Journal of Neuroinflammation

BioMed Central

Case report

Open Access

Rapid cognitive improvement in Alzheimer's disease following
perispinal etanercept administration
Edward L Tobinick*1,2 and Hyman Gross1,2
Address: 1Department of Medicine, Institute for Neurological Research, a private medical group, inc., Los Angeles, USA and 2Department of
Neurology, USC School of Medicine, Los Angeles, USA
Email: Edward L Tobinick* - etmd@ucla.edu; Hyman Gross - hymangross@yahoo.com* Corresponding author

Published: 9 January 2008
Journal of Neuroinflammation 2008, 5:2

doi:10.1186/1742-2094-5-2

Received: 29 November 2007
Accepted: 9 January 2008

This article is available from: http://www.jneuroinflammation.com/content/5/1/2© 2008 Tobinick and Gross; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Substantial basic science and clinical evidence suggests that excess tumor necrosis factor-alpha(TNF-alpha) is centrally involved in the pathogenesis of Alzheimer's disease. In addition to its proinflammatory functions, TNF-alpha has recently been recognized to be a gliotransmitter that
regulates synaptic function in neural networks. TNF-alpha has also recently been shown to mediate
the disruption in synaptic memory mechanisms, which is caused by beta-amyloid and beta-amyloid
oligomers. The efficacy of etanercept, a biologic antagonist of TNF-alpha, delivered by perispinal
administration, for treatment of Alzheimer's disease over a period of six months has beenpreviously reported in a pilot study. This report details rapid cognitive improvement, beginningwithin minutes, using this same anti-TNF treatment modality, in a patient with late-onset
Alzheimer's disease. Rapid cognitive improvement following perispinal etanercept may be related
to amelioration of the effects of excess TNF-alpha on synaptic mechanisms in Alzheimer's disease
and provides a promising area for additional investigation and therapeutic intervention.

Background
Neuroinflammation with overexpression of cytokines is astandard characteristic of the brain pathology present in
Alzheimer's disease [1-4]. Involvement of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha)in the pathogenesis of Alzheimer's disease has long beensuspected [5-9]. Increasing basic science, genetic, and clinical evidence now supports the concept that excess TNFalpha plays a central role in Alzheimer's disease [5-25].
In 1998 etanercept, a potent anti-TNF therapeutic, wasapproved for human use, with rheumatoid arthritis as theinitial indication. Etanercept is a recombinant dimeric
fusion protein consisting of the extracellular ligand-binding portions of two human p75 TNF-alpha receptors
linked to the Fc fragment of human IgG1. Etanercept

binds to TNF-alpha and blocks its interaction with cellsurface TNF-alpha receptors, thereby reducing the biologic effect of excess TNF-alpha. The medical community
now has more than 1 million patient-years of experience
using etanercept for treatment of a variety of inflammatory disorders in which TNF-alpha has been postulated toplay a role [26].
In 2006 the present authors published a pilot study which
provided proof-of-concept that a novel method of administration of etanercept was efficacious for the treatment of
Alzheimer's disease [20]. This novel method, perispinal
extrathecal administration in the posterior neck, washypothesized to improve delivery of etanercept to thebrain via the cerebrospinal venous system[21,27]. In an
open-label study of 15 patients treated weekly for a period
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of six months, perispinal extrathecal administration ofetanercept led to sustained cognitive improvement in thiscohort of patients with probable Alzheimer's disease ranging in severity from mild to severe [20]. The concept of
TNF-alpha-inhibition for the treatment of Alzheimer's
disease has been recently reviewed[22], and is supported
by additional recent publications [16,18,23-25].
The author's 2006 pilot study was an IRB-approved clinical trial whose protocol included monthly cognitive testing. There was no provision for testing at shorter intervals.
Nevertheless during the six-month duration of this clinical trial, and now for a period of more than three years,
the authors have noted an unexpected and largely unprecedented clinical phenomenon, which they have observed
on a weekly basis in the majority of the patients treated.
This unexpected, but repeatedly observed phenomenon
was a noticeable clinical improvement within minutes of
perispinal etanercept administration[21]. Although this
rapid clinical improvement could not be measured using
the assessment intervals which were included in the original clinical trial protocol, the authors recently had theopportunity to quantitate this rapid treatment effect using
several standardized cognitive tests in a new patient
treated as part of their standard practice of medicine. Thispatient is the subject of the present case report.
Synaptic dysfunction has gained increasing recognition as
an important pathophysiological component of Alzheimer's disease [28-32]. Recent evidence suggests that TNFalpha may be involved in this synaptic dysfunction [3337]. Although TNF-alpha is most widely known as a proinflammatory cytokine, basic science studies suggest that
TNF-alpha may also have entirely different functions in
the Alzheimer brain: as a regulator of synaptic transmission; and as a mediator of β-amyloid and β-amyloid oligomer disruption of memory mechanisms [33-37].
The present report details the clinical observations in thispatient with late-onset Alzheimer's disease. It thenattempts to provide a theoretical framework to explore thepathophysiological mechanisms underlying the rapid
improvement in the patient's behavior and cognition, particularly those involving TNF-alpha and synaptic function, which may account for the rapid clinical effects
observed after perispinal etanercept administration.

Case presentation
History of present illness
The patient is an 81 y.o. physician who was referred in
October 2007 for consideration of perispinal etanercept
treatment by his internist. The patient had been in good
general health until about two years before presentation,
at which time his wife noted progressive memory difficulties and difficulties with mathematical calculation.

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His wife took over check writing, and the patient was evaluated by a neurologist 18 months ago. Donepezil was prescribed but was not tolerated and was discontinued after
four months. Memantine and rivastigmine were prescribed but also were not tolerated by the patient. Galantamine was begun six months prior to presentation, andcontinued to the present at a dose of 8 mg per day,reduced from a maximum attempted dose of 16 mg per
day due to side effects. No beneficial effect from the galantamine has been noted by the patient's family or his primary care physician.
The patient's current medications include atorvastatin,
low dose aspirin, and galantamine 8 mg per day.
Past medical history
The patient's past medical history include a lumbar discectomy and fusion performed twenty years previously, withchronic intermittent low back pain and spinal stenosis;
hypercholesterolemia; and localized prostate cancer, successfully treated with localized radiation without sign ofrecurrence. Otherwise the past medical history was unremarkable, with no history of diabetes, stroke, transientischemic attack, head trauma, epilepsy, loss of consciousness, hallucinations, recent infection, demyelinating disease, or blood or bleeding disorders, lymphoma,
congestive heart failure, autoimmune disease, immunosuppression, tuberculosis or visual disturbance. Purified
protein derivative testing was negative. Family history ofdementia or neurodegenerative disease was negative.
Physical examination
General physical exam was unremarkable. Blood pressure
was 150/90, pulse 80 and regular, afebrile, respirations
12. The chest was clear to percussion and auscultation.
There were no cardiac murmurs and no bruits in the neck.
Neurologic examination one day prior to etanercept
treatment
The results of neurological examination by author HG
one day prior to etanercept administration were as follows:

The cranial nerve examination II-XII was within normal
limits: the pupils were four mm, round, and reactive tolight and accommodation. The discs were flat. The visual
fields were full to confrontation; extraocular movements
were conjugate and full without nystagmus. Facial motion
and sensation were symmetrical and without deficits. The
patient was able to hear finger rustling in both ears, however his auditory processing appeared to be decreased,
and he intermittently asked for questions to be repeated.
Weber was midline, air conduction was greater than bone
conduction bilaterally, palate was normal, sternocleidomastoid strength was normal, trapezius strength was nor-Page 2 of 10(page number not for citation purposes)

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mal, and tongue movements were normal. Tremor wasabsent.
Motor and cerebellar examination was unremarkable.
Deep tendon reflexes were as follows: biceps two plus andsymmetrical, triceps one plus and symmetrical, supinatoron the right absent, on the left one plus, quadriceps one
plus bilaterally, ankles absent on the right and one plus
on the left. Toe signs were flexor. There is no pronatordrift, abnormal involuntary movement, or Romberg.
There was symmetrical muscle tone, bulk, and development throughout. There was normal station and gait, andnormal rapid alternating movement, normal finger to finger, and normal gait. There were no frontal release signs
except for a positive bilateral palmomental sign.
Sensory examination responses were intact throughout tojoint position, pinprick, and light touch. There was mild
decrease in vibratory sense in the right hallux only.
Mental status examination performed one day prior toetanercept administration revealed a dignified appearing
man who appeared younger than his stated age, neatly
groomed and socially outgoing in a superficial engaging
fashion. There was no agitation, suspiciousness, or hostility. He appeared at times to be inappropriately euphoric.
He had difficulty recalling personal autobiographicalinformation such as birthday or his father's occupation.
He could not recall the names of any of the physicians
who treated him. He was not oriented to the calendar
date, day of the week, year, place, city, or state.
His spontaneous speech appeared fluent with normal
prosody, articulation, and rate of speech production without any dysarthria. On detailed examination he hadmarked anomic aphasia, i.e., when shown the first ten pictures of the Boston Naming Test[38] the patient could notname nine out of ten, but used marked circumlocution.
He was able to repeat complex sentences without difficulty. On a verbal fluency task, i.e., when asked to list allof the words that start with the letter F in 60 seconds helisted five words with five perseveratory responses andone neologism. When given a semantic task, i.e. asked tolist all the animals he could in 60 seconds he could only
list two, dog and cat.
The patient was able to copy a three-dimensional cube,
but when asked to draw a clock with the hands placed at
ten minutes after 11, he drew a square without numbers
and one line for the hour or minute hand [see Figure 1].
He could not do the alternating trail making task and wasclearly overwhelmed by the task [see Figure 1]. He wasable to pantomime four out of eight finger constructionsof increasing complexity.

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On memory testing the patient could not recall the nameof physician HG after 90 seconds despite repetitive introductions on at least four occasions throughout the examination. It took three trials for the patient to register fivewords and 90 seconds later the patient could not retrieve
any of the words even with categorical cueing. When given
multiple choice cueing he was able to retrieve two words.
On an A vigilance task, screening for sustained attention,
the patient made four errors of omission. He was able tolist five digits in a forward fashion, but could not list three
digits in a reverse fashion.
The patient could not perform simple calculations andcould not do serial sevens. When asked to add 29 plus 11
after a marked latency he said 31.
Abstract concepts such as a how a train and a bicycle, awatch and a ruler, or music and painting were similar
could not be expressed by the patient.
On the Montreal Cognitive Assessment test (MOCA) [39]the patient scored seven out of 30 possible points, consistent with a moderate to severe cortical dementia.
The patient met the NINCDS-ADRDA Criteria for probable AD[40], and, in addition, met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition(DSM-IV) criteria for AD[41].
Laboratory results
MRI examination in March 2006 showed age-related diffuse central and cortical atrophy. In November 2006 FDG
positron emission tomography brain scan at UCLA
showed moderate to severe cortical atrophy, with atrophyassociated global cortical hypometabolism and superimposed biparietal, left temporal and posterior cingulate
cortex hypometabolism, read as consistent with Alzheimer's disease.

Laboratory examination prior to treatment revealed a stable but borderline elevated blood urea nitrogen and creatinine, but was otherwise unremarkable, including chest xray which was unremarkable, normal thyroid function,
normal liver function tests, normal complete bloodcount, normal serum glucose and electrolytes, normal
prostate specific antigen, cholesterol, triglycerides, serum
folic acid and vitamin B12 levels, non-reactive RPR andnon-reactive FTA-ABS.
Treatment
Written informed consent for administration of etanercept was obtained from the patient and his wife after the
potential risks of etanercept, including infection, cytopenias, possible increased risk of lymphoma and demyeli-

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FigureRapid
treal
Cognitive
and1 sustained
Assessment
improvement in Visuospatial/Executive function following perispinal etanercept documented by the MonRapid and sustained improvement in Visuospatial/Executive function following perispinal etanercept documented by the Montreal Cognitive Assessment. The top panel depicts the first three tasks from the Montreal Cognitive
Assessment completed by the patient one day prior to perispinal etanercept administration. The middle panel depicts thepatient's results two hours after perispinal etanercept administration, showing correct completion of the alternating trail making task documenting improved executive function, and improvement in depiction of a clock face. The bottom panel depicts thepatient's results at seven weeks, fourteen days after receiving his previous dose of perispinal etanercept, showing further
improvement in his drawing of the clock face, with numerals added, and persistence in improvement in completion of the trail
making task. (The instruction for completion of the alternating trail making task are as follows: Please draw a line, going from anumber to a letter in ascending order. Begin here [point to (1)] and draw a line from 1 then to A then to 2 and so on. End here [pointto (E)]).

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nating disease, death, eye inflammation, and congestive
heart failure; and alternative treatment approaches wereenumerated.
Immediately prior to etanercept administration thepatient was questioned by author ET. He could not state
the year nor could he name the state.
Twenty-five mg of etanercept in 1 cc of sterile water wasadministered by posterior cervical interspinous injectionin the midline with a 27 gauge needle at the C6–7 interspace followed by Trendelenburg positioning with thehead dependent for five minutes, as previously described,
to effect entry of etanercept into the cerebrospinal venous
system[21,27]. The patient had no difficulty with thispositioning and resumed sitting posture without incident.
Ten minutes after dosing the patient was reexamined. He
was noticeably calmer, less frustrated, and more attentive.
He was able to correctly identify the state as California,
and he identified the year as 2006. His responses to questioning seemed less effortful and more rapid, with lesslatency. He left for author HG's office for further testing.
Neurologic examination two hours after etanercept
treatment
The patient was retested by author HG two hours after
etanercept administration. He could not recall being inauthor ET's office earlier in the day, but could recall HG'sname. He was now oriented to month, day of week, andplace, and could again correctly name the state as California, which he could not do prior to perispinal etanercept
administration. He was off on the calendar date by twodays, and year by one year. Throughout testing heappeared more aware of his deficient performance.

The patient's ability to name pictures was markedly
improved, correctly naming nine out of the first ten pictures on the Boston Naming Test short form, requiring
phonemic cueing for three of the items (squid, bench, andhammock), a marked improvement from the day priorwhen he could only name one of the ten presented pictures and used marked circumlocution. On the verbal fluency FAS test he was able to list eight words that started
with the letter F in 60 seconds and made only one perseveratory response. On a categories semantic task he wasable to list five animals in 60 seconds.
On visuospatial functioning, the patient could copy athree-dimensional cube, and when asked to draw a clock
he drew a circle with an hour and minute hand [see Figure1]. When given a modified trails B test the patient was
clearly able to sequence and complete the task, alternating
letters and numbers accurately [see Figure 1]. He was able

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to pantomime seven out of eight finger constructions ofincreasing complexity.
On memory testing the patient could not recall any of fivememoranda after five minutes even with categorical cueing. With multiple-choice cueing he could recall one outof five memoranda. However, as mentioned he could
recall the examiner's name without difficulty and without
necessity of repetition of introductions throughout theentire examination.
On attentional testing, the patient could accurately list
five digits in a forward fashion and three digits in a reverse
sequence fashion. On an A vigilance task he made noerrors of omission or commission.
On calculations, he could subtract seven from one hundred correctly, but could not perform serial sevens. He
could not divide 58 by two, nor could he add 29 plus 11.
He could not tell physician HG how many nickels were ina dollar.
On ability to abstract concepts he was able to relate how a
train and bicycle were similar in that they both can beused for transportation. When asked how a watch and aruler were similar he related that they both give information. When asked how music and painting were similar herelated "you draw your painting, however music you
hear".
Montreal Cognitive Assessment performed two hours following the single dose of perispinal etanercept yielded ascore of 15 out of 30 points [see Figure 1].
A collateral interview with the patient's son and wife confirmed their validation of a marked improvement in cognitive
abilities
following perispinal etanercept
administration.
Upon returning to the clinic one week following perispinal etanercept administration for his weekly dose thepatient's wife and son confirmed that he had remained
markedly clinically improved throughout the week, a factwhich was remarked upon by the family [see Additional
file 1]. He was noticed to be less reluctant to join in conversation. On re-examination by author ET prior to repeat
dosing one week after the initial dose, the patient correctly
identified the year, month, season, day of week and state.
He appeared to answer with less frustration, and theexaminer's impression was that there was reduced latencyof response, and his affect seemed improved. On the FAS
test for verbal fluency when asked to list all of the words
that start with the letter F in 60 seconds he listed 8 words,
and named 5 animals in 60 seconds. The patient received
a single dose of perispinal etanercept for each of the first

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five weeks; the next dose was omitted, and the patient
returned after seven weeks and was retested. At sevenweeks, fourteen days after receiving his last dose of perispinal etanercept, his Montreal Cognitive Assessment score
was 14, with persistent improvement in the trail making
task, and improved depiction of the clock face [see Figure
1].

Discussion
The authors' preferred hypothesis to explain the rapid
clinical improvement observed centers on the emerging
evidence, which suggests that TNF-alpha is of criticalimportance in the regulation of synaptic transmission in
the brain. The authors are led in this direction by the combination of:
1. The extreme rapidity of the effect;
2. The extraordinary potency and selectivity of etanercept
as an anti-TNF-alpha agent, due to its biologic nature andmolecular structure;
3. The various lines of scientific evidence which have suggested that synaptic dysfunction may be of key importance in the pathogenesis of Alzheimer's disease [28-32];
4. Evidence suggesting that TNF-alpha regulates synaptictransmission in the brain[33-35,42,43]; and,5. Evidence suggesting that TNF-alpha mediates the synaptic dysfunction underlying cognitive and behavioral
impairment produced by both beta-amyloid and betaamyloid oligomers [36,37].
A weakness of the present study is the fact that all participants, including the examining physicians, were aware of
the treatment modality utilized, which could, potentially,
bias the results, and a placebo effect cannot be ruled out.
However, it should be noted that the clinical, cognitive,
and behavioral improvement in the present patient wasnoted by the patient's family members, family friends,
and both authors, and confirmed by the use of several
objective measures.
The eight point improvement on the MOCA, from a scoreof seven to a score of 15, is notable because it exceeds thenormal test-retest variation (0.9+/-2.5 points[44]) by
more than three standard deviations. The MOCA wasdesigned to measure eight cognitive domains, and is particularly sensitive to changes in executive function[44].
This is illustrated by the patient's results on the trail-making portion of the test, as well as in depicting a clock face[see Figure 1].

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Improved verbal fluency, as suggested by this patient's
improvement in category naming, animal naming, andBoston Naming results, is a characteristic effect of perispinal etanercept, in the authors' experience. This has been
particularly noticeable in patients with probable Alzheimer's disease, such as the present patient, who present
with difficulties in word finding, which has included one
patient with primary progressive aphasia treated by theauthors. Improved behavior, and improvement in affect,as seen in this patient, is another characteristic effect of
perispinal etanercept in the authors' experience.
It should also be emphasized that rapid cognitive
improvement following perispinal etanercept is not limited to the patient of the present report, but has, in fact,
been commonly observed in multiple patients during theauthors' now more than three year clinical experience utilizing perispinal etanercept for treatment of probable
Alzheimer's disease[20,21]. The rapid response to perispinal etanercept may provide an important clue to thepathophysiologic mechanisms underlying not only
Alzheimer's disease, but also other brain disorders involving excess TNF-alpha and cognitive dysfunction, including frontotemporal dementia[45], and traumatic brain
injury [46].
Complex problem solving requires intact pre-frontal andanterior cingulate function allowing recall of appropriate
and relevant past, present, and future deeds, assigningemotional valence to them and comparing them to thepresent situation to manage an anticipated sequence of
events in a flexible and goal-oriented fashion. Prefrontal
neuropathological change of diverse etiologies, including
Alzheimer's disease interferes with such complex functions. The assessment of such executive dysfunction ispoorly reflected in most standard screening psychometrics. Multiple authors have commented on patients withfrontal lobe deficits that perform well on most standardized psychometric tests but have incapacitating disability
to function in a real, complex life environment [47,48].
The screening of isolated cognitive domains without
screening for executive dysfunction, by simple tests suchas the Mini-Mental Status Examination or Cognitive Abilities Screening Instrument, can easily miss critical deficits
in executive functioning in patients with involvement of
the anterior cingulate and pre-frontal lobes.
Executive dysfunction is one of the chief components ofthe final common pathway of disabilities in Alzheimer's
disease that appear to rapidly improve with perispinal
etanercept as documented above. Without quantifying
executive function, a clinician or family observation of an
improvement in a patient's ability or behavior may
improperly be discounted as a subjective interpretation.
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executive dysfunction, including a modified Trails B(alternating trail making task) [see Figure 1] that reflect
the quantum improvement noted in the present patient,
thereby objectifying the patient's family and clinicians'
subjective impressions.
Innate immune regulation of brain function is an area ofintense current interest [34,42,43,49-51]. The rapid clinical improvement which is characteristic of Alzheimer
patients treated with perispinal etanercept and which is
described herein provides a new clue for investigatingthese mechanisms. One suspects that this rapid clinicaleffect is related to the role of TNF-alpha as a regulator ofsynaptic mechanisms in the brain, which was firstdescribed more than a decade ago[52]. Glia are now
known to envelop neuronal synapses in the brain andrelease molecules, gliotransmitters, which regulate synaptic transmission in those enveloped synapses[42,50].
TNF-alpha is one of only a handful of recognized gliotransmitters[33,34,42,50]. In experimental models,
TNF-alpha alters synaptic transmission in rat hippocampal slices, and produces a rapid exocytosis of AMPA receptors in hippocampal pyramidal cells [35,52]. TNF-alphareleased by glia, has been demonstrated to control synaptic strength[33,34,53,54].
Synaptic scaling has been suggested to be centrally
involved in the synaptic dysfunction occurring in Alzheimer's disease[30,55]. Synaptic scaling involves uniform
adjustments in the strength of all synaptic connections fora neuron in response to changes in the neuron's electricalactivity[34,53,54]. Synaptic scaling is a homeostaticmechanism which is necessary for the optimal functioning of neural networks [34,53,54]. Synaptic scaling has
been demonstrated to be regulated by glial TNFalpha[34]. These experimental findings, together with therapid effects of perispinal etanercept shown here, converge to suggest that synaptic dysregulation produced byexcess TNF-alpha [5,7-10,12,14,16,18,23] contributes tocognitive and behavioral dysfunction in Alzheimer's disease. Furthermore, our findings suggest that this synaptic
dysfunction may, at least in part, be reversible with anatomically targeted anti-TNF-alpha treatment.
Of relevance to the present report is recent evidence that
stimulation of a single neuron can cause a change in an
animal's behavior[56]. This may be possible because of
the massively interconnected nature of the brain: a single
cortical pyramidal cell connects to several thousand postsynaptic neurons[56]. In addition, the processes of one
astrocyte may make contact with over 100,000 synapses[50]. Processes affecting glial-neuronal interaction may
therefore have potential for rapid amplification of their
cognitive and behavioral effect.

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One may therefore extrapolate from these findings andtheorize how perispinal etanercept might have rapid
widespread effects.
The authors hypothesize that excess TNF-alpha in Alzheimer's disease[5,7-10,12,14,16,18,23] interferes with thesynaptic regulatory functions of TNF-alpha. When TNFalpha is in a normal physiologic range synaptic scaling isenabled, thereby preserving optimal functioning of thebrain's neural network. When TNF-alpha is overexpressed,
due to glial activation, it is postulated that the synaptic
regulatory activities of TNF-alpha are disturbed. Synaptic
dysfunction is hypothesized to result from this dysregulation, which may provide a basis for reduced functional
connectivity between brain regions in Alzheimer's disease[57,58]. The rapid effects of perispinal etanercept are
hypothesized to be the result of rapid neutralization ofexcess TNF-alpha, which thereby ameliorates this synaptic
dysregulation, allowing normal cross talk between different regions of the brain.
A cytokine concentration-dependent duality of physiologic effect, which the authors hypothesize occurs in TNFalpha modulation of synaptic function, has been
observed with respect to interleukin-1(IL-1) regulation of
long-term potentiation in hippocampal slices[59]. Thisdata suggests that IL-1 is required for LTP under physiological conditions, but at higher doses, as may be encountered in certain pathological conditions, IL-1 inhibits
LTP[59]. The authors suggest that a similar duality occurs
with respect to TNF-alpha in Alzheimer's disease.
It is speculated, on the basis of the clinical results
observed and the studies cited above, that optimal synaptic function in the human brain requires that TNF-alpharemain within a physiologic range; perhaps analogous to
the necessity to maintain serum calcium in a narrow physiologic range to preserve optimal neuronal function. The
positive clinical effects the authors have observed using
perispinal etanercept for chronic treatment of Alzheimer's
disease on an open-label basis [20,21], now for a period
exceeding three years, suggest that maintenance anti-TNFalpha treatment may have prolonged beneficial effects. It
is hoped that future studies may clarify if maintenanceperispinal etanercept treatment will help to maintain or
restore TNF-alpha homeostasis in the brain and/or cerebrospinal fluid in patients with Alzheimer's disease.
Excess TNF-alpha now appears to preliminarily satisfy theneurologic equivalent of Koch's postulates [60] withrespect to being an important component of the pathophysiology of Alzheimer's disease, in that scientific evidence of the following has been published:

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1. Excess TNF-alpha, at a level 25 times higher than controls, has been documented in the cerebrospinal fluid ofpatients with Alzheimer's disease(AD); and elevated CSF
TNF-alpha correlated with progression from mild cognitive impairment to AD [7-9];

HG: Hyman Gross, MD;

2. Examination of TNF-alpha polymorphisms in population studies has provided evidence that genetic polymorphisms associated with increased TNF-alpha production
are associated with increased AD risk and decreased age ofAD onset [10,16,18];

PET: Positron emission tomography;

3. Increased spontaneous production of TNF-alpha byperipheral blood mononuclear cells was associated withincreased AD risk in a population of patients followed aspart of the Framingham study[23];

ET: Edward Tobinick, MD;
MRI: Magnetic resonance imaging;

FDG: Fluorodeoxyglucose.
NINCDS-ADRDA: National Institute of NeurologicalCommunicative Disorders and Stroke-Alzheimer's disease
and Related Disorders Association;
MOCA: Montreal Cognitive Assessment;
IL-1: Interleukin-1;

4. Multiple basic science studies suggest the involvementof TNF-alpha in neuroinflammatory mechanisms whichmay
contributetoAD
pathogenesis[5,6,11,15,17,19,24,25,33-37,51,61-72];
5. TNF-alpha is a gliotransmitter[33-35,42,50,51];
6. Glial TNF-alpha may regulate synaptic mechanisms
involving synaptic function in neural networks[33-35,5054];
7. Disruption of memory mechanisms by beta-amyloid
and beta-amyloid oligomers is mediated by TNF-alpha[36,37]; andLTP: Long-term potentiation.

Competing interests
Author Hyman Gross MD has no competing interests.
Author Edward Tobinick owns stock in Amgen, the manufacturer of etanercept, and has multiple issued and pending patents, assigned to TACT IP LLC, which describe theparenteral and perispinal use of etanercept for the treatment of Alzheimer's disease and other neurological disorders, including, but not limited to, U.S. patents 6015557,
6177077, 6419934, 6419944, 6537549, 6982089,
7214658 and Australian patent 758523.

Authors' contributions
8. Pilot evidence supporting the efficacy of anatomicallytargeted[27] anti-TNF-alpha treatment for Alzheimer's
disease has recently been published[20,21].
The case presented here provides clinical evidence of a
rapidly reversible, TNF-alpha-related component to the
cognitive dysfunction present in Alzheimer's disease. This
reversible mechanism necessarily precedes irreversible
neuronal structural damage, somewhat analogous to thereversible ischemic penumbra that surrounds cerebrovascular infarction. The rapid treatment response is consistent with emerging evidence suggesting that glial-derived
TNF-alpha may regulate brain synaptic mechanisms.
These mechanisms are worthy of further investigation,and may lead to earlier therapeutic intervention which
may have the potential to favorably affect the natural history of Alzheimer's disease.

Both authors take full responsibility for the entire content
of the article, and give approval for the final submitted
version of the article; Edward Tobinick was the principal
author. Hyman Gross performed the neurological examinations before and after perispinal etanercept treatment,
contributed to the discussion section, and reviewed theentire manuscript.

Additional material
Additional file 1
Quicktime movie. video depicting family's description of change in patient
following perispinal etanercept treatment.
Click here for file
[http://www.biomedcentral.com/content/supplementary/17422094-5-2-S1.mov]

Abbreviations
TNF-alpha: Tumor necrosis factor-alpha;Acknowledgements

AD: Alzheimer's disease;

There were no outside funding sources. The authors wish to thank thepatient's family members who have generously agreed to allow their videotaped comments to accompany the publication of this article.

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