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Aging (Albany NY)

. 2016 Jun 12;8(6):1250–1258. doi: 10.18632/aging.100981

Reversal of cognitive decline in Alzheimer's disease

Dale E Bredesen 1,2, Edwin C Amos 3, Jonathan Canick 4, Mary Ackerley 5, Cyrus Raji 6, Milan Fiala 7, Jamila Ahdidan 8

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PMCID: PMC4931830  PMID: 27294343

Abstract

Alzheimer's disease is one of the most significant healthcare problems nationally and globally. Recently, the first description of the reversal of cognitive decline in patients with early Alzheimer's disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), was published [1]. The therapeutic approach used was programmatic and personalized rather than monotherapeutic and invariant, and was dubbed metabolic enhancement for neurodegeneration (MEND). Patients who had had to discontinue work were able to return to work, and those struggling at work were able to improve their performance. The patients, their spouses, and their co-workers all reported clear improvements. Here we report the results from quantitative MRI and neuropsychological testing in ten patients with cognitive decline, nine ApoE4+ (five homozygous and four heterozygous) and one ApoE4−, who were treated with the MEND protocol for 5-24 months. The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective. These results have far-reaching implications for the treatment of Alzheimer's disease, MCI, and SCI; for personalized programs that may enhance pharmaceutical efficacy; and for personal identification of ApoE genotype.

요약

알츠하이머병은

국내 및 전 세계적으로 가장 심각한 의료 문제 중 하나입니다.

최근 초기 알츠하이머병 또는

그 전조 증상인 경도인지장애(MCI) 및 주관적 인지장애(SCI) 환자의 인지 기능 저하 반전에 대한

최초의 설명이 발표되었습니다[1].

사용된 치료적 접근 방식은

단일 치료적이고 불변적인 것이 아니라 프로그램적이고 개인화된 것으로,

신경 퇴화를 위한 대사 증진(MEND)이라고 불렀습니다

 metabolic enhancement for neurodegeneration .

직장을 그만둬야 했던 환자들은 직장에 복귀할 수 있었고,

업무에 어려움을 겪고 있던 환자들은

업무 성과를 개선할 수 있었습니다.

환자, 배우자, 동료 모두 뚜렷한 개선 효과를 보고했습니다.

여기에서는

5-24개월 동안 MEND 프로토콜로 치료받은 인지기능 저하 환자

10명(ApoE4+ 9명(동형접합 5명, 이형접합 4명), ApoE4- 1명)의

정량적 MRI 및 신경심리 검사 결과를 보고합니다.

개선의 정도는 전례가 없는 것으로,

인지 기능 저하에 대한 이 프로그램적 접근 방식이

매우 효과적이라는 객관적인 증거를 추가로 제공합니다.

이러한 결과는

알츠하이머병, MCI 및 SCI 치료, 의약품 효능을 향상시킬 수 있는 개인 맞춤형 프로그램,

ApoE 유전자형의 개인 식별에 광범위한 영향을 미칩니다.

Keywords: neurodegeneration, cognition, biomarkers, dementia, neuropsychology, imaging, Alzheimer's disease, Apolipoprotein E

INTRODUCTION

Alzheimer's disease is now the third leading cause of death in the United States, following only cardio-vascular disease and cancer [1]. There are approximately 5.2 million Americans with AD, but this estimate ignores the many young Americans destined to develop AD during their lifetimes: given the lifetime risk of approximately 15% when including all ApoE genotypes, as many as 45 million of the 318 million Americans now living may develop AD during their lifetimes if no prevention is instituted [2].

Effective treatment of Alzheimer's disease has been lacking, but recently a novel programmatic approach involving metabolic enhancement was described, with promising anecdotal results [3]. This treatment is based on connectomic studies [4] and previous transgenic findings [5] as well as epidemiological studies of various monotherapeutic components of the overall program [6]. The approach is personalized, responsive to suboptimal metabolic parameters that reflect a network imbalance in synaptic establishment and maintenance vs. reorganization, and progressive in that continued optimization is sought through iterative treatment and metabolic characterization.

Here we report the initial follow-up of ten patients who were treated with this metabolic programmatics approach. One patient had well documented mild cognitive impairment (MCI), with a strongly positive amyloid-PET (positron emission tomography) scan, positive FDG-PET scan (fluorodeoxyglucose PET scan), abnormal neuropsychological testing, and hippocampal volume reduced to 17th percentile; after 10 months on the MEND protocol, his hippocampal volume had increased to 75th percentile, in association with a reversal of cognitive decline. Another patient had well documented early Alzheimer's disease, with a positive FDG-PET scan and markedly abnormal neuro-psychological testing. After 22 months on the MEND protocol, he showed marked improvement in his neuropsychological testing, with some improvements reaching three standard deviations from his earlier testing.

The initial results for these patients show greater improvements than have been reported for other patients treated for Alzheimer's disease. The results provide further support for the suggestion that such a comprehensive approach [3] to treat early Alzheimer's disease and its precursors, MCI and SCI, is effective. The results also support the need for a large-scale, personalized clinical trial using this protocol.

소개

알츠하이머병은

현재 미국에서 심혈관 질환과 암에 이어

세 번째 주요 사망 원인입니다[1].

약 520만 명의 미국인이 알츠하이머병을 앓고 있지만, 이 추정치는 일생 동안 알츠하이머병에 걸릴 수 있는 많은 젊은 미국인을 무시한 것입니다. 모든 ApoE 유전자형을 포함할 경우 평생 위험도가 약 15%인 점을 감안하면 현재 살아있는 3억 1800만 명의 미국인 중 4500만 명이 예방 조치를 취하지 않으면 일생 동안 AD에 걸릴 수 있습니다[2].

알츠하이머병에 대한 효과적인 치료법은 아직까지 부족하지만,

최근 신진대사 개선과 관련된 새로운 프로그램적 접근법이

유망한 일화적 결과와 함께 설명되었습니다 [3].

이 치료법은

전체 프로그램의 다양한 단일 치료 성분에 대한 역학 연구 [6]뿐만 아니라

연결체 연구 [4]와 이전의 형질전환 연구 결과 [5]를 기반으로 합니다.

이 접근법은

시냅스 구축 및 유지와 재구성의 네트워크 불균형을 반영하는

차선의 대사 매개변수에 반응하는 개인 맞춤형이며,

반복적인 치료와 대사 특성화를 통해

지속적인 최적화를 추구한다는 점에서 점진적입니다.

여기에서는

이러한 대사 프로그래밍 접근법으로 치료를 받은 10명의 환자들에 대한

초기 추적 관찰 결과를 보고합니다.

한 환자는 아밀로이드-PET(양전자방출단층촬영) 스캔 양성,

FDG-PET(플루오로데옥시글루코스 PET 스캔 양성,

신경심리검사 이상,

해마 용적 17백분위수까지 감소한 경도인지장애(MCI)가 잘 기록되어 있었으나

MEND 프로토콜 10개월 후 인지력 저하가 반전되면서

해마 용적이 75백분위수로 증가했습니다.

또 다른 환자는

초기 알츠하이머병으로 FDG-PET 스캔에서 양성이었고

신경심리 검사에서도 현저하게 비정상적인 결과가 나왔습니다.

MEND 프로토콜을 22개월 동안 시행한 결과,

신경심리 검사에서 현저한 호전을 보였으며,

일부 개선은 이전 검사에서 표준편차 3에 달했습니다.

이 환자들의 초기 결과는

알츠하이머병으로 치료받은 다른 환자들에 대해 보고된 것보다

더 큰 개선 효과를 보여주었습니다.

이 결과는

초기 알츠하이머병과 그 전조 증상인 MCI 및 SCI를 치료하기 위한

이러한 포괄적인 접근법[3]이 효과적이라는 제안을 더욱 뒷받침합니다.

또한 이 연구 결과는

이 프로토콜을 활용한 대규모 개인 맞춤형 임상시험의 필요성을

뒷받침합니다.

RESULTS

Case studiesPatient 1

A 66-year-old professional man presented with what he described as “senior moments” (for example, forgetting where his keys were or forgetting appointments) of two-years duration, and difficulty performing his work. There was a positive family history of dementia in both parents. He was an ApoE4 heterozygote (3/4), his amyloid PET scan was markedly positive, and his fluorodeoxyglucose (FDG) PET scan showed temporoparietal reduced glucose utilization indicative of Alzheimer's disease. An MRI showed hippocampal volume at only 17th percentile for his age. His neuropsychological testing was compatible with a diagnosis of MCI. His hs-CRP was 9.9mg/l, albumin: globulin ratio was 1.6, homocysteine 15.1μmol/l, fasting glucose 96mg/dl, hemoglobin A1c 5.5%, fasting insulin 32mIU/l, 25-hydroxychole-calciferol 21ng/ml, TSH 2.21mIU/l, and testosterone 264ng/dl.

He began the MEND protocol [3], lost 18 pounds, and after three months his wife reported that his memory had improved. He noted that his work came more easily to him. However, after five months, he discontinued the majority of the program for approximately three weeks. His wife came home to find his car in the driveway, idling with the keys in the ignition, while he was inside the house, working and unaware that he had left the car idling in the driveway. He re-initiated the program, and had no further such episodes.

After 10 months on the program, he returned for a follow-up MRI, which was subjected to volumetric analyses by both Neuroquant [7] and Neuroreader [8] programs. The former indicated an increase in hippocampal volume from 17th percentile to 75th percentile, with an associated absolute increase in hippocampal volume of 11.7%. The Neuroreader program showed an absolute increase from 7.65cc to 8.3cc, which represents an 8.5% absolute increase in size. The associated Z-scores were −4.6 and +1.6, respectively, disclosing an increase from <5th percentile to the 90th percentile. Thus although the Neuroquant and Neuroreader analyses differed somewhat in the amplitude of the effect detected, they were in agreement that a relatively large magnitude increase in hippo-campal volume had occurred.

Follow-up metabolic analysis also disclosed improvement, with hs-CRP having decreased from 9.9mg/l to 3mg/l, fasting insulin having decreased from 32mIU/l to 8mIU/l, homocysteine having decreased from 15.1μmol/l to 8μmol/l, and 25-hydroxychole-calciferol having increased from 21ng/ml to 40ng/ml. See Table 1 for a summary of the responses of all patients to the treatment program.

결과사례

연구환자 1

66세의 한 전문직 남성이

2년 전부터 '노인성 순간senior moment'(예: 열쇠가 어디에 있는지 잊어버리거나 약속을 잊어버리는 등)이 나타나고

업무 수행에 어려움을 겪기 시작했습니다.

양쪽 부모 모두 치매 가족력이 있었습니다.

그는 ApoE4 이형접합체(3/4)였고, 아밀로이드 PET 스캔은 현저하게 양성이었으며,

플루오로데옥시글루코스(FDG) PET 스캔은

알츠하이머병을 나타내는 측두정위 포도당 이용률 감소를 보였습니다.

MRI 검사 결과 해마 용적은 나이에 비해 17번째 백분위수에 불과했습니다. 그의 신경심리 검사 결과는 MCI 진단과 일치했습니다. 그의 hs-CRP는 9.9mg/l, 알부민: 글로불린 비율은 1.6, 호모시스테인 15.1μmol/l, 공복 혈당 96mg/dl, 헤모글로빈 A1c 5.5%, 공복 인슐린 32mIU/l, 25-hydroxychole-calciferol 21ng/ml, TSH 2.21mIU/l, 테스토스테론 264ng/dl이었고 수치가 높았습니다.

그는 MEND 프로토콜[3]을 시작하여 18파운드를 감량했고, 3개월 후 아내는 그의 기억력이 좋아졌다고 보고했습니다. 그는 일이 더 쉽게 다가왔다고 말했습니다. 그러나 5개월 후, 그는 약 3주 동안 대부분의 프로그램을 중단했습니다. 그의 아내는 집에 돌아와 차가 시동키를 꽂아둔 채 공회전하고 있는 것을 발견했고, 그는 집 안에서 일을 하느라 차가 차도에 공회전하도록 방치한 사실을 알지 못했습니다. 그는 프로그램을 다시 시작했고 더 이상 그런 에피소드가 발생하지 않았습니다.

프로그램 10개월 후, 그는 후속 MRI를 촬영하기 위해 다시 돌아왔고, 뉴로퀀트[7]와 뉴로리더[8] 프로그램을 통해 체적 분석을 받았습니다. 전자는 해마 용적이 17번째 백분위수에서 75번째 백분위수로 증가했으며, 해마 용적의 절대적인 증가율은 11.7%로 나타났습니다. 뉴로리더 프로그램은 7.65cc에서 8.3cc로 8.5%의 절대적인 크기 증가를 보였습니다. 관련 Z 점수는 각각 -4.6과 +1.6으로, 5번째 백분위수 미만에서 90번째 백분위수까지 증가했음을 보여줍니다. 따라서 뉴로퀀트와 뉴로리더의 분석은 감지된 효과의 크기에서 다소 차이가 있었지만, 하마-뇌량에서 상대적으로 큰 규모의 증가가 일어났다는 점에서는 일치했습니다.

후속 대사 분석에서도 hs-CRP는 9.9mg/l에서 3mg/l로, 공복 인슐린은 32mIU/l에서 8mIU/l로, 호모시스테인은 15.1μmol/l에서 8μmol/l로, 25-하이드록시콜-칼시페롤은 21ng/ml에서 40ng/ml로 감소하는 등 개선된 것으로 밝혀졌습니다. 치료 프로그램에 대한 모든 환자의 반응을 요약한 표 1을 참조하세요.

Table 1. Patient responses to the MEND treatment protocol [3].

PatientDiagnosisApoE GenotypeTreatment Outcome1

66yoM	MCI, type 1 (inflammatory)	3/4	Marked subjective improvement, hippocampal volume increase 17th->75th %ile
69yoM	AD, type 2 (atrophic)	3/4	Marked subjective improvement, quantitative neuropsychological testing improvement
49yoF	MCI, type 2 (and possibly type 3 (toxic))	4/4	Marked subjective improvement, neuropsychological testing improvement
49yoF	MCI, type 2	2/4	Marked subjective improvement, neuropsychological testing improvement
55yoF	MCI, type 2	4/4	Marked subjective improvement, neuropsychological testing improvement
74yoM	AD, type 1	4/4	Subjective improvement, MMSE 23->30
62yoM	AD, type 1.5 (glycotoxic)	4/4	Subjective improvement, MMSE 22->29
68yoM	MCI, type 1.5	3/4	Subjective improvement, neuropsychological testing improvement
54yoF	AD, type 3	3/3	Clear subjective improvement, MoCA 19->21
54yoF	MCI, type 2	4/4	Subjective improvement, neuropsychological testing improvement

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1

See text for details of treatment outcome.

Comment

This patient had well documented Alzheimer's disease, with a strongly positive amyloid PET scan, characteristic FDG PET scan, abnormal neuropsychological studies, positive family history, ApoE4-positive (3/4) genotype, and hippocampal volume of 17th percentile. During his 10 months on the MEND protocol, he interrupted his otherwise good compliance once, and this was associated with an episode of memory loss, in which he failed to remember that he had left his car in the driveway while he was working in his house. He returned to the protocol at that time, and after 10 months in total, he demonstrated not only a marked symptomatic improvement (which had begun after approximately three months on the protocol), but also a dramatic increase in hippocampal volume. More modest hippocampal volumetric increases have been described with exercise [9] and with a brain-training program [10], but to our knowledge the magnitude of hippocampal volume increase that occurred with this patient has not been reported previously.

코멘트

이 환자는 아밀로이드 PET 스캔, 특징적인 FDG PET 스캔, 비정상적인 신경심리 검사, 양성 가족력, ApoE4 양성(3/4) 유전자형, 17번째 백분위수 해마 용적 등 알츠하이머병이 잘 기록된 환자였습니다.

그는 10개월 동안 MEND 프로토콜을 따르는 동안

한 번은 순응도가 좋았던 프로토콜을 중단했는데,

이는 집에서 일하던 중 차를 차도에 두고 왔다는 사실을 기억하지 못하는 기억상실증과 관련이 있었습니다.

그 후 다시 프로토콜에 복귀한 그는

총 10개월이 지난 후,

약 3개월 후부터 시작된 뚜렷한 증상 개선뿐만 아니라

해마 용적의 극적인 증가를 보여주었습니다.

운동 [9] 및 두뇌 훈련 프로그램 [10]을 통해

해마 용적이 더 완만하게 증가한 사례도 보고되었지만,

이 환자에서 발생한 해마 용적 증가의 규모는 이전에 보고된 적이 없습니다.

환자 2

이 글은 이전 글 [3]에서 소개한 환자 2에 대한 후속 사례입니다.

69세의 기업가이자

전문직 남성인 이 환자는

11년 동안 서서히 진행되어 온 기억 상실이

지난 1~2년 동안 가속화되었다고 호소했습니다.

2002년,

58세의 나이에 사물함의 자물쇠 비밀번호를 기억하지 못했고,

그는 이것이 평소와 다르다고 느꼈습니다.

2003년에 그는 FDG PET 스캔을 받았는데,

양측 두정측두피질과 좌측>우측 측두엽의 포도당 이용률은 감소했지만

전두엽, 후두피질, 기저핵의 이용률은

보존된 초기 알츠하이머병의 전형적인 패턴을 보이는 것으로 판독되었습니다.

2003년, 2007년, 2013년에 정량적 신경심리검사를 받은 결과, 캘리포니아 언어 학습 검사(CVLT), 스트룹 색채 검사에서 16번째 백분위수, 청각 지연 기억에서 13번째 백분위수가 감소한 것으로 나타났습니다. 2013년에는 ApoE4(3/4) 이형접합인 것으로 밝혀졌습니다. 그는 직장에서 얼굴을 인식하는 데 점진적으로 어려움을 겪었고(프로소파그노시아), 조수에게 일일 일정을 알려줘야 했다고 말했습니다. 그는 또한 책을 여러 장 읽다가 그제야 이전에 읽었던 책이라는 사실을 깨달은 일화를 회상하기도 했습니다. 또한 그는 평생 동안 가지고 있던 능력, 즉 머릿속에서 숫자를 빠르게 더하는 능력을 잃었습니다.

그는 알츠하이머병 환자라는 상태와 뚜렷한 진행 속도,

그리고 2013년 시험에서의 저조한 성적을 고려할 때

“자신의 일을 정리해야 한다”는 조언을 받았습니다.

그의 사업은 일을 계속할 수 없어 문을 닫는 과정에 있었습니다.

그의 실험실 수치에는

호모시스테인 18μmol/l, CRP <0.5mg/l, 25-하이드록시콜레칼시페롤 28ng/ml, 헤모글로빈 A1c 5.4%, 혈청 아연 78mcg/dl, 혈청 구리 120mcg/dl, 구리:아연 비율 1. 54, 세룰로플라즈민 25mg/dl, 프레그네놀론 6ng/dl, 테스토스테론 610ng/dl, 알부민:글로불린 비율 1.3, 콜레스테롤 165mg/dl(아토르바스타틴 복용), HDL 92mg/dl, LDL 64mg/dl, 중성지방 47mg/dl, AM 코르티솔 14mcg/dl, 유리 T3 3.02pg/ml, 유리 T4 1.27ng/l, TSH 0.58mIU/l 및 BMI 24.9입니다.

그는 MEND 치료 프로그램을 시작했고

6개월 후 아내와 동료,

그리고 자신도 모두 개선된 것을 확인했습니다.

그는 10파운드를 감량했습니다.

그는 이전과 달리 직장에서 얼굴을 알아볼 수 있게 되었고,

하루 일정을 기억할 수 있게 되었으며,

업무도 무리 없이 수행할 수 있게 되었습니다.

또한 반응 속도도 빨라졌다는 평가를 받았습니다.

점진적인 인지 기능 저하로 잃어버렸던 머릿속 숫자 열을 빠르게 더하는 능력도 회복되었습니다.

그의 아내는 남편이 분명 개선된 모습을 보였지만,

더 놀라운 효과는

지난 1~2년 동안 감퇴 속도가 빨라지던 것이

완전히 멈췄다는 점이라고 지적했습니다.

프로그램 22개월 후,

그는 후속 정량적 신경심리 검사를 위해 다시 돌아왔고,

그 결과 CVLT-IIB는 3백분위수에서 84백분위수(3표준편차)로,

총 인지 적중률은 1백분위수 미만에서 50백분위수, CVLT-II는 54백분위수에서 96백분위수, 청각 지연 기억은 13백분위수에서 79백분위수, 역 숫자 범위는 24백분위수에서 74백분위수, 처리 속도는 93백분위수에서 98백분위수로 크게 개선된 것으로 밝혀졌습니다.

폐업 중이던 그의 사업은 다시 활기를 되찾았고,

이전 운영 사이트에 새로운 사이트가 추가되었습니다.

Comment

This patient had well-documented Alzheimer's disease, with an ApoE4-positive genotype, characteristic FDG-PET scan, characteristic abnormalities on neuropsychological testing, well documented decline on longitudinal quantitative neuropsychological testing, and progression of symptoms. After two years on the protocol, his symptoms and neuropsychological testing improved markedly. The neuropsychologist who performed and eval‎uated his testing pointed out that his improvement was beyond that which had been observed in the neuropsychologist's 30 years of practice.

코멘트
이 환자는 ApoE4 양성 유전자형, 특징적인 FDG-PET 스캔, 신경심리검사의 특징적인 이상, 종단적 정량적 신경심리검사에서 잘 기록된 감소, 증상의 진행 등 알츠하이머병이 잘 기록된 환자였습니다. 프로토콜에 따라 2년이 지난 후, 그의 증상과 신경심리검사는 현저하게 개선되었습니다. 그의 검사를 수행하고 평가한 신경심리학자는 그의 개선이 신경심리학자의 30년 진료 경력에서 관찰된 것 이상의 개선이라고 지적했습니다.

Patient 3

A woman late in her fifth decade began to note episodes of forgetfulness, such as returning home from shopping without the items she had purchased. She also placed household items in the wrong locations repeatedly, and frequently failed to recognize previously familiar faces. She had difficulty remembering which side of the road on which to drive. A male cousin had developed Alzheimer's disease in his fifth decade. She was found to be an ApoE4 homozygote. On-line cognitive eval‎uation showed her to be at the 35th percentile for her age, despite her having been an excellent student earlier in her life.

She began various parts of the MEND protocol, and slowly added protocol features over several months. She began to note improvement, and her on-line cognitive eval‎uation improved to the 98th percentile, where it has remained to the current time, with her having been on the protocol for 3.5 years.

환자 3

50대 후반의 한 여성은 쇼핑을 마치고 집에 돌아와서 

구입한 물건이 없는 등 건망증 증상을 보이기 시작했습니다. 

또한 가정용품을 엉뚱한 위치에 반복해서 놓는가 하면, 

익숙한 얼굴을 자주 알아보지 못했습니다. 

도로의 어느 쪽에서 운전해야 하는지 기억하는 데 어려움을 겪었습니다. 

한 남성 사촌은 50대에 알츠하이머병에 걸렸습니다. 

그녀는 ApoE4 동형 접합자인 것으로 밝혀졌습니다. 

온라인 인지 평가 결과, 그녀는 어렸을 때 우수한 학생이었음에도 불구하고 

나이에 비해 35번째 백분위수에 속하는 것으로 나타났습니다.

그녀는 

MEND 프로토콜의 다양한 부분을 시작했고, 

몇 달에 걸쳐 프로토콜 기능을 천천히 추가했습니다. 

그녀는 개선되는 것을 느끼기 시작했고, 

온라인 인지 평가는 98번째 백분위수까지 향상되었으며, 

3.5년 동안 프로토콜을 사용하면서 현재까지도 그 상태를 유지하고 있습니다.

Comment

This patient showed early but definite cognitive decline, documented by on-line quantitative cognitive testing. Her marked improvement has now been sustained for 3.5 years. As described for patient 3 in a previous report [3], her improvement was iterative, with continued optimization over several months.

코멘트

이 환자는 온라인 정량적 인지 테스트를 통해 초기에 분명한 인지 기능 저하를 보였습니다.

이 환자의 현저한 개선은 현재 3.5년 동안 지속되고 있습니다.

이전 보고서 [3]에서 환자 3에 대해 설명한 것처럼,

그녀의 개선은 몇 달에 걸쳐 지속적으로 최적화되면서 반복적으로 이루어졌습니다.

Patient 4

A 49-year-old woman noted progressive difficulty with word finding, and noted that her vocabulary had become more limited. She also began to feel unsure about her navigation during driving. She also complained of difficulty with facial recognition (prosopagnosia). Her recall was affected, and she described the requirement of “more energy” for recall of events. She had difficulty with remembering scheduled events. She also noted that her clarity and sharpness were reduced, leading to difficulties assisting her children with schoolwork. She had difficulty with complex conversations, and with reading comprehension. She also lost the ability she had had to speak two foreign languages.

Her family history was positive for Alzheimer's disease in her father, and her ApoE genotype was 2/4. Her MRI was read as normal, but volumetrics were not included. She underwent quantitative neuropsychological testing at a major university center, and was told that she was in the early stages of cognitive decline and therefore ineligible for the Alzheimer's prevention program, since she was already too late in the disease course for prevention. Her homocysteine was 10μM, hs-CRP 0.6mg/l, hemoglobin A1c 5.2%, fasting insulin 7mIU/l, TSH 1.6mIU/l, and 25-hydroxycholecalciferol 35ng/ml.

She began on the MEND protocol, and over the next several months she noted a clear improvement in recall, reading, navigating, vocabulary, mental clarity, and facial recognition. Her foreign language abilities returned. Nine months after her initial neuro-psychological testing, the testing was repeated at the same university site, and she was told that she no longer showed evidence of cognitive decline. Immediate and delayed recall, as well as semantic knowledge, executive function, and processing speed, had all shown improvement.

환자 4
49세의 한 여성은 단어 찾기가 점차 어려워지고 어휘력이 점점 더 제한되고 있다고 말했습니다. 또한 운전 중 내비게이션에 대해 불안감을 느끼기 시작했습니다. 또한 얼굴 인식에 어려움을 호소했습니다(프로소파그노시아). 기억력도 영향을 받아 사건을 기억하는 데 “더 많은 에너지”가 필요하다고 설명했습니다. 예정된 이벤트를 기억하는 데 어려움을 겪었습니다. 또한 명료성과 예리함이 감소하여 자녀의 학업을 돕는 데 어려움을 겪고 있다고 언급했습니다. 복잡한 대화와 독해력에도 어려움을 겪었습니다. 또한 두 가지 외국어를 구사할 수 있는 능력도 잃었습니다.

그녀의 가족력은 아버지가 알츠하이머병에 양성 반응을 보였고, 그녀의 ApoE 유전자형은 2/4였습니다. 그녀의 MRI 판독은 정상으로 나왔지만 체적은 포함되지 않았습니다. 그녀는 주요 대학 센터에서 정량적 신경심리 검사를 받았는데, 인지 기능 저하 초기 단계에 있어 예방을 위한 알츠하이머 예방 프로그램을 받을 자격이 없다는 말을 들었습니다. 그녀의 호모시스테인은 10μM, hs-CRP 0.6mg/l, 헤모글로빈 A1c 5.2%, 공복 인슐린 7mIU/l, TSH 1.6mIU/l, 25-하이드록시콜레칼시페롤 35ng/ml였습니다.

MEND 프로토콜을 시작한 후 몇 달 동안 그녀는 

기억력, 읽기, 탐색, 어휘력, 정신 명료성, 얼굴 인식 능력이 뚜렷하게 개선되었습니다. 

외국어 능력도 회복되었습니다. 

처음 신경심리 검사를 받은 지 9개월 후, 

같은 대학에서 같은 검사를 반복한 결과 

더 이상 인지 기능 저하의 증거가 보이지 않는다는 결과를 받았습니다. 

즉각 및 지연 회상, 의미적 지식, 실행 기능, 처리 속도 모두 개선된 것으로 나타났습니다.

Comment

This patient had typical early amnestic MCI, which reverted over several months, resulting in a normal neuropsychological examination after nine months. She remains asymptomatic after one year on the program.

코멘트

이 환자는 전형적인 초기 기억상실성 MCI를 보이다가 

수개월에 걸쳐 회복되어 9개월 후 신경심리검사에서 정상 판정을 받았습니다. 

이 환자는 프로그램 참여 1년 후에도 무증상을 유지하고 있습니다.

Patient 5

A 55-year-old woman presented with memory concerns of two-years duration. She had a positive family history of dementia in an aunt and a grandmother. She was an ApoE4 homozygote and a TOMM40 homozygote (G/G).

She experienced difficulties with word recall several times a day, either being unable to recall the word at all or substituting the wrong word in its place. For example, she would say a word like “tweezers” when she meant to say “tongs” (semantic paraphasic errors). She also experienced an increase in spelling errors as she typed on her computer. As a professional writer and editor with a master's degree in English, she found these issues very troubling. She often lost her train of thought while speaking, requiring her to ask others what she had just said. In addition, she would misplace items and forget why she had walked into a room. She would also forget some things her husband had told her or asked her to do.

She began the MEND protocol, and after four months her husband reported that her memory had improved. She noted that her word recall was as good as it had ever been, and she was no longer experiencing an increase in spelling errors. She also reported that she rarely lost her train of thought, but if she went off on a tangent or if someone interrupted her, that issue might return. However, if she paused and gave herself a few seconds, she could find her way back to her original train of thought without asking for help. In addition, she no longer forgot why she had entered a room, and only rarely misplaced items.

Her primary care provider noted that, in her professional opinion, her cognition had returned to normal after four months on the protocol, and an on-line cognitive test (CNS Vital Signs), performed prior to the start of the protocol and then again after five months on the protocol, confirmed this opinion: her overall cognitive assessment (neurocognitive index) had increased from 16th percentile to 73rd percentile; composite memory from 1st percentile to 61st percentile; verbal memory from 3rd percentile to 93rd percentile; visual memory from 5th percentile to 14th percentile; executive function from 14th percentile to 58th percentile; and processing speed from 37th percentile to 81st percentile. Improvement had occurred in all sub-tests.

환자 5

55세 여성이 2년간 지속된 기억력 문제를 호소했습니다. 그녀는 이모와 할머니에게 치매 가족력이 있었습니다. 그녀는 ApoE4 동형접합체이자 TOMM40 동형접합체(G/G)였습니다.

그녀는 하루에 여러 번 단어를 전혀 기억하지 못하거나 잘못된 단어를 그 자리에 대입하는 등 단어 회상에 어려움을 겪었습니다. 예를 들어, '집게'라고 말해야 할 때 '핀셋'과 같은 단어를 말하기도 했습니다(의미상 의역 오류). 또한 컴퓨터로 타이핑할 때 철자 오류가 늘어나는 것을 경험했습니다. 영어 석사 학위를 가진 전문 작가이자 편집자인 그녀는 이러한 문제를 매우 괴롭게 여겼습니다. 그녀는 종종 말하는 도중 생각의 흐름을 잃어버려 방금 말한 내용을 다른 사람에게 물어봐야 했습니다. 또한 물건을 잘못 놓거나 방에 들어온 이유를 잊어버리기도 했습니다. 또한 남편이 말했거나 부탁한 것을 잊어버리기도 했습니다.

그녀는 MEND 프로토콜을 시작했고, 

4개월 후 남편은 그녀의 기억력이 좋아졌다고 보고했습니다. 

그녀는 단어 기억력이 예전만큼 좋아졌고 

철자 오류도 더 이상 증가하지 않았다고 말했습니다. 

또한 그녀는 생각의 흐름을 잃는 일은 거의 없었지만, 다른 길로 가거나 누군가가 방해하면 그 문제가 재발할 수 있다고 보고했습니다. 하지만 잠시 멈추고 몇 초만 시간을 내면 도움을 요청하지 않고도 원래의 생각의 궤도로 돌아갈 수 있었습니다. 또한 그녀는 더 이상 방에 들어온 이유를 잊어버리지 않았고 물건을 잘못 놓는 일도 거의 없었습니다.

그녀의 주치의는 

프로토콜 4개월 후 그녀의 인지가 정상으로 돌아왔다는 전문적인 의견을 제시했으며, 

프로토콜 시작 전과 프로토콜 5개월 후 다시 실시한 온라인 인지 테스트(CNS 바이탈 사인)를 통해 

이러한 의견을 확인했습니다: 

전반적인 인지 평가(신경인지 지수)는 16백분위수에서 73백분위수로, 종합 기억력은 1백분위수에서 61백분위수로, 언어 기억력은 3백분위수에서 93백분위수로, 시각 기억력은 5백분위수에서 14백분위수로, 실행 기능은 14백분위수에서 58백분위수로, 처리 속도는 37백분위수에서 81백분위수로 증가했음을 확인할 수 있었습니다. 모든 하위 테스트에서 개선이 이루어졌습니다.

Comment

This patient is homozygous for ApoE4, and presented with amnestic MCI. She showed a clear response, both subjectively and objectively, to the metabolic protocol, and has sustained improvement over seven months.

Patient 6

A 74-year-old attorney presented with a five-year history of memory loss and word-finding difficulty. His family history was positive for dementia in his mother, beginning at the age of 75 years. He had been eval‎uated at an Alzheimer's disease center at the onset of his memory loss, and was found to be ApoE4/4, with MRI showing ventricular enlargement and temporal lobe atrophy, right > left, and FDG-PET showing reduced glucose utilization in the temporal lobes and the precuneus, compatible with Alzheimer's disease. Neuropsychological testing was compatible with a diagnosis of amnestic MCI. He was treated with donepezil, memantine, and intravenous immunoglobulin, and his MMSE fell from 27 to 23 over three years. He noted no improvement with the treatment.

He began the MEND protocol, and after six months, his MFI (phagocytosis index) was measured at 1260, with normal being >500 and most Alzheimer's patients scoring <500 [11, 12]. His MMSE was 29. He returned three months later, his MMSE was 30, and his MFI was 1210. He then returned three months after that, complaining that he had taken a trip, gone off much of the protocol, come under stress, and he felt that his memory had declined. His MFI at that visit had dropped to 230, a typical score for a patient with Alzheimer's disease, and his MMSE was 28. He was placed back on the protocol, and returned two months later, with MFI of 1100 and MMSE of 30. Over the ensuing 12 months, his MFI remained >1000 and his MMSE remained at 30.

환자 6

74세의 한 변호사가 5년 전부터 기억력 감퇴와 단어 찾기가 어려워졌다고 내원했습니다.

그의 가족력은 어머니가 75세부터 치매를 앓았다는 양성 판정을 받았습니다.

기억력 감퇴가 시작되었을 때 알츠하이머병 센터에서 검사를 받았는데,

MRI에서 우측>좌측으로 심실 비대 및 측두엽 위축이 관찰되었고, FDG-PET에서 측두엽과 전두엽의 포도당 이용률 감소가 알츠하이머병과 일치하는 ApoE4/4로 판명되었습니다. 신경심리검사는 기억상실성 MCI 진단과 일치했습니다. 그는 도네페질, 메만틴, 정맥 내 면역글로불린으로 치료를 받았고 3년 동안 MMSE가 27에서 23으로 떨어졌습니다. 그는 치료에도 호전이 없었다고 말했습니다.

그는 MEND 프로토콜을 시작했고 6

개월 후 MFI(식세포증식지수)가 1260으로 측정되었으며 정상은 500 이상이고

대부분의 알츠하이머 환자는 500 미만이었습니다 [11, 12].

그의 MMSE는 29점이었습니다. 3개월 후 재방문했을 때 MMSE는 30이었고 MFI는 1210이었습니다. 그 후 3개월 후 다시 내원한 그는 여행을 다녀왔고, 프로토콜을 많이 어겼으며, 스트레스를 받았고, 기억력이 저하되었다고 불평했습니다. 그 방문 당시 그의 MFI는 230으로 알츠하이머병 환자의 일반적인 점수인 230으로 떨어졌고, MMSE는 28이었습니다.

그는 다시 프로토콜에 따라 치료를 받았고,

두 달 후 다시 방문했을 때 MFI는 1100, MMSE는 30이었습니다.

그 후 12개월 동안 그의 MFI는 1000을 넘지 않았고 MMSE는 30을 유지했습니다.

Comment

This patient, homozygous for ApoE4/4, had a typical amnestic presentation and well documented Alzheimer's disease, unresponsive to donepezil, memantine, and intravenous immunoglobulin. His MMSE improved to a perfect 30 on the metabolic protocol, where it has remained for over one year. His longitudinal MFI supports the notion that MFI may provide a “real time” method for following inflammatory/metabolic status, given the marked reduction when off the protocol with return to normal when he re-initiated the protocol.

코멘트
ApoE4/4 동형 접합자인 이 환자는 전형적인 기억상실증 증상을 보였고 도네페질, 메만틴, 정맥 내 면역글로불린에 반응하지 않는 알츠하이머병이 잘 기록되어 있었습니다. 대사 프로토콜에서 MMSE는 30점 만점으로 개선되었으며, 1년 이상 그 상태를 유지하고 있습니다. 그의 종단적 MFI는 프로토콜을 중단했을 때 현저하게 감소했다가 프로토콜을 다시 시작했을 때 정상으로 돌아온 것을 고려할 때 MFI가 염증/대사 상태를 추적하는 “실시간” 방법을 제공할 수 있다는 개념을 뒷받침합니다.

Patient 7

A 57-year-old man began to have difficulty with memory and in work performance as a computer programmer, leading to dismissal from his job. Over the next five years his cognition continued to decline, he developed navigational difficulties, had difficulty with attention and multi-tasking, and became quieter and less self-assured. He had been a superb guitarist, and he lost both the chord progression memory and the nuance in his playing. Family history was positive for dementia in his mother, in her ninth decade. Eval‎uation by a neurologist included an unremarkable brain MRI without volumetrics, and he was placed on Aricept, which he discontinued after two months.

Seven years after his symptom onset, he was again eval‎uated, and found to be homozygous for ApoE4. An FDG PET scan was strongly suggestive of Alzheimer's disease, with reductions in glucose utilization in the temporal, parietal, posterior cingulate, and frontal regions, with some asymmetry. He scored 22/30 on the mini-mental state examination, having lost points for failing to know the date or day, location, and failing tasks of attention and short-term recall. His BMI was 23.

A diagnosis of Alzheimer's disease was made. His laboratory eval‎uation included an hs-CRP of 0.2mg/l, homocysteine 9.5μmol/l, albumin:globulin ratio of 1.6, hemoglobin A1c 5.7%, fasting insulin 4.9mIU/l, free T3 2.8pg/ml, free T4 1.3ng/l, TSH 2.1mIU/l, testosterone 281ng/dl, pregnenolone 44ng/dl, 25-hydroxychole-calciferol 38ng/ml, total cholesterol 145mg/dl (on atorvastatin), RBC magnesium 4.7mg/dl, serum copper 93mcg/dl, serum zinc 76mcg/dl, copper:zinc ratio 1.22, and AM cortisol 6.8mcg/dl. His Cyrex Array 2 was positive for gastrointestinal hyperpermeability, Cyrex Array 3 (for gluten sensitivity) was negative, and Cyrex Array 20 (for blood-brain barrier disruption) was negative.

He was placed on the MEND protocol, and his MMSE increased to 26 after four months, and to 29 after 10 months. His wife noticed clear improvement in his memory and navigation. His guitar skills improved, both his chord progressions and the nuances of his playing, such that he was able to play several pieces for the neurologist.

환자 7
57세의 한 남성은 컴퓨터 프로그래머로서 기억력과 업무 수행에 어려움을 겪기 시작했고, 결국 직장에서 해고당했습니다. 그 후 5년 동안 인지능력이 계속 저하되었고, 길 찾기에 어려움을 겪었으며, 주의력과 멀티태스킹에 어려움을 겪었고, 조용해지고 자신감이 떨어졌습니다. 뛰어난 기타리스트였던 그는 코드 진행에 대한 기억과 연주의 뉘앙스를 모두 잃었습니다. 가족력은 90대인 그의 어머니가 치매에 걸린 적이 있다는 것이었습니다. 신경과 전문의의 평가 결과, 볼륨이 없는 뇌 MRI에서 별다른 이상이 발견되지 않았고, 아리셉트를 복용하다가 두 달 만에 중단했습니다.

증상 발현 7년 후, 다시 검사를 받은 결과 ApoE4 동형접합인 것으로 밝혀졌습니다. FDG PET 스캔 결과 측두엽, 두정엽, 후대상회, 전두엽의 포도당 이용률 감소와 약간의 비대칭으로 알츠하이머병을 강력하게 시사하는 소견을 보였습니다. 그는 미니 정신 상태 검사에서 22/30점을 받았으며, 날짜나 요일, 장소를 알지 못하고 주의력 및 단기 기억력 과제에 실패하여 감점을 받았습니다. BMI는 23이었습니다.

알츠하이머병 진단이 내려졌습니다. 그의 실험실 평가에는 hs-CRP 0.2mg/l, 호모시스테인 9.5μmol/l, 알부민:글로불린 비율 1.6, 헤모글로빈 A1c 5.7%, 공복 인슐린 4.9mIU/l, 유리 T3 2.8pg/ml, 유리 T4 1.3ng/l, TSH 2. 1mIU/l, 테스토스테론 281ng/dl, 프레그네놀론 44ng/dl, 25-하이드록시콜-칼시페롤 38ng/ml, 총 콜레스테롤 145mg/dl(아토르바스타틴 복용), RBC 마그네슘 4.7mg/dl, 혈청 구리 93mcg/l, 혈청 아연 76mcg/l, 구리:아연 비율 1.22, AM 코르티솔 6.8mcg/dl. 위장관 과투과성 검사(Cyrex Array 2)는 양성, 글루텐 민감성 검사(Cyrex Array 3)는 음성, 혈액뇌장벽 장애 검사(Cyrex Array 20)는 음성이었습니다.

그는 MEND 프로토콜에 따라 치료를 받았고 

4개월 후 MMSE는 26점으로, 10개월 후에는 29점으로 증가했습니다. 그

의 아내는 그의 기억력과 지남력이 뚜렷하게 개선된 것을 발견했습니다. 

기타 실력도 향상되어 코드 진행과 연주의 뉘앙스가 모두 좋아져 신경과 의사를 위해 여러 곡을 연주할 수 있게 되었습니다.

Comment

This patient had well documented Alzheimer's disease, with a characteristic presentation, characteristic FDG-PET scan, and an ApoE4 homozygous genotype. For the seven years prior to beginning the MEND protocol, his cognition declined, again in keeping with the diagnosis of Alzheimer's disease. Therefore, the chance that his MMSE improved from 22 to 26 and then to 29 over the 10 months on the protocol, as a random event unrelated to the MEND protocol, is slim. Although a score of 29 on the MMSE is within the normal range, both the patient and his wife recognize that subjectively he has not returned completely to normal, and continued optimization of his metabolic status is ongoing.

Patient 8

A 68-year-old business executive presented with a five-year history of progressive memory loss, forcing him to retire from his company. He had difficulty navigating while driving, as well. Family history was positive in his mother. He underwent amyloid PET imaging, which was positive. His ApoE genotype was 3/4.

After six months on the MEND protocol, his BMI improved from 27.7 to 24.6, and his hemoglobin A1c improved from 5.9% to 5.7%. Both he and his family noted improvement in memory and navigation. His improvement was documented by on-line neuropsychological testing (Brain HQ), which showed increase from 0 (baseline) to 2221, which represented 52nd percentile for his age.

Comment

This patient had typical Alzheimer's disease with mnemonic and visuospatial deficits, progressive course, positive family history, ApoE4 heterozygosity, and a positive amyloid PET scan. He responded to treatment with an improvement in BMI, reduction in hemoglobin A1c, symptomatic improvements in both memory and navigation, and objective improvement in on-line neuropsychological testing.

환자 8

68세의 한 기업 임원은 5년 전부터 점진적인 기억 상실 증상을 보여 회사에서 은퇴할 수밖에 없었습니다. 그는 운전 중에도 길을 찾는 데 어려움을 겪었습니다. 가족력은 어머니에게서 양성이었습니다. 그는 아밀로이드 PET 촬영을 받았는데 양성 판정을 받았습니다. 그의 ApoE 유전자형은 3/4였습니다.

MEND 프로토콜 6개월 후, 그의 BMI는 27.7에서 24.6으로 개선되었고 헤모글로빈 A1c는 5.9%에서 5.7%로 개선되었습니다. 그와 그의 가족 모두 기억력과 탐색 능력이 개선되었다고 말했습니다. 온라인 신경심리 검사(Brain HQ)에서 0(기준선)에서 2221(나이 대비 52번째 백분위수)로 개선된 것으로 나타났습니다.

댓글
이 환자는 전형적인 알츠하이머병으로 기억력 및 시공간 결손, 진행성 경과, 가족력, ApoE4 이형접합성, 아밀로이드 PET 스캔 양성 소견을 보였습니다. 그는 치료에 반응하여 BMI가 개선되고 헤모글로빈 A1c가 감소했으며 기억력과 지남력 모두에서 증상이 개선되었고 온라인 신경심리 검사에서 객관적인 개선이 나타났습니다.

Patient 9

This is a follow-up description of a patient presented in a previous publication [13]. A 50-year-old woman developed depression following a hysterectomy. She received hormone replacement therapy, but the depression continued. At the age of 54, she began to have word-finding difficulty, disorientation, difficulty driving, difficulty following recipes and other instructions, and memory complaints, and these problems progressed. She became quieter and slower to respond. Her depression deepened when her son left home.

She underwent neuropsychological testing, which disclosed frontal, temporal, and parietal abnormalities. A PET scan was typical for Alzheimer's disease, with temporoparietal decreases in glucose utilization as well as a modest frontal decrease. She was placed on duloxetine, which reduced her depression, and donepezil, which improved her cognition. However, she continued to decline.

At the age of 57, she was again eval‎uated. Her ApoE genotype was 3/3, MoCA was 19/30, BMI was 18, hs-CRP 0.2mg/l, homocysteine 8μM, fasting insulin 4.2uIU/ml, hemoglobin A1c 5.1%, free T3 2.1pg/ml, free T4 1.33ng/dl, reverse T3 23ng/dl, fT3:rT3 9, TSH 1.16uIU/ml, progesterone 0.3ng/ml, AM cortisol 7.2mcg/dl, pregnenolone 19ng/dl, 25-hydroxycholecalciferol 37ng/ml, vitamin B12 799pg/ml, alpha-tocopherol 12.5mg/l, zinc 82mcg/l, copper 99mcg/l, copper:zinc ratio 1.2, ceruloplasmin 20mg/dl, total cholesterol 221mg/dl, HDL cholesterol 67mg/dl, non- HDL cholesterol 167mg/dl, triglycerides 82mg/dl, urinary mercury:creatinine < 2.8, Lyme antibodies negative, C4a 5547ng/ml, TGF-β1 7037pg/ml, and VEGF (vascular endothelial growth factor) 56pg/ml (normal range 31-86pg/ml). VIP (vasoactive intestinal peptide) was not eval‎uated. HLA-DR/DQ was 13-6-52A (mycotoxin sensitive) and 15-6-51 (Borrelia sensitive). MARCoNS (multiple-antibiotic-resistant coagulase-negative Staph) culture was negative. Anti-thyroglobulin antibodies were strongly positive at 2076IU/ml (normal range 0-0.9IU/ml) and anti-thyroid peroxidase antibodies positive at 58IU/ml (normal range 0-34IU/ml).

She was placed on the MEND protocol, and intranasal VIP (vasoactive intestinal peptide) was administered. After three months, she showed improvement. She was able to babysit her grandchildren. She was able to follow written and verbal instructions without any problems, which had not been possible prior to treatment. She was able to read and remember overnight, and discuss her reading with her husband, which she had not been able to do prior to treatment. She also routinely remembered events of the previous day, which had not occurred in the few years prior to treatment. She had a follow-up MoCA test, and scored 21/30.

환자 9

이것은 이전 간행물 [13]에 소개된 환자에 대한 후속 설명입니다. 50세 여성이 자궁 적출술을 받은 후 우울증이 발생했습니다. 그녀는 호르몬 대체 요법을 받았지만 우울증은 계속되었습니다. 54세부터 단어 찾기 어려움, 방향 감각 상실, 운전 곤란, 요리법 및 기타 지침 따르기 어려움, 기억력 장애가 나타나기 시작했고 이러한 문제는 점점 더 심해졌습니다. 그녀는 점점 더 조용해지고 반응이 느려졌습니다. 아들이 집을 떠나자 그녀의 우울증은 더욱 깊어졌습니다.

그녀는 신경심리 검사를 받았고, 그 결과 전두엽, 측두엽, 두정엽에 이상이 있는 것으로 밝혀졌습니다. PET 스캔은 전형적인 알츠하이머병의 양전자방출단층촬영으로 측두정두엽의 포도당 이용률 감소와 약간의 전두엽 감소가 관찰되었습니다. 그녀는 우울증을 완화하는 둘록세틴과 인지능력을 개선하는 도네페질을 투여받았습니다. 그러나 그녀는 계속 쇠퇴했습니다.

57세에 그녀는 다시 검사를 받았습니다. 그녀의 ApoE 유전자형은 3/3, MoCA는 19/30, BMI는 18, hs-CRP 0.2mg/l, 호모시스테인 8μM, 공복 인슐린 4.2uIU/ml, 헤모글로빈 A1c 5.1%, 유리 T3 2.1pg/ml, 유리 T4 1. 33ng/dl, 역 T3 23ng/dl, fT3:rT3 9, TSH 1.16uIU/ml, 프로게스테론 0.3ng/ml, AM 코르티솔 7.2mcg/dl, 프레그네놀론 19ng/dl, 25-hydroxycholecalciferol 37ng/ml, 비타민 B12 799pg/ml, 알파-토코페롤 12. 5mg/l, 아연 82mcg/l, 구리 99mcg/l, 구리:아연 비율 1.2, 세룰로플라즈민 20mg/dl, 총 콜레스테롤 221mg/dl, HDL 콜레스테롤 67mg/dl, 비 HDL 콜레스테롤 167mg/dl, 트리글리세리드 82mg/dl, 요 수은:크레아티닌 <2. 8, 라임 항체 음성, C4a 5547ng/ml, TGF-β1 7037pg/ml, VEGF(혈관내피세포 성장인자) 56pg/ml(정상 범위 31-86pg/ml). VIP(혈관 활성 장 펩타이드)는 평가되지 않았습니다. HLA-DR/DQ는 13-6-52A(마이코톡신 민감) 및 15-6-51(보렐리아 민감)이었습니다. MARCoNS(다중 항생제 내성 응고효소 음성 포도상구균) 배양은 음성이었습니다. 항티로글로불린 항체는 2076IU/ml(정상 범위 0-0.9IU/ml)로 강하게 양성, 항갑상선 퍼옥시다제 항체는 58IU/ml(정상 범위 0-34IU/ml)로 양성으로 나타났습니다.

그녀는 MEND 프로토콜에 따라 비강 내 VIP(혈관 활성 장 펩타이드)를 투여받았습니다. 3개월 후, 그녀는 호전을 보였습니다. 그녀는 손자를 돌볼 수 있게 되었습니다. 치료 전에는 불가능했던 서면 및 구두 지시를 아무런 문제 없이 따를 수 있게 되었습니다. 그녀는 밤새 책을 읽고 기억할 수 있었고, 치료 전에는 할 수 없었던 남편과 독서 내용을 토론할 수 있었습니다. 또한 치료 전에는 몇 년 동안 일어나지 않았던 전날의 사건도 일상적으로 기억할 수 있게 되었습니다. 그녀는 후속 MoCA 검사를 받았고 21/30의 점수를 받았습니다.

Comment

This patient had progressed beyond MCI to Alzheimer's disease, well documented by characteristic PET scan abnormalities, neuropsychological testing deficits, and progression. Despite an initial subjective response to donepezil, she continued to decline and displayed significant impairment. She was diagnosed with type 3 Alzheimer's disease [13, 14], and laboratory data supported this diagnosis with characteristic HLA-DR/DQ and abnormal C4a and TGF-β1, as well as anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies, although MARCoNS culture was negative. After three months of therapy, she showed clear subjective improvement and modest objective improvement. Her previous three years of relentless decline argued against the possibility that the improvement was random and unrelated to her treatment.

Patient 10

A 54-year-old woman presented with a two-year history of memory loss. She noted that she did not retain new information the way she formerly had, she had to re-read information a number of times to remember it, especially technical or scientific information, and noted that her reading speed had decreased. She also noted a reduction in vocabulary, word-finding problems, and repeated use of the same word instead of using synonyms. She also noted increased difficulty with grammar and spelling, as well as loss of names of friends and of famous people. Her writing declined, her typographical errors increased, and she had difficulty remembering passwords. She had increasing difficulty driving, organizing, and with her motivation. Activities of daily living were preserved.

Her ApoE genotype was 4/4, homocysteine 7.5μmol/l, hs-CRP 0.26mg/l, albumin:globulin ratio 2.0, hemoglobin A1c 5.3%, fasting insulin 2.7mIU/l, fasting glucose 81mg/dl, alpha-tocopherol 18.3mg/l, and 25-hydroxycholecalciferol 188ng/ml.

On-line quantitative neuropsychological testing disclosed a composite memory score at the 32nd percentile, visual memory at 10th percentile, and verbal memory at 73rd percentile. This testing was repeated after four months on the protocol, at which time the composite memory score was at the 61st percentile, visual memory score at the 25th percentile, and verbal memory score at the 84th percentile.

Comment

This person, who is homozygous for the ApoE ε4 allele, demonstrated both subjective and objective evidence of cognitive decline, with preserved activities of daily living, and thus would fit best with a diagnosis of mild cognitive impairment. After four months on the protocol, repeat on-line quantitative neuropsychological testing revealed improvements in visual and verbal memory. Although these improvements were relatively modest, they are in contrast to the natural history of progressive decline in cognition for MCI associated with ApoE4 homozygosity.

환자 10
54세 여성이 2년간의 기억 상실 증상을 호소했습니다. 그녀는 새로운 정보를 이전과 같은 방식으로 기억하지 못하고, 특히 기술 정보나 과학 정보를 기억하기 위해 여러 번 다시 읽어야 하며, 읽기 속도가 느려졌다고 언급했습니다. 또한 어휘력 감소, 단어 찾기 문제, 동의어 대신 같은 단어를 반복해서 사용한다는 점도 지적했습니다. 또한 문법과 철자법이 어려워지고 친구나 유명인의 이름을 잊어버리는 일이 잦아졌다고 말했습니다. 글쓰기 능력이 저하되고 오타가 증가했으며 비밀번호를 기억하는 데 어려움을 겪었습니다. 운전, 정리 정돈, 동기 부여에도 점점 더 어려움을 겪었습니다. 일상 생활 활동은 보존되었습니다.
그녀의 ApoE 유전자형은 4/4, 호모시스테인 7.5μmol/l, hs-CRP 0.26mg/l, 알부민:글로불린 비율 2.0, 헤모글로빈 A1c 5.3%, 공복 인슐린 2.7mIU/l, 공복 포도당 81mg/dl, 알파-토코페롤 18.3mg/l, 25-hydroxycholecalciferol 188ng/ml였습니다.

온라인 정량적 신경심리 검사 결과 종합 기억력은 32번째 백분위수, 시각 기억력은 10번째 백분위수, 언어 기억력은 73번째 백분위수로 나타났습니다. 이 테스트는 프로토콜에 따라 4개월 후에 반복되었으며, 이 때 종합 기억력 점수는 61번째 백분위수, 시각 기억력 점수는 25번째 백분위수, 언어 기억력 점수는 84번째 백분위수로 나타났습니다.

댓글
ApoE ε4 대립유전자를 가진 이 사람은 주관적 및 객관적인 인지 기능 저하의 증거를 모두 보였으며, 일상 생활 활동은 보존되었으므로 경도 인지 장애 진단에 가장 적합했습니다. 프로토콜 4개월 후, 반복적인 온라인 정량적 신경심리검사를 통해 시각 및 언어 기억력이 개선된 것으로 나타났습니다. 이러한 개선은 비교적 미미한 수준이었지만, ApoE4 동형접합과 관련된 MCI의 인지 능력이 점진적으로 저하되는 자연스러운 현상과는 대조적인 결과입니다.

DISCUSSION

These observations provide further support for the previously reported finding that the personalized protocol for metabolic enhancement (note that the metabolic eval‎uation included parameters shown to affect Alzheimer's disease pathophysiology, such as homocysteine [15], glucose [16], and inflammation [17], as well as numerous others as previously described [3]) in Alzheimer's disease leads to the reversal of cognitive decline in at least some patients with early Alzheimer's disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment). To our knowledge, the magnitude of the improvements documented in patients 1 and 2 is unequaled in previous reports: in patient 1, the increase in hippocampal volume from 17th percentile to 75th percentile supports the marked symptomatic improvement that he (and others) achieved on the protocol. In patient 2, quantitative neuropsychological testing demonstrated improvements of up to three standard deviations (CVLT-IIB, from 3rd percentile to 84th percentile), with multiple tests all showing marked improvements. These findings complement and support the marked subjective improvement already published for this patient [3].

It is noteworthy that these patients met criteria for Alzheimer's disease or MCI prior to treatment, but failed to meet criteria for either Alzheimer's disease or MCI following treatment—i.e., following treatment, most had returned to the normal range for their cognitive testing. Furthermore, as noted in the initial description of the protocol used here [3], discontinuation of the protocol was associated with cognitive decline (here, in patient 1). It is not yet known for how many months or years the marked improvements will be sustained, but loss of improvement in patients maintaining the protocol has not yet been observed, and follow-ups of up to four years have now occurred.

The hippocampal volumetric increase observed for patient 1 does not discriminate between the possibility that synaptic number increased, or glial cell number or volume increased, or endogenous stem cell survival increased, or neuronal cell number or volume increased, or the vascular compartment increased, or some combination of these possibilities. This volumetric increase, and the marked symptomatic improvement that accompanied it, raises the question of whether it is possible that the patient's diagnosis of mild cognitive impairment associated with Alzheimer's disease was incorrect. However, the diagnostic eval‎uation makes this possibility extremely unlikely: given the strong family history of dementia, the ApoE4 heterozygosity, markedly positive amyloid PET scan, the FDG-PET scan characteristic of Alzheimer's disease with reduced glucose utilization in a temporoparietal distribution, the abnormal neuropsychological testing, and the MRI showing hippocampal volume at 17th percentile for age, the possibility that the underlying pathological process was something other than Alzheimer's disease is remote. Thus it would be expected that hippocampal volume would decrease over time, and that cognitive decline would occur. Therefore, the likelihood that his improvement was random and unrelated to the intervention is extremely low.

Similarly, for patient 2, it is highly unlikely that the diagnosis of Alzheimer's disease was incorrect: the ApoE4-positive genotype, the FDG-PET scan typical of Alzheimer's disease with temporoparietal reduction in glucose utilization, the pattern and severity of quantitative neuropsychological abnormalities, and the well documented progressive nature of the deficits all provide strong support for the diagnosis of Alzheimer's disease. Furthermore, the severity of the abnormalities documented by the quantitative neuropsychological assessment was also compatible with the diagnosis of Alzheimer's disease. The variations that may occur when different examiners perform the same set of quantitative neuropsychological tests is an obvious concern when there is a significant change in the results of the tests in one subject. However, in this case, the same examiner performed the same set of tests in each instance, arguing against the possibility that the major improvement observed was simply the result of examiner-related variability. The magnitude of the improvement also argued against this possibility.

In each of these cases, obvious subjective improvement, noted by the patient, his/her significant other, and his/her co-workers, was accompanied by clear, quantitated, objective improvement. In the cases of patients 1 and 2, the improvement was of a magnitude not reported previously for patients with Alzheimer's disease. None of the 10 patients exhibited the cognitive decline that is characteristic of Alzheimer's disease, and the improvement experienced by all 10 has been sustained, with the longest time on the program being four years.

토론

이러한 관찰은 이전에 보고된 신진대사 향상을 위한 개인 맞춤형 프로토콜(신진대사 평가에는 호모시스테인 [15], 포도당 [16] 및 염증 [17 ] 등 알츠하이머병 병리 생리학에 영향을 미치는 것으로 보이는 매개변수가 포함됨)이 적어도 일부 알츠하이머병 환자의 인지 기능 저하를 반전시킨다는 결과를 더욱 뒷받침합니다, 및 염증 [17], 그리고 앞서 설명한 바와 같이 수많은 다른 것들[3])이 알츠하이머병의 초기 알츠하이머병 또는 그 전구 증상인 MCI(경도 인지 장애) 및 SCI(주관적 인지 장애)를 가진 적어도 일부 환자에서 인지 기능 저하를 역전시킵니다.

우리가 아는 한, 환자 1과 환자 2에서 기록된 개선의 정도는 이전 보고서에서 비교할 수 없는 수준으로, 환자 1의 경우 해마 부피가 17번째 백분위수에서 75번째 백분위수로 증가하여 프로토콜을 통해 달성한 현저한 증상 개선을 뒷받침하고 있습니다(그리고 다른 환자들도 마찬가지입니다). 환자 2의 경우 정량적 신경심리검사에서 최대 3표준편차(CVLT-IIB, 3백분위수에서 84백분위수로)의 개선이 입증되었으며, 여러 검사에서 모두 뚜렷한 개선이 나타났습니다. 이러한 결과는 이 환자에 대해 이미 발표된 뚜렷한 주관적 개선 결과를 보완하고 뒷받침합니다[3].

주목할 만한 점은 이 환자들은 치료 전에는 알츠하이머병 또는 MCI 기준을 충족했지만 치료 후에는 알츠하이머병 또는 MCI 기준을 충족하지 못했다는 점, 즉 치료 후 대부분 인지 테스트에서 정상 범위로 돌아왔다는 점입니다. 또한, 여기에 사용된 프로토콜의 초기 설명에서 언급했듯이[3], 프로토콜의 중단은 인지 기능 저하와 관련이 있었습니다(여기서는 환자 1의 경우). 뚜렷한 개선이 몇 개월 또는 몇 년 동안 지속될지는 아직 알려지지 않았지만, 프로토콜을 유지한 환자에서 개선의 손실은 아직 관찰되지 않았으며 최대 4년간의 추적 관찰이 이루어졌습니다.

환자 1에서 관찰된 해마의 용적 증가는 시냅스 수 증가, 신경교세포 수 또는 부피 증가, 내인성 줄기세포 생존 증가, 신경세포 수 또는 부피 증가, 혈관 구획 증가 또는 이러한 가능성의 일부 조합을 구분할 수 없습니다. 이러한 부피 증가와 그에 따른 현저한 증상 개선은 알츠하이머병과 관련된 환자의 경도 인지 장애 진단이 잘못되었을 가능성이 있는지에 대한 의문을 제기합니다. 그러나 진단 평가 결과, 치매의 강한 가족력, ApoE4 이형접합성, 아밀로이드 PET 스캔에서 현저하게 양성, 측두정위 분포에서 포도당 이용이 감소한 알츠하이머병의 특징인 FDG-PET 스캔, 비정상적인 신경심리검사, 연령 대비 17번째 백분위수로 나타난 해마 용적의 MRI 등을 고려할 때 알츠하이머병 이외의 기저 병리 과정이 있었을 가능성은 극히 희박한 것으로 판단됩니다. 따라서 시간이 지남에 따라 해마 용적이 감소하고 인지 기능 저하가 발생할 것으로 예상할 수 있습니다. 따라서 그의 개선이 개입과 무관하게 무작위로 이루어졌을 가능성은 극히 낮습니다.

마찬가지로 환자 2의 경우, 알츠하이머병 진단이 틀렸을 가능성은 매우 낮습니다. ApoE4 양성 유전자형, 측두정위 포도당 이용 감소를 동반한 알츠하이머병의 전형적인 FDG-PET 스캔, 정량적 신경심리 이상 패턴과 심각도, 잘 기록된 결손의 진행성 등이 모두 알츠하이머병 진단에 강력한 근거를 제공합니다. 또한 정량적 신경심리 평가에 기록된 이상 증상의 심각도 역시 알츠하이머병 진단과 양립할 수 있었습니다. 한 피험자에서 검사 결과에 큰 변화가 있을 때 다른 검사자가 동일한 정량적 신경심리 검사를 수행할 때 발생할 수 있는 편차는 명백한 우려 사항입니다. 그러나 이 사례에서는 동일한 검사자가 각 사례에서 동일한 검사 세트를 수행했기 때문에 관찰된 주요 개선이 단순히 검사자 관련 변동성의 결과일 가능성에 반대합니다. 개선의 규모 또한 이러한 가능성을 반박하는 근거가 되었습니다.

각 사례에서 환자, 환자의 배우자 및 동료가 지적한 명백한 주관적 개선은 명확하고 정량화된 객관적 개선을 동반했습니다. 환자 1과 2의 경우, 알츠하이머병 환자에게서 이전에는 보고되지 않았던 정도의 개선이 있었습니다. 10명의 환자 중 누구도 알츠하이머병의 특징적인 인지 기능 저하를 보이지 않았으며, 10명 모두 최장 4년 동안 프로그램에 참여하면서 개선이 지속되었습니다.

It has been claimed that there is nothing that will prevent, delay, or reverse Alzheimer's disease (http://www.nih.gov/news-events/news-releases/independent-panel-finds-insufficient-evidence-support-preventive-measures-alzheimers-disease). Therefore, it is typically recommended that the ApoE genotype, which represents the most important genetic risk factor for Alzheimer's disease, not be eval‎uated in asymptomatic individuals, and many physicians do not eval‎uate ApoE genotype even in symptomatic patients. However, the examples described here complement and extend previously published data that argue that these claims are no longer valid. Thus, given the success of the therapeutic regimen used with these patients, it may be appropriate to eval‎uate the ApoE genotype as part of prevention and early reversal of symptoms. Given the approximately 75 million Americans who are heterozygous for the ApoE ε4 allele, and the approximately seven million Americans who are homozygous, early identification and treatment (presymptomatic or symptomatic) could potentially have a major impact on the preval‎ence of Alzheimer's disease-mediated cognitive decline.

알츠하이머병을 예방, 지연 또는 되돌릴 수 있는 방법은 없다고 주장되어 왔습니다(http://www.nih.gov/news-events/news-releases/independent-panel-finds-insufficient-evidence-support-preventive-measures-alzheimers-disease).

따라서 일반적으로

알츠하이머병의 가장 중요한 유전적 위험 인자인 ApoE 유전자형은 무

증상 환자에게는 평가하지 않는 것이 권장되며,

많은 의사들은 증상이 있는 환자에서도 ApoE 유전자형을 평가하지 않습니다.

그러나 여기에 설명된 사례는

이러한 주장이 더 이상 유효하지 않다고 주장하는

이전에 발표된 데이터를 보완하고 확장한 것입니다.

따라서

이러한 환자에게 사용된 치료 요법의 성공을 고려할 때,

예방 및 증상 조기 반전의 일환으로 ApoE 유전자형을 평가하는 것이 적절할 수 있습니다.

ApoE ε4 대립 유전자를 가진 약 7,500만 명의 미국인과 동형 접합 유전자를 가진 약 700만 명의 미국인을 고려할 때, 알츠하이머병의 조기 발견과 치료(증상 전 또는 증상 발생)는 알츠하이머병 매개 인지 기능 저하의 유병률에 큰 영향을 미칠 수 있습니다.

Acknowledgments

I thank Dr. Rammohan Rao, Dr. Aida Lasheen Bredesen, and Dr. Alexei Kurakin for discussions, and Ms. Rowena Abulencia for preparing the manuscript.

Footnotes

Funding

I am grateful for support from James and Phyllis Easton, the NIH (AG16570, AG034427 and AG036975), the Mary S. Easton Center for Alzheimer's Disease Research at UCLA, the Douglas and Ellen Rosenberg Foundation, the Stephen D. Bechtel, Jr. Foundation, the Joseph Drown Foundation, the Alzheimer's Association, the Accelerate Fund, the Buck Institute and Marin Community Foundation, the Michael and Catherine Podell Fund, Mr. Craig Johnson, Mr. Allan Bortel, Mr. Wright Robinson, Mr. Jeffrey Lipton, Mr. Lawrence Dingus, and Ms. Michaela Hoag.

Conflict of interest statement

The author of this manuscript declares no conflict of interest.

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