The authors' preferred hypothesis to explain the rapid clinical improvement observed centers on the emerging evidence, which suggests that TNF-alpha is of critical importance 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 and molecular 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
4. Evidence suggesting that TNF-alpha regulates synaptic transmission in the brain[33
5. Evidence suggesting that TNF-alpha mediates the synaptic dysfunction underlying cognitive and behavioral impairment produced by both beta-amyloid and beta-amyloid oligomers [36
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 was noted 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 score of seven to a score of 15, is notable because it exceeds the normal test-retest variation (0.9+/-2.5 points[44
]) by more than three standard deviations. The MOCA was designed 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 ].
Improved verbal fluency, as suggested by this patient's improvement in category naming, animal naming, and Boston 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 the authors. 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 the authors' now more than three year clinical experience utilizing perispinal etanercept for treatment of probable Alzheimer's disease[20
]. The rapid response to perispinal etanercept may provide an important clue to the pathophysiologic 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 and anterior cingulate function allowing recall of appropriate and relevant past, present, and future deeds, assigning emotional valence to them and comparing them to the present 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 is poorly reflected in most standard screening psychometrics. Multiple authors have commented on patients with frontal lobe deficits that perform well on most standardized psychometric tests but have incapacitating disability to function in a real, complex life environment [47
]. The screening of isolated cognitive domains without screening for executive dysfunction, by simple tests such as 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 of the 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. The Montreal Cognitive Assessment has several screens for executive dysfunction, including a modified Trails B (alternating trail making task) [see Figure ] 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 of intense current interest [34
]. The rapid clinical improvement which is characteristic of Alzheimer patients treated with perispinal etanercept and which is described herein provides a new clue for investigating these mechanisms. One suspects that this rapid clinical effect is related to the role of TNF-alpha as a regulator of synaptic mechanisms in the brain, which was first described more than a decade ago[52
]. Glia are now known to envelop neuronal synapses in the brain and release molecules, gliotransmitters, which regulate synaptic transmission in those enveloped synapses[42
]. TNF-alpha is one of only a handful of recognized gliotransmitters[33
]. 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
]. TNF-alpha released by glia, has been demonstrated to control synaptic strength[33
Synaptic scaling has been suggested to be centrally involved in the synaptic dysfunction occurring in Alzheimer's disease[30
]. Synaptic scaling involves uniform adjustments in the strength of all synaptic connections for a neuron in response to changes in the neuron's electrical activity[34
]. Synaptic scaling is a homeostatic mechanism which is necessary for the optimal functioning of neural networks [34
]. Synaptic scaling has been demonstrated to be regulated by glial TNF-alpha[34
]. These experimental findings, together with the rapid effects of perispinal etanercept shown here, converge to suggest that synaptic dysregulation produced by excess TNF-alpha [5
] contributes to cognitive 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.
One may therefore extrapolate from these findings and theorize how perispinal etanercept might have rapid widespread effects.
The authors hypothesize that excess TNF-alpha in Alzheimer's disease[5
] interferes with the synaptic regulatory functions of TNF-alpha. When TNF-alpha is in a normal physiologic range synaptic scaling is enabled, thereby preserving optimal functioning of the brain'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
]. The rapid effects of perispinal etanercept are hypothesized to be the result of rapid neutralization of excess 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 TNF-alpha modulation of synaptic function, has been observed with respect to interleukin-1(IL-1) regulation of long-term potentiation in hippocampal slices[59
]. This data 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-alpha remain 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
], now for a period exceeding three years, suggest that maintenance anti-TNF-alpha treatment may have prolonged beneficial effects. It is hoped that future studies may clarify if maintenance perispinal 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 the neurologic equivalent of Koch's postulates [60
] with respect to being an important component of the pathophysiology of Alzheimer's disease, in that scientific evidence of the following has been published:
1. Excess TNF-alpha, at a level 25 times higher than controls, has been documented in the cerebrospinal fluid of patients with Alzheimer's disease(AD); and elevated CSF TNF-alpha correlated with progression from mild cognitive impairment to AD [7
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 of AD onset [10
3. Increased spontaneous production of TNF-alpha by peripheral blood mononuclear cells was associated with increased AD risk in a population of patients followed as part of the Framingham study[23
4. Multiple basic science studies suggest the involvement of TNF-alpha in neuroinflammatory mechanisms which may contribute to AD pathogenesis [5
5. TNF-alpha is a gliotransmitter[33
6. Glial TNF-alpha may regulate synaptic mechanisms involving synaptic function in neural networks[33
7. Disruption of memory mechanisms by beta-amyloid and beta-amyloid oligomers is mediated by TNF-alpha [36
8. Pilot evidence supporting the efficacy of anatomically targeted[27
] anti-TNF-alpha treatment for Alzheimer's disease has recently been published[20
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 the reversible 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.