Total Amyloid Load Research Articles

Prediction of electroconvulsive therapy response and remission in late-life depression: a review.

Electroconvulsive therapy is an effective and well-tolerated antidepressant treatment for the elderly population. The place of electroconvulsive therapy in the treatment sequence for depression in the elderly is currently not well established. This review aims to identify the factors that contribute to a positive response and remission in elderly patients with depression undergoing electroconvulsive therapy treatment. We searched five bibliographic databases (Medline ALL Ovid, Embase.com, APA PsycInfo Ovid, Cochrane Library Wiley and Web of Science Core Collection) for articles published between 1995 and June 2023. Of the 2149 articles screened, 19 were included in the review. No significant associations were found between remission and/or response and salivary cortisol, baseline hippocampal and white matter hyperintensities, total amyloid load or global cortical atrophy. The reviewed articles did not show a significant difference in remission between unilateral and bilateral electroconvulsive therapy treatment. Other interesting findings are that moderately elevated levels of CRP and S100B levels, lower retardation scores, poorer performance on the word reading task at baseline and longer post-ictal reorientation time may be associated with higher remission and/or response rates. Medial temporal atrophy can be associated with lower Montgomery-Åsberg Depression Rating Scale (MADRS) decrease after electroconvulsive therapy. Finally, elderly patients had higher rates of electroconvulsive therapy response; retardation and psychotic features may mediate this association. Incorporation of this data into clinical practice may facilitate a personalised approach to electroconvulsive therapy. However, research on this topic is scarce and there are few studies that focus specifically on older people.

Brain tocopherol levels are associated with lower activated microglia density in elderly human cortex

AbstractBackgroundHigher intake of vitamin E has been associated with a lower risk of Alzheimer’s disease (AD), however the underlying mechanisms are unclear. One explanation might be that anti‐inflammatory properties of tocopherols prevent microglia activation. In this study we investigated the association of brain tocopherol levels with microglia activation in elderly humans.MethodWe included 113 deceased participants (88.5±6 years, 60% female) from the prospective Memory and Aging Project. Brain levels of α‐ and γ‐tocopherol were measured by HPLC coupled to electrochemical detection. Microglia presence was assessed in three stages of activation, based on morphology; i.e. I – not activated, II – activated, III – most activated. Microglia densities and tocopherol levels were log‐transformed when not normally distributed, standardized and averaged across two cortical and two subcortical brain regions. Linear regression analyses examined associations between tocopherol levels and microglia densities (outcome) in two models; a model adjusted for age, sex, education, APOE ε4 genotype and post mortem time interval (model 1), and a model additionally adjusted for total amyloid load and neurofibrillary tangles severity (model 2).ResultTotal microglia density (stage I‐III) was lower in cortical versus subcortical brain regions (153.2 (111.2‐194.0); 209.2 (175.8‐224.1), p<0.001). Levels of α‐ and γ‐tocopherol and activated microglia (II/III or III only) density did not differ between brain regions. Higher α‐ and γ‐tocopherol levels were associated with lower total and activated microglia densities in cortical (range (B(SE) ‐0.25,‐0.19 (0.09,0.10) p<0.05) but not in subcortical brain regions (range B(SE) ‐0.01, 0.12 (0.09,0.10) p>0.05). When we additionally adjusted for AD neuropathology effect estimates diminished and lost significance except for the association between α‐tocopherol and total microglia density in cortical brain regions (B(SE) ‐0.20 (0.09), p=0.03).ConclusionThese results suggest that the relation between tocopherols and AD might be partly explained by the alleviating effects of tocopherols on microglia activation.

Brain tocopherol levels are associated with lower activated microglia density in elderly human cortex.

IntroductionHigher brain tocopherol levels have been associated with lower levels of Alzheimer's disease (AD) neuropathology; however, the underlying mechanisms are unclear.MethodsWe studied the relations of α‐ and γ‐tocopherol brain levels to microglia density in 113 deceased participants from the Memory and Aging Project. We used linear regression analyses to examine associations between tocopherol levels and microglia densities in a basic model adjusted for age, sex, education, apolipoprotein E (APOE)ε4 genotype (any ε4 allele vs. none) , and post‐mortem time interval, and a second model additionally adjusted for total amyloid load and neurofibrillary tangle severity.ResultsHigher α‐ and γ‐tocopherol levels were associated with lower total and activated microglia density in cortical but not in subcortical brain regions. The association between cortical α‐tocopherol and total microglia density remained statistically significant after adjusting for AD neuropathology.DiscussionThese results suggest that the relation between tocopherols and AD might be partly explained by the alleviating effects of tocopherols on microglia activation.

Electroconvulsive therapy response in late-life depression unaffected by age-related brain changes

BackgroundGray matter volume decrease, white matter vascular pathology and amyloid accumulation are age-related brain changes that have been related to the pathogenesis of late life depression (LLD). Furthermore, lower hippocampal volume and more white matter hyperintensities (WMH) may contribute to poor response to electroconvulsive therapy (ECT) in severely depressed older adults. We hypothesized that the accumulation of age-related brain changes negatively affects outcome following ECT in LLD. Methods34 elderly patients with severe LLD were treated twice weekly with ECT until remission. All had both 3T structural magnetic resonance imaging (MRI) and β-amyloid positron emission tomography (PET) imaging using 18F-flutemetamol at baseline. MADRS and MMSE were obtained weekly which included 1 week prior to ECT (T0), after the sixth ECT (T1), and one week (T2) after the last ECT as well as at four weeks (T3) and 6 months (T4) after the last ECT. We conducted a multiple logistic regression analysis and a survival analysis with neuroimaging measures as predictors, and response, remission and relapse as outcome variable. ResultsWe did not find any association between baseline hippocampal volume, white matter hyperintensity volume and total amyloid load and response or remission at 1 and 4 weeks post ECT, nor with relapse at week 4. LimitationsThe present exploratory study was conducted at a single center academic hospital, the sample size was small, the focus was on hippocampal volume and the predictive effect of structural and molecular changes associated with aging were used. ConclusionsOur study shows no evidence of relationship between response to ECT and age-related structural or molecular brain changes, implying that ECT can be applied effectively in depressed patients irrespective of accumulating age-related brain changes.

Relative Apical Sparing of Myocardial Longitudinal Strain Is Explained by Regional Differences in Total Amyloid Mass Rather Than the Proportion of Amyloid Deposits

ObjectivesThis study sought to test whether relative apical sparing (RELAPS) of left ventricular (LV) longitudinal strain (LS) in cardiac amyloidosis (CA) is explained by regional differences in markers of amyloid burden (18F-florbetapir uptake by positron emission tomography [PET] and/or extracellular volume fraction [ECV] by cardiac magnetic resonance (CMR)]. BackgroundFurther knowledge of the pathophysiological basis for RELAPS can help understand the adverse outcomes associated with apical LS impairment. MethodsThis was a prospective study of 32 subjects (age 62 ± 7 years; 50% males) with light chain CA. All subjects underwent two-dimensional echocardiography for LS estimation and 18F-florbetapir PET for quantification of LV florbetapir retention index (RI). A subset also underwent CMR (n = 22) for ECV quantification. Extracellular LV mass (LV mass*ECV) and total florbetapir binding (extracellular LV mass*florbetapir RI) were also calculated. All parameters were measured globally and regionally (base, mid, and apex). ResultsThere was a significant base-to-apex gradient in LS (−7.4 ± 3.2% vs. −8.6 ± 4.0% vs. −20.8 ± 6.6%; p < 0.0001), maximal LV wall thickness (15.7 ± 1.9 cm vs. 15.4 ± 2.9 cm vs. 10.1 ± 2.4 cm; p < 0.0001), and LV mass (74.8 ± 21.2 g vs. 60.8 ± 17.3 g vs. 23.4 ± 6.2 g; p < 0.0001). In contrast, florbetapir RI (0.089 ± 0.03 μmol/min/g vs. 0.097 ± 0.03 μmol/min/g vs. 0.085 ± 0.03 μmol/min/g; p = 0.45) and ECV (0.53 ± 0.08 vs. 0.49 ± 0.08 vs. 0.49 ± 0.07; p = 0.15) showed no significant base-to-apex gradient in the tissue concentration or proportion of amyloid infiltration, whereas markers of total amyloid load, such as total florbetapir binding (3.4 ± 1.7 μmol/min vs. 2.8 ± 1.5 μmol/min vs. 0.93 ± 0.49 μmol/min; p < 0.0001) and extracellular LV mass (40.0 ± 15.6 g vs. 30.2 ± 10.9 g vs. 11.6 ± 3.9 g; p < 0.0001), did show a marked base-to-apex gradient. ConclusionsSegmental differences in the distribution of the total amyloid mass, rather than the proportion of amyloid deposits, appear to explain the marked regional differences in LS in CA. Although these 2 matrices are clearly related concepts, they should not be used interchangeably.

Semantic Intrusions and Failure to Recover From Semantic Interference in Mild Cognitive Impairment: Relationship to Amyloid and Cortical Thickness.

Accumulating evidence indicates that the failure to recover from the effects of proactive semantic interference [frPSI] represents an early cognitive manifestation of preclinical Alzheimer's disease. A limitation of this novel paradigm has been a singular focus on the number of targets correctly recalled, without examining co-occurring semantic intrusions [SI] that may highlight specific breakdowns in memory. We focused on SI and their relationship to amyloid load and regional cortical thickness among persons with amnestic mild cognitive impairment (aMCI). Thirty-three elders diagnosed with aMCI underwent F-18 florbetaben amyloid PET scanning with MRI scans of the brain. We measured the correlation of SI elicited on cued recall trials of the Loewenstein-Acevedo Scales for Semantic Interference and Learning [LASSI-L] with mean cortical amyloid load and regional cortical thickness in AD prone regions. SI on measures sensitive to frPSI was related to greater total amyloid load and lower overall cortical thickness [CTh]. In particular, SI were highly associated with reduced CTh in the left entorhinal cortex [r=-.71; p<.001] and left medial orbital frontal lobe [r=-.64; p<.001]; together accounting for 66% of the explained variability in regression models. Semantic intrusions on measures susceptible to frPSI related to greater brain amyloid load and lower cortical thickness. These findings further support the hypothesis that frPSI, as expressed by the percentage of intrusions, may be a cognitive marker of initial neurodegeneration and may serve as an early and distinguishing test for preclinical AD that may be used in primary care or clinical trial settings.

Proactive Semantic Interference is Associated with Total and Regional Abnormal Amyloid Load in Non-Demented Community-Dwelling Elders: A Preliminary Study.

To evaluate the relationship between susceptibility to proactive semantic interference (PSI) and retroactive semantic interference (RSI) and brain amyloid load in non-demented elders. 27 participants (11 cognitively normal [CN] with subjective memory complaints, 8 CN without memory complaints, and 8 with mild cognitive impairment [MCI]) underwent complete neurological and neuropsychological evaluations. Participants also received the Semantic Interference Test (SIT) and AV-45 amyloid PET imaging. High levels of association were present between total amyloid load, regional amyloid levels, and the PSI measure (in the entire sample and a subsample excluding MCI subjects). RSI and other memory measures showed much weaker associations or no associations with total and regional amyloid load. No associations between amyloid levels and non-memory performance were observed. In non-demented individuals, vulnerability to PSI was highly associated with total and regional beta-amyloid load and may be an early cognitive marker of brain pathology.

Target Mediated Drug Disposition Model of CPHPC in Patients with Systemic Amyloidosis.

The amyloid deposits that cause disease in systemic amyloidosis always contain the normal plasma protein, serum amyloid P (SAP) component. SAP is the target of a novel immunotherapy approach now being developed to eliminate amyloid deposits. The treatment is enabled by, and critically depends on, the use of the drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, GSK2315698, Ro 63-8695), which depletes circulating SAP almost completely but leaves some SAP in amyloid deposits for specific recognition by subsequently administered therapeutic anti-SAP antibodies. Herein, we report a mechanistic model that predicts, with clinically acceptable precision, the exposure-response relationship for CPHPC, both in healthy individuals and in patients with systemic amyloidosis. The model covariates are gender, renal function, total amyloid load, and presence of hepatic amyloid, all of which are known at baseline. The model is being used to predict individualized dosing regimens in an ongoing, first-in-human study with anti-SAP antibodies.

Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

In brains from patients with Alzheimer's disease (AD), expression of insulin receptor (IR), insulin-like growth factor-1 receptor (IGF-1R), and insulin receptor substrate proteins is downregulated. A key step in the pathogenesis of AD is the accumulation of amyloid precursor protein (APP) cleavage products, β-amyloid (Aβ)(1-42) and Aβ(1-40). Recently, we and others have shown that central IGF-1 resistance reduces Aβ accumulation as well as Aβ toxicity and promotes survival. To define the role of IR in this context, we crossed neuron-specific IR knockout mice (nIR(-/-)) with Tg2576 mice, a well-established mouse model of an AD-like pathology. Here, we show that neuronal IR deficiency in Tg2576 (nIR(-/-)Tg2576) mice leads to markedly decreased Aβ burden but does not rescue premature mortality of Tg2576 mice. Analyzing APP C-terminal fragments (CTF) revealed decreased α-/β-CTFs in the brains of nIR(-/-)Tg2576 mice suggesting decreased APP processing. Cell based experiments showed that inhibition of the PI3-kinase pathway suppresses endosomal APP cleavage and decreases α- as well as β-secretase activity. Deletion of only one copy of the neuronal IGF-1R partially rescues the premature mortality of Tg2576 mice without altering total amyloid load. Analysis of Tg2576 mice expressing either a dominant negative or constitutively active form of forkhead box-O (FoxO)1 did not reveal any alteration of amyloid burden, APP processing and did not rescue premature mortality in these mice. Thus, our findings identified IR signaling as a potent regulator of Aβ accumulation in vivo. But exclusively decreased IGF-1R expression reduces AD-associated mortality independent of β-amyloid accumulation and FoxO1-mediated transcription.

A novel technique for simultaneous bilateral brain infusions in a mouse model of neurodegenerative disease

A common problem faced by researchers using transgenic models to study disease is the phenotypic variability that exists within a group or colony of animals. Significant pathological analyses thus often require large numbers of mice to perform. Many lines of transgenic mice harboring the gene for human amyloid precursor protein (APP) with different mutations causing familial Alzheimer's disease have been developed over the past decade to study plaque deposition and other aspects of AD. However, variations in size, density, plaque number, and total amyloid load between animals of the same age and genotype have been identified by our lab and others. Therefore, to study the effects of compounds on amyloid pathology, it was imperative to develop a technique that would allow each brain hemisphere to receive different infusions. We have developed catheters that facilitate simultaneous bilateral infusion in mouse brains, thereby using the contralateral hemisphere of the same animal as an internal control while studying, for example, the effect of compounds on amyloid plaques, a pathological hallmark of the progression of Alzheimer's disease (AD). Several molecules have been identified within the plaques including the major component, the Aβ peptide, and two inflammation-related proteins, apolipoprotein E (apoE) and the serine protease inhibitor α-1-antichymotrypsin (ACT). In these experiments, ACT was infused unilaterally over a period of 28 days into the parenchyma and lateral ventricles of PS/APP mice and observed to associate with amyloid plaques, with minimal mortality. Utilizing the ACT/Aβ interaction, details of this procedure are discussed here in detail.

A Computational Positron Emission Tomography Simulation Model for Imaging ?-Amyloid in Mice

We aimed to develop a computational simulation model for beta-amyloid (Abeta) positron emission tomography (PET) imaging. Model parameters were set to reproduce levels of Abeta within the PDAPP mouse. Pharmacokinetic curves of virtual tracers were computed and a PET detector simulator was configured for a commercially available preclinical PET-imaging system. We modeled the effects of Abeta therapy and tracer affinity on the ability to differentiate Abeta levels by PET. Varying affinity had a significant effect on the ability to quantitate Abeta. Further, PET tracers for Abeta monomers were more sensitive to the therapeutic reduction in Abeta levels than total brain amyloid. Following therapy, the decrease in total brain Abeta corresponded to the slow rate of change in total amyloid load as expected. We have developed a first proof-of-concept Abeta-PET simulation model that will be a useful tool in the interpretation of preclinical Abeta imaging data and tracer development.