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Reversal of Cognitive Decline: 100 Patients

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Volume 8 Issue 5 • 1000450
J Alzheimers Dis Parkinsonism, an open access journal
ISSN:2161-0460
Open Access
Case Report
Bredesen et al., J Alzheimers Dis Parkinsonism 2018, 8:5
DOI: 10.4172/2161-0460.1000450
Journal of
Alzheimer’s Disease & Parkinsonism
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ISSN: 2161-0460
disease [1,2,5,7] in which APP, the amyloid precursor protein, functions
as a molecular switch due to its activity as an integrating dependence
receptor [8-10]: in the presence of sucient support from trophic
signaling, APP is cleaved at the alpha site, leading to the production
of two synaptoblastic peptides, sAPPα and αCTF. In contrast, in the
absence of sucient support from trophic signaling, APP is cleaved
at the beta, gamma, and caspase sites, leading to the production
of four synaptoclastic peptides, sAPPβ, Aβ, Jcasp, and C31. In this
model, inammation exerts an anti-trophic eect on APP signaling,
at least in part via the NF-κB (nuclear factor κ-light chain enhancer
of B cells) induction of BACE (beta-amyloid cleaving enzyme) and
gamma-secretase activity. Similarly, toxins such as divalent metals (e.g.,
mercury) also exert an anti-trophic eect on APP signaling, since these
lead to a net increased production of the toxin-binding peptide, Aβ. is
*Corresponding author: Dale E Bred esen, Department of Molecular and Medical
Pharmac ology, David G effen Sc hool of Me dicine, Universit y of Califo rnia, Los
Angele s, CA, USA , Tel: +014152541041; E-mail: dbredesen@buckinstitute.org
Received: October 08, 2018; Accepted: October 12, 2018; Published: October
19, 2018
Citation: Bredesen DE, Sharlin K, Jenkins D, Okuno M, Youngberg W, et al. (2018)
Reversal of Cognitive Decline: 100 Patients. J Alzheimers Dis Parkinsonism 8: 450.
doi: 10.4172/2161-0460.1000450
Copyright: © 2018 Bredesen DE, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original
author and source are credited.
Keywords: Alzheimer’s; Mild cognitive impairment; Programmatics;
ReCODE; Precision medicine; Amyloid precursor protein;
Synaptoblastic; Synaptoclastic
Introduction
Alzheimer’s disease is now the third leading cause of death in
the United States [1-6], and the development of eective treatment
and prevention is a major healthcare goal. However, clinical trials of
drug candidates for Alzheimer’s disease treatment have been almost
uniformly unsuccessful. ere may be several reasons for such repeated
failure: (1) given the long pre-symptomatic period, treatment is typically
initiated late in the pathophysiological process; (2) what is referred
to as Alzheimer’s disease is not a single disease, but rather exhibits
several dierent subtypes [3,4]; (3) just as for other complex chronic
illnesses such as cardiovascular disease, there may be many potential
contributors to Alzheimer’s disease, such as inammation, various
chronic pathogens, trophic withdrawal, insulin resistance, vascular
compromise, trauma, and exposure to specic toxins. erefore, a
monotherapeutic, monophasic approach is likely to be suboptimal, and
personalized, multiphasic programs based on each individual’s genetics
and biochemistry may be preferable. Indeed, such personalized programs
may oer advantages in future clinical trials of drug candidates. (4) e
model of Alzheimer’s disease on which the drug targets (e.g., amyloid-β
peptide) have been based may be an inaccurate or incomplete model of
the disease.
We have argued for a fundamentally dierent view of Alzheimer’s
Reversal of Cognitive Decline: 100 Patients
Dale E Bredesen1*, Kenneth Sharlin2, David Jenkins3, Miki Okuno3, Wes Youngberg4, Sharon Hausman Cohen5, Anne Stefani5, Ronald
L Brown6, Seth Conger6, Craig Tanio7, Ann Hathaway8, Mikhail Kogan9, David Hagedorn10, Edwin Amos11, Amylee Amos12, Nathaniel
Bergman13, Carol Diamond14, Jean Lawrence15, Ilene Naomi Rusk16, Patricia Henry16 and Mary Braud16
1Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
2Sharlin Health and Neurology/Functional Medicine, Ozark, MO, USA
3NeuroHub, Sydney, Australia
4Youngberg Lifestyle Medicine Clinic, Temecula, CA, USA
5Resilient Health, Austin, TX, USA
6Carolina Healthspan Institute, Charlotte, NC, USA
7Rezilir Health, Hollywood, FL, USA
8Integrative Functional Medicine, San Rafael, CA, USA
9GW Center for Integrative Medicine, George Washington University, Washington, DC, USA
10Coastal Integrative Medicine, Jacksonville, NC, USA
11Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA
12Amos Institute, Los Angeles, CA, USA
13Center for Functional Medicine, Cleveland Clinic, Cleveland, OH, USA
14Mount Sinai Hospital, New York, NY, USA
15Lawrence Health and Wellness, Toccoa, GA, USA
16Brain and Behavior Clinic, Boulder, CO, USA
Abstract
The rst examples of reversal of cognitive decline in Alzheimer’s disease and the pre-Alzheimer’s disease
conditions MCI (Mild Cognitive Impairment) and SCI (Subjective Cognitive Impairment) have recently been published.
These two publications described a total of 19 patients showing sustained subjective and objective improvement in
cognition, using a comprehensive, precision medicine approach that involves determining the potential contributors
to the cognitive decline (e.g., activation of the innate immune system by pathogens or intestinal permeability,
reduction in trophic or hormonal support, specic toxin exposure, or other contributors), using a computer-based
algorithm to determine subtype and then addressing each contributor using a personalized, targeted, multi-factorial
approach dubbed ReCODE for reversal of cognitive decline.
An obvious criticism of the initial studies is the small number of patients reported. Therefore, we report here
100 patients, treated by several different physicians, with documented improvement in cognition, in some cases
with documentation of improvement in electrophysiology or imaging, as well. This additional report provides further
support for a randomized, controlled clinical trial of the protocol and the overall approach.
Citation: Bredesen DE, Sharlin K, Jenkins D, Okuno M, Youngberg W, et al. (2018) Reversal of Cognitive Decline: 100 Patients. J Alzheimers Dis
Parkinsonism 8: 450. doi: 10.4172/2161-0460.1000450
Page 2 of 6
Volume 8 Issue 5 • 1000450
J Alzheimers Dis Parkinsonism, an open access journal
ISSN:2161-0460
model is compatible with the nding that the Aβ peptide functions as
an antimicrobial peptide [11], together suggesting that what is referred
to as Alzheimer’s disease is a protective, network-downsizing response
to several classes of insults: pathogens/inammation, toxins, and
withdrawal of nutrients, hormones, or trophic factors [5].
is model suggests that the probability of developing Alzheimer’s
disease is proportional to the ratio of synaptoclastic signaling to
synaptoblastic signaling [5]. is notion has led to a treatment regimen
in which the dozens of contributors to synaptoblastic and synaptoclastic
signaling are measured for each patient, and a personalized program
is generated to target each contributor, thus increasing synaptoblastic
signals and reducing identied synaptoclastic signals. Some examples
include: (1) identifying and treating pathogens such as Borrelia,
Babesia, or Herpes family viruses; (2) identifying gastrointestinal
hyperpermeability, repairing the gut, and enhancing the microbiome;
(3) identifying insulin resistance and protein glycation, and returning
insulin sensitivity and reduced protein glycation; (4) identifying and
correcting suboptimal nutrient, hormone, or trophic support (including
vascular support); (5) identifying toxins (metallotoxins and other
inorganics, organic toxins, or biotoxins), reducing toxin exposure, and
detoxifying. Since each patient has a dierent combination of the many
potential contributors to cognitive decline, the approach to treatment is
targeted and personalized.
Here we describe 100 patients with cognitive decline treated with
this multi-component, precision medicine approach, and showing
documented improvement.
Case Studies
Patient 1
A 68-year-old professional woman began to note paraphasic errors
in her speech, severe enough that it created confusion in her listeners.
She also developed depression, and was treated with an antidepressant.
She began to have diculty with everyday work such as shopping,
cooking, and working at the computer. She struggled to complete a
gingerbread man with her granddaughter, even though she had done
this without diculty many times before. She confused the minute
hand and hour hand on a clock. She had diculty with spelling. Her
symptoms progressed, and she began to forget daily tasks. She became
very concerned when she forgot to pick up her grandchildren at school
twice in a two-week period.
She was found to be heterozygous for the ε4 allele of apolipoprotein
E (ApoE 3/4). An amyloid PET scan (orbetapir) was positive. MRI
demonstrated a hippocampal volume of 14th percentile for her
age. High-sensitivity C-reactive protein (hs-CRP) was 1.1 mg/L,
fasting insulin 5.6 mIU/L, hemoglobin A1c 5.5%, homocysteine 8.4
micromolar, vitamin B12 471 pg/mL, free triiodothyronine (free T3)
2.57 pg/mL, thyroid-stimulating hormone (TSH) 0.21 mIU/L, albumin
3.7 g/dL, globulin 2.7 g/dL, total cholesterol 130 mg/dL, triglycerides
29 mg/dL, serum zinc 49 mcg/dL, complement factor 4a (C4a) 7990
ng/mL, transforming growth factor beta-1 (TGF-β1) 4460 pg/ml, and
matrix metalloprotease-9 497 ng/mL.
A diagnosis of Mild Cognitive Impairment (MCI) was made, and
she was placed on a trial of an anti-amyloid antibody. However, with
each administration, her cognition became worse for 3-5 days, then
returned toward her previous MCI status. Aer she had become worse
with each of the rst four treatments, she discontinued her participation
in the study.
She began treatment with the programmatic approach described
previously [1]. Her MoCA increased from 24 to 30 over 17 months,
and has remained stable for 18 months. Hippocampal volume increased
from 14th percentile to 28th. Her symptoms improved markedly: her
ability to spell returned, her speech improved, and her ability to shop,
cook, and work at the computer all improved and have remained stable
on follow-up.
Patient 2
A 73-year-old female physician presented with a history of memory
decline and word-nding problems that had begun insidiously nearly
20 years previously, but had accelerated over the past year, leading her
signicant other to describe her memory as “disastrous.” She could
not remember recent conversations, plays she had seen, or books she
had read, and mixed up the names of people and pets. She had trouble
navigating, even diculty nding her way back to her restaurant table
aer using the restroom.
Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET)
scan revealed a decrease in glucose utilization in the anterior superior
precuneus bilaterally, as well as the anterolateral le temporal lobe.
MRI revealed mild biparietal atrophy, with decreased hippocampal
volume (16th percentile for age). On-line cognitive testing placed her at
the 9th percentile for her age. ApoE genotype was 3/3, fasting glucose 90
mg/dL, hemoglobin A1c 5.3%, fasting insulin 1.6 mIU/L, homocysteine
14.1 micromolar, TSH 4.1 mIU/mL, free T3 2.6 pg/mL, reverse T3 22.6
ng/dL, vitamin B12 202 pg/mL, vitamin D 27.4 ng/mL, total cholesterol
226 mg/dL, LDL 121 mg/dL, HDL 92 mg/dL, and mercury 7 ng/mL.
She was treated with the programmatic approach described
previously [1], and over 12 months, her on-line cognitive assessment
improved from the 9th percentile to the 97th percentile. Her signicant
other noted that her memory had improved from “disastrous” to “just
plain lousy” and nally to “normal.” She remains on the therapeutic
program, and has sustained her improvement.
Patient 3
A 62-year-old woman presented with cognitive decline, fatigue,
poor sleep, and depression. She had lost the ability to remember names,
do the accounting she had done previously, and run her business.
Body mass index was 24, with increased abdominal fat. MoCA
was 20. She was ApoE4 heterozygous (3/4). Fasting serum glucose 101
mg/dL, hemoglobin A1c 6.1%, fasting insulin 14 mIU/L, hs-CRP 1.7
mg/L, 25-hydroxycholecalciferol 24 ng/mL, TSH 2.4 mIU/L, free T3
2.9 pg/mL, reverse T3 19 ng/dL, estradiol<6 pg/mL, and pregnenolone
38 ng/dL. Pathogen testing was negative for Borrelia, other tick-borne
infections, and Herpes family viruses. Toxin testing showed no evidence
of mercury or lead toxicity.
She was treated with the personalized program described previously
[1], which in her case included bio-identical hormone replacement,
restoring insulin sensitivity with a mildly ketogenic, plant-rich diet,
regular exercise, and stress reduction; enhancing her microbiome with
probiotics and prebiotics; reducing systemic inammation with omega-3
fats; enhancing vitamin D and vitamin K2; enhancing methylation with
methyl-cobalamin and methyl-tetrahydrofolate; and brain training.
Over the next 12 months she improved her metabolic status: her
BMI dropped to 21.8, fasting glucose 87 mg/dL, hemoglobin A1c 5.2%,
fasting insulin 5.5 mIU/L, hs-CRP 0.5 mg/L, free T3 3.2 pg/mL, TSH
2.1 mIU/L, estradiol 51 pg/mL. Her symptoms resolved, she was able to
reopen her business, and her follow-up MoCA score had risen from 20
to 28. Her improvement has been sustained.
Citation: Bredesen DE, Sharlin K, Jenkins D, Okuno M, Youngberg W, et al. (2018) Reversal of Cognitive Decline: 100 Patients. J Alzheimers Dis
Parkinsonism 8: 450. doi: 10.4172/2161-0460.1000450
Page 3 of 6
Volume 8 Issue 5 • 1000450
J Alzheimers Dis Parkinsonism, an open access journal
ISSN:2161-0460
(Table 1) lists 100 patients with cognitive decline due to Alzheimer’s
disease, pre-Alzheimer’s conditions MCI (Mild Cognitive Impairment)
or SCI (Subjective Cognitive Impairment), or cognitive decline
without denitive diagnosis, all of whom demonstrated documented
improvement using the same targeted, multi-component program used
for the three patients described above.
Patient ApoE Sx Dx Evaluation F/u Comment
1) 68F 3/4 Exec, calc MCI Am-PET+ MoCA 2430 Patient 1 (above)
2) 73F 3/3 Amnestic MCI FDG-PET+ 997%ile on-line Patient 2 (above)
3) 59F 3/4 Exec AD HC vol <1%ile MoCA 1421
4) 62F ND Multi-domain AD MoCA 917 Returned to work
5) 75F 3/4 Multi-domain MCI CSF ATI+ MoCA 2125; MSQ 476
6) 65M 3/4 Multi-domain AD CSF ATI+ MoCA 812; MSQ 4520
7) 69M ND Amnestic, VS, calc AD MRI, CSF ATI+ MoCA 1926
8) 57M ND Amnestic, exec, VS AD CSF ATI+ MoCA 1527
9) 68F ND Amnestic, exec MCI MRI MoCA 2627; MSQ 3418 Marked functional improvement
10) 85M 3/3 Amnestic, VS MCI HC vol 9%ile MoCA 2021; MSQ 117
11) 86M ND Amnestic, exec, VS MCI CSF ATI+ MoCA 2224
12) 60M 3/4 Amnestic, exec, VS AD MRI, NP MoCA 1721; MSQ 4325 Improved QOL
13) 64F ND Amnestic, exec, VS AD MRI MoCA 2024; MSQ 4010
14) 77M ND Amnestic, VS, calc MCI MRI MoCA 2428; MSQ 9142
15) 64M ND Amnestic, exec,
calc, VS AD FDG-PET+ MoCA 1319
16) 50M 3/3 Amnestic, aphasic SCI MRI MoCA 2728; MSQ 8857
17) 70M ND Amnestic, exec,
aphasic, VS AD FDG-PET+ MoCa 1924; MSQ 164Marked subjective improvement;
cont’d high-level employment
18) 80M 3/4 Amnestic, exec, VS MCI CSF ATI+ MoCA 1920
19) 57M ND Severe multi-domain AD MRI, NP, CSF MoCA 05; MSQ 3616
20) 80M 3/3 Amnestic SCI MoCA 2629; MSQ 254
21) 69M ND Amnestic MCI MoCA 2630; MSQ 3120
22) 56F 4/4 Amnestic, exec, VS AD FDG-PET+ MoCA 58; MSQ 148
23) 69M ND Amnestic AD MRI MoCA 1926; MSQ 2917 Doing well at work
24) 83F 3/4 Amnestic MCI MRI MoCA 2327; MSQ 3120
25) 71F 3/3 Amnestic, exec AD qEEG
MoCA 1823; CNS-VS exec
163%ile; cog ex 158%ile;
qEEG 2SD increase beta power
Marked memory improvement; return
to driving and independence
26) 75M ND Exec MCI qEEG MoCA 2129; qEEG normalized
27) 67F 3/4 Amnestic, exec AD qEEG MoCA 1519 Insomnia resolved
28) 61F ND Amnestic, exec SCI qEEG CNS-VS NCI 4073%ile; qEEG
global beta power normalized Marked subjective improvement
29) 61F 2/4 Exec MCI qEEG CNS-VS 468%ile Able to DC stimulant medication
30) 71M 3/3 Amnestic, exec SCI qEEG CNS-VS 3081%ile
31) 63F 4/4 Amnestic, exec AD qEEG MoCA 34Decline halted
32) 78M 3/3 Amnestic, exec AD qEEG MoCA 913
Marked subjective improvement,
regained dressing and independent
bathroom use
33) 50M 3/4 Amnestic, exec, calc AD Am-PET+, FDG-PET+ MoCA 09Marked subjective improvement
34) 71M 2/3 Amnestic MCI MoCA 2429
35) 81F 3/4 Amnestic AD HC atrophy MoCA 1012 Marked subjective improvement
36) 78M 4/4 Amnestic AD HC volume <1%ile MoCA 1620 Able to run his business
37) 77M 3/4 Amnestic AD FDG-PET+ MoCA 1418 Clear subjective improvement
38) 85F 3/4 Amnestic AD MoCA 2124, stable 1.5y+ Word recall markedly improved
39) 70M ND Amnestic AD FDG-PET+, CSF ATI+ MoCA 1927; MSQ 167
40) 54F ND Amnestic AD MoCA 1923; MSQ 8441
41) 70F 3/3 Amnestic SCI CVLT 3959%ile
42) 79M 3/4 Amnestic AD SLUMS 1418
43) 85M 3/4 Amnestic, exec AD SLUMS 1722
44) 84M 3/3 Amnestic, exec MCI MRI SLUMS 1926
45) 79F 3/3 Amnestic AD MoCA 1418
46) 65M 4/4 Amnestic, exec MCI MRI, PET SLUMS 2128
47) 68F 3/3 Amnestic MCI CVLT 1826%ile
48) 54M 4/4 Amnestic SCI CVLT 5462%ile
49) 77F 4/4 Amnestic MCI MRI MoCA 2325; MSQ 177
Citation: Bredesen DE, Sharlin K, Jenkins D, Okuno M, Youngberg W, et al. (2018) Reversal of Cognitive Decline: 100 Patients. J Alzheimers Dis
Parkinsonism 8: 450. doi: 10.4172/2161-0460.1000450
Page 4 of 6
Volume 8 Issue 5 • 1000450
J Alzheimers Dis Parkinsonism, an open access journal
ISSN:2161-0460
50) 64M 3/3 AD SLUMS 1520
51) 58F 3/3 Amnestic, exec AD CT: Cerebral atrophy CNS-VS memory
127%ile Marked subjective improvement
52) 70M 3/4 Amnestic AD MoCA 1821
53) 62M 3/4 Amnestic, calc MCI MRI NP on-line 3653%ile Marked subjective improvement
54) 58F 3/3 Exec, calc MCI NP CNS-VS 2355%ile
55) 77M 3/4 Amnestic AD CT: cerebral atrophy CNS-VS 3355%ile
56) 66F 4/4 Amnestic AD Cerebral atrophy CNS-VS 114%ile Returned independence
57) 72M 4/4 Amnestic MCI HC vol <5%ile CNS-VS 712%ile
58) 77M 3/4 Amnestic MCI MoCA 2325
59) 83M 3/3 Amnestic AD Am-PET+ MMSE 2428
60) 64M 4/4 Amnestic AD HC atrophy MMSE 2229
61) 71M 3/4 Aphasic, exec AD MRI MoCA 5 Declined
Vastly improved, conversing
again, dressing himself, calling
grandchildren by name, working
again
62) 73F 3/4 Amnestic AD qEEG, evoked
potentials
MoCA 920; AQ21 208;
P300b lat. 608576; P300b amp.
1315.6
63) 62F ND Amnestic MCI/
AD MoCA 2028 Patient 3 (above)
64) 73M 4/4 Amnestic MCI MoCA 2530
65) 69F 3/4 Amnestic, exec AD MoCA 1619 Minimal speechuid normal speech
66) 58M 3/4 Amnestic MCI MRI; HC vol 12%ile MoCA 2628; HC vol 1224%ile Rapid decline prior to treatment
67) 70F 3/3 Amnestic MCI CNS-VS NCI 3261%ile; psych speed
368%ile
68) 91M ND Exec AD MMSE 2227
69) 76F 3/4 Amnestic, exec AD MRI; HC vol 47%ile MoCA 1725 Returned ability to read
70) 69M 3/3 Amnestic, calc AD Am-PET+ MoCA 1525
71) 80M 3/4 Amnestic AD FDG-PET+ Memory score 15% Able to DC anti-hyp., statin; glucose
improved
72) 64M 4/4 Amnestic, exec AD MRI: HC vol 10%ile,
gen. atrophy MoCA 2024
73) 75M 3/4 Amnestic, exec, VS AD MRI: HC vol 12%ile MoCA 69Declined off protocol, improved back
on
74) 62M ND Amnestic, exec AD MMSE 2024 Improved writing and map following
75) 76M 3/3 Amnestic AD MRI MoCA 2022 Improved memory
76) 50M 3/3 Exec AD FDG-PET+ MMSE 2327 Marked subjective improvement
77) 53F 3/3 Exec, calc AD Am-PET+ MoCA 1016
78) 50F 2/4 Amnestic MCI NP NP normalized, prosop. cleared,
word nding improved
Regained ability to play piano;
sustained improvement 3y ongoing;
f/u of pt. reported previously [4]
79) 68F 2/4 Amnestic, exec MCI MoCA 2529 Memory, driving directions much
improved
80) 80F 3/3 Amnestic, exec AD MoCA 1824 Memory much improved
81) 61F 3/3 Exec AD FDG-PET: temp
hypometab
NCI 3379%ile; exec 177%ile;
cog ex 177%ile Marked subjective improvement
82) 54F 3/3 Amnestic, exec AD FDG-PET+ MoCA 1921 Reading, navigating again; earlier f/u
reported [4]
83) 78F 3/4 Amnestic, exec,
praxis AD MRI: HC vol <1%ile MoCA 03
Striking change: speaking, dressing,
dancing, biking, emailing, kayaking
all returned
84) 74M 3/4 Amnestic AD FDG-PET+ CVLT-IIB 384%ile Improvement sustained at 4.5 yr; f/u
to initial report [4]
85) 69F 3/4 Exec AD MRI: cerebral atrophy MoCA 1827
Driver’s license returned; follows
recipes again; nurse asked, “What
happened?!”
86) 68M 3/4 Amnestic MCI Am-PET+; FDG-PET+ HC vol 1775%ile Sustained improvement 4 yr; f/u to
initial report [4]
87) 56M 3/3 Amnestic, exec, calc MCI FDG-PET+ Improved math, memory, able to play
poker at high level again
88) 54F 4/4 Amnestic MCI NP: cog assessment 3598%ile Sustained improvement 6 yr; f/u to [4]
89) 57F 4/4 Amnestic MCI NP NCI 1673%ile Sustained improvement 2y; f/u to [4]
90) 76M 4/4 Amnestic AD FDG-PET+ MMSE 2330 Declined when DC’d protocol,
improved back on; f/u to [4]
Citation: Bredesen DE, Sharlin K, Jenkins D, Okuno M, Youngberg W, et al. (2018) Reversal of Cognitive Decline: 100 Patients. J Alzheimers Dis
Parkinsonism 8: 450. doi: 10.4172/2161-0460.1000450
Page 5 of 6
Volume 8 Issue 5 • 1000450
J Alzheimers Dis Parkinsonism, an open access journal
ISSN:2161-0460
91) 56F 4/4 Amnestic, exec,
word nding MCI Composite memory 3261%ile F/u to [4]
92) 48F 3/4 Amnestic MCI MoCA 2330 Marked symptomatic improvement
93) 72M ND Amnestic, behavioral AD Improved memory, writing, reduced
anxiety
94) 73F 3/4 Exec MCI MoCA 2327
95) 70M 3/4 Amnestic, VS MCI Am-PET+ NP 3050%ile Improved memory, navigation
96) 67F 4/4 Amnestic, exec,
calc, behavioral AD SAGE 0
Return of addition, subtraction,
multiplication, division; holding
conversations again
97) 63M 3/4 Amnestic, exec, calc AD MRI: gray matter
atrophy MoCA 1729 Able to return to work
98) 74F 4/4 Amnestic, exec AD MRI: HC vol 18%ile,
cortical atrophy MoCA 1421
99) 79M 3/3 Amnestic AD MRI MoCA 1115; MSQ 4734
100) 78M 4/4 Amnestic AD MRI MoCA 2023; MSQ 4010
AD: Alzheimer’s Disease; Am-PET: Amyloid Positron Emission Tomography Scan; Anti-hyp: Antihypertensive; ApoE: Apolipoprotein E; ATI: Beta-Amyloid-Tau Index; Calc:
Dyscalculia; CNS-VS: CNS Vital Signs; Cog: Cognitive; CSF: Cerebrospinal Fluid; CVLT: California Verbal Learning Test; DC: Discontinue; Dx: Diagnosis; Exec: Executive
Function; F: Female; F/u: Follow-up; FDG-PET: Fluorodeoxyglucose Positron Emission Tomography Scan; Flex: Flexibility; HC vol: Hippocampal Volume; Hypometab:
Hypometabolism; M: Male; MCI: Mild Cognitive Impairment; MMSE: Mini-Mental Status Exam; MoCA: Montreal Cognitive Assessment; MRI: Magnetic Resonance Imaging;
MSQ: Mental Symptoms Questionnaire (score 0-284, higher=more symptomatic); NCI: Neurocognitive Index; ND: Not Done; NP: Neuropsychology; Prosop: Prosopagnosia;
Psych: Psychomotor; Pt: Patient; qEEG: Quantitative Electroencephalogram; QOL: Quality of Life; SAGE: Self-Administered Gerocognitive Exam; SCI: Subjective Cognitive
Impairment; SD: Standard Deviation(s); SLUMS: St. Louis University Mental Status Exam; Sx: Symptoms; Temp: Temporal; VS: Visuospatial Dysfunction.
Table 1: Summary of 100 patients treated with a multi-factorial, precision medicine approach to cognitive decline [1,2] and showing improvement.
Discussion
Alzheimer’s disease represents a major healthcare problem, and the
failure to develop eective treatment and prevention for Alzheimer’s
would have dire consequences nationally and globally, the bankruptcy
of Medicare being among them. erefore, the development of
eective treatments is a high priority for translational biomedicine and
public health programs throughout the world. However, the area of
neurodegenerative diseases is arguably the area of greatest biomedical
therapeutic failure from Alzheimer’s to Parkinson’s to Lewy body
disease to amyotrophic lateral sclerosis to frontotemporal dementia to
progressive supranuclear paralysis to macular degeneration and other
neurodegenerative diseases, there has been no eective treatment with
a sustainable, disease-modifying eect.
ere may be several reasons for such uniform failure: attempting to
treat without identifying the cause(s) and contributors for each patient
may be one reason. Assuming a single cause, attempting to treat with a
monotherapy, uniform and monophasic, may all contribute to previous
suboptimal and ineective approaches. Furthermore, targeting the
mediators (e.g., Aβ peptides) instead of the root causes (e.g., pathogens,
toxins, and insulin resistance) may be yet another reason for the lack of
success to date.
Here we have taken a very dierent approach, evaluating and
addressing the many potential contributors to cognitive decline for
each patient. is has led to unprecedented improvements in cognition.
Most importantly, the improvement is typically sustained unless the
protocol is discontinued, and even the initial patients treated in 2012
have demonstrated sustained improvement. is eect implies that the
root cause(s) of the degenerative process are being targeted, and thus the
process itself is impacted, rather than circumventing the process with
a monotherapeutic that does not aect the pathophysiology. erefore,
the sustained eect of the protocol represents a major advantage over
monotherapeutics.
e current study expands on results reported earlier for 19
patients [1,2], here describing 100 patients with cognitive decline
and documented improvement. Most of these patients were shown
to have Alzheimer’s disease or a pre-Alzheimer’s condition, MCI or
SCI; the remainder may or may not have had Alzheimer’s disease,
since the evaluations in those cases did not provide denitive evidence
of Alzheimer’s, nor did they provide denitive evidence of any other
specic degenerative condition. e patients shown to improve
included some whose laboratory values suggested each of the major
subtypes [3,5] Inammatory, atrophic, glycotoxic (insulin resistant),
and toxic suggesting that the ecacy of this general approach is not
restricted to a single subtype of Alzheimer’s disease.
e results presented here were obtained by multiple physicians
at multiple sites, suggesting that the approach should be scalable and
practicable for many physicians. ese results should also provide
background to support randomized, controlled, prospective clinical
trials. Gaining approval for such trials may be dicult, however,
since they will necessarily be multi-variable and non-uniform (i.e.,
personalized). Furthermore, it is highly unlikely that the therapeutic
response will act as a linear system, and thus the eect of the program
as a whole is unlikely to equal the sum of the eects of each component,
making the dissection of the protocol components dicult. However,
alternative approaches, such as the removal of single components
systematically, or the comparison of large numbers of program eects
diering by a few components, may oer some insight into the most
and least important components (although of course these may vary
from patient to patient).
In the current set of 100 patients, for those evaluated by MoCA,
MMSE, or SLUMS pre- and post-treatment (72 of the 100), there was
a mean improvement of 4.9 points, with a standard deviation of 2.6
and a range of 1-12. Since the natural history is one of decline, the
improvements that were documented must be considered as additional
to the prevention of decline that would otherwise have occurred. Of
course these numbers must be tempered with any failures that occur, so
that it will be important to revise these in the context of a randomized,
controlled clinical trial.
One of the benets of the protocol used here is that it may enhance
pharmaceutical testing and clinical trials: given the lack of improvement
in the vast majority of monotherapeutic trials to date, it is possible that
one problem results from a oor eect, i.e., there may be a threshold
Citation: Bredesen DE, Sharlin K, Jenkins D, Okuno M, Youngberg W, et al. (2018) Reversal of Cognitive Decline: 100 Patients. J Alzheimers Dis
Parkinsonism 8: 450. doi: 10.4172/2161-0460.1000450
Page 6 of 6
Volume 8 Issue 5 • 1000450
J Alzheimers Dis Parkinsonism, an open access journal
ISSN:2161-0460
eect needed to measure improvement. However, the positive eects
described here might conceivably place the patients in a dynamic range
in many cases, such that smaller eects both positive and negative
might be detectable.
As more patients are treated with this approach, patterns of
improvement vs. lack of improvement, timing, which domains typically
improve and which do not, and related insights are likely to emerge.
Although this was not a focus of the cases reported here, certain
observations were made repeatedly. One of these was that the signicant
others of the patients typically reported that the patients were “more
engaged” and more responsive with treatment. Facial recognition,
navigation, and memory were oen improved, whereas calculation and
aphasia were less oen improved. For those in whom specic pathogens
or toxins were identied, either improvement did not occur until
those were targeted therapeutically, or further improvement occurred
when they were targeted. Not surprisingly, those patients showing less
decline at the time of initiation of treatment responded more readily
and completely than those who were further along in the course of
the illness. However, there were examples of improvement even with
MoCA scores as low as zero.
In summary, a targeted, personalized, precision medicine approach
that addresses the multiple potential contributors to cognitive decline
for each patient shows promise for the treatment of Alzheimer’s disease
and its harbingers, MCI and SCI. e improvements documented in
the 100 patients reported here provide support for the performance
of a prospective, randomized, controlled clinical trial, especially given
the current lack of eective treatment for this common and otherwise
terminal illness.
Acknowledgment
We are grateful to the many practitioners evaluating and treating patients with
cognitive decline, using this comprehensive protocol. We are especially grateful
to Dr. Mary Kay Ross, Hilary Shafto, and Margaret Conger for seeing some of
the patients reported here, to Dr. Kristine Lokken, Dr. Jonathan Canick, and Dr.
Katayoon Shahrokh Walters for some of the neuropsychological evaluations, to
Amanda Williams and Cytoplan Ltd. for providing some of the supplements for
some patients, to James and Phyllis Easton for critical research support, and to the
Evanthea Foundation for support in preparation of a clinical trial.
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... Thus, a therapeutic strategy to identify and attenuate all the risk factors specific to each affected individual may have a significant impact on disease progression, as has been shown recently [10][11][12][13][14]. Here we present pilot data that a comprehensive and personalized therapeutic program designed to mitigate AD risk factors can improve several risk factor scores and stabilize cognitive function, warranting prospective, longitudinal cohort studies, and controlled clinical trials. ...
... ReCODE is a comprehensive and personalized multi-therapeutic program for reversing symptoms of cognitive decline and optimizing brain health, using a targeted algorithm based on biochemical and genetic risk factors for cognitive decline. It is intended for individuals experiencing symptoms of subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and those with early stage AD, although some with later stages of AD have shown improvement, as well [13]. The ReCODE program includes information on the metabolic factors that drive the symptoms of cognitive decline and provides detailed, personalized recommendations to address these factors, such as nutrition, exercise (physical and mental), sleep, stress management, detoxification, supplements, and hormones. ...
... The ReCODE program includes information on the metabolic factors that drive the symptoms of cognitive decline and provides detailed, personalized recommendations to address these factors, such as nutrition, exercise (physical and mental), sleep, stress management, detoxification, supplements, and hormones. The ReCODE program evolved from other similar programs that used precision medicine approaches to identify and target the drivers of Alzheimer's or pre-Alzheimer's [13][14][15]. Following the completion of labs, medical questionnaires, and cognitive testing, a softwarebased algorithm generates a personalized report that addresses the identified putative contributors to cognitive decline, such as specific pathogens, toxins, or hormonal alterations. ...
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Background: Alzheimer's disease (AD) is the major cause of age-associated cognitive decline, and in the absence of effective therapeutics is progressive and ultimately fatal, creating a dire need for successful prevention and treatment strategies. We recently reported results of a successful proof-of-concept trial, using a personalized, precision medicine protocol, but whether such an approach is readily scalable is unknown. Objective: In the case of AD, there is not a single therapeutic that exerts anything beyond a marginal, unsustained, symptomatic effect. This suggests that the monotherapeutic approach of drug development for AD may not be an optimal one, at least when used alone. Using a novel, comprehensive, and personalized therapeutic system called ReCODE (reversal of cognitive decline), which proved successful in a small, proof-of-concept trial, we sought to determine whether the program could be scaled to improve cognitive and metabolic function in individuals diagnosed with subjective cognitive impairment, mild cognitive impairment, and early-stage AD. Methods: 255 individuals submitted blood samples, took the Montreal Cognitive Assessment (MoCA) test, and answered intake questions. Individuals who enrolled in the ReCODE program had consultations with clinical practitioners, and explanations of the program were provided. Participants had follow-up visits that included education regarding diet, lifestyle choices, medications, supplements, repeat blood sample analysis, and MoCA testing between 2 and 12 months after participating in the ReCODE program. Pre- and post-treatment measures were compared using the non-parametric Wilcoxon signed rank test. Results and conclusions: By comparing baseline to follow-up testing, we observed that MoCA scores either significantly improved or stabilized in the entire participant pool-results that were not as successful as those in the proof-of-concept trial, but more successful than anti-amyloid therapies-and other risk factors including blood glucose, high-sensitivity C-reactive protein, HOMA-IR, and vitamin D significantly improved in the participant pool. Our findings provide evidence that a multi-factorial, comprehensive, and personalized therapeutic program designed to mitigate AD risk factors can improve risk factor scores and stabilize or reverse the decline in cognitive function. Since superior results were obtained in the proof-of-concept trial, which was conducted by a small group of highly trained and experienced physicians, it is possible that results from the use of this personalized approach would be enhanced by further training and experience of the practicing physicians. Nonetheless, the current results provide further support indicating the potential of such an approach for the prevention and reversal of cognitive decline.
... It has been hypothesized that AD and MCI are not due to one cause, but instead multiple contributing factors and that to improve outcomes in Alzheimer's and MCI these multiple contributing factors must be addressed simultaneously (Bredesen et al., 2018). In the manuscript presented here, we take the hypothesis one step further and suggest that the lack of success in identifying a cure, or even a treatment for Alzheimer's, is because common diseases of aging such as cognitive decline, are due to a collection of genetic predispositions interacting with diet, environment, and lifestyle. ...
... Lifestyle changes of proper sleep and exercise (swimming), brain exercises (Brain HQ), and stress reduction methods were prescribed. The importance of these interventions in ApoE ε4 individuals with early Alzheimer's or cognitive decline has been discussed and published previously by Dr. Dale Bredesen (Bredesen et al., 2016;Bredesen et al., 2018;Toups et al., 2021). Additionally, because ApoE ε4 codes for a lipoprotein that interacts with 1,700 different gene promoters, there are many other interventions that make sense for individuals with ApoE ε4 that were referenced by the CDS, and some of these were selected and prescribed (Liao et al., 2017). ...
... As discussed in cases above, carrying the ApoE ε4 allele has been shown to be associated with improper cleavage of APP, mitochondrial dysfunction, oxidative stress, and TNFα mediated inflammation (Kim et al., 2009;Ramirez-Ramirez et al., 2013;Fan et al., 2017;Simonovitch et al., 2019). Thus, many of the basic interventions of the ReCODE protocol were also added empirically (Bredesen et al., 2016;Bredesen et al., 2018). These included a micronized bioavailable curcumin, Omega 3s, CDP-Choline, vitamin D3-K2, sulforaphane, mitochondrial support vitamin, coenzyme q10 (CoQ10), and magnesium threonate. ...
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The landscape of therapeutics for mild cognitive impairment and dementia is quite limited. While many single-agent trials of pharmaceuticals have been conducted, these trials have repeatedly been unable to show improvement in cognition. It is hypothesized that because Alzheimer’s, like many other chronic illnesses, is not a monogenic illness, but is instead caused by the downstream effects of an individual’s genetic variants interacting with each other, the environment, and lifestyle, that improving outcomes will require a personalized, precision medicine approach. This approach requires identifying and then addressing contributing genomic and other factors specific to each individual in a simultaneous fashion. Until recently, the utility of genomics as part of clinical decision-making for Alzheimer’s and cognitive decline has been limited by the lack of availability of a genomic platform designed specifically to evaluate factors contributing to cognitive decline and how to respond to these factors The clinical decision support (CDS) platform used in the cases presented focuses on common variants that relate to topics including, but not limited to brain inflammation, amyloid processing, nutrient carriers, brain ischemia, oxidative stress, and detoxification pathways. Potential interventions based on the scientific literature were included in the CDS, but the final decision on what interventions to apply were chosen by each patient’s physician. Interventions included supplements with “generally regarded as safe (GRAS)” rating, along with targeted diet and lifestyle modifications. We hypothesize that a personalized genomically targeted approach can improve outcomes for individuals with mild cognitive impairment who are at high risk of Alzheimer’s. The cases presented in this report represent a subset of cases from three physicians’ offices and are meant to provide initial proof of concept data demonstrating the efficacy of this method and provide support for this hypothesis. These patients were at elevated risk for Alzheimer’s due to their apolipoprotein E ε4 status. While further prospective and controlled trials need to be done, initial case reports are encouraging and lend support to this hypothesis of the benefit of a genomically targeted personalized medicine approach to improve outcomes in individuals with cognitive decline who are at high risk for Alzheimer’s.
... Individual patients having TDP-43 aberrations can share clinical symptoms within MND, FTD, ALS-FTD, AD, dementia, and several other neurological disorders or combinations of the above. 11,153 For clinicians and doctors, treating the sporadic ALS patients and w90% of FTD patients comprised of FTD-tau or FTD-TDP, which have pivotal TDP-43 pathology, initiating trials addressing therapeutic drugs gap/limitations is of great importance. 154 TDP-43 most likely shares disease etiology with FTD-U patient groups that, until recently, were considered to encompass a blend of several disease entities. ...
... A single arm, expanded case study of the MEND program enrolled 100 patients with mild or subjective cognitive impairment (MCI or SCI, respectively), or AD. 153 The patients in this study were accessed at the beginning and end of treatments using Mini-Mental Status Examination (MMSE) Montreal Cognitive Assessment (MoCA), or Saint Louis University Mental Status (SLUMS) exams and there was a mean improvement of 4.9 points (SD 2.6), which is notable as the trend toward deterioration rather than improvement is normally observed, and, as the authors note, it will be important to confirm these findings in an RCT. ...
... Individual patients having TDP-43 aberrations can share clinical symptoms within MND, FTD, ALS-FTD, AD, dementia, and several other neurological disorders or combinations of the above. 11,153 For clinicians and doctors, treating the sporadic ALS patients and w90% of FTD patients comprised of FTD-tau or FTD-TDP, which have pivotal TDP-43 pathology, initiating trials addressing therapeutic drugs gap/limitations is of great importance. 154 TDP-43 most likely shares disease etiology with FTD-U patient groups that, until recently, were considered to encompass a blend of several disease entities. ...
... A single arm, expanded case study of the MEND program enrolled 100 patients with mild or subjective cognitive impairment (MCI or SCI, respectively), or AD. 153 The patients in this study were accessed at the beginning and end of treatments using Mini-Mental Status Examination (MMSE) Montreal Cognitive Assessment (MoCA), or Saint Louis University Mental Status (SLUMS) exams and there was a mean improvement of 4.9 points (SD 2.6), which is notable as the trend toward deterioration rather than improvement is normally observed, and, as the authors note, it will be important to confirm these findings in an RCT. ...
Chapter
Over the years the transactive response DNA-binding protein (TDP-43), a highly conserved 43 kDa nuclear protein, has been acknowledged as a vital protein in brain health and neuropathological disorders such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Lewy body dementia (LBD), and Parkinson disease (PD). Description of TDP-43 dates back to 1892 when neurologist Arnold Pick first described progressive dementia characterized by atrophy that diverged both clinically and pathophysiologically from AD. In 2006, TDP-43 was identified in ALS and FTD recognized by cytoplasmic inclusions that label ubiquitin (+), whereas tau and α-synuclein stains were negative. Since then, several discoveries have been made which have led to a better understanding of the pathophysiological function of TDP-43 and its intricate links to ALS, FTD, AD, PD, dementia, and few other neurological diseases, all of which shared some common disease mechanisms. In this book chapter, we précis past findings, up-to-date evidence of common physiological function of TDP-43 and the TDP-43 pathobiology witnessed in FTD-TDP, ALS-TDP, and other neurodegenerative diseases such as AD, PD, and LBD. In addition, we deliberate on the accumulating data indicating FTD-TDP and ALS-TDP as two ends of a disease spectrum characterized by a fundamental, main TDP-43 proteinopathy and, thus, contemplate on its implication in precision medicine. Finally, we discuss the status of new advances in TDP-43-associated discovery to neurological practice and care, including the novel prospects to develop better precision diagnostics kits and disease-modifying therapies for ALS-TDP, FTD-TDP, AD, LBD, PD, and other related neurological disorders showing characteristic TDP-43 pathological symptoms.
... Cette intervention consiste à déterminer les caractéristiques métaboliques individuelles afin de permettre une optimisation 740 métabolique, notamment au niveau synaptique. Selon les premiers résultats prometteurs, le nombre de patients qui ont connu une amélioration cognitive dépasserait la centaine à ce jour (Bredesen et al., 2018). D'autres interventions personnalisées pour prévenir les difficultés cognitives qui utilisent des moyens interventionnels maximisant des paramètres physiologiques importants pour favoriser une meilleure adaptation au monde pourraient aboutir à des résultats 745 positifs similaires. ...
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... Cette intervention consiste à déterminer les caractéristiques métaboliques individuelles afin de permettre une optimisation métabolique, notamment au niveau synaptique. Selon les premiers résultats prometteurs, le nombre de patients qui ont connu une amélioration cognitive dépasserait la centaine à ce jour (Bredesen et al., 2018). D'autres interventions personnalisées pour prévenir les difficultés cognitives qui utilisent des moyens interventionnels maximisant des paramètres physiologiques importants pour favoriser une meilleure adaptation au monde pourraient aboutir à des résultats positifs similaires. ...
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... Cette intervention consiste à déterminer les caractéristiques métaboliques individuelles afin de permettre une optimisation métabolique, notamment au niveau synaptique. Selon les premiers résultats prometteurs, le nombre de patients qui ont connu une amélioration cognitive dépasserait la centaine à ce jour (Bredesen et al., 2018). D'autres interventions personnalisées pour prévenir les difficultés cognitives qui utilisent des moyens interventionnels maximisant des paramètres physiologiques importants pour favoriser une meilleure adaptation au monde pourraient aboutir à des résultats positifs similaires. ...
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... These trials have focused on healthy people not yet on the AD spectrum and monized the risk categories including chronic stress, immune dysfunction, cardiovascular risk, glucose dysregulation, and detailed assessments for cognitive decline in each risk category to develop a custom intervention.19,20 Dr. Dale Bredesen has trailblazed the field of clinical, multi-component, precision medicine for the treatment of cognitive decline with promising results.21 However, these approaches have yet to be rigorously tested.vene ...
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Background: Effective therapeutics for Alzheimer's disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy. Objective: To determine whether a precision medicine approach to Alzheimer's disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial. Methods: Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t = 0, 3, 6, and 9 months. Results: All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer's Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved. Conclusion: Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.
Chapter
For most progressively crippling neurocognitive disorders, treatment options are scarce and inadequate. For these refractory neuropathologies, for example, Alzheimer's disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration, alterations in the transactive response DNA-binding protein TDP-43 is commonly encountered. TDP-43 is an evolutionarily well-conserved protein, indispensable for embryonic development in nearly all species, and is ubiquitously expressed in mammalian adult tissue. It is part of the family of heterogeneous nuclear ribonucleoproteins which bind to DNA and RNA. It is associated with many aspects of RNA processing (e.g., transcription, splicing, miRNA biogenesis, and RNA transport and stability) and with the coregulation of translation. In many nervous system disorders, TDP-43's normal functions are attenuated and new aberrant functions emerge. Loss- and gain-of-function may emanate from DNA mutation, mislocalization, posttranslational modification, abnormal interaction partners, or cleavage into truncated forms which have a propensity to aggregate and to cause inclusion bodies. Under normal conditions TDP-43 is enriched in the nucleus, but in neuropathology it is markedly reduced in the nucleus and full-length or fragmented conformations accumulate in other compartments, i.e., in the cytoplasm, rough ER, micronuclei, stress granules, and mitochondria. Aggregates and alternative forms may be released from a single cell, through exosomes, and incorporated into nearby cells, thereby propagating pathogenic versions. Pathologic changes in TDP-43 are hallmarks in the etiology of several neuropathologies and can sometimes occur where there are no discernible TARDBP mutations but where mutations have occurred in interaction partners that impede TDP-43's pleiotropic activities. This chapter describes new interventions for treating gravely disabling cognitive and neurodegenerative disorders, and for exploring how such interventions might oppose TDP-43 proteinopathy as an integral part of the described interventions mechanisms of action.
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