The Differential Diagnosis of Alzheimer's Disease: Conceptual and Methodological Issues

Abstract:The study of Alzheimer's disease is hampered by insufficient knowledge of its cause. It can best be described as a syndrome whose clinical and pathological features, and their associations over time, need to be more carefully examined. Issues which impede our understanding of this syndrome include the lack of: (a) a singular “gold standard” for its identification; (b) longitudinal studies with appropriate comparison groups and neuropathological follow-up; and (c) standardized multifaceted clinical assessment procedures. Our awareness of the significance of these issues has led us to undertake a large-scale prospective, longitudinal investigation of 399 dementing and normal individuals at Sunnybrook Medical Centre. As a result of problems identified, it is proposed that research efforts across various Canadian centres be coordinated to best utilize available resources and expertise.

Download Full-text

Prospective longitudinal study of depression and anosognosia in Alzheimer's disease

The British Journal of Psychiatry ◽

10.1192/bjp.171.1.47 ◽

1997 ◽

Vol 171 (1) ◽

pp. 47-52 ◽

Cited By ~ 92

Author(s):

Sergio E. Starkstein ◽

Erán Chemerinski ◽

Liliana Sabe ◽

Gabriela Kuzis ◽

Gustavo Petracca ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Major Depression ◽

Cognitive Status ◽

Initial Evaluation ◽

Consecutive Series ◽

Psychiatric Interview ◽

Prospective Longitudinal Study ◽

Prospective Longitudinal

BackgroundThe aim was to examine the longitudinal evolution of depression and anosognosia in patients with probable Alzheimer's disease (AD).MethodSixty-two of a consecutive series of 116 AD patients that were examined with a structured psychiatric interview had a follow-up evaluation between one and two years after the initial evaluation.ResultsAt the initial evaluation 19% of the 62 patients had major depression, 34% had dysthymia, and 47% were not depressed. After a mean follow-up of 16 months, 58% of patients with major depression at the initial evaluation were still depressed, whereas only 28% of patients with initial dysthymia and 21% of the non-depressed patients were depressed at follow-up. During the follow-up period, all three groups showed similar declines in cognitive status and activities of daily living. At the initial evaluation, 39% of the patients had anosognosia, and there was a significant increment of anosognosia during the follow-up period.ConclusionsWhile dysthymia in AD is a brief emotional disorder, major depression is a longer-lasting mood change. Anosognosia is another prevalent disorder among AD patients, and increases with the progression of the illness.

Download Full-text

Profiling spontaneous speech decline in Alzheimer's disease: a longitudinal study

Acta Neuropsychiatrica ◽

10.1017/neu.2013.16 ◽

2013 ◽

Vol 25 (6) ◽

pp. 320-327 ◽

Cited By ~ 24

Author(s):

Katrina Forbes-McKay ◽

Michael F Shanks ◽

Annalena Venneri

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Phonological Processing ◽

Longitudinal Design ◽

Spontaneous Speech ◽

Speech Impairment ◽

Cross Sectional ◽

Description Task ◽

Prospective Longitudinal

ObjectiveThis study aims to document the nature and progression of spontaneous speech impairment suffered by patients with Alzheimer's disease (AD) over a 12-month period, using both cross-sectional and prospective longitudinal design.MethodsThirty one mild–moderate AD patients and 30 controls matched for age and socio-cultural background completed a simple and complex oral description task at baseline. The AD patients then underwent follow-up assessments at 6 and 12 months.ResultsCross-sectional comparisons indicated that mild–moderate AD patients produced more word-finding delays (WFDs) and empty and indefinite phrases, while producing fewer pictorial themes, repairing fewer errors, responding to fewer WFDs, produce shorter and less complex phrases and produce speech with less intonational contour than controls. However, the two groups could not be distinguished on the basis of phonological paraphasias. Longitudinal follow-up, however, suggested that phonological processing deteriorates over time, where the prevalence of phonological errors increased over 12 months.DiscussionConsistent with findings from neuropsychological, neuropathological and neuroimaging studies, the language deterioration shown by the AD patients shows a pattern of impairment dominated by semantic errors, which is later joined by a disruption in the phonological aspects of speech.

Download Full-text

ASSESSMENT OF CLINICAL MEANINGFULNESS OF ENDPOINTS IN THE GENERATION PROGRAM BY THE INSIGHTS TO MODEL ALZHEIMER’S PROGRESSION IN REAL LIFE (IMAP) STUDY

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2018.49 ◽

2018 ◽

pp. 1-5

Author(s):

A. Graf ◽

V. Risson ◽

A. Gustavsson ◽

V. Bezlyak ◽

A. Caputo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

Real Life ◽

Primary Objective ◽

Cognitive Test ◽

Clinical Dementia Rating ◽

Life Study ◽

Prospective Longitudinal ◽

Clinical Meaningfulness

We are launching the Insights to Model Alzheimer’s Progression in Real Life study in parallel with the Alzheimer Prevention Initiative Generation Program. This is a 5-year, multinational, prospective, longitudinal, non-interventional cohort study that will collect data across the spectrum of Alzheimer’s disease. The primary objective is to assess the ability of the Alzheimer’s Prevention Initiative Cognitive Composite Test Score and Repeatable Battery for the Assessment of Neuropsychological Status to predict clinically meaningful outcomes such as diagnosis of mild cognitive impairment or dementia due to Alzheimer’s disease, and change in Clinical Dementia Rating – Global Score. This study is the first large-scale, prospective effort to establish the clinical meaningfulness of cognitive test scores that track longitudinal decline in preclinical Alzheimer’s disease. This study is also expected to contribute to our understanding of the relationships among outcomes in different stages of Alzheimer’s disease as well as models of individual trajectories during the course of the disease.

Download Full-text

Charting the decline in spontaneous writing in Alzheimer's disease: a longitudinal study

Acta Neuropsychiatrica ◽

10.1017/neu.2014.2 ◽

2014 ◽

Vol 26 (4) ◽

pp. 246-252 ◽

Cited By ~ 6

Author(s):

Katrina Forbes-McKay ◽

Mike Shanks ◽

Annalena Venneri

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Phonological Processing ◽

Visual Processing ◽

Longitudinal Design ◽

Cross Sectional ◽

Spontaneous Writing ◽

Description Task ◽

Prospective Longitudinal

ObjectiveThis study aims to document the nature and progression of the spontaneous writing impairment observed in patients with Alzheimer's disease (AD) over a 12-month period using both a cross-sectional and prospective longitudinal design.MethodsThirty-one minimal–moderate AD patients and 30 controls matched for age and socio-cultural background completed a simple and complex written description task at baseline. The AD patients then had follow-up assessments at 6 and 12 months.ResultsCross-sectional comparisons indicated that minimal–moderate AD patients produced more semantic paraphasias, phonological paraphasias, and empty and indefinite phrases, whilst producing fewer pictorial themes, repairing fewer errors, and producing shorter and less complex sentences than controls. The two groups could not be distinguished on visual paraphasias. Longitudinal follow-up, however, suggested that visual processing deteriorates over time, where the prevalence of visual errors increased over 12 months.DiscussionThe findings suggest that the deterioration of writing skills observed in the spontaneous writings of AD patients shows a pattern of impairment dominated by semantic errors with a secondary impairment in phonological processing, which is later joined by a disruption of visuospatial and graphomotor processing.

Download Full-text

1153 Association Of Nocturnal Sleep Disturbance And Prospective Cognitive Decline In Cognitive Normal Elderly: Findings From The National Alzheimer’s Coordinating Center Uniform Dataset

SLEEP ◽

10.1093/sleep/zsaa056.1147 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A439-A440

Author(s):

O M Bubu ◽

A K Mbah ◽

N J Williams ◽

A D Turner ◽

A Parekh ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Sleep Disturbance ◽

Time Dependent ◽

Nocturnal Sleep ◽

Prospective Longitudinal Study ◽

Logistic Mixed Effects Model ◽

Prospective Longitudinal

Abstract Introduction We determined whether nocturnal sleep disturbance (NSD) is associated with prospective cognitive decline in clinically normal older adults Methods Prospective longitudinal study utilizing data from the National Alzheimer’s Coordinating Center (NACC) Uniform Data set (UDS). NSD data, as characterized by the Neuropsychiatric Inventory Questionnaire (NPI-Q), were derived from 10,600 participants at baseline, with at least one UDS follow-up visit, from 32 National Institute of Aging Alzheimer’s Disease Research Centers (ADRC). Prospective cognitive decline was characterized as incident mild cognitive impairment (MCI) diagnosis during UDS follow-up. Logistic mixed-effects model with random intercept and slope examined associations between the NSD and longitudinal cognitive decline. All models included age at baseline, sex, years of education, APOE ε4 status and their interactions with time. Time was operationalized as years from baseline for each participant. Results Of the 10,600 cognitively normal participants at baseline, 1,017 (8.6%) had NSD. The proportion of males versus females with sleep problems was 10.1% vs. 9.3% respectively. For participants with NSD and no NSD, the mean (SD) age was 71 (7.3) and 70 (5.7) years and average follow-up time was 5.2 (2.6) and 4.9 (2.7) years, respectively. Participants with NSD were significantly more likely to develop incident MCI during UDS follow-up (OR: 1.42, p =.003). The interaction of NSD with time was significant (p< .001) suggesting an increase in the likelihood of conversion to MCI increased over time. Furthermore, there were significant differences in mean conversion rates to MCI in the NSD group when the previous time-point was compared to the next (p<01), with a time dependent dose response in the risk of conversion to MCI observed. Conclusion In elderly cognitive-normal individuals, nocturnal sleep disturbance is associated with a time-dependent progression risk to MCI. These findings are consistent with the role of disturbed sleep in the development of Alzheimer’s Disease. Support NIH/NIA/NHLBI (L30-AG064670, CIRAD P30AG059303 Pilot, T32HL129953, R01HL118624, R21AG049348, R21AG055002, R01AG056031, R01AG022374, R21AG059179, R01AG056682, R01AG056531, K07AG05268503, K23HL125939)

Download Full-text

Longitudinal Changes in Individual BrainAGE in Healthy Aging, Mild Cognitive Impairment, and Alzheimer’s Disease

GeroPsych ◽

10.1024/1662-9647/a000074 ◽

2012 ◽

Vol 25 (4) ◽

pp. 235-245 ◽

Cited By ~ 64

Author(s):

Katja Franke ◽

Christian Gaser

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Healthy Aging ◽

Brain Aging ◽

Elderly Subjects ◽

Additional Increase ◽

Longitudinal Changes ◽

Novel Method ◽

The Brain

We recently proposed a novel method that aggregates the multidimensional aging pattern across the brain to a single value. This method proved to provide stable and reliable estimates of brain aging – even across different scanners. While investigating longitudinal changes in BrainAGE in about 400 elderly subjects, we discovered that patients with Alzheimer’s disease and subjects who had converted to AD within 3 years showed accelerated brain atrophy by +6 years at baseline. An additional increase in BrainAGE accumulated to a score of about +9 years during follow-up. Accelerated brain aging was related to prospective cognitive decline and disease severity. In conclusion, the BrainAGE framework indicates discrepancies in brain aging and could thus serve as an indicator for cognitive functioning in the future.

Download Full-text

Elucidating the risk factors for progression from amyloid-negative amnestic mild cognitive impairment to dementia

Current Alzheimer Research ◽

10.2174/1567205017666201130094259 ◽

2020 ◽

Vol 17 ◽

Author(s):

Hyung-Ji Kim ◽

Jae-Hong Lee ◽

E-nae Cheong ◽

Sung-Eun Chung ◽

Sungyang Jo ◽

...

Keyword(s):

Risk Factors ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Amnestic Mild Cognitive Impairment ◽

Amyloid Pet ◽

Clinical Progression ◽

Amnestic Mci

Background: Amyloid PET allows for the assessment of amyloid β status in the brain, distinguishing true Alzheimer’s disease from Alzheimer’s disease-mimicking conditions. Around 15–20% of patients with clinically probable Alzheimer’s disease have been found to have no significant Alzheimer’s pathology on amyloid PET. However, a limited number of studies had been conducted this subpopulation in terms of clinical progression. Objective: We investigated the risk factors that could affect the progression to dementia in patients with amyloid-negative amnestic mild cognitive impairment (MCI). Methods: This study was a single-institutional, retrospective cohort study of patients over the age of 50 with amyloidnegative amnestic MCI who visited the memory clinic of Asan Medical Center with a follow-up period of more than 36 months. All participants underwent brain magnetic resonance imaging (MRI), detailed neuropsychological testing, and fluorine-18[F18]-florbetaben amyloid PET. Results: During the follow-up period, 39 of 107 patients progressed to dementia from amnestic MCI. In comparison with the stationary group, the progressed group had a more severe impairment in verbal and visual episodic memory function and hippocampal atrophy, which showed an Alzheimer’s disease-like pattern despite the lack of evidence for significant Alzheimer’s disease pathology. Voxel-based morphometric MRI analysis revealed that the progressed group had a reduced gray matter volume in the bilateral cerebellar cortices, right temporal cortex, and bilateral insular cortices. Conclusion: Considering the lack of evidence of amyloid pathology, clinical progression of these subpopulation may be caused by other neuropathologies such as TDP-43, abnormal tau or alpha synuclein that lead to neurodegeneration independent of amyloid-driven pathway. Further prospective studies incorporating biomarkers of Alzheimer’s diseasemimicking dementia are warranted.

Download Full-text

Dehydroepiandrosterone (DHEA) and its Sulphate (DHEAS) in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205017666200317092310 ◽

2020 ◽

Vol 17 (2) ◽

pp. 141-157 ◽

Cited By ~ 2

Author(s):

Dubravka S. Strac ◽

Marcela Konjevod ◽

Matea N. Perkovic ◽

Lucija Tudor ◽

Gordana N. Erjavec ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

Therapeutic Potential ◽

Relevant Literature ◽

Comprehensive Overview ◽

Brain Functions ◽

Specific Effects ◽

And Behavior

Background: Neurosteroids Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulphate (DHEAS) are involved in many important brain functions, including neuronal plasticity and survival, cognition and behavior, demonstrating preventive and therapeutic potential in different neuropsychiatric and neurodegenerative disorders, including Alzheimer’s disease. Objective: The aim of the article was to provide a comprehensive overview of the literature on the involvement of DHEA and DHEAS in Alzheimer’s disease. Method: PubMed and MEDLINE databases were searched for relevant literature. The articles were selected considering their titles and abstracts. In the selected full texts, lists of references were searched manually for additional articles. Results: We performed a systematic review of the studies investigating the role of DHEA and DHEAS in various in vitro and animal models, as well as in patients with Alzheimer’s disease, and provided a comprehensive discussion on their potential preventive and therapeutic applications. Conclusion: Despite mixed results, the findings of various preclinical studies are generally supportive of the involvement of DHEA and DHEAS in the pathophysiology of Alzheimer’s disease, showing some promise for potential benefits of these neurosteroids in the prevention and treatment. However, so far small clinical trials brought little evidence to support their therapy in AD. Therefore, large-scale human studies are needed to elucidate the specific effects of DHEA and DHEAS and their mechanisms of action, prior to their applications in clinical practice.

Download Full-text