2020년 JAMA 치매의 진단과 치료

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현재 전세계 4천 7백만명 치매환자

2050년 1억 3천만명 치매환자

대부분 알츠하이머 치매이고

혈관성 치매가 복합된 형태

루이소체 치매

전두측두 치매

+ 가성치매

https://www.youtube.com/watch?v=PMuzvyMqVOc

https://www.youtube.com/watch?v=z110iTx77HI

The loss of cognitive abilities must be: 반드시 인지능력의 손상이 있어야
  • Present in several cognitive domains (often memory with at least one other domain such as language, visuospatial, executive, or other), and

여러 인지 영역(종종 언어, 시공간, 집행 또는 기타 영역과 같은 하나 이상의 다른 영역에 대한 기억력)에서 나타나야 하며, 다음을 충족해야
  • Represent a decline from the prior level of function, and

이전 기능 수준에서 감소를 나타내야
  • Impair functional abilities in day-to-day life (e.g., social, occupational, self-care)

일상 생활에서의 기능적 능력(예: 사회적, 직업적, 자기 관리) 손상

JAMA. Author manuscript; available in PMC 2020 Sep 1.

Published in final edited form as:

JAMA. 2019 Oct 22; 322(16): 1589–1599.

doi: 10.1001/jama.2019.4782

PMCID: PMC7462122

NIHMSID: NIHMS1622652

PMID: 31638686

Diagnosis and Management of Dementia: A Review

Zoe Arvanitakis, MD, MS,1,2 Raj C. Shah, MD,1,3 and David A. Bennett, MD1,2

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The publisher's final edited version of this article is available at JAMA

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Abstract

Importance

Worldwide, 47 million people live with dementia and, by 2050, the number is expected to increase to 131 million.

Observations

Dementia is an acquired loss of cognition in multiple cognitive domains sufficiently severe to affect social or occupational function. In the US, Alzheimer’s disease (AD) affects 5.8 million people. However, dementia is commonly associated with more than one neuropathology, usually AD with cerebrovascular pathology. Diagnosing dementia requires a history eval‎uating for cognitive decline and impairment in daily activities, with corroboration from a close friend or family member, in addition to a moderately extended mental status examination by a clinician to delineate impairments in memory, language, attention, visuospatial cognition such as spatial orientation, executive function, and mood. Brief cognitive impairment screening questionnaires can assist in initiating and organizing the cognitive assessment.

However, if the assessment is inconclusive (e.g., symptoms present, but normal examination), neuropsychological testing can help with a diagnosis. Physical examination may help identify the etiology of dementia. For example, focal neurologic abnormalities suggest stroke. Brain neuroimaging may demonstrate structural changes including, but not limited to, focal atrophy, infarcts, and tumor, that may not be identified on physical examination. Additional eval‎uation with cerebrospinal fluid assays or genetic testing should be considered in atypical dementia cases, such as age of onset under 65 years, rapid symptom onset, and/or impairment in multiple cognitive domains but not episodic memory. For treatment, patients benefit from non-pharmacologic approaches, including cognitively engaging activities such as reading, physical exercise such as walking, and socialization such as family gatherings. Pharmacologic approaches can provide modest symptomatic relief. For AD, this includes an acetylcholinesterase inhibitor such as donepezil for mild-to-severe dementia, and memantine (used alone or as an add-on therapy) for moderate-to-severe dementia. Rivastigmine is approved for the symptomatic treatment of Parkinson’s disease dementia.

치매는 후천적으로 여러 인지 영역에서 사회적 또는 직업적 기능에 영향을 미칠 정도로 심각한 인지 기능의 상실을 말합니다. 미국에서는 580만 명이 알츠하이머병(AD)에 걸렸습니다. 그러나 치매는 일반적으로 두 가지 이상의 신경 병리, 일반적으로 뇌혈관 병리를 동반한 알츠하이머병과 관련이 있습니다. 치매를 진단하려면 가까운 친구나 가족의 확인을 받아 인지 기능 저하와 일상 활동의 장애를 평가하는 병력 청취와 함께 기억력, 언어, 주의력, 공간지각과 같은 시공간 인지, 실행 기능, 기분 등의 장애를 설명하기 위해 임상의가 적당히 확장된 정신 상태 검사가 필요합니다. 간단한 인지 장애 선별 설문지는 인지 평가를 시작하고 정리하는 데 도움이 될 수 있습니다. 

그러나 평가가 결정적이지 않은 경우(예: 증상은 있지만 검사 결과는 정상인 경우) 신경심리검사가 진단에 도움이 될 수 있습니다. 신체 검사는 치매의 원인을 파악하는 데 도움이 될 수 있습니다. 예를 들어, 국소 신경학적 이상은 뇌졸중을 시사합니다. 뇌 신경 영상은 신체 검사에서 확인되지 않는 국소 위축, 경색, 종양 등의 구조적 변화를 보여줄 수 있으며, 이에 국한되지 않습니다. 발병 연령이 65세 미만, 빠른 증상 발현 및/또는 일시적 기억력이 아닌 여러 인지 영역의 장애와 같은 비정형 치매의 경우 뇌척수액 분석 또는 유전자 검사를 통한 추가 평가를 고려해야 합니다. 치료를 위해 환자는 독서와 같은 인지적 활동, 걷기와 같은 신체 운동, 가족 모임과 같은 사교 활동 등 비약물적 접근을 통해 도움을 받을 수 있습니다. 약리학적인 접근법은 약간의 증상 완화를 제공할 수 있습니다. 알츠하이머병의 경우 경증에서 중증 치매에는 도네페질과 같은 아세틸콜린에스테라아제 억제제를, 중등도에서 중증 치매에는 메만틴(단독 또는 추가 치료제로 사용)을 사용할 수 있습니다. 리바스티그민은 파킨슨병 치매의 증상 치료제로 승인되었습니다.

Conclusions and Relevance

AD currently affects 5.8 million persons in the US, and is a common cause of dementia which is usually accompanied by other neuropathology. Causes of dementia can be diagnosed by medical history, cognitive and physical examination, laboratory testing, and brain imaging. Management should include both non-pharmacologic and pharmacologic approaches.

치매의 원인은 병력, 인지 및 신체 검사, 실험실 검사, 뇌 영상 검사로 진단

INTRODUCTION

Dementia is a common public health problem.1 Worldwide, approximately 47 million people have dementia and this number is expected to increase to 131 million by 2050.1 Reductions in age-adjusted incidence of dementia have occurred in the United States (US) and other developed countries over the last 20 years, perhaps associated with increasing formal educational attainment. However, without improved treatments or preventive therapy, the adverse consequences of dementia will continue to increase.2

치매는 흔한 공중 보건 문제입니다.1 전 세계적으로 약 4,700만 명의 치매 환자가 있으며 2050년에는 1억 3,100만 명으로 증가할 것으로 예상됩니다.1 지난 20년 동안 미국 및 기타 선진국에서 연령 조정 치매 발병률이 감소했는데, 이는 아마도 정규 교육 성취도의 증가와 관련이 있을 것입니다. 그러나 치료법이나 예방 요법이 개선되지 않는다면 치매로 인한 부작용은 계속 증가할 것입니다.2

In the US, the preval‎ence of dementia is 15% in people older than 68 years.3 Dementia is most commonly attributed to Alzheimer’s disease (AD), with over five million people currently affected by AD, and 13.8 million are projected to be affected by the year 2050.4 AD is the 6th leading cause of death, and the 5th leading cause among persons older than 65 years.5,6 This review summarizes diagnosis and management of dementia, defined as significant cognitive impairment in two or more cognitive domains.

미국에서는 68세 이상 인구의 치매 유병률이 15%에 달합니다.3 치매는 알츠하이머병(AD)이 가장 흔한 원인으로, 현재 500만 명 이상이 알츠하이머병에 걸렸으며 2050년에는 1,380만 명이 치매에 걸릴 것으로 예상됩니다.4 치매는 6번째 주요 사망 원인이며 65세 이상 인구의 5번째 주요 원인입니다.5,6 이 리뷰에서는 두 개 이상의 인지 영역에서 심각한 인지 장애로 정의되는 치매의 진단 및 관리에 대해 요약하여 설명합니다.

METHODS

We conducted a literature search in PubMed, using the search terms “dementia and (diagnosis or management)” in the title field. The following inclusion criteria were applied: a publication date from November 19, 2013 to June 29, 2019; English language; female or male sex; and “aged, 65 + years” (to exclude studies about less common causes of dementia). Original research studies with sample sizes less than 100 persons were excluded.

OBSERVATIONS

The search yielded 200 articles published in the past five and a half years. We excluded 37 studies with fewer than 100 persons, 52 on topics not relevant to this review, 41 about non-US public policy or practice, 20 about caregivers, 7 about pathology, 5 about medical record documentation or coding, and 11 that were not original research. The remaining 27 articles of original research, including 22 observational studies and 5 randomized clinical trials, informed this review.

Risk factors and Neuropathology

Aging is an important risk factor for all-cause dementia. AD affects 5–10% of people older than 65 years, and 50% of those 85 years old.7 Non-modifiable risk factors for AD include female sex, Black race, Hispanic ethnicity, and genetic factors such as the apolipoprotein E (APOE) gene.8–13 Modifiable risk factors for all-cause dementia include hypertension and diabetes, diet, and limited cognitive, physical, and social activities.14–18 Pathologically, “mixed dementia” is the most common form of dementia, found in 46% of persons with clinically diagnosed AD, and most commonly consisting of AD neurodegeneration and cerebrovascular disease.19 Other neurodegenerative pathologies such as Lewy body disease (pathologically confirmed in 17% of cases) and frontotemporal lobar degeneration (in <5% of cases) are less frequent.19–25

노화는 모든 원인성 치매의 중요한 위험 요인입니다. 알츠하이머병은 65세 이상의 5~10%, 85세 이상의 50%에서 발병합니다.7 알츠하이머병의 수정 불가능한 위험 요인으로는 여성 성별, 흑인 인종, 히스패닉 인종, 아포지단백질 E(APOE) 유전자와 같은 유전적 요인이 있습니다.8-13 모든 원인 치매의 수정 가능한 위험 요인으로는 고혈압과 당뇨병, 식이, 제한된 인지, 신체 및 사회적 활동 등이 있습니다.14 -병리학적으로 "혼합형 치매"는 가장 흔한 형태의 치매로, 임상적으로 알츠하이머병 진단을 받은 사람의 46%에서 발견되며, 가장 흔히 알츠하이머병 신경 퇴행과 뇌혈관 질환으로 구성됩니다.19 루이체병(17%에서 병리학적으로 확인)과 전측두엽 변성(5% 미만에서 발생)과 같은 다른 신경 퇴행성 병리는 덜 흔합니다.19-25

Definition and Characterization

Dementia is defined by chronic, acquired loss of two or more cognitive abilities caused by brain disease or injury (Box 1). This definition has been used in clinical practice for decades, although recent changes in the Diagnostic Statistical Manual, 5th Edition, have moved away from using the term dementia and have recognized that dementia can be present with impairment in a single domain (i.e. by this definition, a patient with a severe expressive aphasia could be classified as having dementia).26,27 Memory requires the recording, storage, and retrieval‎ of information. The most common clinical presentation of AD is a slow onset and gradually progressive loss of memory, typically with inability to learn new information and particularly autobiographical information, such as recent events in ones’ life. This is because AD preferentially affects brain networks involved in episodic memory. Examples of episodic memory loss include forgetting appointments, to pay bills or to take medication. Typically, a person with AD repeats questions and conversations. The memory loss is often accompanied by subjective memory complaints. Difficulty recalling names which are recalled later, is common in aging but is not a typical early sign of dementia. Mild cognitive impairment (MCI) is defined by performance that is lower than normal on objective neuropsychological testing of cognition, but with maintained daily functions (e.g., maintained abilities to function within society such as for daily activities at work, home, and in social settings, and maintained activities of daily living such as for personal care) and therefore not consistent with dementia (Box 1).28 MCI can be categorized into “amnestic” MCI, in which reduced performance on memory is the key finding, versus “non-amnestic” MCI, in which reduced cognitive performance is in a non-memory domain such as language. MCI can also be characterized into “single domain” versus “multi-domain” MCI, in which multiple cognitive performance measures are impaired. MCI does not always progress to dementia, and a patient’s cognitive status may become normal or fluctuate between MCI, normal cognition, and dementia. Fluctuations in cognition are also present in some conditions including neurodegenerative diseases (such as in early stages of Lewy body disease), cerebrovascular disease (e.g., intermittent small strokes), and psychiatric conditions (e.g., depression, anxiety), and with medications affecting cognition (e.g., opioids), and variability in cognitive test results.

치매는 뇌 질환이나 부상으로 인한 두 가지 이상의 인지 능력의 만성적, 후천적 상실로 정의됩니다(박스 1). 이 정의는 수십 년 동안 임상에서 사용되어 왔지만, 최근 진단 통계 편람 5판에서는 치매라는 용어를 사용하지 않고 치매가 단일 영역의 장애와 함께 나타날 수 있음을 인정했습니다(즉, 이 정의에 따르면 심한 표현 실어증이 있는 환자도 치매로 분류될 수 있음).26,27 기억은 정보의 기록, 저장 및 검색을 필요로 합니다. 알츠하이머병의 가장 흔한 임상 증상은 느리게 시작되어 점진적으로 진행되는 기억력 상실이며, 일반적으로 새로운 정보, 특히 최근의 사건과 같은 자서전적인 정보를 학습하지 못하는 것입니다. 이는 알츠하이머병이 에피소드 기억에 관여하는 뇌 네트워크에 우선적으로 영향을 미치기 때문입니다. 일과성 기억 상실의 예로는 약속을 잊어버리거나 청구서를 지불하거나 약을 복용하는 것 등이 있습니다. 일반적으로 알츠하이머병 환자는 질문과 대화를 반복합니다. 기억 상실은 종종 주관적인 기억력 불만을 동반합니다. 나중에 기억해낸 이름을 기억하기 어려워하는 것은 노화 과정에서 흔히 발생하지만 치매의 전형적인 초기 징후는 아닙니다. 

경도 인지 장애(MCI)는 객관적인 신경심리학적 인지 테스트에서 정상보다 낮은 수행 능력을 보이지만 일상적인 기능은 유지되는 경우(예, 직장, 가정, 사회적 환경에서의 일상 활동과 같은 사회 내 기능 유지, 개인 관리와 같은 일상 생활 활동 유지), 따라서 치매와 일치하지 않는 것으로 정의됩니다(상자 1).28 MCI는 기억력 저하가 주요 발견인 "기억상실" MCI와 언어와 같은 비기억 영역에서 인지 기능 저하가 나타나는 "비기억" MCI로 분류할 수 있습니다. 또한 MCI는 "단일 영역"과 여러 인지 능력 측정이 손상된 "다중 영역" MCI로 구분할 수 있습니다. MCI가 항상 치매로 진행되는 것은 아니며, 환자의 인지 상태가 정상이 되거나 MCI, 정상 인지, 치매 사이에서 변동될 수 있습니다. 신경 퇴행성 질환(예: 루이소체 질환의 초기 단계), 뇌혈관 질환(예: 간헐적인 작은 뇌졸중), 정신과 질환(예: 우울증, 불안), 인지에 영향을 미치는 약물(예: 오피오이드), 인지 테스트 결과의 변동성 등 일부 질환에서도 인지의 변동이 나타날 수 있습니다.

Box 1.

Characteristics of dementia and mild cognitive impairment

Dementia27

 The loss of cognitive abilities must be:

  • Present in several cognitive domains (often memory with at least one other domain such as language, visuospatial, executive, or other), and

  • Represent a decline from the prior level of function, and

  • Impair functional abilities in day-to-day life (e.g., social, occupational, self-care)

 The most common form of dementia is a “mixed dementia”,* usually a combination of a:

  • Common neurodegenerative disease in aging, most often Alzheimer’s disease (AD), and

  • Vascular contributions to cognitive impairment and dementia (VCID)

 Common neurodegenerative diseases causing dementia include the following, in decreasing order of frequency:**

  • AD

  • Lewy body disease

  • Frontotemporal dementia***

Mild cognitive impairment (MCI)28

 The loss of cognitive abilities must be:

  • Demonstrable on cognitive testing, whether amnestic versus non-amnestic MCI, or single versus multi-domain MCI (present in several cognitive domains),**** and

  • Not sufficient to significantly impair functional abilities or independence, such that criteria for dementia are NOT met

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*Mixed dementias have overlapping clinical features and more than one pathologic diagnosis.

**Other less common neurodegenerative and other diseases are not listed that can be identified during life include: vascular dementia, Parkinson disease, Huntington disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, Creutzfeldt-Jakob disease, and others; in younger people, consider acute conditions (e.g., motor vehicle accident or war-related traumatic brain injury), chronic traumatic encephalopathy (e.g., repetitive sports-related head injuries), and multiple sclerosis. Note that for some neurodegenerative diseases causing dementia in older people, there are currently no means to make the diagnosis during life, such as for Transactive response DNA-binding Protein 43 (TDP-43) form of frontotemporal dementia and for hippocampal sclerosis.

***Some data suggest this condition is a common cause of dementia in young-onset cases (onset before age 65 years).114

****Amnestic MCI is defined by neuropsychological test proven impairment in the memory domain, and can be “single domain amnestic MCI” or “multi-domain amnestic MCI”; non-amnestic MCI is defined by impairment in one or more cognitive domains other than memory (such as language, executive function, and/or attention), but not in the memory domain, and can be “single domain non-amnestic MCI” or “multi-domain non-amnestic MCI”.

Dementia is a clinical syndrome with variable manifestations (Table 1), which help attribute the cause of dementia and guide management. While research studies have defined a “preclinical” AD,27,29 in clinical care, AD is not diagnosed before symptom onset. Differentiating AD from other causes of dementia is easiest in the early stage of illness, as dementias in the late stage look similar (Table 2).30–34

Table 1.

Manifestations of dementia*

AREA**EARLIER-STAGE MANIFESTATIONSEXAMPLES OF EARLIER-STAGE MANIFESTATIONSLATER-STAGE MANIFESTATIONSEXAMPLES OF LATER-STAGE MANIFESTATIONS

Cognitive	Short-term memory loss (episodic memory impairment)	Forgetting appointments, to pay bills, recent events (such as family outing in last few weeks)	Memory loss in working memory (the ability to immediately process and store information)	Forgetting how to use household technology (e.g., how to use the microwave, dial phone numbers, etc.)
	Word-finding difficulties (anomia) or loss of word meaning (semantic deficits)	Frequent trouble finding exact words to express oneself, word substitutions, imprecise language (“what you eat with” for “fork”)	More marked expressive difficulties and eventual loss of language (e.g., global aphasia)	Paraphrasic errors while speaking, paucity of words in sentence, lack of initiation of conversations, muteness
Psychological	Apathy	Lack of initiation of thought or actions (e.g., not preparing meals)	Delusions	False belief system such as a deceased relative is still alive, the caregiver is stealing money
	Depressive symptoms	Hopelessness and loss of purpose in life	Anosognosia	Lack of insight into cognitive problems with attempts to continue to drive or manage money
Behavioral	Withdrawal from social engagement	Inability to participate meaningfully in casual conversations	Aggression	Verbal aggression such as screaming, physical aggression such as throwing things
	Disinhibition	Excesses in speech (e.g., echolalia, palilalia) and actions (e.g., hyperorality such as eating off others’ plate)	Hallucinations	Visual hallucinations such as seeing small people on table; auditory hallucinations such as hearing singing
			Wandering	Walking out of home in middle of night and getting lost
Sleep	Rapid eye movement behavior disorder (RBD)	Acting out dreams such as running while dreaming one is being chased	Altered sleep-wake cycle	Frequent awakening at night and getting out of bed, sleeping in late in the morning and repeated daytime napping
Physical	Gait impairment	Falls	Repetitive purposeless movements	Fidgeting with buttons on shirt for hours at a time
			Parkinsonism	Stooped posture, short stride, unsteady gait, rigidity
			Seizures	Involuntary repetitive limb jerking while unconscious

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*Note that these manifestations do not occur in all types of dementia; not all examples provided here occur in each individual, and several less common manifestations not listed may occur. This table does not aim to describe the trajectories of conditions within each area, but rather provide examples of manifestations. Variability in individual presentations is common; see text and Table 2 for pathognomonic characteristics of particular dementia etiologies

**Note the range of functional areas affected in dementia, beyond cognition

Table 2.

Clinical and pathologic characteristics differentiating select causes of dementia

DISEASE*Alzheimer’s disease (AD)Cerebrovascular Disease***Lewy body diseaseFrontotemporal dementia

PATHOLOGIC CHARACTERISTICS	Brain atrophy especially of the mesial temporal lobe; histologic hallmarks of neuritic plaques containing β amyloid and neurofibrillary tangles containing phosphorylated tau	Small, often cystic chronic infarcts (lacunar infarcts), multiple microinfarcts, or large infarcts including intracerebral hemorrhage; age of infarcts may be variable in the same person, including chronic and acute; cerebral vessel pathology such as atherosclerosis and arteriolosclerosis; white matter gliosis; focal brain atrophy	Brain atrophy, often generalized; intraneuronal Lewy body inclusions containing α synuclein, including in the neocortex (as opposed to inclusions restricted to the substantia nigra, as seen in Parkinson disease)	Focal brain atrophy affecting frontal**** and/or anterior temporal lobes, histologic hallmarks of phosphorylated Transactive response DNA-binding Protein 43 (TDP-43), microtubule-associated protein tau (MAPT), or fused-in-sarcoma (FUS) protein
ONSET AND COURSE	Slow onset and gradual progression over months or years	Temporal relation between acute vascular event (stroke) and onset of cognitive impairment, within minutes or days; stepwise course	Slow onset and gradual progression over months or years; fluctuations in levels of alertness and cognition	Slow onset and gradual progression over months or years
HISTORY, EXAM, AND COGNITIVE FEATURES IN THE EARLY STAGE**	History: presenting symptoms is typically short-term memory loss Exam and/or cognitive testing: episodic memory impairment accompanied by other subtle cognitive deficits, such as visuospatial problems and anomia	History: vascular risk factors (e.g., hypertension, diabetes) or prior stroke or other vascular events (myocardial infarction) Exam: focal neurologic deficits consistent with stroke such as unilateral weakness and hyperreflexia, Babinski sign Neuroimaging: evidence of cerebrovascular disease, such as infarcts or significant white matter changes (unilateral or bilateral) on magnetic resonance imaging (MRI)	History: Rapid Eye Movement (REM) Behavior Disorder (RBD) for years preceding the cognitive impairment; visual and other hallucinations Exam and/or cognitive testing: marked visuospatial problems with relative preservation of memory; parkinsonism, especially with bradykinesia and rigidity, but also stooped posture and slow and shuffling gait	History: marked changes in behaviors such as in personality (e.g., disinhibition, apathy) Exam and/or cognitive testing documenting disinhibition and inappropriate behaviors; in language variant, impaired fluency in speech, semantic paraphrasias; other significant executive or language problems, with relative preservation of memory

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*Diseases are listed in decreasing order of frequency, from left to right (see text for details)

**Includes characteristics often present or notably absent

***Includes more advanced stage of the syndrome, of “vascular dementia”

****One specific form is “Pick’s disease”

Because mixed dementia is common, the eval‎uation focuses on identifying conditions likely to contribute to dementia (Box 1 and Table 2). Cerebrovascular disease is the most frequent co-morbid condition with AD, and evidence of cerebrovascular disease does not reduce the likelihood of AD. However, approximately five percent of people with dementia show evidence of only cerebrovascular disease. After AD, the most common neurodegenerative dementias are Lewy body disease, characterized by chronic REM behavior disorder with early visuospatial impairment and parkinsonism,21,22,32,33 and frontotemporal dementia, characterized by a behavioral variant (the most common presentation is disinhibition) or less often, a language impairment variant (such as a semantic dementia, in which the meaning of the patient’s speech is unclear; Table 2).23, 34

혼합형 치매는 흔하기 때문에 평가에서는 치매를 유발할 가능성이 있는 질환을 식별하는 데 중점을 둡니다(상자 1 및 표 2). 뇌혈관 질환은 알츠하이머병의 가장 흔한 동반 질환이며, 뇌혈관 질환의 증거가 있다고 해서 알츠하이머병의 가능성을 낮추지는 않습니다. 그러나 치매 환자의 약 5%는 뇌혈관 질환의 증거만 보입니다. AD 이후 가장 흔한 신경 퇴행성 치매는 초기 시공간 장애와 파킨슨병을 동반한 만성 렘수면 행동 장애를 특징으로 하는 루이체 치매,21,22,32,33 그리고 행동 장애(가장 흔한 증상은 억제 장애) 또는 드물게는 언어 장애(환자의 말의 의미가 불분명한 의미 치매 등, 표 2)를 특징으로 하는 전두측두엽 치매입니다.23, 34

Diagnosis and Management

Clinical eval‎uations, differential diagnosis, and management of dementia most commonly occur in the primary care setting, with appropriate specialist input as needed.

Clinical Eval‎uation for Diagnosis 

The 2014 US Preventive Services Task Force indicated that there was insufficient evidence to eval‎uate the balance of benefits and harms for universal screening for cognitive impairment using formal screening instruments in community-dwelling adults age 65 years and older.35 While the Task Force concluded that adequate evidence existed for some screening tools that have sufficiently high sensitivity and specificity for identifying dementia, there is no published evidence of the effect of screening on decision making or planning by patients, clinicians, or caregivers.35 However, report of memory complaints36–38 or rapidly-progressive cognitive problems over several months may indicate an underlying medical condition that warrants further eval‎uation with cognitive, laboratory, and other tests.39–40

Eval‎uation of possible dementia requires a brief medical history and a cognitive and neurologic examination (Box 2). The history remains the most important diagnostic tool and should be obtained from both the patient and a close family member or friend. While some patients complain of forgetfulness, others are unable to recall details of their history and in some instances have anosognosia (i.e., lack of insight into one’s disease). One clue that a patient has a memory problem occurs when the person accompanying them provides the medical history. The history should characterize the nature, magnitude, and course of cognitive changes. The nature refers to the cognitive domains affected. Is there loss of episodic memory (e.g., what the patient did that morning, yesterday, and last week), or language abilities (e.g., word finding difficulties with circumlocutions)? The magnitude refers to the severity: does the cognitive loss affect daily functions, such as the patient’s ability to manage her own affairs (e.g., does she get lost while driving, not pay her bills, forget to take medications)? Is the course with an insidious onset and a slow progression (as in neurodegeneration) or a rapid onset and fluctuating and stepwise progression (as in cerebrovascular disease)? The history should focus on medical conditions that could affect cognition including vascular disease risk factors (such as hypertension and diabetes), existing brain conditions (such as stroke, Parkinson’s Disease, head trauma), and use of medications that can impair cognition (e.g., sleep aids and anxiolytics such as benzodiazepines; analgesics such as codeine containing agents; anticholinergics such as tricyclic antidepressants and bladder antimuscarinics).41,42 A family history might identify young-onset dementia (onset in persons younger than 65 years) in first-degree relatives, suggesting one of the rare inherited genetic forms of dementia.

치매 가능성을 평가하려면 간단한 병력과 인지 및 신경학적 검사가 필요합니다(박스 2). 병력은 여전히 가장 중요한 진단 도구이며 환자와 가까운 가족이나 친구 모두로부터 얻어야 합니다. 건망증을 호소하는 환자도 있지만, 병력에 대한 세부 사항을 기억하지 못하거나 자신의 질병에 대한 통찰력 부족으로 인한 무인지증(anosognosia)을 호소하는 경우도 있습니다. 환자에게 기억력 문제가 있다는 단서는 환자와 동행하는 사람이 병력을 제공할 때 발견할 수 있습니다. 병력은 인지 변화의 성격, 정도, 경과를 특징짓는 것이어야 합니다. 성격은 영향을 받은 인지 영역을 나타냅니다. 

에피소드 기억력(예: 환자가 그날 아침, 어제, 지난 주에 무엇을 했는지) 또는 언어 능력(예: 단어 찾기에 어려움을 겪는 경우)의 상실이 있나요? 

심각도는 인지 기능 상실이 환자의 자기 관리 능력(예: 운전 중 길을 잃거나, 공과금을 내지 않거나, 약 복용을 잊어버리는 등)과 같은 일상적인 기능에 영향을 미치는지 여부를 나타냅니다. 

신경 퇴행성 질환과 같이 교활하게 발병하고 느리게 진행되는 과정인가, 아니면 뇌혈관 질환과 같이 빠르게 발병하고 변동이 심하고 단계적으로 진행되는 과정인가? 

병력은 혈관 질환 위험 요인(예: 고혈압 및 당뇨병), 기존 뇌 질환(예: 뇌졸중, 파킨슨병, 두부 외상), 인지능력을 손상시킬 수 있는 약물 사용(예: 수면제, 항우울제) 등 인지에 영향을 미칠 수 있는 의학적 상태에 초점을 맞춰야 합니다,  벤조디아제핀과 같은 수면제 및 항불안제, 코데인 함유 제제와 같은 진통제, 삼환계 항우울제 및 방광 항무스카린제와 같은 항콜린제).41,42 

가족력은 1급 친척에서 젊은 발병 치매(65세 미만에서 발병)를 확인할 수 있으며 이는 드물게 유전되는 유전적 치매 형태 중 하나를 시사할 수 있습니다.

Box 2.

Clinical eval‎uation of suspected dementia

Dementia is identified based on:

 • Medical history, including from family, friend, or caregiver, focusing on cognition and function

 • Brief outpatient or bedside cognitive examination

 • If needed, neuropsychological testing

The etiology of dementia is determined based on:

 • Medical history

  ➢ Neurologic history

  ➢ General medical history

  ➢ Family history

 • Physical examination

  ➢ Neurologic signs (e.g., cognitive impairment, focal signs, parkinsonism, other)

  ➢ Pertinent systemic signs (e.g., for vascular and metabolic diseases)

 • Neuropsychological testing

 • Laboratory testing

  ➢ Thyroid function and vitamin B12 level

  ➢ Other tests as indicated, such as for metabolic, infectious, autoimmune, and other etiologies*

 • Structural brain imaging with CT or MRI

  ➢ AD: generalized or focal cortical atrophy, often asymmetric (hippocampal atrophy)

  ➢ Vascular contributions to cognitive impairment and dementia: brain infarcts or white matter lesions

  ➢ Frontotemporal dementia: frontal lobe or anterior temporal lobe atrophy

  ➢ Other abnormalities such as brain mass (e.g., tumor) and hydrocephalus

 • Referral to a specialist, for additional neurologic and medical testing, if specific etiologies suspected

  ➢ Brain tests: electroencephalogram [EEG]

  ➢ Vascular tests: head and neck magnetic resonance angiogram (MRA) or computed tomography angiogram (CTA)

  ➢ Cardiac tests: electrocardiogram [ECG], echocardiography, ambulatory cardiac rhythm monitoring

치매는 다음을 기준으로 확인됩니다:
 - 인지 및 기능에 초점을 맞춘 가족, 친구, 간병인 등의 병력 기록
 - 간단한 외래 또는 병상 인지 검사
 - 필요한 경우, 신경심리 검사

치매의 원인은 다음을 기준으로 결정됩니다:
 - 병력
  신경학적 병력
  일반 병력
  가족력
 - 신체 검사
  신경학적 징후(예: 인지 장애, 초점 징후, 파킨슨병, 기타)
  관련 전신 징후(예: 혈관 및 대사 질환)
 - 신경심리 검사
 - 실험실 검사
  갑상선 기능 및 비타민 B12 수치
  대사성, 감염성, 자가면역성 및 기타 원인에 대한 기타 검사* 등 필요에 따른 기타 검사
 - CT 또는 MRI를 이용한 뇌 구조 영상 촬영
  알츠하이머병: 전신 또는 국소 피질 위축, 종종 비대칭(해마 위축)
  인지 장애 및 치매에 대한 혈관 기여도: 뇌경색 또는 백질 병변
  전두측두엽 치매: 전두엽 또는 전두측두엽 위축
  뇌종양(예: 종양), 수두증 등 기타 이상 소견이 있는 경우
 - 특정 원인이 의심되는 경우, 추가적인 신경학적 및 의학적 검사를 위해 전문의에게 진료 의뢰
  뇌 검사: 뇌전도[EEG] 검사
  혈관 검사: 두경부 자기공명혈관조영술(MRA) 또는 컴퓨터단층촬영혈관조영술(CTA)
  심장 검사: 심전도[ECG], 심장 초음파 검사, 외래 심장 리듬 모니터링

*Depending on the clinical presentation, consider blood tests for a CBC, ESR, chem 7 which includes a glucose level, renal and liver function tests, folic acid, and a RPR.

The cognitive examination identifies the presence, severity, and nature of cognitive impairment (e.g., memory versus language), and should consider cultural, linguistic, educational, and other factors such as anxiety and sleep deprivation. One commonly used screening tool is the Montreal Cognitive Assessment (MoCA; range 0–30, follow-up eval‎uation to screening recommended if score <24/30). The MoCA requires about 10 minutes to administer and is useful in early detection of cognitive impairment, including MCI with executive dysfunction.43 The Mini-Mental State Exam was developed more than 4 decades ago. It is less sensitive to the presence of MCI and less thoroughly eval‎uates the domains of executive function, higher-level language skills, and complex visuospatial processing.43–47

The neurologic examination eval‎uates for objective evidence of neurocognitive problems such as aphasia, apraxia, and agnosia. Unusual behaviors, such as disinhibition with hyperorality or hypersexuality, suggest a frontotemporal dementia, which comprises a group of uncommon conditions associated with neuronal loss beginning in the frontal and/or temporal regions of the brain while other areas are relatively spared. The examination may demonstrate focal neurologic signs or parkinsonism (e.g., as typically seen in the early stages of Lewy body disease). The routine eval‎uation also includes physical examination to identify systemic vascular disease and systemic signs which may be pertinent to rarer causes of dementia (e.g., golden-brown eye discoloration [Kayser-Fleischer rings] of Wilson’s disease).

The routine work-up typically includes a limited number of blood tests (e.g., B12 and TSH) and neuroimaging to identify cortical and hippocampal atrophy (as seen in AD), or neuropathology including potentially treatable causes of dementia (e.g., resectable tumor, or normal pressure hydrocephalus which may be shunted), using brain imaging with either MRI or CT (Box 2).48–53 Additional eval‎uation is sometimes warranted. For example, in highly-educated and highly-functioning individuals, a compelling history of cognitive decline (e.g., no longer able to perform a complex task which could easily be done a year ago, such as filling a tax return or working at a cognitively demanding job such as doctor or lawyer), can suggest dementia despite the presence of “normal” function on a brief, screening cognitive test. In this instance, referral for detailed neuropsychological testing should be considered to assess a broader range of cognitive abilities (e.g., memory, executive function, language, attention, visuospatial abilities) with increased levels of difficulty.54

인지 검사는 인지 장애의 유무, 심각도, 성격(예: 기억력 대 언어)을 파악하고 문화적, 언어적, 교육적 요인 및 불안과 수면 부족과 같은 기타 요인을 고려해야 합니다.

일반적으로 사용되는 선별 도구 중 하나는 몬트리올 인지 평가(MoCA, 0~30점 범위, 24/30점 미만인 경우 선별 검사에 대한 후속 평가 권장)입니다. MoCA는 시행하는 데 약 10분이 소요되며, 실행 기능 장애를 동반한 MCI를 포함한 인지 장애를 조기에 발견하는 데 유용합니다.43

https://new.neuro.or.kr/file/K-MoCA.pdf

미니 정신 상태 검사는 40여 년 전에 개발되었습니다. 이 검사는 MCI의 존재 여부에 덜 민감하며 실행 기능, 고차원 언어 능력, 복잡한 시공간 처리 영역을 덜 철저하게 평가합니다.43-47

신경학적 검사는 실어증, 실어증, 실어증과 같은 신경인지 문제의 객관적인 증거가 있는지 평가합니다. 과성욕 또는 과성욕을 동반한 억제 장애와 같은 비정상적인 행동은 뇌의 전두엽 및/또는 측두엽 영역에서 시작하여 다른 영역은 상대적으로 보존되는 신경세포 손실과 관련된 드문 질환 그룹으로 구성된 전두측두엽 치매를 시사합니다. 검사를 통해 국소 신경학적 징후나 파킨슨병(예: 루이소체 질환의 초기 단계에서 흔히 볼 수 있는 증상)이 나타날 수 있습니다. 일상적인 평가에는 전신 혈관 질환과 드물게 치매의 원인과 관련이 있을 수 있는 전신 징후(예: 윌슨병의 황금빛 갈색 눈 변색[카이저-플라이셔 고리])를 확인하기 위한 신체 검사도 포함됩니다.

일상적인 건강 검진에는 일반적으로 제한된 수의 혈액 검사(예: B12 및 TSH)와 신경 영상 검사를 통해 대뇌 피질 및 해마 위축(알츠하이머병에서 볼 수 있음)을 확인하거나, MRI 또는 CT로 뇌 영상을 촬영하여 잠재적으로 치료 가능한 치매 원인(예: 절제 가능한 종양 또는 션트될 수 있는 정상압 수두증)을 포함한 신경 병리를 확인합니다(박스 2).48-53 추가 평가가 필요한 경우도 있습니다. 예를 들어, 고학력 고기능자의 경우 인지 기능 저하가 뚜렷한 경우(예: 세금 신고서 작성이나 의사 또는 변호사와 같이 인지적으로 까다로운 직종에서 일하는 등 1년 전에는 쉽게 할 수 있었던 복잡한 작업을 더 이상 수행하지 못하는 경우)에는 간단한 선별 인지 검사에서 "정상" 기능을 보였음에도 치매를 의심해 볼 수 있습니다. 이 경우, 난이도가 높은 광범위한 인지 능력(예: 기억력, 실행 기능, 언어, 주의력, 시공간 능력)을 평가하기 위해 자세한 신경심리 검사를 의뢰하는 것을 고려해야 합니다.54

If the etiology of dementia is unclear after a brief history and examination, additional history and examination, and select blood, neurologic and medical tests should be considered (Box 2).

Recent biomedical advances have led to additional tests that may be helpful in the differential diagnosis of dementia, in particular disease biomarkers which are still commonly used in research.55 For a patient whose presentation is not consistent with AD (commonly called “atypical dementia”; see Supplemental Materials, eTable 1) and for patients in whom diagnostic certainty is low, clinicians may consider specialist referral and additional testing. Functional neuroimaging56 such as positron emission tomography (PET)57 can show changes suggestive of AD, usually asymmetric, bilateral temporal-parietal hypometabolism with routine tracers such as fluorodeoxyglucose (FDG) which has a sensitivity of 91% and a specificity of 85% for AD.58–59 FDG PET, covered by health insurance for suspected frontotemporal dementia, may differentiate this etiology from AD, facilitating diagnosis of this less common cause of dementia. For patients with frontotemporal dementia, FDG PET typically shows decreased, asymmetric frontal lobe hypometabolism in the behavioral variant, and anterior temporal lobe hypometabolism in the language (semantic) variant.60 Amyloid PET can also be used in patients with cognitive impairment who are eval‎uated for AD or other causes of cognitive decline.58–59,61 In a recent observational, multisite, longitudinal study of Medicare beneficiaries, amyloid PET results were associated with change in management plans in more than 60% of patients, compared to pre-PET scan. Change in management plans consisted of change in AD medication or other medication therapy, and changes in counseling about safety and future planning.62 However, there is no evidence that PET scan changes clinical outcomes. Functional neuroimaging with tau radioligands are only appropriate for research purposes.63

최근 생물 의학의 발전으로 치매 감별 진단에 도움이 될 수 있는 추가 검사, 특히 연구에서 여전히 일반적으로 사용되는 질병 바이오마커가 개발되었습니다.55 증상이 AD(일반적으로 "비정형 치매"라고 함, 보충 자료, e표 1 참조)와 일치하지 않는 환자 및 진단의 확실성이 낮은 환자의 경우 임상의는 전문의 의뢰 및 추가 검사를 고려할 수 있습니다. 양전자방출단층촬영(PET)57과 같은 기능적 신경영상56은 AD를 암시하는 변화, 즉 대개 비대칭적인 양측 측두엽-두정엽 저대사를 보여줄 수 있으며, 플루오로데옥시글루코스(FDG)와 같은 일상적인 추적자를 사용하면 민감도는 91%, 특이도는 85%입니다.58-59 전두측두엽 치매 의심 시 건강보험이 적용되는 FDG PET는 이 원인과 AD를 감별하여 흔하지 않은 치매의 원인을 진단하는 데 도움이 될 수 있습니다. 전두측두엽 치매 환자의 경우, FDG PET는 일반적으로 행동 변이형에서는 비대칭적인 전두엽 저대사 감소를, 언어(의미) 변이형에서는 전두측두엽 저대사 감소를 보여줍니다.60 아밀로이드 PET는 알츠하이머병 또는 기타 인지 기능 저하의 원인으로 평가되는 인지 장애 환자에게도 사용될 수 있습니다.58-59,61 최근 메디케어 수혜자를 대상으로 한 관찰, 다기관, 종단 연구에서 아밀로이드 PET 결과는 PET 스캔 전과 비교하여 60% 이상의 환자에서 관리 계획의 변화와 관련이 있는 것으로 나타났습니다. 관리 계획의 변화는 AD 약물 또는 기타 약물 요법의 변화, 안전 및 향후 계획에 대한 상담의 변화로 구성되었습니다.62 그러나 PET 스캔이 임상 결과를 변화시킨다는 증거는 없습니다. 타우 방사성 리간드를 사용한 기능적 신경 영상은 연구 목적으로만 적합합니다.63

Cerebrospinal fluid (CSF) testing may be considered to obtain evidence of AD (low amyloid and high tau levels), other neurodegenerative disease (e.g., elevated protein 14–3-3 for Creutzfeldt-Jakob disease) or other etiologies (e.g., positive cultures in infection, oligoclonal bands in demyelination; improved gait after high volume CSF removal in normal pressure hydrocephalus).64–68 Genetic testing may be reasonable, usually for young patients with a history of first-degree relatives with young-onset dementia (e.g., parents or siblings with dementia in their fourth or fifth decade of life). Rare autosomal dominant forms of dementia (e.g., presenilin gene mutations) warrant genetic counseling to determine whether other family members need to be screened.69 Assessment for the APOE genotype is not recommended for routine eval‎uation of AD because most people with AD dementia do not have either the protective ε2 allele or the ε4 allele (associated with increased risk) and, more importantly, because currently, medical management would not be altered by the test results.8 Additional neurologic work-up, such as for amyotrophic lateral sclerosis and medical work-up, such as for cardiac, metabolic, and other etiologies, may be considered with particular attention to ruling out reversible causes of cognitive impairment such as psychiatric disorders (depression) and thyroid dysfunction (see Supplemental Materials, eTable 2).70

뇌척수액(CSF) 검사는 AD(낮은 아밀로이드 및 높은 타우 수치), 기타 신경 퇴행성 질환(예: 크로이츠펠트-야콥병의 경우 단백질 14-3-3 상승) 또는 기타 원인(예, 감염에서 양성 배양, 탈수초화에서 올리고클로날 밴드, 정상압 수두증에서 대량의 CSF 제거 후 보행 개선).64-68 

유전자 검사는 일반적으로 젊은 발병 치매를 가진 1급 친척 병력이 있는 젊은 환자(예: 40대 또는 50대에 치매를 가진 부모 또는 형제자매)에게 적합할 수 있습니다. 상염색체 우성 형태의 희귀 치매(예: 프레세닐린 유전자 돌연변이)는 다른 가족 구성원의 검사 필요 여부를 결정하기 위해 유전 상담이 필요합니다.69 

대부분의 알츠하이머 치매 환자는 ε2 대립유전자 또는 ε4 대립유전자(위험 증가와 관련)를 가지고 있지 않으며, 무엇보다도 현재 의료 관리가 검사 결과에 의해 변경되지 않기 때문에 일상적인 AD 평가에는 APOE 유전자형 평가가 권장되지 않습니다.8 근위축성 측삭 경화증과 같은 추가적인 신경학적 검사와 심장, 대사 및 기타 원인에 대한 의학적 검사는 정신과적 장애(우울증) 및 갑상선 기능 장애와 같은 인지 장애의 가역적 원인을 배제하기 위해 특히 주의하여 고려할 수 있습니다(보충 자료, e표 2 참조).70

Management 

The overall goals are to reduce suffering caused by the cognitive and accompanying symptoms (e.g., in mood and behavior), while delaying progressive cognitive decline. Both non-pharmacologic and pharmacologic approaches are used to achieve the overall goals.

전반적인 목표는 인지 및 수반되는 증상(예: 기분 및 행동)으로 인한 고통을 줄이는 동시에 점진적인 인지 기능 저하를 지연시키는 것입니다. 전반적인 목표를 달성하기 위해 비약물학적 접근법과 약물학적 접근법이 모두 사용됩니다.

Non-pharmacologic management 

For complex manifestations of dementia, referrals to specialists, such as clinician managers (e.g., geriatric nurse practitioners), social workers, occupational or speech therapists, and others may be helpful. Evidence primarily from observational studies and a few randomized controlled trials suggest potential benefits of select non-pharmacologic approaches in dementia (Box 3). Although data demonstrating benefit are limited, they are inexpensive and generally safe. Cognitive training and activities such as reading and playing cognitively engaging games (e.g., chess, bridge) may help maintain cognition and function, as shown in randomized trials.71–73 However, frustration and stress from challenging tasks should be avoided. Music or art therapy, and other experiential approaches, may help maintain cognition or improve quality of life.74 Because old memories of childhood are preserved the longest, reminiscence therapy, consisting of psychotherapy using the personal history of an individuals’ early-life stories and events, may improve psychological well-being.75

복잡한 치매 증상을 보이는 경우에는 임상 관리자(예: 노인전문간호사), 사회복지사, 작업치료사, 언어치료사 등의 전문가에게 의뢰하는 것이 도움이 될 수 있습니다. 주로 관찰 연구와 몇 가지 무작위 대조 시험에서 나온 증거는 치매에 대한 일부 비약물학적 접근법의 잠재적 이점을 시사합니다(상자 3). 효과를 입증하는 데이터는 제한적이지만 비용이 저렴하고 일반적으로 안전합니다. 무작위 시험에서 나타난 바와 같이, 인지 훈련과 독서, 인지적 참여 게임(예: 체스, 브리지) 등의 활동은 인지 및 기능 유지에 도움이 될 수 있습니다.71-73 그러나 어려운 과제로 인한 좌절과 스트레스는 피해야 합니다. 음악이나 미술 치료 및 기타 경험적 접근 방식은 인지력을 유지하거나 삶의 질을 개선하는 데 도움이 될 수 있습니다.74 

어린 시절의 오래된 기억이 가장 오래 보존되기 때문에 개인의 어린 시절 이야기와 사건에 대한 개인사를 활용한 심리 치료로 구성된 회상 치료는 심리적 웰빙을 개선할 수 있습니다.75

Box 3.

Non-pharmacologic approaches to dementia

• Cognitively stimulating activities (e.g., reading, games)

• Physical exercise (e.g., aerobic and anaerobic)

• Social interactions with others (e.g., family events)

• Healthy diet such as the Mediterranean diet (e.g., high in green leafy vegetables)

• Adequate sleep (e.g., uninterrupted sleep and with sufficient number of hours)

• Proper personal hygiene (e.g., regular bathing)

• Safety, including inside the home (e.g., with kitchen appliances) and outside (e.g., driving)

• Medical and advances care directives (e.g., designation of power of attorney)

• Long-term health care planning (e.g., for living arrangement in the late stage of dementia)

• Financial planning (e.g., for allocation of assets)

• Effective communication (e.g., for expressing needs and desires, such as with visual aids)

• Psychological health (e.g., participating in personally meaningful activities such as playing music)

- 인지 자극 활동(예: 독서, 게임)
- 신체 운동(예: 유산소 및 무산소 운동)
- 다른 사람들과의 사회적 교류(예: 가족 행사)
- 지중해식 식단과 같은 건강한 식단(예: 녹색 잎채소 많이 섭취)
- 적절한 수면(예: 방해받지 않고 충분한 시간 동안 수면)
- 적절한 개인 위생(예: 정기적인 목욕)
- 집 안(예: 주방 가전제품 사용) 및 외부(예: 운전 중)를 포함한 안전
- 의료 및 사전 의료 의향서(예: 위임장 지정)
- 장기 건강 관리 계획(예: 치매 말기 생활 준비)
- 재무 계획(예: 자산 배분)
- 효과적인 의사소통(예: 시각 보조 도구 등 필요와 욕구 표현)
- 심리적 건강(예: 음악 연주와 같이 개인적으로 의미 있는 활동 참여)

Physical exercise, both aerobic (e.g., walking, swimming) and non-aerobic/conditioning (e.g., weights), improves cardiovascular health through benefits on blood pressure and stroke risk, and randomized trials suggest these interventions may positively affect cognitive and physical function.76–78 But, not all randomized trials have shown benefits from exercise for cognition.79–80 In a randomized clinical trial, a comprehensive sleep education training program reduced night-time awakenings, total time awake at night, and depressive symptoms over 6 months.81 Social activities may be beneficial, including participating in birthday parties, holidays, support groups with cognitively impaired individuals, and interacting with trained pets (e.g., dog therapy). Eating a brain-healthy diet (e.g., nuts, berries, leafy greens, fish) or a Mediterranean diet is also suggested.82–85 A randomized clinical trial found that a combined diet, exercise, cognitive training, and vascular risk monitoring intervention improved cognition in people at-risk for cognitive decline.86 However, patients with moderate-to-severe dementia have difficulty participating in cognitive, physical, and social activities, and activities should be limited when patients can no longer participate safely and productively.

유산소 운동(예: 걷기, 수영)과 무산소/유산소 운동(예: 웨이트)을 포함한 신체 운동은 혈압과 뇌졸중 위험을 낮춰 심혈관 건강을 개선하며, 무작위 시험에 따르면 이러한 운동이 인지 및 신체 기능에 긍정적인 영향을 미칠 수 있다고 합니다.76-78 그러나 모든 무작위 시험에서 운동이 인지 기능에 도움이 되는 것으로 밝혀진 것은 아닙니다.79 -80 무작위 임상 시험에서 종합적인 수면 교육 훈련 프로그램은 6개월 동안 야간 각성, 밤에 깨어 있는 총 시간, 우울 증상을 줄였습니다.81 생일 파티, 명절, 인지 장애인을 위한 지원 그룹 참여, 훈련된 반려동물과의 상호작용(예: 개 치료) 등 사회 활동은 도움이 될 수 있습니다. 뇌 건강에 좋은 식단(예: 견과류, 베리류, 잎채소, 생선) 또는 지중해식 식단을 섭취하는 것도 좋습니다.82-85 무작위 임상시험에 따르면 식단, 운동, 인지 훈련, 혈관 위험 모니터링 중재를 병행하면 인지 저하 위험이 있는 사람의 인지가 개선되는 것으로 나타났습니다.86 그러나 중등도에서 중증 치매 환자는 인지, 신체, 사회 활동에 참여하는 데 어려움이 있으며 환자가 더 이상 안전하고 생산적으로 참여할 수 없을 때는 활동을 제한해야 합니다.

Day care centers and assisted living facilities may also be helpful for either the patient or caregiver, but may not delay nursing home admission.87 A randomized trial of staff and persons in residential care facilities showed that a clinical protocol for behavioral and psychological symptoms of dementia used by staff, improved patients’ behavioral symptoms and staff stress.86 In the terminal phase of dementia, palliative care may be helpful.

Clinical attention for the caregiver, often a close relative, is important. While efforts continue to effectively deliver primary care for dementia,88 caregiver education and interventions may improve outcomes for patients with dementia, and inexpensive and useful information is available (See Supplemental Materials, eTable 3). Safety, including for the patient’s mental, physical, and financial well-being, should be monitored by the caregiver, with attention to home safety, such as risk of kitchen fires which may be associated with patient burns.89 Other home safety measures include controlling medication intake, limiting access to firearms and other weapons, and monitoring for elder abuse. Safety outside the home includes at work, where the caregiver may facilitate the patient cutting back or stopping work, for instance if managing machinery or making decisions regarding a company’s finances. Also, driving may need to be modified, including limiting driving to neighborhood and daytime driving to prevent getting lost. While no single test is associated with better driving safety, driving ability should be re-assessed periodically and cessation recommended based on dementia severity, to prevent accidents and injuries.90 The caregiver can assist in planning for health care and finances as soon as possible in the course of the illness, to determine advanced directives before late-stage dementia.91 Educating the family on effective communication with a person with dementia, who eventually develop aphasia, is important. Similarly, family should be educated on promoting psychological health and socially adaptive behaviors (e.g., simple and clear instructions to encourage cooperation with activities to address physical and mental health needs, without inciting agitation or aggression).

가까운 친척인 간병인에 대한 임상적 관심은 중요합니다. 치매에 대한 일차 진료를 효과적으로 제공하기 위한 노력이 계속되고 있지만,88 간병인 교육 및 중재는 치매 환자의 결과를 개선할 수 있으며, 저렴하고 유용한 정보를 이용할 수 있습니다(보충 자료, e표 3 참조). 간병인은 환자의 정신적, 신체적, 재정적 안녕을 포함한 안전을 모니터링해야 하며, 환자의 화상과 관련될 수 있는 주방 화재 위험과 같은 가정 안전에 주의를 기울여야 합니다.89 기타 가정 내 안전 조치에는 약물 섭취 조절, 총기 및 기타 무기 접근 제한, 노인 학대 모니터링이 포함됩니다. 집 밖에서의 안전에는 직장에서의 안전이 포함되며, 간병인은 환자가 기계 관리나 회사 재정 관련 결정을 내릴 때 업무를 줄이거나 중단할 수 있도록 도울 수 있습니다. 또한 길을 잃지 않도록 근거리 및 주간 운전으로 운전을 제한하는 등 운전을 수정해야 할 수도 있습니다. 한 가지 검사만으로 운전 안전성이 향상되는 것은 아니지만, 사고와 부상을 예방하기 위해 주기적으로 운전 능력을 재평가하고 치매 중증도에 따라 운전 중단을 권고해야 합니다.90 간병인은 치매 말기 전에 사전의료의향서를 결정하기 위해 질병이 진행되는 동안 가능한 한 빨리 건강 관리 및 재정 계획을 세우는 데 도움을 줄 수 있습니다.91 결국 실어증이 발생하는 치매 환자와의 효과적인 의사소통에 대해 가족을 교육하는 것이 중요합니다. 마찬가지로, 가족은 심리적 건강 및 사회적 적응 행동 증진에 대한 교육을 받아야 합니다(예: 동요나 공격성을 유발하지 않으면서 신체적, 정신적 건강 요구를 해결하기 위한 활동에 협력을 장려하는 간단하고 명확한 지침).

Behavioral problems, such as physical aggression, are a main cause of emergency room visits and institutionalization, and are associated with poor outcomes for patients (e.g., psychological and medical complications) and families.92,93 Caregiver interventions may prevent patient institutionalization. For example, the family can learn to recognize fear, frustration, and anger (e.g., yelling, lashing out), and address signs of aggression (e.g., by redirecting the patients’ attention to something they enjoy), potentially preventing negative outcomes.94

An important consideration for families with a member who has dementia, is the high burden of caregiving.95 This burden may be physical/medical (e.g., neglect of caregiver’s own health, with potential medical complications), emotional and psychological (stress, burnout, depression), and/or financial. Prevention, early recognition, and treatment of these issues (e.g., referrals to social work for additional support), are integral to an effective management plan. A randomized trial demonstrated that delivering caregiver assistance in-person versus by telephone only, both improved care quality and without differences in effectiveness.96

신체적 공격성과 같은 행동 문제는 응급실 방문 및 시설 입소의 주요 원인이며, 환자(예: 심리적 및 의학적 합병증) 및 가족의 좋지 않은 결과와 관련이 있습니다.92,93 간병인의 개입은 환자의 시설 입소를 예방할 수 있습니다. 예를 들어, 가족은 두려움, 좌절, 분노(예: 고함, 화풀이)를 인식하는 방법을 배우고 공격성의 징후를 해결(예: 환자가 좋아하는 것으로 주의를 돌림)하여 부정적인 결과를 예방할 수 있습니다.94

치매 환자가 있는 가족에게 중요한 고려 사항은 간병 부담이 크다는 점입니다.95 이러한 부담은 신체적/의료적(예: 간병인 자신의 건강 관리 소홀, 잠재적 의료 합병증), 정서적/심리적(스트레스, 소진, 우울증) 및/또는 재정적 부담일 수 있습니다. 이러한 문제의 예방, 조기 인식 및 치료(예: 추가 지원을 위한 사회 복지 서비스 의뢰)는 효과적인 관리 계획에 필수적입니다. 무작위 시험에 따르면 간병인 지원을 대면으로 제공할 때와 전화로만 제공할 때 모두 치료의 질이 향상되고 효과에는 차이가 없는 것으로 나타났습니다.96

Pharmacologic management 

Table 3 shows the Food and Drug Administration (FDA) approved drugs for AD dementia. Five drugs, four of which are currently available for prescription, yield modest symptomatic benefit for cognitive symptoms. Acetylcholinesterase inhibitors were the first drugs approved in the US for AD. These drugs inhibit the brain acetylcholinesterase enzyme, thereby promoting relative increases in acetylcholine abundance at the synaptic cleft for cholinergic neurotransmission. In a meta-analysis review of 10 randomized, double blind, placebo controlled trials each with a six month duration of drug exposure, acetylcholinesterase inhibitors were associated with 2.4 points slower decline (95%CI −2.7 to −2.0; p<0.00001) in a research measure of cognition spanning 70 points.97 This is equivalent to about 6 months of decline from natural history studies of AD dementia, but the magnitude of the clinically relevant benefit is uncertain.35 Also, modest improvements were observed in activities of daily living and behaviors. The efficacy of anticholinesterase inhibitors is similar among the individual drugs (donepezil, rivastigmine, galantamine).96 Given the modest benefits and known risks, clinicians should engage in shared decision making regarding the initiation of an acetylcholinesterase inhibitor for the symptomatic treatment of AD dementia.90

Table 3.

Approved* pharmacologic treatments for dementia attributed to AD

Acetylcholinesterase inhibitorsNMDA** receptor antagonistCombination drugsDonepezilRivastigmineGalantamineMemantineMemantine and donepezil

STAGE INDICATED	All stages of dementia	Mild-to moderate***	Mild-to moderate	Moderate-to-severe	Moderate-to-severe
DOSAGE TITRATION AND TARGET	Tablet or orally disintegrating tablet: starting dose is 5 mg once daily for 6 weeks; if tolerated, increase to 10 mg once daily (typical target dose); if tolerated and needed, may increase to 23 mg once daily (note: 23 mg dose available as brand-name tablet only).	Capsule: starting dose is 1.5 mg twice daily for two weeks; if tolerated, increase to 3 mg twice daily for 2 weeks, then 4.5 mg twice daily for 2 weeks, then 6 mg twice daily. Maximum recommended dose: 6 mg twice daily. Transdermal patch: starting dose is 4.6 mg/24 hours patch once daily for 4 weeks; if tolerated, increase to 9.5 mg/24 hours for ≥4 weeks; if tolerated and needed, increase to 13.3 mg/24 hours. Recommended effective dose: 9.5 to 13.3 mg/24 hours patch.	Extended-release capsule: starting dose is 8 mg once daily for 4 weeks; if tolerated, increase to 16 mg once daily for ≥4 weeks; if tolerated and needed, increase to 24 mg once daily. Recommended target dose range: 16 to 24 mg once daily. Immediate-release tablet or oral solution: starting dose is 4 mg twice daily for 4 weeks; if tolerated, increase to 8 mg twice daily for ≥4 weeks; if tolerated and needed, increase to 12 mg twice daily. Recommended target dose range: 8 to 12 mg twice daily.	Extended-release capsule: starting dose is 7 mg once daily for one week; if tolerated, may increase to 14 mg once daily, then 21mg once daily, and then 28 mg once daily, at a minimum of 1 week intervals. Recommended target dose: 28 mg once daily. Tablet or oral solution: starting dose is 5 mg once daily for one week; if tolerated, may increase to 5 mg twice daily, then 5 mg in am and 10 mg in pm, and then 10 mg twice daily, at a minimum of 1 week intervals. Recommended target dose: 10 mg twice daily.	Capsule: target dose is 28 mg memantine extended-release with 10 mg donepezil, once daily in the evening. For patients with severe renal impairment: maximum dose is 14 mg memantine extended-release with 10 mg donepezil once daily.
ADVANTAGES	Among drugs listed, this has been available for the longest time and, with prescriber familiarity, remains commonly used; available as generic drug and covered by most health insurance plans.	Also available as a skin patch application, which is a good option for when a patient has barriers to using an oral route of administration; also indicated for mild-to-moderate dementia associated with Parkinson disease.	The most recent option for use in mild-to-moderate stage.	May be used in combination with one of the acetylcholinesterase inhibitors, or as monotherapy.	Singe pill combination is best for patients already exposed to one or both of these individual drugs in the past, and who have not experienced adverse effects.
ADVERSE EFFECTS	Nausea, vomiting, loss of appetite, increased frequency of bowel movements, vivid dreams, insomnia; use with caution in patients with peptic ulcer disease, respiratory disease, seizure disorder and urinary tract obstruction; contraindicated in bradycardia. Patch formulation (for rivastigmine) can cause local skin irritation and reactions.			Headache, constipation, confusion and dizziness; use with caution in patients with cardiovascular disease, seizure disorder, and severe hepatic and renal impairment.	(see both cells to the left).

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*Approved by the US Food and Drug Administration (FDA); refer to current, established sources of data (e.g., www.pdr.net/drug-summary) for most-to-date prescribing information, including for indications, dosages, adverse effects, risks, and contraindications; note that tacrine, another anticholinesterase inhibitor, was the first drug approved for AD in the US, but is no longer in use because of related toxicity

**NMDA: N-Methyl-D-Aspartic acid

***Note that a transdermal patch formulation is also approved for the severe stage of dementia

Each drug shown in Table 3 is available for use orally, and one is also available for transdermal use (rivastigmine). A slow titration dosing regimen over 4–8 weeks is recommended to reach the target dose and minimize adverse effects for all of the drugs. Some drugs are used at different maintenance doses depending on effects/adverse effects. For example, donepezil maintenance can be at 5 mg (e.g., if higher dose is associated with poor tolerability), 10mg (typical target), or 23 mg (rarely used), once daily. Despite a slow titration, adverse effects, such as gastrointestinal (e.g., nausea, vomiting, and diarrhea; in about 5 percent of users) may occur (Table 3). Adverse effects may be higher than previously recognized.98 If encountered, dosage may be lowered (e.g., from 10 mg of donepezil to 5 mg), either temporarily (e.g., days to weeks) before re-escalating more slowly and monitoring for recurrence of adverse effects (family instructed to call clinician if adverse effects). Alternatively, the drug can be discontinued and a different drug can be prescribed even in the same class (another acetylcholinesterase inhibitor), given that adverse effects vary among same-class drugs.99 Approximately 5 percent of patients discontinue the drug due to adverse effects. If tolerated, annual brief assessments using the history (e.g., progression of cognitive problems, new cognitive problems, functional status) and a brief cognitive test can be used in the absence of new problems. Often, clinicians cannot appreciate a benefit and must rely on caregiver reports. A good response to a drug would result in the caregiver noticing a slight improvement in day-to-day life (e.g., improved ability to function at home). Routine cognitive tests such as the MoCA,43 can be used to monitor disease course on treatment, and to identify unexpected trends such as rapid decline which would prompt consideration for a medical eval‎uation (e.g., for systemic infection). However, benefits are typically not seen on such routine tests. Monitoring requires periodic re-eval‎uation of cognition, function, neuropsychiatric and behavioral symptoms, and medication reconciliation.100–103

As neurodegeneration in AD progresses, further cognitive and functional decline invariably occur, and consideration should be given in the moderate-to-severe stages of dementia for adding memantine (Table 3). Memantine can also be used as a first-line drug, for instance when a patient with moderate dementia presents for a first eval‎uation but is not taking any medication for cognition. Another use is for patients who cannot tolerate an acetylcholinesterase inhibitor. Adverse effects of memantine include headaches and constipation.

Aside from AD, few other dementia etiologies have approved pharmacologic treatments for cognitive symptoms, and no disease specific treatments exist for Lewy body disease or frontotemporal dementia. In addition to AD, rivastigmine has also received approval for Parkinson disease dementia. There are currently no FDA-approved drugs for MCI,104 and studies of acetylcholinesterase inhibitors failed to show benefit in this population.105 At this time, more than 100 drugs are being investigated for dementia and cognition, and include potential disease modifying agents.106–107

Medical management should address common causes of cognitive impairment and dementia, including polypharmacy which affects a third of persons older than 60 years.108–109 Special considerations may be appropriate for patients with medical comorbidities (e.g., kidney dysfunction). Another approach in dementia management is reducing brain ischemia and stroke risk by treating vascular risk factors (hypertension, diabetes, hyperlipidemia) and consideration of the risk-benefit ratio for anti-thrombotics and anticoagulants (if prior stroke or atrial fibrillation are present). A recent randomized clinical trial of dementia prevention showed that intensive blood pressure lowering in persons with hypertension (comparing a target systolic blood pressure below 120mmHg, to a pressure between 120–140mmHg) did not reduce risk of dementia, but did reduce the combined rate of MCI or probable dementia in a post-hoc analysis.110

Dementia is often accompanied by neuropsychiatric and behavioral problems. About 95% of patients have at least mild symptoms, most commonly apathy (83%) and depression (63%).111 Approved treatments do not exist for these non-cognitive manifestations in the setting of dementia. For depression, a low dose antidepressant can be tried such as with a selective serotonin-reuptake inhibitor (e.g., escitalopram). Management of agitation and aggression can be challenging. Conventional antipsychotics such as haloperidol, should be avoided.112 Newer generation “atypical” antipsychotics such as risperidone and quetiapine fumarate, should be avoided if possible, given their association with serious risks, especially in older patients.113 Specifically, death, cardiac effects such as heart failure, and stroke, have resulted in a black box warning. Therefore, antipsychotics should only be used in controlled environments (e.g., under close medical supervision) and for a limited time only (e.g., a few weeks) when all other non-pharmacologic approaches have failed or the patient’s behavior poses a substantial threat to themselves or others.112

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CONCLUSIONS

AD currently affects 5.8 million persons in the US, and is a common cause of dementia which is usually accompanied by other neuropathology. The cause of dementia can be diagnosed by medical history, cognitive and physical examination, laboratory testing, and brain imaging. Management should include both non-pharmacologic approaches with cognitive, physical, and social activities, and pharmacologic approaches such as with an acetylcholinesterase inhibitor for AD, although efficacy of treatments remains limited.

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Supplementary Material

Supplemental material

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ACKNOWLEDGEMENTS

This study was supported by the National Institutes of Health, grant numbers P30 AG010161, R01 AG040039, R01 NS084965, and RF1 AG059621; the Health Resources and Services Administration for HRSA-15-057; and the Illinois Department of Public Health. The study funders had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript, or decision to submit the manuscript for publication.

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