Exploring Alzheimer’s Disease Subtypes At The Prodromal Stage
Magdalena A. Kolanko Paresh A. Malhotra
Brain. 2018 141:3285-3287.
Figure 1.
Amyloid PET scan in Alzheimer’s disease. Colour image of an amyloid PET scan from a patient with increasing episodic memory impairment. There is loss of grey/white matter differentiation in multiple regions strongly suggestive of widespread amyloid deposition. Courtesy of Dr Zarni Win.
Incorporation Of Plasma Abeta Ratios Into The Trc
In a newly funded revision of the TRC-PAD program, we are now in the process of integrating plasma amyloid peptide ratio assays into the final risk assessment in-person screening prior to brain amyloid testing. The promise of plasma amyloid ratio testing has been confirmed by two independent labs using different immunoprecipitation/mass spectrometry approaches each finds a strong association between plasma ratios and brain amyloid load. Encouraging results have also been reported using an automated immunoassay . We will assess these methods by obtaining plasma prior to brain amyloid testing for the initial few hundred APT Webstudy participants to undergo brain amyloid PET. The optimal pre-processing approach and assay methodology will then be incorporated into the risk algorithm for the remaining participants. We expect a substantial improvement in accuracy of our algorithm, as well as a significant reduction the number of negative amyloid PET scans and CSF draws, reducing burden to participants and high cost of screening.
A42 Oligomers Trigger Neuroglobin Expression Via Oxidative Stress
As shown in the above series of results, even in the presence of high levels of toxic forms of A over a long period of time, we could not find broad pathology in the cortex of this mouse model of AD. Hence, we envisioned that these mice put to work very robust defense mechanisms against the toxic effects of A, perhaps similar to those operating in individuals without cognitive deficits but with a high amyloid load. To identify these mechanisms in these mice, we analyzed the expression levels of selected toxic and survival genes whose levels of expression were found altered in the brains of individuals affected by AD. Of the 9 genes studied, only Neuroglobin mRNA levels increased with aging in the hAPP NL/F mice but not in WT mice . The increase in Ngb was also observed at the protein level only in the hAPP NL/F mice, whereas in the WT mice remained stable a long time .
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Grey Matter Network Markers Identify Individuals With Prodromal Alzheimers Disease Who Will Show Rapid Clinical Decline
Data used in preparation of this article were obtained from the Alzheimers Disease Neuroimaging Initiative database . As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at:
Interpretable Ml: Variable Importance And Partial Dependence Plot
For each optimized model examined the variable importance criterion, which measures the relative prediction power by using mean decreased accuracy or Gini index. For each analysis, variable importance was estimated to find which independent variables were influential features for an accurate classification. Influential variables were ranked by calculating relative importance values. In the tree-based model such as GBM and RF, when the variables split the tree, the relative importance value of that variable was estimated by the discrepancy of the squared error loss over all trees. A higher relative importance value indicated a greater influence of the variables for classifying tau positivity.
We conducted a PDP proposed by J.H. Friedman, which can provide information on whether the feature is positively or negatively correlated to the final prediction. In order to avoid over-weighted or underweighted results, a MinMax normalisation was conducted. PDP is a graphical representation tool, which can provide information on whether the feature is positively or negatively related to the final prediction, it is shown as follows.
Let \ be the space of input variables consisting of a chosen subset space and \ be the complemental space,
\ Then the functional form of approximation \\) depends on both subset space
If the dependency of the complemental space is not too strong, the average function
where \\) is a marginal probability density function of \.
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Analysis Of Dendritic Complexity
In order to study the complexity of the dendritic tree, dendrites were immunostained with anti-tGFP for neurons of animals injected with virus or anti-MAP2 for primary neurons infected in culture. In both cases, confocal images of isolated neurons at several planes were taken with an overlap of 40%. The 8-bit images were processed with the Simple Neurite Tracer program of the FIJI software. Subsequently, the morphological complexity was studied by means of the Sholl analysis, in which the number of neurites crossing each of the imaginary circles of increasing radius that are drawn around the soma is determined. A graph is obtained in which the number of intersections from the cellular soma to the periphery is represented. The number of primary dendrites and secondary or higher dendrites , as well as the number of bifurcation points were also quantified.
How Is Prodromal Alzheimers Diagnosed
Memory loss is a natural part of aging. Everyone finds that over time their memory is diminished, so how is Prodromal Alzheimers diagnosed? If you are experiencing significant memory impairment issues, then you should go in to a doctor for biomarker test. A biomarker test will scan your body for the presence of the amyloid protein, the protein that is common in the brain of those with Alzheimers disease. If the amyloid protein is present, it is likely Prodromal Alzheimers.
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Prodromal Or Mild Alzheimers Disease
Core Clinical Research is looking for adults with early to mild Alzheimers Disease to participate in an Alzheimers Disease clinical trial. Early detection and intervention are important factors in the treatment of Alzheimers Disease. To find out more about this paid investigational medication research study, or learn about other study treatment options, please contact Core Clinical Research to see if you may qualify.
Alzheimers Disease, a type of neurological disorder that causes problems with thinking, memory, and behaviors, currently affects more than five million people in the United States. It is ranked as the sixth leading cause of death. If you or a loved one have been diagnosed with, or suspect, Mild or Early Alzheimers Disease you may qualify for an investigational treatment. To date, there is no cure for Alzheimers Disease, however there are medication options to treat symptoms. Research studies in Early to Mild Alzheimers Disease aim to find treatments that may suppress or stop the development of the disease before moderate to severe symptoms become present.
Signs of Early or Mild Alzheimers Disease to consider include, but are not limited to:
If you or a loved one worry that memory loss might be something bigger, like Mild or Early Alzheimers Disease, you may qualify for a full no-cost evaluation for a clinical trial.
Some key entry criteria to consider for potential study participants are:
Defining Prodromal Alzheimers Disease Frontotemporal Dementia And Lewy Body Dementia: Are We There Yet
Since the development of diagnostic criteria for Alzheimers disease nearly twenty-five years ago , there has been an exponential growth in the number of published studies characterizing the clinical expression of the condition and its complex environmental and genetic determinants. With the advances in scientific discovery, there has been a push to refine the clinical diagnosis at earlier points in the illness with an eye towards eventual intervention. The question is, with all the progress made in clinical diagnosis, are we there yet? Are we able to take what is known about the clinical expression of AD and push back the diagnostic envelope to the early prodrome stage? Said differently, are we able to diagnose AD as the symptoms emerge and distinguish this condition from other similar brain disorders affecting cognition, behavior, and function in late life? The articles in this special issue tackle this important question, discussing the current understanding of the three known major neurodegenerative disorders: AD, Dementia with Lewy Bodies , and Frontotemporal Lobar Dementia . Each article explores the unique clinical and neuropsychological characteristics of the disorders and addresses whether there is an identifiable prodromal stage in each condition.
Chronic Disease Model of AD
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Study Of Mitochondrial Activity
Mitochondrial activity was assessed by 3- -2,5-diphenyltetrazolium bromide . For this experiment, 10,000 neurons per well were plated in a 96-well plate and at 6 DIV they were infected with a control lentivirus or a lentivirus expressing Ngb. After the corresponding treatments at 10 DIV, the medium was replaced by 100 l of 0.5% MTT diluted in N2-supplemented medium. The cells were kept at 37°C for 4 h to allow formation of formazan crystals, which were subsequently dissolved by adding 50 l of DMSO. After 15 min at 37°C, the absorbance at 560 nm was read.
Experiences Of The Received Information About The Study
This category is presented as two subcategories focusing on participants experiences of the received information regarding the MIND-ADMINI prevention trial.
Understanding of the MIND-AD MINI Prevention Trial
During the initial phase of the study, the participants received oral and written information about the study aim and the contents of the trial. The written information in the informed consent form, was perceived as hard to understand by the participants and did not help them to fully comprehend the extent of engagement that was demanded. Several participants expressed that they did not have a clear understanding of the number of interventions and study visits that were required.
The information then, in the beginning, was that it would be a group with some members, that it would be about training memory, diet, and physical training. You did not know in what way, but it is just as well that you do not know everything from the beginning .
Although the participants could not recall all the contents of the study at the time of the interview, all of them perceived that they had received good information at the time for informed consent. The positive reflections on receiving information at this time refers to interactions with the study physician and the study team, as well as feelings of being taken care of, being listened to and being important, and that they built a trusting relationship with the study team.
Trust in Different Levels
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Quantification Of A In The Cerebral Cortex Of App Nl/f Mice
A was extracted from the cerebral cortex of 3, 9, and 24 months APP NL-F mice. The mice were deeply sedated with an intraperitoneal injection of sodium pentobarbital and perfused with 0.9% sodium chloride. After perfusion, the brain was removed and the cortices were dissected and homogenized in 500 l of homogenization buffer with protease inhibitors . The sample was then ultracentrifuged at 200,000 g for 20 min at 4°C to separate the soluble and insoluble fraction. The supernatant was reserved for further analysis, and the pellet was resuspended in guanidinium chloride HCl 6 M, sonicated and stirred for 1 h at 23°C, to solubilize the insoluble A. Then, it was ultracentrifuged at 200,000 g for 20 min at 4°C and the supernatant was collected .
The levels of A38, A40, and A42 were measured by MSD multiplex immunoassay following the instructions of the manufacturer. Briefly, after blocking the wells with 150 l of blocking buffer for 2 h at RT, they were washed 5 times with 200 l of wash buffer . Next, test samples or standard peptides were diluted and prepared with the detection antibody conjugated to an electrochemiluminescence label and loaded 50 l in each well of the MSD multiplex plate. The plates were incubated at 4°C overnight and the next day they were washed 2 times with 150 l of commercial development buffer . Electrochemiluminescence was evaluated with the MSD Sector Imager 6000 apparatus.
Motives For Study Participation
The participants described a complex and multifaced picture of their motives for participating in the study. Two participants stated only one main motive for participating in the trial. It was either pure altruistic motives or hope for personal benefits. Six participants described a combination of both.
The participants described that being able to contribute to the scientific knowledge of AD and prevention and thereby helping others in the same situation was a strong motive for them to participate, and for one participant, it was their only reason. The participants strongly expressed the importance of being acknowledged as a person with an important task in the research. The participants described this motive as essential to actively participate in this study and to take responsibility for their contribution as a significant member in the intervention study.
I think that maybe I can be involved and contribute with something. I can leave something behind. That is the only reason I am in the study .
Personal experiences of having persons with AD in the family strongly influenced their motives. They described that having such personal experiences might result in great fear for the disease and its consequences, especially the burden it would bring to children and relatives. Even if they hoped that the intervention would slow down their disease, the main goal for them to participate in the study was to minimize the burden for their families.
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Early Motor Features Of Parkinsons Disease
According to the Braak hypothesis, once Lewy bodies have propagated into the substantia nigra , motor symptoms appear. Current diagnostic criteria for PD require bradykinesia plus either rigidity or tremor. Although postural instability is also a core feature of PD, early falls should alert the examiner to the possibility of an atypical parkinsonian syndrome such as progressive supranuclear palsy . It is important to be familiar with the core motor features of early PD and and be able both to detect early PD and distinguish it from common mimics.
RigidityRigidity is defined as velocity-independent passive resistance to movement. Rigidity in PD is typically cogwheeling, with a ratchet-like quality. Subtle rigidity can be enhanced by asking the patient to open and close the contralateral hand, known as Froments maneuver. Reduced arm swing is considered to be more closely associated with rigidity than bradykinesia.17 Like bradykinesia, the rigidity of PD is unilateral at the onset of motor symptoms and usually remains asymmetric throughout the disease course. Symmetric rigidity or spasticity should raise the possibility of vascular parkinsonism or another atypical syndrome.
Clinical And Neuropsychological Assessments
Clinical assessments were undertaken according to the recommendations in the European Federation of Neurological Societies guideline . All subjects were examined with a clinical interview including Clinical Dementia Rating and GDS. Two activities of daily living scales were included in the battery: the basic ADL and the instrumental ADL . Demographic data included age, sex, and years of education. Global cognitive function was measured by the Korean version of the Mini-Mental State Examination .
Neuropsychological assessment was conducted using the Seoul Neuropsychological Screening Battery, which measures attention, language and associated functions, visuospatial, memory, and frontal/executive functions . Attention was evaluated using the digit span test . Language was evaluated using the Korean version of the Boston Naming Test. Visuospatial function was tested using the copy score of the Rey-Osterrieth Complex Figure Test. Memory was evaluated using the Seoul Verbal Learning Test and Rey-Osterrieth Complex Figure Test immediate recall and a 20-min delayed recall and recognition. Frontal/executive function was evaluated using the go-no-go test/contrasting program test, the Controlled Oral Word Association Test, and Stroop test. Cognitive impairment was defined as a Z-score < 1.5 standard deviation on at least one of the neuropsychological tests, which could be a memory, language, visuospatial function, attention, or frontal/executive test.
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Cognitive Decline In The Prodromal Phase Of Ad
The 2,071 persons without dementia at study enrollment had up to 16 years of annual follow-up . During this period, 462 persons developed incident AD. For these analyses, we excluded the 20 people who developed other forms of dementia. Those who developed AD were older than those who did not , but the groups were similar in education and sex distribution .
At baseline, 552 subjects had MCI. To assess how this subgroup affected results, we excluded them and repeated the analyses in the remaining 1,499, of whom 217 developed AD. The best fitting change point was at 54 months before AD was diagnosed. Global cognition declined a mean of 0.016 unit per year before this point . Rate of annual decline increased more than 15-fold to 0.262 unit during the 54 month prodromal period and to 0.314 unit after AD was diagnosed.
To see if results varied across cognitive domains, we conducted separate analyses using composite measures of specific cognitive functions . As shown in , the prodromal period began about 63 months before dementia onset for episodic memory, 76 months for semantic memory, 75 months for working memory, 70 months for perceptual speed, and 65 months for visuospatial ability. Prior to the prodromal period, episodic memory was stable and there was very gradual decline in the other domains. Decline in all functions increased sharply during the prodromal period with a further less marked acceleration after AD was diagnosed.
Csf Biomarkers Between Prodromal Ad And Amyloid
The analysis of CSF biomarkers revealed that they differed significantly between prodromal AD and amyloid-negative aMCI. We generated ROC curves to identify CSF biomarkers that differentiated the two groups. The cutoff values that yielded the best index for prodromal AD were 749.5 pg/mL for A142, 225.6 pg/mL for t-Tau, 43.5 pg/mL for p-Tau181, 0.095 for A142/A140, 0.298 for t-Tau/A142, and 0.059 for p-Tau181/A142. The AUCs, the sensitivity, and the specificity of each CSF biomarker are shown in Table 3. The ROC curve and AUC for prodromal AD and amyloid-negative aMCI are illustrated in online supplementary Figure 1. The cutoff ratio indicative of prodromal AD from amyloid-negative aMCI was set at A142/A140< 0.095, t-tau/A142> 0.298, and p-Tau181/A142> 0.059 based on the amyloidosis with florbetaben PET .
Table 3.
Sensitivity and specificity of CSF biomarkers in prodromal AD of the aMCI group
Table 4.
Diagnostic cutoff values in differentiating patients with preclinical AD , prodromal AD , and amyloid-positive AD dementia from normal amyloid-negative subjects
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