Low Dose RT to Reduce Cerebral Amyloidosis in Early Alzheimer's

Alzheimer's disease (AD) is currently the 7th leading cause of death in the United States
with approximately 5.9 million Americans living with the progressive and debilitating
condition. AD predominantly affects older individuals as 86% of AD cases are in individuals
65 years of age and older. Further, approximately $172 billion of health care spending
annually can be attributed to costs associated with AD care on top of the 11 million
caregivers that provide care in unpaid capacities, such as family members, friends, etc.

In 1975, a cohort of nearly 2,800 people who were 65 years of age and free of dementia
provided a basis for an incident study of dementia, as well as for Alzheimer's disease. This
cohort was followed for almost 29 years and its sentinel findings included a significantly
higher lifetime risk for both Alzheimer's and dementia in women compared to men. The
estimated lifetime risk was nearly one in five for women compared to one in ten for men. In
addition to the higher lifetime risk in women, expectancy of longer life and the aging of the
"baby boomers" combined with improved healthcare is expected to increase the number of
Americans who will reach 85 years of age or more. It is very clear that as the age increases,
so does the incidence of Alzheimer's and other forms of dementia.

Between 2010 and 2050, it is expected that there will be a 30% increase in the number of
individuals greater that 85 years of age. Although the absolute number may not appear to be
significant, this increase of approximately 17 million people will challenge the healthcare
system because of the cost associated with dealing various acute and chronic medical
conditions including AD.

While other major causes of death continue to experience decline, those from AD continues to
rise. In 1991, only approximately 14,000 death certificates recorded Alzheimer's disease as
an underlying cause. In 2006, it was noted that there was an increase of approximately 46% in
which Alzheimer's disease was listed as the direct cause of death. This is significant when
compared to the present leading cause of death, heart disease, which decreased by 11% in the
same time.

From a neurophysiological standpoint, what is known about Alzheimer's disease is that there
appears to be a progressive process that is associated with the deposition of β Amyloid. This
appears to have a triggering mechanism, which causes the phosphorylation of a TAU protein,
which then leads to development neurofibrillary tangles (NFT), which are believed to be
responsible for memory loss, especially short-term and other associated problems with
Alzheimer's related dementia. It also appears that there may be a selective deposition of the
β Amyloid in the hippocampus and the prefrontal regions, which are the major short-term
memory regions of the brain.

Extensive research has been ongoing to try to find various ways in which the excess
deposition of β Amyloid, the removal of excess β Amyloid, the initiation sequence that it is
involved in with phosphorylated TAU and other selective processes can be altered in an effort
to mitigate the devastating end term results. To date, there have been several trials,
including a vaccine trial performed in Europe and in the United States, which seem to show
that clearance of the β Amyloid is possible. However, there was not significant improvement
in neurocognitive function (NCF), which led to the discontinuation of these trials.

This lack of improvement in NCF was believed to be secondary to the fact that the β Amyloid
had already resulted in the phosphorylation of the TAU protein and development of NFT. Thus
removal of the initiator was accomplished, but only after the end damage had developed. Then
why consider irradiation?

The use of radiation in the treatment of non-oncologic human populations has enjoyed a long
history and a more recent renaissance. It is now commonly used to prevent heterotopic bone
formation and re-development of keloids or heterotrophic scars post-operatively. It has been
shown in a randomized trial to effectively treat planter fasciitis and has been used in
post-operative treatment of resected pterygium. It has been used in the treatment of
Hidradenitis suppurativa, Duputryen's disease and Ledderhose's disease. These sites routinely
are treated with low dose fractionated external beam irradiation, commonly in doses that
ranging from 7 to 24 Gy.

The use of external irradiation has also been reported in the treatment of symptomatic
systemic amyloidosis. In published peer reviewed articles treatment sites have include
trachea-pulmonary, ocular, laryngeal and for use as a conditioning agent for autologous BMT
in patients with systemic amyloidosis. These reports used external beam irradiation that
ranged from 5.5 - 45 Gy and detail durable local control with these doses.

Because of this effect, a series of basic science experiments were initiated with genetically
altered mice: the B6; Cg - Tg 85 Dbo/J over express amyloid and the B6; 129-Psen1tm1MpmTg
over express both amyloid and TAU, making them prone to early Alzheimer's disease
development.

Both single and fractionated CNS irradiation in a genetically altered mouse model were
tested, and have shown similar results with reduction in amyloid plaque number, size and
volume. Moreover, the fractionated studies the investigators have demonstrated statistically
significant improvement in the treated mice using the Morris Water Maze Test when compared to
control non-treated animals, an effect which held up whether the animals were adolescent,
mature or aged (up to 18 months old).

The exact mechanism by which radiation therapy confers benefit in the Alzheimer's disease
mouse model will be difficult to elucidate as the exact pathobiology of Alzheimer's disease
is not known. Possible mechanisms include the following: reduction of β amyloid by reducing
production or increasing clearance; reduction in Tau; induction of beneficial inflammatory
mechanisms; induction or inhibition of heat shock proteins; altering cerebral
microvasculature; and/or reversal of maladaptive neuroplasticity in the hippocampus.
Investigations of these possible mechanisms are currently underway.

One of the complications related to studying Alzheimer's disease is the actual diagnosis.
Unlike malignancies where a biopsy can be obtained, Alzheimer's disease is a diagnosis of
exclusion or made at autopsy. While the Europeans have recently identified and agreed on CSF
biomarkers for diagnosis of Alzheimer's disease, the investigators have not accepted that
premise in the United States. At the present time, PET imaging which utilizes various
compounds has been utilized to identify depositions of amyloid in the CNS. More recently,
there is some suggestive evidence that a specific type of cataract may be seen in a high
percentage of patients with Alzheimer's disease related to possible β Amyloid deposition in
the lens region (29-30). Many rely on the NINCDS-ADRDA criteria for clinical diagnosis of
Alzheimer's disease.

While it is a diagnosis of exclusion, there are well-accepted neurocognitive tests (NCT) used
to monitor Alzheimer's disease progression. The Mini Mental exam is one of the general NCT
used to help establish the diagnosis of Alzheimer's dementia. There are other more sensitive
neurocognitive tests available to track progression of Alzheimer's dementia, which the
investigators will use in this study. Note estimation of premorbid IQ is only completed at
the screening appointment and administration of the BNT and JLO only occur at the baseline
pre-treatment visit and the 12-months post-treatment follow up visit to minimize participant
fatigue and familiarity with the test materials. Administration of the NCT at the screening
visit will serve two purposes. Data obtained from the screening visit will ensure that
subjects who are enrolled in the trial meet criteria for early AD based on the more
comprehensive battery of tests, as diagnosis of dementia is improved with use of quantitative
measurement of multiple domains. The NCT at this screening visit will also expose
participants to the NCT and since practice effects are greatest between the first and second
exposure to NCT, practice effects will be minimized using this exposure and repeated measures
ANOVAs.

Psychological functioning and quality of life (QOL) will also be evaluated to monitor
participants' emotional status throughout the trial. The Patient Health Questionnaire-9 and
the Generalized Anxiety Disorder-7 questionnaires will be used to assess depression and
anxiety, respectively. If any participant endorses suicidal ideation on the PHQ-9, the
Suicide Behaviors Questionnaire-Revised (SBQ-R) will be administered to fully evaluate the
participant's suicidal ideation and study stopping rules will be implemented as needed to
ensure the individual's safety. QOL will be evaluated by the Quality of Life in Alzheimer's
disease (QOL-AD) and Quality of Life in Late-stage Dementia (QUALID) and Everyday Cognition
(ECog) questionnaires (patient and caregiver forms).

Concern may be raised regarding the use of whole brain irradiation and its potential
deleterious effect on neurocognitive testing. There have been reports on post-radiation
neurocognitive testing in the setting of prophylactic cranial irradiation (PCI), which is
whole brain fractionated RT commonly employed for patients with pulmonary small cell
carcinoma. The standard whole brain PCI dose is 2.5 Gy x 10, considerably higher than the 2.0
Gy x 5 or 2.0 Gy x 10 schemes planned in the present study. Furthermore, patients in the PCI
studies also received chemotherapy in addition to whole brain irradiation, and chemotherapy
itself effects long-term NCF. In these PCI reports, if any neurocognitive decline was
identified, it was modest, occurred within a short interval, e.g. 6-9 months, and improved.
The investigators are thus proposing a 9-month follow up period for the 1st subject cohort
(2.0 Gy x 5) before proceeding with the 2nd cohort (2.0 Gy x 10), although both cohorts will
undergo NCF and QOL testing through 12 months.

Grosshans and colleagues from M. D. Anderson found that PCI is "unlikely to significantly
affect NCF." They evaluated cognitive function in small cell lung cancer patients who
received PCI (mean 2.5 Gy x 10). After chemotherapy, but before PCI, 47% already had evidence
of impaired cognitive function. On multivariate analysis, there were no significant further
declines after PCI. On univariate analysis, there were unsustained, early decreases in
executive and language function, which did not persist with follow-up. A Japanese group
applied the Hopkins Verbal Learning Test (revised Japanese version, HVLT-R) in 40 whole brain
RT patients, at baseline, 4 months, and 8 months. Whole brain fractionation was either 2.5 Gy
x 4, 3.0 Gy x 10, or 2.5 Gy x 10. The respective probabilities of decline in HVLT-R total
recall at 4 months were, respectively, 40%, 7%, and 0%, and at 8 months 13%, 14% and 0% (48).

Also applicable is a recent report of whole brain (and whole spine) RT for medulloblastoma in
children, a population believed more vulnerable to cognitive decline from RT. They did not
receive chemotherapy, rather RT alone, 36 Gy in 36 fractions (1.0 Gy BID) to the entire brain
and spine, followed by a boost to 68 Gy in 68 fractions to the tumor bed, typically posterior
fossa. Using the Wechsler Intelligence Scale for Children to give verbal quotient,
performance quotient, and full-scale intelligence quotient, cognitive function was preserved
for all test domains throughout the study at 3 months, 1 year, and 2 years, with no decline
over time.

Low dose whole brain RT has demonstrated safety in many studies, and the investigators will
be using even lower doses. These lower radiation therapy doses have a history of excellent
success for patients with non-cerebral amyloidosis, and have had durable response combined
with the necropsy / neurocognitive testing in genetically altered Alzheimer's disease mouse
model, the investigators decided to proceed with a human trial, using fractionated whole
brain radiation doses of 2.0 Gy x 5, then 2.0 Gy x 10. Subjects will be followed with
neurocognitive testing at 6 weeks, 3, 9 and 12 months post RT. Additionally, given that the
development of supranuclear cataract has been reported in a high percent of AD patients, the
investigators will recommend ocular testing at baseline and at 1 year to assess a potential
abscopal effect, collateral benefit to the non-targeted lenses from treatment of the primary
disease in the brain.

With respect to the development of cataracts in association with AD, early and accurate
diagnosis of Alzheimer's disease (AD) is still a challenge and the confirmatory diagnosis is
made by presence of features including beta-amyloid plaques postmortem. In 2014, Tian et al
suggested that AD may have a common pathophysiology with supranuclear deposits of
beta-amyloid in the human lens. The brain and the lens tissue both arise from the ectoderm
tissue (neuroectoderm and surface ectoderm respectively). Their conclusions were based on a
meta-analysis of studies, which provided mixed data regarding the correlation of beta-amyloid
in the lens samples of patients with AD, Down syndrome and controls. Given the chronicity of
the terminally differentiated cell types in the lens that may be affected by Alzheimer
disease's pathology, they concluded that there is a possibility than an ocular biomarker for
early AD may exist in the lens. This would suggest that an early ophthalmic examination may
provide a window of hope into early diagnosis of AD. It may also provide an opportunity for
early treatment and perhaps monitoring of improvement in supranuclear cataracts with systemic
therapy.

A precedent for this is already found in Wilson's disease. Kayser-Fleischer (K-F) ring seen
in Wilson's disease (WD) is due to copper deposition in the Descemet's membrane in the
sclero-corneal junction in the eye. Although believed to be pathognomic of WD, it may be seen
in many other hepatic conditions and intraocular copper-containing foreign bodies. The K-F
ring detected in pre-symptomatic cases of WD may lead to speedy diagnosis and early
management. Co-relation of K-F ring in WD to the disease severity, disappearance with
successful treatment, reappearance with non-compliant treatment aids in management of WD. K-F
ring detection in first-degree relatives of the index case is also important.

With the proposed ocular exams at baseline and at 9-months post treatment, the investigators
hope to detect any cataracts in the subjects and effects of the proposed radiation
treatments. The questions the investigators will have are how often they encounter them in
early Alzheimer's and whether they improve (an abscopal effect) after radiation therapy, even
though the lenses will be excluded from the RT treatment fields. Exams will only be done for
subjects who have at least one natural lense still present. Subjects with previous cataract
corrections will not have ocular exams performed.

Inclusion Criteria:

- Must be a native English speaker with a LAR available for consenting.

- Able to complete neurocognitive function assessments, psychological function
assessments, and QOL assessments administered at screening visit.

- Rosen Modified Hachinski Ischemic Score less than or equal to 4

- Estimated Survival of greater than 12 months

- Meets the clinical definition of AD based on NINCDS-ADRDA criteria, with confirmatory
F-2-DG and F-Florbetapir (Amyvid) PET scan findings

- If on any of the following medications, must be on a stable dose for 60 days or
greater: Rivastigmine, Donepezil, Memantine, Glantamine, Tacrine.

Exclusion Criteria:

- Current or past history of any oncologic disease mitigating low dose whole brain RT

- Evidence of substance abuse (Alcohol/or other drugs or dependences during previous 12
months (DSM-V criteria)

- Clinically or radiographically significant evidence of stroke

- Evidence of subdural hygromas or subdural hematomas

- Active or recent (defined as within 3 months of screening) cerebral infection or
hemorrhage

- Any current conditions that may lead to the subject being in an immuno-compromised
state

- Any previous history of cranial radiation

- History of seizure activity

- History of Hydrocephalus

- Evidence of active dermatological skin disease of the scalp (except Actinic Keratosis)

- Evidence of clinically significant major depressive disorder identified in a
psychological diagnostic interview according to the criteria of the Diagnostic and
Statistical Manual of Mental Disorder, Fifth Edition (DSM-V)

- Evidence of psychotic disorder or psychotic episode or bipolar affective disorder
identified in a psychological diagnostic interview according to the criteria of the
Diagnostic and Statistical Manual of Mental Disorder, Fifth Edition (DSM-V)

- Evidence of active suicidal or homicidal ideation according to psychological
diagnostic interview

- Currently receiving other experimental treatments

- Currently requiring full-time institutional care