P1-391: EVIDENCE FOR A QUADRATIC RELATION BETWEEN ACTIVATION AND NEURODEGENERATION IN THE PRODROMAL PHASE OF ALZHEIMER'S DISEASE

The purpose of this review is to compare and highlight the clinical and pathological aspects of genetic versus acquired Alzheimer’s disease: Down syndrome-associated Alzheimer’s disease in (DSAD) and Autosomal Dominant Alzheimer’s disease (ADAD) are compared with the late-onset form of the disease (LOAD). DSAD and ADAD present in a younger population and are more likely to manifest with non-amnestic (such as dysexecutive function features) in the prodromal phase or neurological features (such as seizures and paralysis) especially in ADAD. The very large variety of mutations associated with ADAD explains the wider range of phenotypes. In the LOAD, age-associated comorbidities explain many of the phenotypic differences.

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Neuroscience-based Tests for Assessing Cognitive Changes in Normal Aging and in the Prodromal Phase of Alzheimer’s Disease

Current Translational Geriatrics and Experimental Gerontology Reports ◽

10.1007/s13670-011-0001-2 ◽

2012 ◽

Vol 1 (1) ◽

pp. 1-10

Author(s):

Diana S. Woodruff-Pak ◽

Jacob Raber

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Normal Aging ◽

Cognitive Changes ◽

Prodromal Phase

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Deep and Frequent Phenotyping study protocol: an observational study in prodromal Alzheimer’s disease

BMJ Open ◽

10.1136/bmjopen-2018-024498 ◽

2019 ◽

Vol 9 (3) ◽

pp. e024498 ◽

Cited By ~ 3

Author(s):

Ivan Koychev ◽

Jennifer Lawson ◽

Tharani Chessell ◽

Clare Mackay ◽

Roger Gunn ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Observational Study ◽

Outcome Measures ◽

Pet Imaging ◽

Repeated Measures ◽

Disease Process ◽

Csf Biomarkers ◽

Prodromal Phase ◽

South Central

IntroductionRecent failures of potential novel therapeutics for Alzheimer’s disease (AD) have prompted a drive towards clinical studies in prodromal or preclinical states. However, carrying out clinical trials in early disease stages is extremely challenging—a key reason being the unfeasibility of using classical outcome measures of dementia trials (eg, conversion to dementia) and the lack of validated surrogate measures so early in the disease process. The Deep and Frequent Phenotyping (DFP) study aims to resolve this issue by identifying a set of markers acting as indicators of disease progression in the prodromal phase of disease that could be used as indicative outcome measures in proof-of-concept trials.Methods and analysisThe DFP study is a repeated measures observational study where participants will be recruited through existing parent cohorts, research interested lists/databases, advertisements and memory clinics. Repeated measures of both established (cognition, positron emission tomography (PET) imaging or cerebrospinal fluid (CSF) markers of pathology, structural MRI markers of neurodegeneration) and experimental modalities (functional MRI, magnetoencephalography and/or electroencephalography, gait measurement, ophthalmological and continuous smartphone-based cognitive and other assessments together with experimental CSF, blood, tear and saliva biomarkers) will be performed. We will be recruiting male and female participants aged >60 years with prodromal AD, defined as absence of dementia but with evidence of cognitive impairment together with AD pathology as assessed using PET imaging or CSF biomarkers. Control participants without evidence of AD pathology will be included at a 1:4 ratio.Ethics and disseminationThe study gained favourable ethical opinion from the South Central—Oxford B NHS Research Ethics Committee (REC reference 17/SC/0315; approved on 18 August 2017; amendment 13 February 2018). Data will be shared with the scientific community no more than 1 year following completion of study and data assembly.

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Usefulness of CSF Biomarkers in Predicting the Progression of Amnesic and Nonamnesic Mild Cognitive Impairment to Alzheimer’s Disease

Current Aging Science ◽

10.2174/1874609812666190112095430 ◽

2019 ◽

Vol 12 (1) ◽

pp. 35-42

Author(s):

Ricard L. Ortega ◽

Farida Dakterzada ◽

Alfonso Arias ◽

Ester Blasco ◽

Alba Naudí ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Csf Biomarkers ◽

Prodromal Phase ◽

Diagnosis And Prognosis ◽

Amnestic Mci ◽

Atypical Presentations ◽

T Tau

Objective: The aim of this study was to investigate the usefulness of Alzheimer’s disease Cerebrospinal Fluid (CSF) biomarkers in predicting the progression to dementia in patients with Mild Cognitive Impairment (MCI). Methods: One hundred and thirteen patients were consecutively recruited from April 2012 to April 2014. Measurement of CSF biomarkers (amyloid-β42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau)) and a neuropsychological evaluation were performed for all patients. We categorized patients with MCI as A+A- and N+N- based on the presence/absence of amyloid pathology and neurodegeneration, respectively. Results: Of 72 patients with MCI, 26 (36%) progressed to dementia. These patients had lower CSF Aβ42 levels and higher p-tau and t-tau levels at baseline. The proportion that progressed to dementia was 14.3% (2/14), 36.8% (7/19), 66.7% (4/6) and 75% (12/16) in the A-N-, A+N-, A-N+ (SNAP), and A+N+ patients, respectively (p < 0.05). There were significant differences in the probability of progression from amnestic MCI (aMCI) to AD between the A+N+ and A-N- patients (OR = 8.1, 95% CI 1.5-42.3, p = 0.001) but not between SNAP (OR = 7.3, 95% CI 0.9-61, p = 0.02) or A+N- (OR = 2.1, 95% CI 0.4 to 10.4, p = 0.15) patients compared to the A-N- subgroup. None of the biomarker profiles of the subgroups predicted the time until the progression to AD. Conclusion: The use of CSF AD biomarkers in clinical practice improves the certainty of diagnosis and prognosis of patients, especially in patients in the prodromal phase or in patients with atypical presentations.

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Approach to atypical Alzheimer’s disease and case studies of the major subtypes

CNS Spectrums ◽

10.1017/s109285291600047x ◽

2017 ◽

Vol 22 (6) ◽

pp. 439-449 ◽

Cited By ~ 19

Author(s):

Bradford C. Dickerson ◽

Scott M. McGinnis ◽

Chenjie Xia ◽

Bruce H. Price ◽

Alireza Atri ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuropsychiatric Symptoms ◽

Current Approach ◽

Molecular Biomarkers ◽

Diagnostic Tools ◽

Prodromal Phase ◽

Atypical Form ◽

Atypical Symptoms

Alzheimer’s disease (AD) has long been recognized as a heterogeneous illness, with a common clinical presentation of progressive amnesia and less common “atypical” clinical presentations, including syndromes dominated by visual, aphasic, “frontal,” or apraxic symptoms. Our knowledge of atypical clinical phenotypes of AD comes from clinicopathologic studies, but with the growing use of in vivo molecular biomarkers of amyloid and tau pathology, we are beginning to recognize that these syndromes may not be as rare as once thought. When a clinician is evaluating a patient whose clinical phenotype is dominated by progressive aphasia, complex visual impairment, or other neuropsychiatric symptoms with relative sparing of memory, the differential diagnosis may be broader and a confident diagnosis of an atypical form of AD may require the use of molecular biomarkers. Despite the evolving sophistication in our diagnostic tools, and the acknowledgment of atypical AD syndromes in the 2011 revised diagnostic criteria for AD, the assessment of such patients still poses substantial challenges. We use a case-based approach to review the clinical and imaging phenotypes of a series of patients with typical and atypical AD, and discuss our current approach to their evaluation. One day, we hope that regardless of whether a patient exhibits typical or atypical symptoms of AD pathology, we will be able to identify the condition at a prodromal phase and institute a combination of symptomatic and disease-modifying therapies to support cognitive processes, function, and behavior, and slow or halt progression to dementia.

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Age-related cognitive decline in baboons: modeling the prodromal phase of Alzheimer's disease and related dementias

Aging ◽

10.18632/aging.103272 ◽

2020 ◽

Vol 12 (11) ◽

pp. 10099-10116

Author(s):

Stephanny Lizarraga ◽

Etienne W. Daadi ◽

Gourav Roy-Choudhury ◽

Marcel M. Daadi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Prodromal Phase ◽

Age Related ◽

Age Related Cognitive Decline

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The role of epileptic activity in the prodromal phase of Alzheimer's disease

Journal of the Neurological Sciences ◽

10.1016/j.jns.2021.117846 ◽

2021 ◽

Vol 429 ◽

pp. 117846

Author(s):

András Horváth ◽

Dalida Berente ◽

Janos Zsuffa ◽

Anita Kamondi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Epileptic Activity ◽

Prodromal Phase

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PON-1 and ferroxidase activities in older patients with mild cognitive impairment, late onset Alzheimer’s disease or vascular dementia

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2014-0803 ◽

2015 ◽

Vol 53 (7) ◽

Cited By ~ 17

Author(s):

Carlo Cervellati ◽

Arianna Romani ◽

Carlo M. Bergamini ◽

Cristina Bosi ◽

Juana Maria Sanz ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Vascular Dementia ◽

Late Onset ◽

Large Body ◽

Multivariate Logistic Regression Analysis ◽

Paraoxonase 1 ◽

Prodromal Phase

AbstractA large body of evidence suggests that not only cerebral but also systemic oxidative stress (OxS) might be involved in the pathogenesis of late onset Alzheimer’s disease (LOAD) and vascular dementia (VAD), as well as of the prodromal phase of dementia, the so-called mild cognitive impairment (MCI). In the present study, we evaluated whether paraoxonase 1 (PON-1) and ferroxidase (FeOx) activities, because of their well acknowledged effectiveness as systemic antioxidants, might be associated with dementia and/or MCI.Serum arylesterase and paraoxonase of PON-1, along with FeOx I (ceruloplasmin-related) and II activities were assessed in 223 MCI, 162 LOAD, 65 VAD patients, and in 143 older normal cognitive controls.Among the enzymatic activities examined, only arylesterase significantly changed across the groups (ANOVA: p<0.001), with similar lower levels in MCI, LOAD, and VAD compared to controls. By multivariate logistic regression analysis we showed that, in respect to controls, low levels (under the median value) of serum arylesterase were independently associated with an increase in the likelihood of being affected by LOAD [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.5–5.0], VAD (OR 2.7, 95% CI 1.2–6.2), or MCI (OR 2.3, 95% CI 1.3–3.8).Overall, our results suggest that depression of PON-1, and in particular, of arylesterase activity, in serum might be an early feature of dementia-related diseases. Further longitudinal exploration of the role of this enzyme in the onset and progression of these disorders are required.

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Longitudinal Assessment of Working Memory Performance in the APPswe/PSEN1dE9 Mouse Model of Alzheimer’s Disease Using an Automated Figure-8-Maze

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2021.655449 ◽

2021 ◽

Vol 15 ◽

Author(s):

Fran C. van Heusden ◽

Sara Palacín i Bonsón ◽

Oliver Stiedl ◽

August B. Smit ◽

Ronald E. van Kesteren

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Functioning ◽

Acute Stress ◽

Neurodegenerative Disorder ◽

Memory Performance ◽

Longitudinal Assessment ◽

Experimental Conditions ◽

Prodromal Phase ◽

Model Of Alzheimer’S Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, with a long preclinical and prodromal phase. To enable the study of disease mechanisms, AD has been modeled in many transgenic animal lines and cognitive functioning has been tested using several widely used behavioral tasks. These tasks, however, are not always suited for repeated longitudinal testing and are often associated with acute stress such as animal transfer, handling, novelty, or stress related to the task itself. This makes it challenging to relate cognitive dysfunction in animal models to cognitive decline observed in AD patients. Here, we designed an automated figure-8-maze (F8M) to test mice in a delayed alternation task (DAT) in a longitudinal manner. Mice were rewarded when they entered alternate sides of the maze on subsequent trials. Automation as well as connection of the F8M set-up with a home cage reduces experimenter interference and minimizes acute stress, thus making it suitable for longitudinal testing and facilitating clinical translation. In the present study, we monitored cognitive functioning of 2-month-old APPswe/PSEN1dE9 (APP/PS1) mice over a period of 4 months. The percentage of correct responses in the DAT did not differ between wild-type and transgenic mice from 2 to 6 months of age. However, 6-month-old mice displayed an increase in the number of consecutive incorrect responses. These results demonstrate the feasibility of longitudinal testing using an automated F8M and suggest that APP/PS1 mice are not impaired at delayed spatial alternation until 6 months of age under the current experimental conditions.

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