Clinical Correlates of the PET-based Braak Staging Framework in Alzheimer's Disease.

In vivo Alzheimer's disease diagnosis and staging is traditionally based on clinical features. However, the agreement between clinical and pathological Alzheimer's disease diagnosis, whose diagnosis assessment includes amyloid and Braak histopathological tau staging, is not completely convergent. The development of positron emission tomography (PET) tracers targeting neurofibrillary tangles offers prospects for advancing the staging of Alzheimer's disease from both biological and clinical perspectives. Recent advances in radiochemistry made it possible to apply the postmortem Braak staging framework to tau-PET images obtained in vivo. Here, our aim is to provide a narrative review of the current literature on the relationship between Alzheimer's disease clinical features and the PET-based Braak staging framework. Overall, the available studies support the stepwise increase in disease severity following the advance of PET-based Braak stages, with later stages being associated with worse cognitive and clinical symptoms. In line with this, there is a trend for unimpaired cognition, mild cognitive impairment, and Alzheimer's disease dementia to be compatible with early, intermediate, and late patterns of tau deposition based on PET-based Braak stages. Moreover, neuropsychiatric symptom severity seems to be linked to the extent of tau-PET signal across Braak areas. In sum, this framework seems to correspond well with the clinical progression of Alzheimer's disease, which is an indication of its potential utility in research and clinical practice, especially for detecting preclinical tau levels in individuals without symptoms. However, further research is needed to improve the generalizability of these findings and to better understand the applications of this staging framework.

Viewpoint: Clinicians' Perspectives on How Disease Modifying Drugs for Alzheimer's Disease Impact Specialty Care.

Clinicians specialized in the diagnosis and management of persons living with early-stage Alzheimer's disease need to enable access, for those meeting criteria, to the new class of disease modifying drugs (DMDs). These drugs act on amyloid ß42 and delay progression of symptoms. Thus, there will be interest from patients and families. Over the short term, the use of antibodies administered intravenously with serial MRIs to detect amyloid-related imaging abnormalities (ARIA) may require participation in structured phase 4 studies or in registries with third party funding for support staff and MRI scans. In the mid term, the availability of oral anti-amyloid therapy, likely with lower risk of ARIA, may transform clinical practice to a model of screening suitable patients using plasma biomarkers, with a subsequent rapid referral to a specialized memory clinic. Eventually, the biological profile of patients for amyloid, tau, and inflammation will determine which type of DMD to use. We are optimistic that clinicians will gain confidence with the use DMDs and answer the increasing needs of our aging population.

Adding the Topographical Information from Tau-PET to the A/T/(N) Framework: Steps Towards Staging AD in Vivo.

Biomarkers have revolutionized the study and clinical diagnosis of Alzheimer's disease (AD). While amyloid-ß accumulation begins decades before the onset of clinical dementia in AD, tau pathology is more closely associated in both space and time to neurodegeneration and to clinical dysfunction. Correspondingly, tau-PET may prove useful in determining the severity of AD. Building on the biological research framework for AD, we review here methods and rationale to stage the severity of AD in vivo using the topographical distribution of tau-PET. We discuss how tau-PET can be used to detect early and subthreshold tau accumulation in medial temporal cortices prior to the onset of cognitive symptoms. Furthermore, tau-PET can be used to monitor the severity of AD as tau-PET spreads to association cortices and finally primary sensory cortices. We discuss the utility of tau-PET to monitor the progression of AD, the flexibility of potential approaches, and applications for clinical trials. In this regard, topographical information from tau-PET is a useful addition to the A/T/(N) framework.

White Matter Hyperintensity as a Vascular Contribution to the AT(N) Framework.

The AT(N) framework enables the classification of an individual within the biological Alzheimer's disease (AD) continuum by pairing the cognitive stage with the biomarker status of amyloid-beta (Aß, A), tau (T) and neurodegeneration (N). AD is a multifactorial disease that may involve different pathogenic mechanisms such as cerebrovascular disease (CVD). Therefore, biomarkers of these mechanisms can be added to the AT(N) framework to enhance the biomarker characterization of individuals within the AD continuum. In AD, white matter hyperintensities (WMH) which are postulated to develop as a result of chronic ischemia from small vessel CVD are shown to play a role in the aetiology. However, the interplay of WMH with Aß and tau pathophysiology in AD remains unclear. In this review, we summarized the studies that evaluated the associations between WMH and AD pathophysiology (Aß and tau). We found that the evidence supporting the association of WMH with Aß was mixed, and this may be explained by the relative contributions of WMH due to its differential load and anatomical distribution. More studies are also needed to determine the association of WMH with tau pathology. Future longitudinal studies with harmonized methodologies to quantify WMH and account for the anatomical differences of WMH are required to validate the relationship between WMH and AT(N) biomarkers. This will allow a clearer understanding of the utility of WMH as a vascular biomarker in the AT(N) framework. Novel CVD biomarkers will also have the potential to further elucidate the contributions of CVD to the AD pathophysiology.

Neuroinflammation Biomarkers in the AT(N) Framework Across the Alzheimer's Disease Continuum.

In the past years, neuroinflammation has been widely investigated in Alzheimer's disease (AD). Evidence from animal, in vivo and post-mortem studies has shown that inflammatory changes are a common feature of the disease, apparently happening in response to amyloid-beta and tau accumulation. Progress in imaging and fluid biomarkers now allows for identifying surrogate markers of neuroinflammation in living individuals, which may offer unprecedented opportunities to better understand AD pathogenesis and progression. In this context, inflammatory mediators and glial proteins (mainly derived from microglial cells and astrocytes) seem to be the most promising biomarkers. Here, we discuss the biological basis of neuroinflammation in AD, revise the proposed neuroinflammation biomarkers, describe what we have learned from anti-inflammatory drug trials, and critically discuss the potential addition of these biomarkers in the AT(N) framework.

Consequences of Metabolic Disruption in Alzheimer's Disease Pathology.

Alzheimer's disease (AD) is an irreversible, progressive disease that slowly destroys cognitive function, such as thinking, remembering, and reasoning, to a level that one cannot carry out a daily living. As people live longer, the risk of developing AD has increased to 1 in 10 among people who are older than 65 and to almost 1 in 2 among those who are older than 85 according to a 2019 Alzheimer's Association report. As a most common cause of dementia, AD accounts for 60-80% of all dementia cases. AD is characterized by amyloid plaques and neurofibrillary tangles, composed of extracellular aggregates of amyloid-ß peptides and intracellular aggregates of hyperphosphorylated tau, respectively. Besides plaques and tangles, AD pathology includes synaptic dysfunction including loss of synapses, inflammation, brain atrophy, and brain hypometabolism, all of which contribute to progressive cognitive decline. Recent genetic studies of sporadic cases of AD have identified a score of risk factors, as reported by Hollingworth et al. (Nat Genet 43:429-435, 2001) and Lambert et al. (Nat Genet 45:1452-1458, 2013). Of all these genes, apolipoprotein E4 (APOE4) still presents the biggest risk factor for sporadic cases of AD, as stated in Saunders et al. (Neurology 43:1467-1472, 1993): depending on whether you have 1 or 2 copies of APOE4 allele, the risk increases from 3- to 12-fold, respectively, in line with Genin et al. (Mol Psychiatry 16:903-907, 2011). Besides these genetic risk factors, having type 2 diabetes (T2D), a chronic metabolic disease, is known to increase the AD risk by at least 2-fold when these individuals age, conforming to Sims-Robinson et al. (Nat Rev Neurol 6:551-559, 2010). Diabetes is reaching a pandemic scale with over 422 million people diagnosed worldwide in 2014 according to World Health Organization. Although what proportion of these diabetic patients develop AD is not known, even if 10% of diabetic patients develop AD later in their life, it would double the number of AD patients in the world. Better understanding between T2D and AD is of paramount of importance for the future. The goal of this review is to examine our current understanding on metabolic dysfunction in AD, so that a potential target can be identified in the near future.

Rostral-Caudal Hippocampal Functional Convergence Is Reduced Across the Alzheimer's Disease Spectrum.

Beginning in the early stages of Alzheimer's disease (AD), the hippocampus reduces its functional connections to other cortical regions due to synaptic depletion. However, little is known regarding connectivity abnormalities within the hippocampus. Here, we describe rostral-caudal hippocampal convergence (rcHC), a metric of the overlap between the rostral and caudal hippocampal functional networks, across the clinical spectrum of AD. We predicted a decline in rostral-caudal hippocampal convergence in the early stages of the disease. Using fMRI, we generated resting-state hippocampal functional networks across 56 controls, 48 early MCI (EMCI), 35 late MCI (LMCI), and 31 AD patients from the Alzheimer's Disease Neuroimaging Initiative cohort. For each diagnostic group, we performed a conjunction analysis and compared the rostral and caudal hippocampal network changes using a mixed effects linear model to estimate the convergence and differences between these networks, respectively. The conjunction analysis showed a reduction of rostral-caudal hippocampal convergence strength from early MCI to AD, independent of hippocampal atrophy. Our results demonstrate a parallel between the functional convergence within the hippocampus and disease stage, which is independent of brain atrophy. These findings support the concept that network convergence might contribute as a biomarker for connectivity dysfunction in early stages of AD.

Impact of the biological definition of Alzheimer's disease using amyloid, tau and neurodegeneration (ATN): what about the role of vascular changes, inflammation, Lewy body pathology?

BACKGROUND: The NIA-AA research framework proposes a biological definition of Alzheimer's disease, where asymptomatic persons with amyloid deposition would be considered as having this disease prior to symptoms. DISCUSSION: Notwithstanding the fact that amyloid deposition in isolation is not associated with dementia, even the combined association of amyloid and tau pathology does not inevitably need to dementia over age 65. Other pathological factors may play a leading or an accelerating role in age-associated cognitive decline, including vascular small vessel disease, neuroinflammation and Lewy Body pathology. CONCLUSION: Research should aim at understanding the interaction between all these factors, rather than focusing on them individually. Hopefully this will lead to a personalized approach to the prevention of brain aging, based on individual biological, genetic and cognitive profiles.

Quantification of brain cholinergic denervation in Alzheimer's disease using PET imaging with [18F]-FEOBV.

18F-fluoroethoxybenzovesamicol (FEOBV) is a new PET radiotracer that binds to the vesicular acetylcholine transporter. In both animals and healthy humans, FEOBV was found sensitive and reliable to characterize presynaptic cholinergic nerve terminals in the brain. It has been used here for we believe the first time in patients with Alzheimer's disease (AD) to quantify brain cholinergic losses. The sample included 12 participants evenly divided in healthy subjects and patients with AD, all assessed with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) cognitive scales. Every participant underwent three consecutive PET imaging sessions with (1) the FEOBV as a tracer of the cholinergic terminals, (2) the 18F-NAV4694 (NAV) as an amyloid-beta tracer, and (3) the 18F-Fluorodeoxyglucose (FDG) as a brain metabolism agent. Standardized uptake value ratios (SUVRs) were computed for each tracer, and compared between the two groups using voxel wise t-tests. Correlations were also computed between each tracer and the cognitive scales, as well as between FEOBV and the two other radiotracers. Results showed major reductions of FEOBV uptake in multiple cortical areas that were evident in each AD subject, and in the AD group as a whole when compared to the control group. FDG and NAV were also able to distinguish the two groups, but with lower sensitivity than FEOBV. FEOBV uptake values were positively correlated with FDG in numerous cortical areas, and negatively correlated with NAV in some restricted areas. The MMSE and MoCA cognitive scales were found to correlate significantly with FEOBV and with FDG, but not with NAV. We concluded that PET imaging with FEOBV is more sensitive than either FDG or NAV to distinguish AD patients from control subjects, and may be useful to quantify disease severity. FEOBV can be used to assess cholinergic degeneration in human, and may represent an excellent biomarker for AD.

Amyloid-ß and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer's disease.

This study was designed to test the interaction between amyloid-ß and tau proteins as a determinant of metabolic decline in preclinical Alzheimer's disease (AD). We assessed 120 cognitively normal individuals with [18F]florbetapir positron emission tomography (PET) and cerebrospinal fluid (CSF) measurements at baseline, as well as [18F]fluorodeoxyglucose ([18F]FDG) PET at baseline and at 24 months. A voxel-based interaction model was built to test the associations between continuous measurements of CSF biomarkers, [18F]florbetapir and [18F]FDG standardized uptake value ratios (SUVR). We found that the synergistic interaction between [18F]florbetapir SUVR and CSF phosphorylated tau (p-tau) measurements, rather than the sum of their independent effects, was associated with a 24-month metabolic decline in basal and mesial temporal, orbitofrontal, and anterior and posterior cingulate cortices (P<0.001). In contrast, interactions using CSF amyloid-ß1-42 and total tau biomarkers did not associate with metabolic decline over a time frame of 24 months. The interaction found in this study further support the framework that amyloid-ß and hyperphosphorylated tau aggregates synergistically interact to cause downstream AD neurodegeneration. In fact, the regions displaying the metabolic decline reported here were confined to brain networks affected early by amyloid-ß plaques and neurofibrillary tangles. Preventive clinical trials may benefit from using a combination of amyloid-ß PET and p-tau biomarkers to enrich study populations of cognitively normal subjects with a high probability of disease progression in studies, using [18F]FDG as a biomarker of efficacy.

Combination Therapy of Anti-Tau and Anti-Amyloid Drugs for Disease Modification in Early-stage Alzheimer's Disease: Socio-economic Considerations Modeled on Treatments for Tuberculosis, HIV/AIDS and Breast Cancer.

Current drugs for treatment of mild to severe dementia of the Alzheimer's type include cholinesterase inhibitors and the NMDA non-competitive receptor antagonist memantine. There is controversy as to the additive benefit of these symptomatic drugs, and their effects are clinically modest. Patients with Alzheimer's disease (AD) are known to have characteristic pathology, including senile plaques with amyloid beta-protein aggregates and neurofibrillary tangles with assembled tau proteins, which start in the hippocampus and spread to neighboring areas. Amyloid and tau modifying drugs are under clinical testing. Based on this pathophysiology, it is crucial to investigate whether anti-amyloid and anti-tau combined therapy would show efficacy in early stage of AD, beyond what could be achieved with anti-amyloid or anti-tau monotherapy. It is equally important to consider the socio-economic implications of such a combination therapy, if effective. We hypothesize that the high costs of combination therapy for early-stage AD patients will require societal and public health initiatives to ensure universal access to AD treatment. In order to better predict these socio-economic implications, we summarize the management of other combination therapies used for tuberculosis, HIV/AIDS, and breast cancer, based on a database search of PubMed and other relevant sources. We put forward a framework for testing a potential anti-amyloid and anti-tau disease modifying combination therapy for early-stage AD patients and present an analysis of the socio-economic implications of such a combination therapy.

Limbic system mGluR5 availability in cocaine dependent subjects: a high-resolution PET [(11)C]ABP688 study.

Cocaine self-administration decreases type 5 metabotropic glutamate receptor (mGluR5) tissue concentrations in laboratory rats during early abstinence. These changes are thought to influence the drug's reinforcing properties and the ability of drug-related cues to induce relapse. Here, our goal was to measure brain regional mGluR5 availability in recently abstinent cocaine dependent humans. Participants meeting DSM-IV diagnostic criteria for current cocaine dependence (n=9) were recruited from the general population. mGluR5 availability (binding potential, non-displaceable; BPND) was measured with high-resolution positron emission tomography (PET HRRT) and [(11)C]ABP688. Compared to age- and sex-matched healthy controls (n=9), cocaine dependent subjects showed significantly lower BPND values in the ventral (bilateral: -28.2%, p=0.011), associative (right: -21.4%, p=0.043), and sensorimotor striatum (bilateral: -21.7%, p=0.045), amygdala (left: -26%, p=0.046) and insula (right: -23.3%, p=0.041). Among the cocaine users, receptor availabilities were related to abstinence (range: 2 to 14days). The longer the duration of abstinence, the lower the BPND values in the sensorimotor striatum (r=-0.71, p=0.034), left amygdala (r=-0.73, p=0.026) and right insula (r=-0.67, p=0.046). Compared to healthy controls, BPND values were significantly reduced in those who tested negative for cocaine on the PET test session in the ventral (p=0.018) and sensorimotor striatum (p=0.017), left amygdala (p=0.008), and right insula (p=0.029), but not in those who tested positive. Together, these results provide evidence of time-related mGluR5 alterations in striatal and limbic regions in humans during early cocaine abstinence.

How can we improve transfer of outcomes from randomized clinical trials to clinical practice with disease-modifying drugs in Alzheimer's disease?

BACKGROUND: Randomized clinical trials (RCTs) for putative disease-modifying drugs in Alzheimer's disease (AD) are using cognitive outcomes, such as the Alzheimer's Disease Assessment Scale--cognitive subscale, activities of daily living scales, such as the Alzheimer's Disease Cooperative Study Activities of Daily Living, and time from mild cognitive impairment to AD dementia. OBJECTIVE: It was the aim of this study to build clinically relevant outcomes for future use in clinical practice into RCT designs and help third-party payers to measure benefit. METHODS: We used a literature review for analysis. RESULTS: The Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) appears to be the most reliable primary outcome for RCT at different stages of AD, with the Relevant Outcome Scale for Alzheimer's Disease (ROSA) as a suitable alternative. The importance of current AD biomarkers vis-à- vis determination of efficacy of disease-modifying drugs has yet to be established; however, it is likely that at least one amyloid-specific test will be required prior to treatment with a drug acting predominantly on ß-amyloid (Aß42). Furthermore, serial MRI may be required to monitor adverse side effects associated with such drugs. CONCLUSIONS: Global clinical scales such as CDR-SB and ROSA should be considered for use with treatments aiming at slowing disease progression.

Diagnosis and management of Alzheimer's disease: past, present and future ethical issues.

There is great interest in the ethical issues associated with Alzheimer's disease (AD) and related dementias given the prevalence of AD and the evolving neuroscience landscape in matters of diagnoses and therapeutics. Much of the ethics discussion arises in the tension between the principle of not doing harm (principle of non-maleficence) in this vulnerable population and the development of effective treatments (principle of beneficence). Autonomy and capacity issues are also numerous, wide-ranging, and concern (1) day to day affairs such as driving safely and spending money wisely, (2) life-time events such as designating a legal representative in case of incapacity, making a will, (3) consenting to treatment and diagnostic procedures, (4) participating in research. The latter issue is particularly thorny and illustrates well the complexity of tackling concerns related to capacity. The impetus to protect AD patients has partly led to ethics regulation and policies making research on inapt patients more difficult because of stringent requirements for signed informed consent or for showing the value of the research to this specific patient population. New issues are arising that relate to earlier diagnosis using biomarkers and (possibly soon) the use of drugs that modify disease progression. We here summarize and discuss the different ethical issues associated with AD from a historical perspective, with emphasis on diagnostic and treatments issues.

TLN-4601 peripheral benzodiazepine receptor (PBR/TSPO) binding properties do not mediate apoptosis but confer tumor-specific accumulation.

TLN-4601 is a farnesylated dibenzodiazepinone isolated from Micromonospora sp. with an antiproliferative effect on several human cancer cell lines. Although the mechanism of action of TLN-4601 is unknown, our earlier work indicated that TLN-4601 binds the PBR (peripheral benzodiazepine receptor; more recently known as the translocator protein or TSPO), an 18 kDa protein associated with the mitochondrial permeability transition (mPT) pore. While the exact function of the PBR remains a matter of debate, it has been implicated in heme and steroid synthesis, cellular growth and differentiation, oxygen consumption and apoptosis. Using the Jurkat immortalized T-lymphocyte cell line, documented to have negligible PBR expression, and Jurkat cells stably transfected with a human PBR cDNA, the present study demonstrates that TLN-4601 induces apoptosis independently of PBR expression. As PBRs are overexpressed in brain tumors compared to normal brain, we examined if TLN-4601 would preferentially accumulate in tumors using an intra-cerebral tumor model. Our results demonstrate the ability of TLN-4601 to effectively bind the PBR in vivo as determined by competitive binding assay and receptor occupancy. Analysis of TLN-4601 tissue and plasma indicated that TLN-4601 preferentially accumulates in the tumor. Indeed, drug levels were 200-fold higher in the tumor compared to the normal brain. TLN-4601 accumulation in the tumor (176 µg/g) was also significant compared to liver (24.8 µg/g; 7-fold) and plasma (16.2 µg/mL; 11-fold). Taken together our data indicate that while PBR binding does not mediate cell growth inhibition and apoptosis, PBR binding may allow for the specific accumulation of TLN-4601 in PBR positive tumors.

Motion compensation for fully 4D PET reconstruction using PET superset data.

Fully 4D PET image reconstruction is receiving increasing research interest due to its ability to significantly reduce spatiotemporal noise in dynamic PET imaging. However, thus far in the literature, the important issue of correcting for subject head motion has not been considered. Specifically, as a direct consequence of using temporally extensive basis functions, a single instance of movement propagates to impair the reconstruction of multiple time frames, even if no further movement occurs in those frames. Existing 3D motion compensation strategies have not yet been adapted to 4D reconstruction, and as such the benefits of 4D algorithms have not yet been reaped in a clinical setting where head movement undoubtedly occurs. This work addresses this need, developing a motion compensation method suitable for fully 4D reconstruction methods which exploits an optical tracking system to measure the head motion along with PET superset data to store the motion compensated data. List-mode events are histogrammed as PET superset data according to the measured motion, and a specially devised normalization scheme for motion compensated reconstruction from the superset data is required. This work proceeds to propose the corresponding time-dependent normalization modifications which are required for a major class of fully 4D image reconstruction algorithms (those which use linear combinations of temporal basis functions). Using realistically simulated as well as real high-resolution PET data from the HRRT, we demonstrate both the detrimental impact of subject head motion in fully 4D PET reconstruction and the efficacy of our proposed modifications to 4D algorithms. Benefits are shown both for the individual PET image frames as well as for parametric images of tracer uptake and volume of distribution for (18)F-FDG obtained from Patlak analysis.