Perispinal Etanercept Produces Rapid Improvement in Primary Progressive Aphasia: Identification of a Novel, Rapidly Reversible TNF-Mediated Pathophysiologic Mechanism

Abstract

Primary progressive aphasia (PPA) is an uncommon form of progressive dementia for which there exists no established treatment. The underlying pathology may be that of either frontotemporal dementia or Alzheimer's disease. Increasing evidence suggests that excess tumor necrosis factor (TNF) may play a central role in Alzheimer's disease. Additionally, excess TNF has been documented in patients with frontotemporal dementia. Excess TNF may therefore represent a therapeutic target in PPA. Etanercept, an anti-TNF fusion protein, binds to TNF, thereby reducing its biologic effect. Emerging evidence suggests that perispinal administration of etanercept may have therapeutic efficacy for Alzheimer's disease. This evidence, in combination, supports a rationale for the use of perispinal etanercept for the treatment of PPA. This report documents rapid improvement in verbal abilities, beginning within 20 minutes of perispinal etanercept, in a patient with severe PPA. With repeated weekly dosing, sustained improvement at 1 month is documented, with a more than 10-point improvement in the patient's abilities to perform activities of daily living as measured by a standardized instrument, the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory. Rapid clinical improvement in PPA following perispinal etanercept administration may be related to TNF's role as a gliotransmitter and modulator of synaptic communication in the brain. These results may provide insight into the basic pathophysiologic mechanisms underlying PPA and related forms of dementia and suggest the existence of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in both PPA and Alzheimer's disease. Further study of this therapeutic method is indicated.

Introduction

Primary progressive aphasia (PPA) is an uncommon form of progressive dementia without established treatment. One third of these patients have underlying Alzheimer's disease pathology, and two thirds have pathology characteristic of frontotemporal dementia.[1] These patients characteristically present with progressive difficulty with language as the most prominent initial manifestation of the disease, which advances in an unrelenting fashion until all language abilities are lost.[2] No effective treatment has been established.[1,2]

Basic science and genetic, epidemiologic, and clinical evidence suggest that excess tumor necrosis factor-alpha (TNF-alpha) may play a central role in the pathogenesis of Alzheimer's disease.[3–23] In addition, excess TNF has been documented in the cerebrospinal fluid of patients with frontotemporal dementia.[24] Excess TNF may, therefore, represent a therapeutic target in PPA. Etanercept, a recombinant dimeric anti-TNF fusion protein, binds to TNF and blocks its interaction with cell-surface TNF receptors, thereby reducing the biologic effect of excess TNF. Emerging evidence suggests that perispinal administration of etanercept may have therapeutic efficacy in Alzheimer's disease.[25–29] This evidence, in combination, supports a rationale for the use of perispinal etanercept for the treatment of PPA.

Case Report

The patient is a 78-year-old right-handed woman who began having difficulty finding words 5 years before this presentation. In 2001, while she was playing bridge, she experienced a transient event during which she was speaking incoherently; this resolved after a few minutes. The subsequent word-finding difficulty had an insidious onset but became increasingly severe and later was accompanied by difficulties with pronunciation, followed by difficulties with language comprehension. Her memory for the first 2 years seemed preserved, as were her activities of daily living. The patient had a history of poor spelling, but denied any head trauma or other neurologic disorder except for a remote history of migraine headaches.

In January 2004, neuropsychological testing revealed deficiencies in sustained attention, processing speed, visual delayed recall, verbal fluency, verbal abstract reasoning, and judgment suggestive of moderate executive dysfunction. In October 2004 her Mini-mental State Examination (MMSE)[30] score was 26/30 and neuropsychological testing revealed inattention and halting speech, word-retrieval difficulty, and reduced verbal fluency. In January 2005 she was still driving and playing bridge, but her word-finding difficulties had become severe, and she was diagnosed with primary progressive aphasia. At that time, her neurologic examination was most remarkable for nonfluent aphasia, with multiple word-finding pauses but no dysarthria. She had difficulty with verbal fluency, repetition of complex phrases, execution of multistep commands, and spelling of irregular words. Her Western Aphasia Battery[31] score (Aphasia Quotient) was 88, consistent with a mild, nonfluent aphasia. Her MMSE score was 25/30. Verbal fluency testing documented 6 words beginning with “A” in 60 seconds, and naming was preserved. Comprehension seemed to be excellent, with no difficulty with simple arithmetic. Cranial nerves were intact except for slight hearing loss on the left. Strength and sensation were intact, and reflexes were symmetrical. Cerebellar testing was normal.

The diagnosis made at that time (January 2005) was PPA, with a possible contribution of vascular changes. Treatment with memantine and donepezil did not result in improvement.

She came to our clinic with her husband and daughter in February 2008. The family related that in the preceding 3 years she had experienced serious and progressive clinical decline and was now nearly mute. She had not been able to say her husband's name for more than 1 year.

Medical history was positive for hypertension, gastric reflux, coronary artery disease with stent placement, and hypothyroidism. The family specifically denied a history of demyelinating disease, congestive heart failure, bleeding disorder, diabetes mellitus, lymphoma, blood disorder, hepatitis, immunosuppression, or exposure to tuberculosis. Current medications included levothyroxine, esomeprazole, trospium, amlodipine, ezetimibe, buproprion, atorvastatin, metoprolol, alendronate, and escitalopram. Laboratory evaluation included normal chest x-ray, complete blood count, serum folate, serum vitamin B12, hemoglobin A1c, creatinine, rapid plasma reagin, and a negative purified protein derivative skin test for tuberculosis.

Magnetic resonance imaging of the brain in September 2004 showed bilateral perisylvian atrophy, primarily on the left, together with moderate to marked white matter changes suggestive of microvascular pathology together with atrophy. Medial temporal lobes on this scan appeared normal. Magnetic resonance angiography was unremarkable. A single proton emission computerized tomography scan in 2004 showed reduced activity in the left temporal and parietal cortices and the thalamus. FDG-PET scan on February 28, 2006, showed mild hypometabolism of the inferior pole of the temporal lobes and the frontal lobes (predominantly the left frontal lobe), with milder hypometabolism of the posterior parietal areas, a pattern favoring frontotemporal dementia, with Alzheimer's disease less likely, according to the neuroradiologist who read the scan.

We reviewed the previous medical records and laboratory testing with the patient's husband and daughter. On examination, the patient's blood pressure was 122/74, pulse 87, respirations 12, temperature 98.4, and her chest was clear. The patient was pleasant and cooperative. She walked slowly. We observed no obvious focal neurologic symptoms other than her speech deficits. The patient was unable to give any history. She was devoid of spontaneous speech, could not count at all, and could not give the name of either her husband or her daughter. She could follow only simple commands and was able to order 6 coins in a line in order of size with 1 error (penny after dime). She was not oriented to time or place. Her baseline Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL)[32] score was 16/78, indicating severe dementia. Measured with a related inventory, the ADCS-ADL modified for severe dementia, her score just before the initiation of perispinal etanercept treatment was 15/54.[33]

We obtained written informed consent and administered perispinal etanercept (25 mg) by injection to the posterior neck in the midline followed by Trendelenburg positioning, as previously described.[27] This procedure was tolerated without difficulty. Twenty minutes after the dose, the patient's language abilities were clearly improved. She was able to count to 7, give her daughter's name, and was more alert. For the first time in an entire year, she was able to give her husband's name. In conversation 20 minutes after perispinal etanercept administration, her daughter noted how significant these changes were. A video documenting the patient's clinical status just before perispinal etanercept and her improvement 30 minutes after her first dose is included as part of this report (video 1).

Video 1.

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Patient with primary progressive aphasia before and 30 minutes after receiving perispinal etanercept.

At 1 week following the first dose, the patient returned to receive her second dose of perispinal etanercept. The patient continued to demonstrate clinical improvement at this time, as discussed by her daughter. At 1 month, the patient returned for her third dose. At this time, the daughter reported continued improvement in verbal abilities, behavior, and cognition. Testing of the patient 10 minutes after her third dose of perispinal etanercept 25 mg showed that the patient was able to correctly name 7 out of 10 objects on the Boston Naming Test (video 2). Comments by the patient's daughter at this time are also included as part of this report (video 2). Before beginning perispinal etanercept, the patient was unable to participate in the Boston Naming Test because of the severity of her aphasia. At 1 month, the daughter reported that patient's ADCS-ADL score improved to 31/78, a 15-point improvement as measured by this standardized instrument. Her related ADCS-ADLsev score improved to 28/54, a 13-point improvement in this standardized and validated test for measuring daily functional ability. The improvements included the following: she began mixing or combining food items for a meal or snack, without cooking or microwaving; with supervision, she began selecting her first set of clothes for the day; she began asking for a particular television program; she cleared dishes from the table after a meal or snack; she began disposing of garbage or litter in an appropriate place or container at home. The patient was able to take off her own shoes and socks, something she had not been able to do for more than 1 year. The informant for completion of the ADL inventory (the patient's daughter) and the staff member conducting the inventory interview were the same at the initiation of treatment with perispinal etanercept and 1 month later.

Video 2.

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1-month follow-up with patient and her daughter, following the patient's third dose of perispinal etanercept.

Discussion

The data reported here, along with confirmatory clinical experience of more than 3 years duration in patients with Alzheimer's disease, provide the first preliminary evidence that perispinal etanercept may have potential therapeutic utility for selected patients with PPA.[26–28] In addition, these data, combined with those from previous reports, suggest that positive clinical effects may begin rapidly, within minutes, thereby suggesting the participation of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in PPA and Alzheimer's disease.[26–28]

Of particular note in this patient is the more than 10-point improvement in the activities of daily living (ADL) over the course of 1 month following the initiation of perispinal etanercept, as measured by the ADCS-ADL and the ADCS-ADL sev.[32,33] The ADCS-ADL was developed by a subcommittee of the ADCS composed of clinicians with expertise in dementia assessment and clinical trials to assess a wide range of ADL.[32] Functional assessment of ADL is a critical element of patient care and may also be used to quantify the clinical relevance of cognitive or other effects of a drug intervention.[32] Treatment that enhances cognitive function should lead to an improvement in ADCS-ADL.[32] The ADCS-ADL is a standard instrument used in clinical trials for Alzheimer's disease. It has broad applicability, good test-retest reliability, and sensitivity to detect change in disease progression.[32] A modified version, the ADCS-ADL modified for severe dementia (ADCS-ADLsev, also called the ADCS-ADL₁₉), has been developed and validated for patients with severe dementia.[33] The ADCS-ADL is scored from 0 to 78; the ADCS-ADLsev is scored from 0 to 54, with lower scores indicating more severe functional impairment. The initial scores of the patient, 16/78 on the ADCS-ADL and 15/54 on the ADCS-ADLsev, both indicate severe dementia. A 2006 meta-analysis of memantine for Alzheimer's disease and other forms of dementia documents the use of the ADCS-ADLsev instrument in multiple studies; in two 4- to 6-week studies with a total of 126 patients, the effect size was -1.34 points.[34]

As an example of the use of the ADCS-ADLsev in clinical trials, this inventory was used as one of the main outcome measures in a 24-week trial of memantine given to a group of patients with moderate to severe Alzheimer's disease who were already receiving donepezil.[35] During the course of the 24 weeks, scores of the placebo group declined by 3.4 points in the ADCS-ADLsev, while the scores in the group treated with memantine declined by 2.0 points, a significant difference (P = .03).[35] In a 28-week study of memantine in another group of patients with moderate to severe Alzheimer's disease, the memantine group also declined less than the placebo group (−3.1 vs −5.2, P = .02).[36] The effects in these studies, although small, were statistically significant. A more recent 24-week study of memantine did not show a significant difference from the placebo group with respect to ADCS-ADLsev.[37]

As recently discussed, the rapid effects noted may occur through modulation of synaptic mechanisms that have been dysregulated by excess TNF-alpha.[28] This hypothesis is supported by recent evidence suggesting both a role for TNF in the amyloid oligomer disruption of long-term potentiation and other memory mechanisms and its function as a gliotransmitter.[3,4,38,39]

Further study will be necessary to characterize response rates, dosing schedules, and duration of response in patients with PPA and to determine whether patients with PPA associated with frontotemporal dementia respond in a different manner from patients with PPA associated with Alzheimer's disease.

Potential side effects of the use of perispinal etanercept for the treatment of dementia, an off-label use, include all of the risks inherent in the use of etanercept for its labeled indications, which may include death, infection, decreased blood cell counts, congestive heart failure, lymphoma, demyelinating disease, and reactivation of tuberculosis.[40] PPD skin testing before initiation of etanercept treatment is mandatory, and a black box warning highlighting the risk of tuberculosis, sepsis, and severe infection has been added to the package insert.

The unmet medical need in primary progressive aphasia, with not even a single approved therapeutic agent; the scientific rationale, including basic science and clinical data; and these promising preliminary results together support the initiation of further clinical study. In addition, these results may provide insight into the basic pathophysiologic mechanisms underlying PPA and related forms of dementia and suggest the existence of novel, rapidly reversible, TNF-mediated pathophysiologic mechanisms in both PPA and Alzheimer's disease.