Abstract Thanks to its safety and accessibility, magnetic resonance imaging (MRI) is extensively used in clinical routine and research field, largely contributing to our understanding of the ...pathophysiology of neurodegenerative disorders such as Alzheimer’s disease (AD). This review aims to provide a comprehensive overview of the main findings in AD and normal aging over the past twenty years, focusing on the patterns of gray and white matter changes assessed in vivo using MRI. Major progresses in the field concern the segmentation of the hippocampus with novel manual and automatic segmentation approaches, which might soon enable to assess also hippocampal subfields. Advancements in quantification of hippocampal volumetry might pave the way to its broader use as outcome marker in AD clinical trials. Patterns of cortical atrophy have been shown to accurately track disease progression and seem promising in distinguishing among AD subtypes. Disease progression has also been associated with changes in white matter tracts. Recent studies have investigated two areas often overlooked in AD, such as the striatum and basal forebrain, reporting significant atrophy, although the impact of these changes on cognition is still unclear. Future integration of different MRI modalities may further advance the field by providing more powerful biomarkers of disease onset and progression.
The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to ...neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD.
Purpose
The purpose of this paper is to systematically review the available literature to understand the effectiveness, the survivorship, the clinical outcomes and the complications of lateral UKA.
...Methods
A review of the current literature available about lateral UKA was performed in March 2020, according to the PRISMA guidelines. Selection was based on the following inclusion criteria: (1) clinical reports of any level of evidence, (2) written in English language, (3) published from 1996 to 2020, (4) dealing with clinical data on lateral UKA. A total of 47 articles, published between 1996 and 2020, were included in the review. Quality of every article was assessed using the Modified Coleman Methodology Score.
Results
A total of 47 studies were included. Mean mCMS was 45.27 (range 30–62). Mean age at surgery was 64.5 years (range 34.1–88.0 years). In 1741 patients (65.5%) a metal back implant was used and in 421 patients (15.8%) an all poly design was used. Several scores were used to evaluate clinical results (OKS, AKSS, IKS, KOOS, WOMAC, VAS). Range of motion improved with an overall mean value of 120.3° (range: 105.9°–143.3°). The mean follow-up was 60.7 months (range, 7–204 months), mean survivorship (absence of a revision) with a minimum 60 months of follow-up was 88.6% (range 74.5–100) and mean satisfaction of patients was 78.5% (range 41.0–97.9).
Conclusions
Lateral UKA seems to be an effective solution to manage lateral osteoarthritis (OA), based on preliminary results, with survivorship and satisfaction rate comparable to medial UKA and total knee arthroplasty (TKA). Nonetheless, this review highlights that the quality of studies available in current literature is low.
Level of evidence
Systematic review of level IV studies.
Purpose
We aim to report the quality of accuracy studies investigating the utility of
18
Ffluorodeoxyglucose (FDG)-PET in supporting the diagnosis of prodromal Alzheimer’s Disease (AD), ...frontotemporal lobar degeneration (FTLD) and prodromal dementia with Lewy bodies (DLB) in mild cognitive impairment (MCI) subjects, and the corresponding recommendations made by a panel of experts.
Methods
Seven panellist, four from the European Association of Nuclear Medicine, and three from the European Academy of Neurology, produced recommendations taking into consideration the incremental value of FDG-PET, as added on clinical-neuropsychological examination, to ascertain the aetiology of MCI (AD, FTLD or DLB). A literature search using harmonized population, intervention, comparison, and outcome (PICO) strings was performed, and an evidence assessment consistent with the European Federation of Neurological Societies guidance was provided. The consensual recommendation was achieved based on Delphi rounds.
Results
Fifty-four papers reported the comparison of interest. The selected papers allowed the identification of FDG patterns that characterized MCI due to AD, FTLD and DLB. While clinical outcome studies supporting the diagnosis of MCI due to AD showed varying accuracies (ranging from 58 to 100%) and varying areas under the receiver-operator characteristic curves (0.66 to 0.97), no respective data were identified for MCI due to FTLD or for MCI due to DLB. However, the high negative predictive value of FDG-PET and the existence of different disease-specific patterns of hypometabolism support the consensus recommendations for the clinical use of this imaging technique in MCI subjects.
Conclusions
FDG-PET has clinical utility on a fair level of evidence in detecting MCI due to AD. Although promising also in detecting MCI due to FTLD and MCI due to DLB, more research is needed to ultimately judge the clinical utility of FDG-PET in these entities.
Purpose
Assess the individual and combined diagnostic value of amyloid-PET and tau-PET in a memory clinic population.
Methods
Clinical reports of 136 patients were randomly assigned to two diagnostic ...pathways: AMY-TAU, amyloid-PET is presented before tau-PET; and TAU-AMY, tau-PET is presented before amyloid-PET. Two neurologists independently assessed all reports with a balanced randomized design, and expressed etiological diagnosis and diagnostic confidence (50–100%) three times: (i) at baseline based on the routine diagnostic workup, (ii) after the first exam (amyloid-PET for the AMY-TAU pathway, and tau-PET for the TAU-AMY pathway), and (iii) after the remaining exam. The main outcomes were changes in diagnosis (from AD to non-AD or vice versa) and in diagnostic confidence.
Results
Amyloid-PET and tau-PET, when presented as the first exam, resulted in a change of etiological diagnosis in 28% (
p
= 0.006) and 28% (
p
< 0.001) of cases, and diagnostic confidence increased by 18% (
p
< 0.001) and 19% (
p
< 0.001) respectively, with no differences between exams (
p
> 0.05). We observed a stronger impact of a negative amyloid-PET versus a negative tau-PET (
p
= 0.014). When added as the second exam, amyloid-PET and tau-PET resulted in a further change in etiological diagnosis in 6% (
p
= 0.077) and 9% (
p
= 0.149) of cases, and diagnostic confidence increased by 4% (
p
< 0.001) and 5% (
p
< 0.001) respectively, with no differences between exams (
p
> 0.05).
Conclusion
Amyloid-PET and tau-PET significantly impacted diagnosis and diagnostic confidence in a similar way, although a negative amyloid-PET has a stronger impact on diagnosis than a negative tau-PET. Adding either of the two as second exam further improved diagnostic confidence.
Trial number
PB 2016-01346.
Purpose
To review how outcomes of clinical utility are operationalized in current amyloid-PET validation studies, to prepare for formal assessment of clinical utility of amyloid-PET-based diagnosis.
...Methods
Systematic review of amyloid-PET research studies published up to April 2020 that included outcomes of clinical utility. We extracted and analyzed (a) outcome categories, (b) their definition, and (c) their methods of assessment.
Results
Thirty-two studies were eligible. (a) Outcome categories were
clinician-centered
(found in 25/32 studies, 78%),
patient-/caregiver-centered
(in 9/32 studies, 28%), and
health economics-centered
(5/32, 16%). (b) Definition: Outcomes were mainly defined by clinical researchers; only the ABIDE study expressly included stakeholders in group discussions. Clinician-centered outcomes mainly consisted of incremental diagnostic value (25/32, 78%) and change in patient management (17/32, 53%); patient-/caregiver-centered outcomes considered distress after amyloid-pet-based diagnosis disclosure (8/32, 25%), including quantified burden of procedure for patients’ outcomes (
n
= 8) (1/8, 12.5%), impact of disclosure of results (6/8, 75%), and psychological implications of biomarker-based diagnosis (75%); and health economics outcomes focused on costs to achieve a high-confidence etiological diagnosis (5/32, 16%) and impact on quality of life (1/32, 3%). (c) Assessment: all outcome categories were operationalized inconsistently across studies, employing 26 different tools without formal rationale for selection.
Conclusion
Current studies validating amyloid-PET already assessed outcomes for clinical utility, although non-clinician-based outcomes were inconsistent. A wider participation of stakeholders may help produce a more thorough and systematic definition and assessment of outcomes of clinical utility and help collect evidence informing decisions on reimbursement of amyloid-PET.
Although prevention of dementia and late-life cognitive decline is a major public health priority, there are currently no generally established prevention strategies or operational models for ...implementing such strategies into practice. This article is a narrative review of available evidence from multidomain dementia prevention trials targeting several risk factors and disease mechanisms simultaneously, in individuals without dementia at baseline. Based on the findings, we formulate recommendations for implementing precision risk reduction strategies into new services called Brain Health Services. A literature search was conducted using medical databases (MEDLINE via PubMed and SCOPUS) to select relevant studies: non-pharmacological multidomain interventions (i.e., combining two or more intervention domains), target population including individuals without dementia, and primary outcomes including cognitive/functional performance changes and/or incident cognitive impairment or dementia. Further literature searches covered the following topics: sub-group analyses assessing potential modifiers for the intervention effect on cognition in the multidomain prevention trials, dementia risk scores used as surrogate outcomes in multidomain prevention trials, dementia risk scores in relation to brain pathology markers, and cardiovascular risk scores in relation to dementia. Multidomain intervention studies conducted so far appear to have mixed results and substantial variability in target populations, format and intensity of interventions, choice of control conditions, and outcome measures. Most trials were conducted in high-income countries. The differences in design between the larger, longer-term trials that met vs. did not meet their primary outcomes suggest that multidomain intervention effectiveness may be dependent on a precision prevention approach, i.e., successfully identifying the at-risk groups who are most likely to benefit. One such successful trial has already developed an operational model for implementing the intervention into practice. Evidence on the efficacy of risk reduction interventions is promising, but not yet conclusive. More long-term multidomain randomized controlled trials are needed to fill the current evidence gaps, especially concerning low- and middle-income countries and integration of dementia prevention with existing cerebrovascular prevention programs. A precision risk reduction approach may be most effective for dementia prevention. Such an approach could be implemented in Brain Health Services.
The recent development of techniques to assess plasma biomarkers has changed the way the research community envisions the future of diagnosis and management of Alzheimer's disease (AD) and other ...neurodegenerative disorders. This work aims to provide real world evidence on the clinical impact of plasma biomarkers in an academic tertiary care center.
Anonymized clinical reports of patients diagnosed with AD or Frontotemporal Lobar Degeneration with available plasma biomarkers (Aβ
, Aβ
/Aβ
, p-tau
, p-tau
, NfL, GFAP) were independently assessed by two neurologists who expressed diagnosis and diagnostic confidence three times: (T0) at baseline based on the information collected during the first visit, (T1) after plasma biomarkers, and (T2) after traditional biomarkers (when available). Finally, we assessed whether clinicians' interpretation of plasma biomarkers and the consequent clinical impact are consistent with the final diagnosis, determined after the conclusion of the diagnostic clinical and instrumental work-up by the actual managing physicians who had complete access to all available information.
Clinicians assessed 122 reports, and their concordance ranged from 81 to 91% at the three time points. At T1, the presentation of plasma biomarkers resulted in a change of diagnosis in 2% (2/122, p = 1.00) of cases, and in increased diagnostic confidence in 76% (91/120, p < 0.001) of cases with confirmed diagnosis. The change in diagnosis and the increase in diagnostic confidence after plasma biomarkers were consistent with the final diagnosis in 100% (2/2) and 81% (74/91) of cases, respectively. At T2, the presentation of traditional biomarkers resulted in a further change of diagnosis in 13% (12/94, p = 0.149) of cases, and in increased diagnostic confidence in 88% (72/82, p < 0.001) of cases with confirmed diagnosis.
In an academic tertiary care center, plasma biomarkers supported clinicians by increasing their diagnostic confidence in most cases, despite a negligible impact on diagnosis. Future prospective studies are needed to assess the full potential of plasma biomarkers on clinical grounds.
Purpose
A joint effort of the European Association of Nuclear Medicine (EANM) and the European Academy of Neurology (EAN) aims at clinical guidance for the use of FDG-PET in neurodegenerative ...diseases. This paper addresses the diagnostic utility of FDG-PET over clinical/neuropsychological assessment in the differentiation of the three forms of primary progressive aphasia (PPA).
Methods
Seven panelists were appointed by the EANM and EAN and a literature search was performed by using harmonized PICO (Population, Intervention, Comparison, Outcome) question keywords. The studies were screened for eligibility, and data extracted to assess their methodological quality. Critical outcomes were accuracy indices in differentiating different PPA clinical forms. Subsequently Delphi rounds were held with the extracted data and quality assessment to reach a consensus based on both literature and expert opinion.
Results
Critical outcomes for this PICO were available in four of the examined papers. The level of formal evidence supporting clinical utility of FDG-PET in differentiating among PPA variants was considered as poor. However, the consensual recommendation was defined on Delphi round I, with six out of seven panelists supporting clinical use.
Conclusions
Quantitative evidence demonstrating utility or lack thereof is still missing. Panelists decided consistently to provide interim support for clinical use based on the fact that a typical atrophy or metabolic pattern is needed for PPA according to the diagnostic criteria, and the synaptic failure detected by FDG-PET is an earlier phenomenon than atrophy. Also, a normal FDG-PET points to a non-neurodegenerative cause.
Purpose
To compare the incremental diagnostic value of amyloid-PET and CSF (Aβ42, tau, and phospho-tau) in AD diagnosis in patients with mild cognitive impairment (MCI) or mild dementia, in order to ...improve the definition of diagnostic algorithm.
Methods
Two independent dementia experts provided etiological diagnosis and relative diagnostic confidence in 71 patients on 3 rounds, based on (1) clinical, neuropsychological, and structural MRI information alone; (2) adding one biomarker (CSF amyloid and tau levels or amyloid-PET with a balanced randomized design); and (3) adding the other biomarker.
Results
Among patients with a pre-biomarker diagnosis of AD, negative PET induced significantly more diagnostic changes than amyloid-negative CSF at both rounds 2 (CSF 67%, PET 100%,
P
= 0.028) and 3 (CSF 0%; PET 78%,
P
< 0.001); PET induced a diagnostic confidence increase significantly higher than CSF on both rounds 2 and 3.
Conclusions
Amyloid-PET should be prioritized over CSF biomarkers in the diagnostic workup of patients investigated for suspected AD, as it provides greater changes in diagnosis and diagnostic confidence.
Trial registration
EudraCT no.: 2014-005389-31
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