating that copper influx is needed for the action of Neocuproine on intracellular Zn levels. Moreover, Neocuproine decreased the mRNA levels of Synapsin and Dynamin, and did not affect the expression of Bassoon, tubulin or superoxide dismutase (SOD). Western blot analysis showed that protein levels of synapsin and dynamin were also down regulated in the presence of Neocuproine and that these changes were accompanied by a decrease in calcium transients and neuronal activity. Furthermore, Neocuproine decreased the number of active neurons, effect that was blocked by the presence of BC, indicating that copper influx is needed for the action of Neocuproine. We finally show that Neocuproine blocks the epileptiform-like activity induced by bicuculline in hippocampal neurons. Collectively, our data indicates that presynaptic protein configuration and function of primary hippocampal neurons is sensitive to transient changes in transition metal homeostasis. Therefore, small molecules able to coordinate transition metals and penetrate the blood-brain barrier might modify neurotransmission at the Central Nervous System (CNS). This might be useful to establish therapeutic approaches to control the neuronal hyperexcitabiltity observed in brain conditions that are associated to copper dyshomeotasis such as Alzheimer's and Menkes diseases. Our work also opens a new avenue to find novel and effective antiepilepsy drugs based in metal coordinating molecules.Frontiers in Aging Neuroscience 01/2014; 6:319. · 2.84 Impact Factor
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ABSTRACT: Dendritic structure critically determines the electrical properties of neurons and, thereby, defines the fundamental process of input-to-output conversion. The diversity of dendritic architectures enables neurons to fulfill their specialized circuit functions during cognitive processes. It is known that this dendritic integrity is impaired in patients with Alzheimer’s disease and in relevant mouse models. It is unknown, however, whether this structural degeneration translates into aberrant neuronal function. Here we use in vivo whole-cell patch-clamp recordings, high-resolution STED imaging, and computational modeling of CA1 pyramidal neurons in a mouse model of Alzheimer’s disease to show that structural degeneration and neuronal hyperexcitability are crucially linked. Our results demonstrate that a structure-dependent amplification of synaptic input to action potential output conversion might constitute a novel cellular pathomechanism underlying network dysfunction with potential relevance for other neurodegenerative diseases with abnormal changes of dendritic morphology.Neuron 11/2014; · 15.77 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is a devastating disease characterized by synaptic and neuronal loss in the elderly. Compelling evidence suggests that soluble amyloid-beta peptide (Abeta) oligomers induce synaptic loss in AD. Abeta-induced synaptic dysfunction is dependent on overstimulation of N-methyl-D-aspartate receptors (NMDARs) resulting in aberrant activation of redox-mediated events as well as elevation of cytoplasmic Ca2+, which in turn triggers downstream pathways involving phospho-tau (p-tau), caspases, Cdk5/dynamin-related protein 1 (Drp1), calcineurin/PP2B, PP2A, Gsk-3beta, Fyn, cofilin, and CaMKII and causes endocytosis of AMPA receptors (AMPARs) as well as NMDARs. Dysfunction in these pathways leads to mitochondrial dysfunction, bioenergetic compromise and consequent synaptic dysfunction and loss, impaired long-term potentiation (LTP), and cognitive decline. Evidence also suggests that Abeta may, at least in part, mediate these events by causing an aberrant rise in extrasynaptic glutamate levels by inhibiting glutamate uptake or triggering glutamate release from glial cells. Consequent extrasynaptic NMDAR (eNMDAR) overstimulation then results in synaptic dysfunction via the aforementioned pathways. Consistent with this model of Abeta-induced synaptic loss, Abeta synaptic toxicity can be partially ameliorated by the NMDAR antagonists (such as memantine and NitroMemantine). PSD-95, an important scaffolding protein that regulates synaptic distribution and activity of both NMDA and AMPA receptors, is also functionally disrupted by Abeta. PSD-95 dysregulation is likely an important intermediate step in the pathological cascade of events caused by Abeta. In summary, Abeta-induced synaptic dysfunction is a complicated process involving multiple pathways, components and biological events, and their underlying mechanisms, albeit as yet incompletely understood, may offer hope for new therapeutic avenues.Molecular Neurodegeneration 11/2014; 9(1):48. · 5.29 Impact Factor
Epilepsia, 47(5):867–872, 2006
Blackwell Publishing, Inc.
C ?2006 International League Against Epilepsy
Incidence and Predictors of Seizures in Patients
with Alzheimer’s Disease
∗‡Joan C. Amatniek,∗‡W. Allen Hauser, ‡Carrie DelCastillo-Castaneda,∗‡Diane M. Jacobs,
∗‡Karen Marder,∗‡Karen Bell, ?Marilyn Albert, §Joseph Brandt, and∗†Yaakov Stern
Departments of∗Neurology and †Psychiatry and ‡the Gertrude H. Sergievsky Center, Columbia University College of Physicians
and Surgeons, New York, New York; §Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of
Medicine, Baltimore, Maryland; and ?Departments of Psychiatry and Neurology, Massachusetts General Hospital, Harvard Medical
School, Boston, Massachusetts, U.S.A.
Summary: Purpose: To determine cumulative incidence and
predictors of new-onset seizures in mild Alzheimer’s disease
(AD) with a cohort followed prospectively. Limited information
is available on the incidence of seizures, and no reports exist of
seizure predictors in AD patients.
Methods: Mild AD patients were prospectively followed at
6-month intervals to estimate incidence of unprovoked seizures,
compare age-specific risk of unprovoked seizures with popula-
tion norms, and identify characteristics at baseline (demograph-
ics, duration and severity of AD, physical and diagnostic test
findings, and comorbid medical and psychiatric conditions) in-
fluencing unprovoked seizure risk. Review of study charts and
medical records supplemented coded end-point data.
Results: The cumulative incidence of unprovoked seizures at
7 years was nearly 8%. In all age groups, risk was increased
compared with a standard population, with an 87-fold increase
in the youngest group (age 50–59 years) and more than a three-
modeling, independent predictors of unprovoked seizures were
younger age [relative risk (RR), 0.89 per year increase in age;
95% confidence interval (CI), 0.82–0.97], African-American
findings on electroencephalogram (EEG) (RR, 73.36; 95% CI,
Conclusions: Seizure incidence is increased in people start-
ing with mild-to-moderate AD. Younger individuals, African
Americans, and those with more-severe disease or focal epilep-
tiform findings on EEG were more likely to have unpro-
vokedseizures. KeyWords: Alzheimer’sdisease—Seizures—
Cumulative incidence—Predictors—Prospective cohort.
Two prospective studies have noted a significantly
higher incidence of seizures in Alzheimer’s disease (AD)
patients than in nondemented elderly controls (1,2), and
AD was a significant risk factor for seizures in one prior
case–control study (3). These studies did not thoroughly
explore the clinical features that might be predictive of
later seizures. Two studies reported no association be-
tween seizures in AD and age at AD onset (2), prior EEG
findings (2), or apolipoprotein E (ApoE) status (4).
of the same age. We also identified characteristics early in
AD that are predictive of future unprovoked seizures. We
used data from the Predictors study, which has been col-
lecting data semiannually for nearly 10 years on patients
with mild AD at study entry, many of whom had been re-
Accepted January 20, 2006.
Address correspondence and reprint requests to Dr. Y. Stern at
Sergievsky Center, 630 W. 168th Street, New York, NY 10032, U.S.A.
cently diagnosed (5). This study’s prospective design and
regular data collection permitted calculation of the cumu-
lative incidence of unprovoked seizures and appraisal of
baseline characteristics of the cohort as predictors of un-
Starting in 1989, 236 subjects were recruited consec-
utively, except for those unwilling to provide informed
consent or living too far from the centers to be seen reg-
ularly in follow-up, from patients seen by Columbia Uni-
versity’s Neurology Department, Johns Hopkins Univer-
sity’s Psychiatry Department, and Massachusetts General
Hospital’s Geriatric Neurobehavioral Center, including
patients who lived at home or in long-term care facili-
ties. These patients were seen by private physicians or
clinic staffs and were or were not enrolled in clinical tri-
als. All patients met diagnostic criteria for probable AD
868J. C. AMATNIEK ET AL.
based on National Institute of Neurological Disorders and
Stroke—Alzheimer’s Disease and Related Disorders As-
were Modified Mini Mental Status (7) score of ≥30 (16
on the standard Mini Mental State Examination); no an-
tipsychotic medication use for ≥1 month; no abnormality
of head magnetic resonance imaging (MRI) or computed
tomography (CT) scan except for atrophy or small, silent
follow-up; and ability to speak English and to retain an
cohol or drug dependency at time of study entry, CNS
infection or non-AD causes of dementia, clinical or his-
toric evidence of cortical stroke, history of schizophrenia
or schizoaffective disorder before the onset of intellectual
decline, or any electroconvulsive treatment sessions dur-
ing the prior 2 years or ≥10 treatment sessions during the
criterion for enrollment in the Predictors Study, but it was
for this analysis.
Data collected at baseline included medical history, de-
ical, functional, and living status (5). An EEG was not
required but was obtained in nearly 60% of the patients
as part of the routine dementia workup before or at the
patients’ clinicians at these three tertiary care institutions,
were not reanalyzed, but laboratory reports were coded
for the analysis based on specific criteria for slow domi-
epileptiform activity. Race was self-defined, and hyper-
tension was determined in a medical interview.
Seizure end point
The questions in the original database addressing the
occurrence of a seizure were as follows: “In the past
6 months, has the patient been diagnosed or treated for
epilepsy or seizures?” and “Has the patient had a seizure
(fit, faint, or funny spell) since the last visit?” Because the
second question could also be interpreted as asking about
syncope or pseudoseizures, an affirmative response was
considered as a possible not probable seizure. To increase
the likelihood of an event’s being an unprovoked seizure,
additional information was culled by reviewing the orig-
inal questionnaires and medical records of subjects with
an affirmative answer to either of the two questions in
any interval, including baseline, for noncoded informa-
tion. After review of all identified charts, each possible
seizure was evaluated for seizure likelihood by two neu-
response to the first question, or an affirmative response
to the second question and a circle around seizure or an
inserted description of the event consistent with unpro-
voked seizure. Chart information was used to clarify re-
considered the most accurate information. Each neurolo-
gist independently evaluated the study charts and medical
records from the date of the event, reaching consensus if
the two opinions varied on seizure likelihood. These were
not classified as a probable seizure.
After exclusion of prevalent cases, a Kaplan–Meier
survival curve was computed to estimate cumulative
incidence of unprovoked seizures. Data were entered at
6-month intervals for events occurring in the previous pe-
riod. Cases were entered at study recruitment. Seizures
were considered an end point. Subjects were withdrawn
at death (seizure free) or at the date of last follow-up.
We did not have a non-AD control group. Age-specific
incidence in 10-year age groups was calculated and com-
pared with age-specific incidence in a referent cohort (8),
resulting in incidence ratios.
Choice of possible predictors of seizures in patients
with AD was based on clinical, laboratory animal, and
with the variables in this study. The potential predictors
evaluated are listed in Table 1.
Each variable was screened by calculating mean t tests
For variables that showed promise, by strength of associ-
ation or by significance, a univariate Cox Proportional
Hazards regression was performed to determine beta, risk
ratio, and 95% confidence interval. We defined a strong
risk ratio as >1.05 or <0.95 per unit increment for con-
tinuous and >2.00 or <0.50 for categoric variables; and
a promising p value as <0.20. Potential interaction was
explored by constructing and testing interaction terms be-
tween two predictor variables. Possible confounding was
evaluated by comparing the univariate estimate for each
variable that passed screening criteria with the beta from
a bivariate model with age, and vice versa. Confounding
promising significance or that were strong in the univari-
and without EEG findings because EEGs were available
for only 136 of the 233 cases, or 58.37%. If a variable was
not included in the model without EEGs, it was not tested
in the model with EEGs.
Epilepsia, Vol. 47, No. 5, 2006
SEIZURES AND ALZHEIMER’S DISEASE869
TABLE 1. Variables studied as possible predictors
Demographic characteristics Education, gender, race, age at study in-
Disease duration Neurologist’s estimation of duration of illness at re-
Severity Modified Mini Mental Status Examination
Physical examination Presence of any positive finding on neurologic
of dementia such as memory loss
Diagnostic tests EEG-focal epileptiform findings,aslow dominant
rhythm,bhead images, and ApoE-4 status
Factors associated with seizures in general populationscConges-
tive heart failure, head trauma with loss of consciousness, hypertension,
autoimmune disorders, systematic malignancies, thyroid disease, drug
abuse, alcohol use, depression, use of antidepressant medications
aCriteria for focal epileptiform activity were mention in the
narrative report: “cases with focal spikes, multifocal spikes of bilateral
bCriteria for slow dominant rhythm were mention of in the narrative
report: “... .8 Hz. or less... . Thus, any record with a background
frequency of 8 Hz. or less should be considered abnormal in this respect.
However, if a range is mentioned with an upper level >8 Hz. (e.g.,
7–8.5 Hz), then this category is considered normal. If recording during
the awake state was inadequate to allow a statement as to dominant
rhythm, then code as unknown. Low-voltage, fast dominant rhythms
are considered normal.”
cBecause data were not available for family history of seizures
and use of specific antihypertensive medications were not in the data
base, these variables were not studied. Stroke was not investigated
as a variable because it was an exclusion criterion for the study, but
small lacunae were investigated in supplemental analyses. Additionally,
chronic renal disease was not studied because of its absence at baseline
in the cohort.
Three subjects reported a history of seizures at the ini-
the remaining 233 subjects with probable AD who were
riod of 5.99 years), in 12, seizures developed, all of which
were unprovoked. No patients were identified with acute
symptomatic seizures. The initial first seizure occurred at
1 year after enrollment. The last incident seizure in this
series occurred at 6.55 years of follow-up. The median
time to first seizure was 4.06 years. The cumulative inci-
dence of seizures was estimated to be 7.75% by 7 years of
follow-up (Fig. 1).
Unprovoked seizure incidence in the total group
was 0.87% (12 incident seizures/1,374 person-years ob-
served). Unprovoked seizure incidences in 10-year age
intervals were 4.26% (two of 47) for ages 50–59 years,
1.55% (four of 258) for ages 60–69 years, 0.57% (three of
527) for ages 70–79 years, and 0.55% (three of 542) for
ages 80+ years. This incidence was higher than expected
in the general population (8). The increase was greatest
for the youngest group of 50 to 59 (IR, 86.66; 95% CI,
80+ (IR, 3.19; 95% CI, 0.95–10.66; p = 0.08) (Fig. 2).
Cumulative seizure frequency
FIG. 1. Cumulative incidence of seizures in Alzheimer disease:
in all races.
Predictors of unprovoked seizures
In univariate regressions, presented in Table 2, younger
age was predictive (RR, 0.92 continuous; 95% CI, 0.82–
0.97; p = 0.01). In addition, we used the univariate analy-
ses to screen for inclusion in the multivariate analyses,
according to the criteria set forth in the Methods sec-
tion. In these regressions, African-American ethnic back-
ground, greater severity (based on MMSE score) at initial
cal epileptiform findings were also predictive of seizures,
study compared to referent
ge, 10 year intervals
in all races.
Epilepsia, Vol. 47, No. 5, 2006
870J. C. AMATNIEK ET AL.
TABLE 2. Cox regression models of seizure predictors in AD: all races
without EEG variables
with EEG variablesUnivariate
Slow dominant rhythm
RR (95% CI)
RR (95% CI)
RR (95% CI)
aIn the reported multivariate models, a variable was included in the model if its risk ratio was strong, as defined
in the Methods section, or the variable confounded age.
whereas a history of hypertension, depression (based on
Hamilton score), and slow dominant EEG rhythm were
A confounder is an independent risk factor for the dis-
ease (unprovoked seizures) but is also associated with
another independent risk factor for the disease. When
evaluating potential confounders with age, which had the
strongest overall effect, we found that race, duration, hy-
duration. Hypertension, which was protective, was less so
severely demented patients was heightened when patients
were younger. Depression increased risk of seizures at
a younger age. These confounders were included in the
multivariate models as appropriate.
In multivariate models, presented in Table 2, the point
estimates maintained univariate directions. For the en-
tire cohort, younger age (RR, 0.89; 95% CI, 0.82–0.97;
p = 0.01), African-American ethnic background (RR,
7.35; 95% CI, 1.42–37.98; p = 0.02), and greater demen-
tia severity (RR, 4.15; 95% CI, 1.06–16.27; p = 0.04)
TABLE 3. Cox regression models of seizure predictors in AD: whites only
without EEG variables
RR (95% CI)
with EEG variables
RR (95% CI)
RR (95% CI)
Focal epileptiform (0 whites with focal
Slow dominant rhythm
1.11 (1.02–1.20)1.11 (1.03–1.20)1.11 (1.00–1.23)
aIn the reported multivariate models, a variable was included in the model if its risk ratio was strong, as defined in the Methods section, or the
variable confounded age.
were predictive of incident seizures (p < 0.05). Education
dropped out of the model.
formed in the subsample who had EEGs (nine incident
seizures in 114 individuals included in the multivariate
model with data for all variables), with similar findings
Focal epileptiform findings were predictive of seizures
(RR, 73.36; 95% CI, 1.75–3075.25; p = 0.02).
The cumulative incidence of seizures in African Amer-
icans was nearly 18% by 7 years. Because the high inci-
dence of unprovoked seizures in African Americans may
have influenced overall results, we looked at whites inde-
pendently. Too few African Americans (15) were in the
group for multivariate modeling.
After excluding the African Americans, the eight His-
panics and one participant who declined to identify her-
self as white, African American, or Hispanic, univariate
regressions were performed for whites alone (10 incident
seizure cases in 209 white subjects). In whites, younger
Epilepsia, Vol. 47, No. 5, 2006
SEIZURES AND ALZHEIMER’S DISEASE871
age was predictive (RR, 1.11; 95% CI, 1.02–1.20; p =
0.01) of unprovoked seizures (Table 3). Factors included
in the overall analysis were evaluated for whites alone.
Most were no longer significant, although the direction of
the effect remained.
in individuals with AD compared with others of the same
age. This supports the notion that seizures can be a part
of the natural history of AD. A recent review and articles
12). In our study, we found the incidence ratios compared
with those in a reference population ranged from 87 to 3,
a minimal estimate, as the reference population included
people with AD (8).
A yearly unprovoked seizure incidence of nearly 1%,
regardless of years from study entry, was also shown. One
should not conclude from this linear relation that seizures
occur during all stages of the disease. Duration of AD
early stages of AD predicted later unprovoked seizures,
Earlier work (2) did not find younger age at AD onset
to be associated with increasing risk of incident seizure,
but these results are not directly comparable because the
whereas we used the survival approach. In this cohort,
it has been shown that younger people have more rapid
disease progression (13). This supports the notion that
unprovoked seizures are associated with younger age at
onset because this group has a more rapid decline.
The racial findings are difficult to interpret because of
data are relevant to AD or seizures in African Americans
the nearly doubled cumulative incidence of unprovoked
seizures in the African-American group is specific to AD,
is reflective of a greater incidence of seizures in elderly
African Americans, or is an artifact of small sample size.
Depression and hypertension have been identified as a
risk factors for unprovoked seizures (15–18). In this anal-
ysis of people with mild-to-moderate AD, neither depres-
sion nor hypertension increased the risk for seizures. The
observation of a protective effect of hypertension against
seizures in AD requires further confirmation.
Because EEGs were not required at study entry, it is
possible that the selection of cases receiving EEGs may
have been biased by undetermined factors. We think that
this is not the case because the other variables remained
similar in models with and without EEG variables. We
conclude that the presence or an absence of an EEG at
baseline simply reflected the clinical practice of the per-
sonal physicians of the subjects enrolled in the Predictors
study, and no selection bias was present. It appears that
an epileptiform EEG is strongly predictive of unprovoked
We chose not to evaluate the cohort for epilepsy (recur-
rent unprovoked seizures) because some patients received
medications after a first seizure. Neither did we evaluate
seizure type because insufficient detail was present in the
data for accurate categorization. Because we reviewed the
study charts and medical records of these seizure patients,
Acknowledgment: We thank Chi-Cheng Yang, Kristen
Mordecai, and Laura Monsmia for help in locating and abstract-
ing from study charts and medical records.
Supported by: federal grants NIA AG07370, NIA RR00645,
NIA AG 08702, NIH 5-RO1-NS32663, and the Taub Center for
Alzheimer’s Disease Research.
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