ARTICLE IN PRESS
New Findings on the Neurobiology of Dementia and Dementia Risk Carmen Andreescu, M.D., Howard J. Aizenstein, M.D., Ph.D. ver the last two decades there has been considerable progress in our understanding of the neural basis of dementia and associated neuropsychiatric symptoms. This progress has come from research using a variety of paradigms and approaches, including neuroimaging, genetics, peripheral blood markers, and advanced statistical methods. The current issue of the American Journal of Geriatric Psychiatry contains five new reports using these approaches. These articles either describe specific markers of disease progression1,2 or analyze the relationship of various neuropsychiatric symptoms to dementia.3–5 A major theme of current dementia research is to identify early markers of disease progression, with the ultimate aim of developing treatment to prevent illness progression. The prevailing view of Alzheimer disease (AD) pathogenesis6 is that the disease process begins decades before observable functional decline. During the early stages there may be pathophysiologic changes, such as alterations in amyloid processing, that eventually lead to the deposition of amyloid plaques, detectable with amyloid positron emission tomography. Subsequent progressive neurodegeneration, including synaptic and neural loss, is associated with clinical changes such as cognitive and behavioral symptoms. The intermediate stage (mild cognitive impairment [MCI]) is characterized by significant decline, yet not reaching the functional and cognitive impairment threshold of dementia. Among individuals with MCI the rate for progression to AD varies wildly.7 Identifying which individuals with MCI are most likely to progress quickly to AD is critical for identifying more effective prevention and treatment strategies.
O
It has previously been shown that among individuals with MCI, neuropsychiatric symptoms are associated with a faster progression to AD. Forrester et al.5 explore this association using latent class analysis, which is used to cluster MCI individuals into distinct subgroups based on the presence or absence of different neuropsychiatric symptoms. The study used data from over 500 participants of the Alzheimer’s Disease Cooperative Study (ADCS) cohort, who were followed over 2 years. At each visit they were assessed with the Neuropsychiatric Inventory Scale and adjudicated regarding conversion to dementia. The authors identified three clusters of symptoms: asymptomatic, affective, and severe. Progression rate was highest in the severe group, intermediate for the affective group, and lowest for the asymptomatic group. This study confirms the association of neuropsychiatric symptoms with faster progression to AD. The study also identifies a highly prevalent affective subgroup, with primarily depressive and anxiety symptoms. Relative to the group without mood symptoms, this group showed high risk of conversion to dementia. The role of chronic depressive symptoms in dementia progression risk is further examined in the study by Sacuiu et al.3 This study used the data from the Alzheimer’s Disease Neuroimaging Initiative 8 to characterize the relationship of depressive symptoms, regional brain atrophy, and progression to AD. Ninety-four individuals with MCI were included. Each was assessed for 2 years at 6-months intervals. Assessments included Neuropsychiatric Inventory Scale– based depression ratings and magnetic resonance scanning. Similar to the Forrester et al. study, the primary outcome measure was progression to AD. The
Received October 2, 2015; accepted October 5, 2015. From the Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA. Send correspondence and reprint requests to Howard Aizenstein, M.D., Ph.D., Departments of Psychiatry and Bioengineering, University of Pittsburgh, 3811 O’Hara Street, Pittsburgh, PA 15213-2597. e-mail: [email protected] © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jagp.2015.10.003
Am J Geriatr Psychiatry ■■:, ■■ 2016
1
ARTICLE IN PRESS Editorial authors report that chronic depressive symptoms associated with progressive temporal atrophy also carried the risk of a 60% shorter conversion time to AD. These two studies emphasize the association of depression and depressive symptoms with increased dementia risk. For now, it remains unclear whether reducing neuropsychiatric symptoms could modify the risk to conversion to dementia. It is well established that the high burden of amyloid plaques on positron emission tomography is strongly associated with AD and is predictive of progression to AD. Several studies have indicated that participants diagnosed with MCI and carrying a high amyloid burden are the ones most likely to progress to dementia.9 However, what about those 30%–40% of individuals with MCI who do not have a high amyloid burden? The study by Choi et al.1 in the current issue suggests a possible pathogenic mechanism for these individuals. In this study data were collected on 13 amyloid-negative individuals diagnosed with amnestic MCI, 15 amyloid-positive amnestic MCI participants, and 35 cognitively intact comparison participants. Compared with amyloid-positive individuals, amyloidnegative participants had small hippocampi, lower apolipoprotein A1, and a lower risk of progression to AD. The role of low apolipoprotein A1 in contributing to non-AD cognitive impairment is a novel and interesting finding, opening an exciting research direction.
Dementia with Lewy bodies (DLB) is the second leading cause of degenerative dementia, after AD, and the third most common dementia after AD and vascular dementia. Although DLB shares many pathologic and clinical features with AD, much remains unknown about the relationship between AD and DLB. Many DLB cases are misdiagnosed. The study of Mak et al.2 describes imaging markers in the hippocampal subfields that help distinguish DLB from AD. The relative preservation of the hippocampus described in this study is in agreement with previous literature as well as with the phenotypical differences between the two types of dementia (namely the marked memory deficits in AD compared with DLB). Frontotemporal dementia (FTD) is often associated with behavioral symptoms, which overlap with psychiatric diagnoses. The report by Block et al.4 in this issue describes the psychiatric presentation of a case series of five older adults diagnosed with dementia and carrying one of the FTD genes. The chosen cases illustrate the protean nature of FTD’s clinical presentation and also describe possible features (e.g., late-life onset, insidiously worsening course) that may raise the suspicion of a possible FTD diagnosis. In conclusion, these articles advance our understanding of the neurobiology of dementias at both clinical and biologic levels. They further develop homogenous diagnostic constructs vulnerable to targeted treatment modalities.
References 1. Choi HJ, Seo EH, Yi D, et al: Amyloid-independent amnestic Mild cognitive impairment and serum apolipoprotein A1 levels. Am J Geriatr Psychiatry 2015; doi:10.1016/j.jagp.2015.06.004 2. Mak E, Li S, Williams GB, et al: Differential atrophy of hippocampal subfields: a comparative study of dementia with lewy bodies and alzheimer disease. Am J Geriatr Psychiatry 2015; doi:10.1016/ j.jagp.2015.06.006 3. Sacuiu S, Insel PS, Mueller S, et al: Chronic depressive symptomatology in mild cognitive impairment is associated with frontal atrophy rate which hastens conversion to Alzheimer dementia. Am J Geriatr Psychiatry 2015; doi:10.1016/j.jagp.2015.03.006 4. Block NR, Sha SJ, Karydas AM, et al: Frontotemporal dementia and psychiatric illness: emerging clinical and biological links in gene carriers.Am J Geriatr Psychiatry 2015;doi:10.1016/j.jagp.2015.04.007
2
5. Forrester SN, Gallo JJ, Smith GS, et al: Patterns of neuropsychiatric symptoms in mild cognitive impairment and risk of dementia. Am J Geriatr Psychiatry 2015; doi:10.1016/j.jagp.2015.05.007 6. Jack CR Jr: Alzheimer disease: new concepts on its neurobiology and the clinical role imaging will play. Radiology 2012; 263:344– 361 7. Ganguli M, Dodge HH, Shen C, et al: Mild cognitive impairment, amnestic type: an epidemiologic study. Neurology 2004; 63:115–121 8. Jack CR Jr, Bernstein MA, Fox NC, et al: The Alzheimer’s Disease Neuroimaging Initiative (ADNI): MRI methods. J Magn Reson Imaging 2008; 27:685–691 9. Ong KT, Villemagne VL, Bahar-Fuchs A, et al: Abeta imaging with 18F-florbetaben in prodromal Alzheimer’s disease: a prospective outcome study. J Neurol Neurosurg Psychiatry 2015; 86:431–436
Am J Geriatr Psychiatry ■■:, ■■ 2016
New Findings on the Neurobiology of Dementia and Dementia Risk Carmen Andreescu, M.D., Howard J. Aizenstein, M.D., Ph.D. ver the last two decades there has been considerable progress in our understanding of the neural basis of dementia and associated neuropsychiatric symptoms. This progress has come from research using a variety of paradigms and approaches, including neuroimaging, genetics, peripheral blood markers, and advanced statistical methods. The current issue of the American Journal of Geriatric Psychiatry contains five new reports using these approaches. These articles either describe specific markers of disease progression1,2 or analyze the relationship of various neuropsychiatric symptoms to dementia.3–5 A major theme of current dementia research is to identify early markers of disease progression, with the ultimate aim of developing treatment to prevent illness progression. The prevailing view of Alzheimer disease (AD) pathogenesis6 is that the disease process begins decades before observable functional decline. During the early stages there may be pathophysiologic changes, such as alterations in amyloid processing, that eventually lead to the deposition of amyloid plaques, detectable with amyloid positron emission tomography. Subsequent progressive neurodegeneration, including synaptic and neural loss, is associated with clinical changes such as cognitive and behavioral symptoms. The intermediate stage (mild cognitive impairment [MCI]) is characterized by significant decline, yet not reaching the functional and cognitive impairment threshold of dementia. Among individuals with MCI the rate for progression to AD varies wildly.7 Identifying which individuals with MCI are most likely to progress quickly to AD is critical for identifying more effective prevention and treatment strategies.
O
It has previously been shown that among individuals with MCI, neuropsychiatric symptoms are associated with a faster progression to AD. Forrester et al.5 explore this association using latent class analysis, which is used to cluster MCI individuals into distinct subgroups based on the presence or absence of different neuropsychiatric symptoms. The study used data from over 500 participants of the Alzheimer’s Disease Cooperative Study (ADCS) cohort, who were followed over 2 years. At each visit they were assessed with the Neuropsychiatric Inventory Scale and adjudicated regarding conversion to dementia. The authors identified three clusters of symptoms: asymptomatic, affective, and severe. Progression rate was highest in the severe group, intermediate for the affective group, and lowest for the asymptomatic group. This study confirms the association of neuropsychiatric symptoms with faster progression to AD. The study also identifies a highly prevalent affective subgroup, with primarily depressive and anxiety symptoms. Relative to the group without mood symptoms, this group showed high risk of conversion to dementia. The role of chronic depressive symptoms in dementia progression risk is further examined in the study by Sacuiu et al.3 This study used the data from the Alzheimer’s Disease Neuroimaging Initiative 8 to characterize the relationship of depressive symptoms, regional brain atrophy, and progression to AD. Ninety-four individuals with MCI were included. Each was assessed for 2 years at 6-months intervals. Assessments included Neuropsychiatric Inventory Scale– based depression ratings and magnetic resonance scanning. Similar to the Forrester et al. study, the primary outcome measure was progression to AD. The
Received October 2, 2015; accepted October 5, 2015. From the Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA. Send correspondence and reprint requests to Howard Aizenstein, M.D., Ph.D., Departments of Psychiatry and Bioengineering, University of Pittsburgh, 3811 O’Hara Street, Pittsburgh, PA 15213-2597. e-mail: [email protected] © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jagp.2015.10.003
Am J Geriatr Psychiatry ■■:, ■■ 2016
1
ARTICLE IN PRESS Editorial authors report that chronic depressive symptoms associated with progressive temporal atrophy also carried the risk of a 60% shorter conversion time to AD. These two studies emphasize the association of depression and depressive symptoms with increased dementia risk. For now, it remains unclear whether reducing neuropsychiatric symptoms could modify the risk to conversion to dementia. It is well established that the high burden of amyloid plaques on positron emission tomography is strongly associated with AD and is predictive of progression to AD. Several studies have indicated that participants diagnosed with MCI and carrying a high amyloid burden are the ones most likely to progress to dementia.9 However, what about those 30%–40% of individuals with MCI who do not have a high amyloid burden? The study by Choi et al.1 in the current issue suggests a possible pathogenic mechanism for these individuals. In this study data were collected on 13 amyloid-negative individuals diagnosed with amnestic MCI, 15 amyloid-positive amnestic MCI participants, and 35 cognitively intact comparison participants. Compared with amyloid-positive individuals, amyloidnegative participants had small hippocampi, lower apolipoprotein A1, and a lower risk of progression to AD. The role of low apolipoprotein A1 in contributing to non-AD cognitive impairment is a novel and interesting finding, opening an exciting research direction.
Dementia with Lewy bodies (DLB) is the second leading cause of degenerative dementia, after AD, and the third most common dementia after AD and vascular dementia. Although DLB shares many pathologic and clinical features with AD, much remains unknown about the relationship between AD and DLB. Many DLB cases are misdiagnosed. The study of Mak et al.2 describes imaging markers in the hippocampal subfields that help distinguish DLB from AD. The relative preservation of the hippocampus described in this study is in agreement with previous literature as well as with the phenotypical differences between the two types of dementia (namely the marked memory deficits in AD compared with DLB). Frontotemporal dementia (FTD) is often associated with behavioral symptoms, which overlap with psychiatric diagnoses. The report by Block et al.4 in this issue describes the psychiatric presentation of a case series of five older adults diagnosed with dementia and carrying one of the FTD genes. The chosen cases illustrate the protean nature of FTD’s clinical presentation and also describe possible features (e.g., late-life onset, insidiously worsening course) that may raise the suspicion of a possible FTD diagnosis. In conclusion, these articles advance our understanding of the neurobiology of dementias at both clinical and biologic levels. They further develop homogenous diagnostic constructs vulnerable to targeted treatment modalities.
References 1. Choi HJ, Seo EH, Yi D, et al: Amyloid-independent amnestic Mild cognitive impairment and serum apolipoprotein A1 levels. Am J Geriatr Psychiatry 2015; doi:10.1016/j.jagp.2015.06.004 2. Mak E, Li S, Williams GB, et al: Differential atrophy of hippocampal subfields: a comparative study of dementia with lewy bodies and alzheimer disease. Am J Geriatr Psychiatry 2015; doi:10.1016/ j.jagp.2015.06.006 3. Sacuiu S, Insel PS, Mueller S, et al: Chronic depressive symptomatology in mild cognitive impairment is associated with frontal atrophy rate which hastens conversion to Alzheimer dementia. Am J Geriatr Psychiatry 2015; doi:10.1016/j.jagp.2015.03.006 4. Block NR, Sha SJ, Karydas AM, et al: Frontotemporal dementia and psychiatric illness: emerging clinical and biological links in gene carriers.Am J Geriatr Psychiatry 2015;doi:10.1016/j.jagp.2015.04.007
2
5. Forrester SN, Gallo JJ, Smith GS, et al: Patterns of neuropsychiatric symptoms in mild cognitive impairment and risk of dementia. Am J Geriatr Psychiatry 2015; doi:10.1016/j.jagp.2015.05.007 6. Jack CR Jr: Alzheimer disease: new concepts on its neurobiology and the clinical role imaging will play. Radiology 2012; 263:344– 361 7. Ganguli M, Dodge HH, Shen C, et al: Mild cognitive impairment, amnestic type: an epidemiologic study. Neurology 2004; 63:115–121 8. Jack CR Jr, Bernstein MA, Fox NC, et al: The Alzheimer’s Disease Neuroimaging Initiative (ADNI): MRI methods. J Magn Reson Imaging 2008; 27:685–691 9. Ong KT, Villemagne VL, Bahar-Fuchs A, et al: Abeta imaging with 18F-florbetaben in prodromal Alzheimer’s disease: a prospective outcome study. J Neurol Neurosurg Psychiatry 2015; 86:431–436
Am J Geriatr Psychiatry ■■:, ■■ 2016
