Clear‐headed into old age: Resilience and resistance against brain aging—A PET imaging perspective

With the advances in modern medicine and the adaptation towards healthier lifestyles, the average life expectancy has doubled since the 1930s, with individuals born in the millennium years now carrying an estimated life expectancy of around 100 years. And even though many individuals around the globe manage to age successfully, the prevalence of aging-associated neurodegenerative diseases such as sporadic Alzheimer’s disease has never been as high as nowadays. The prevalence of Alzheimer’s disease is anticipated to triple by 2050, increasing the societal and economic burden tremendously. Despite all efforts, there is still no available treatment defeating the accelerated aging process as seen in this disease. Yet, given the advances in neuroimaging techniques that are discussed in the current Review article, such as in positron emission tomography (PET) or magnetic resonance imaging (MRI), pivotal insights into the heterogenous effects of aging-associated processes and the contribution of distinct lifestyle and risk factors already have and are still being gathered. In particular, the concepts of resilience (i.e. coping with brain pathology) and resistance (i.e. avoiding brain pathology) have more recently been discussed as they relate to mechanisms that are associated with the prolongation and/or even stop of the progressive brain aging process. Better understanding of the underlying mechanisms of resilience and resistance may one day, hopefully, support the identification of defeating mechanism against accelerating aging

Gray Matter Volume Loss in Proposed Brain‐First and Body‐First Parkinson's Disease Subtypes

Background: α-Synuclein pathology is associated with neuronal degeneration in Parkinson's disease (PD) and considered to sequentially spread across the brain (Braak stages). According to a new hypothesis of distinct α-synuclein spreading directions based on the initial site of pathology, the "brain-first" spreading subtype would be associated with a more asymmetric cerebral and nigrostriatal pathology than the "body-first" subtype.Objective: Here, we tested if proposed markers of brain-first PD (ie, higher dopamine transporter [DaT] asymmetry; absence of rapid eye movement sleep behavior disorder [RBD]) are associated with a greater or more asymmetric reduction in gray matter volume (GMV) in comparison to body-first PD.Methods: Data of 255 de novo PD patients and 110 healthy controls (HCs) were retrieved from the Parkinson's Progression Markers Initiative. Structural magnetic resonance images were preprocessed, and GMVs and their hemispherical asymmetry were obtained for each of the neuropathologically defined Braak stages. Group and correlation comparisons were performed to assess differences in GMV and GMV asymmetry between PD subtypes.Results: PD patients demonstrated significantly smaller bilateral GMVs compared to HCs, in a pattern denoting stage-dependent disease-related brain atrophy. However, the degree of putaminal DaT asymmetry was not associated with reduced GMV or higher GMV asymmetry. Furthermore, RBD-negative and RBD-positive patients did not demonstrate a significant difference in GMV or GMV asymmetry.Conclusions: Our findings suggest that putative brain-first and body-first patients do not present diverging brain atrophy patterns. Although certainly not disproving the brain-first/body-first spreading hypothesis, this study fails to provide evidence in support of it. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Keywords: dopamine transporter; rapid eye movement sleep; rapid eye movement sleep behavior disorder; α-synuclein spread

The Concept of Motor Reserve in Parkinson's Disease: New Wine in Old Bottles?

Across neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), a disparity between the clinical expression and the extent of pathophysiological burden has been observed. This has fueled the establishment of resilience concepts such as cognitive reserve (CR) and brain reserve (BR) at the beginning of this millennium.1 Since the introduction of these concepts, a plethora of studies have aimed at identifying mechanisms predominantly associated with the mitigation of cognitive decline despite neurodegenerative changes associated with multiple sclerosis, dementia, or healthy aging (ie, resilience).2, 3 In comparison, resilience mechanisms in PD have received far less attention even though they seem equally important given the clinical heterogeneity and long prodromal phase. With the emerging concept of motor reserve (MR), new avenues have opened up focusing on potential neuronal processes providing resilience (ie, relative preservation of motor function) in PD, which can potentially be harnessed for interventional therapies. Importantly, this requires a common understanding of the principles of how to assess resilience in observational studies and how to quantify its underlying mechanisms. Given the head start in identifying pitfalls and precisely delineating the concept of resilience in the AD field, the opportunity lies at hand to benefit from this knowledge for investigations of MR in PD

Unique regional patterns of amyloid burden predict progression to prodromal and clinical stages of Alzheimer's disease

Although beta-amyloid (A beta) positivity has shown to be associated with higher risk of progression to Alzheimer's disease (AD) in mild cognitive impairment (MCI), information on the time to conversion to manifest dementia cannot be readily deduced from this binary classification. Here, we assessed if regional patterns of A beta deposition measured with F-18-florbetapir may serve as biomarker for progression risk in A beta-positive cognitively normal (CN) and MCI patients, including clinical follow-up data and cerebrospinal fluid (CSF) biomarkers. Voxel-wise group comparisons between age and sex-matched A beta-positive groups (i.e., CN-stables [n = 38] vs. CN-to-MCI/AD progressors [n = 38], MCI-stables [n = 104] versus MCI-toAD progressors [n = 104]) revealed higher A beta burden in precuneus, subcortical, and parietal regions in CN-to-MCI/AD progressors and cingulate, temporal, and frontal regions in MCI-to-AD progressors. Importantly, these regional patterns predicted progression to advanced stages on the AD spectrum in the short and the long-term beyond global A beta burden and CSF biomarkers. These results suggest that distinct regional patterns of A beta burden are a valuable biomarker for risk of disease progression in CN and MCI. (C) 2021 The Authors. Published by Elsevier Inc

Impulsive-compulsive behaviour in early Parkinson’s disease is determined by apathy and dopamine receptor D3 polymorphism

Impulsive-compulsive behaviour (ICB) is a frequently observed non-motor symptom in early Parkinson’s disease after initiatingdopamine replacement therapy. At the opposite end of the motivated behaviour spectrum, apathy occurs in early Parkinson’sdisease even before dopamine replacement is started. The co-occurrence of these behavioural conditions in Parkinson’s diseaseraises questions about their relationship and underlying pathophysiological determinants. In previous imaging or genetic studies,both conditions have been associated with the limbic dopaminergic system. The risk variant of the Ser9Gly polymorphism of thedopamine receptor D3 (DRD3) is linked to increased dopamine affinity in the limbic striatum. With this in mind, we investigatedhow ICB expression is explained by apathy and DRD3 polymorphisms and their effects on grey matter volume and dopaminesynthesis capacity. Fifty-four patients with early Parkinson’s disease took part in anatomical T1-weighted MRI. Forty of them alsounderwent dynamic PET imaging using [18F]DOPA to measure striatal dopamine synthesis capacity. Further, Ser9Gly (rs6280) genepolymorphism influencing the DRD3 dopamine-binding affinity was determined in all patients. The severity of impulsivecompulsivebehaviour and apathy was assessed using the Questionnaire for Impulsive-Compulsive Disorders Rating Scale and theApathy Evaluation Scale. ICB and the severity of apathy were indeed positively correlated. Apathy and the DRD3 polymorphismwere interactive risk factors for ICB severity. Apathy was significantly linked to atrophy of the bilateral putamen. Patients with theDRD3 risk type had reduced dopamine synthesis capacity in the putamen and limbic striatum, apathy was associated with reduceddopamine synthesis capacity in the limbic striatum. The results of [18F]DOPA reached only trend significance. Apathy in drug-naïvePD patients might be a consequence of impaired striatal dopaminergic tone. This may represent a predisposing factor for thedevelopment of ICB after the initiation of dopamine replacement therapy. The risk type of DRD3 could further amplify thispredisposition due to its higher affinity to dopamine

Dopamine metabolism of the nucleus accumbens and fronto-striatal connectivity modulate impulse control

Impulsive-compulsive behaviours like pathological gambling or hypersexuality are a frequent side effect of dopamine replacement therapy in patients with Parkinson's disease. Multiple imaging studies suggest a significant reduction of presynaptic dopamine transporters in the nucleus accumbens to be a predisposing factor, reflecting either a reduction of mesolimbic projections or, alternatively, a lower presynaptic dopamine transporter expression per se. Here, we aimed to test the hypothesis of fewer mesolimbic projections as a risk factor by using dopamine synthesis capacity as a proxy of dopaminergic terminal density. Furthermore, previous studies have demonstrated a reduction of fronto-striatal connectivity to be associated with increased risk of impulsive-compulsive behaviour in Parkinson's disease. Therefore, another aim of this study was to investigate the relationship between severity of impulsive-compulsive behaviour, dopamine synthesis capacity and fronto-striatal connectivity. Eighty participants underwent resting state functional MRI and anatomical T-1-weighted images [mean age: 68 +/- 9.9 years, 67% male (patients)]. In 59 participants, F-18-DOPA-PET was obtained and voxel-wise Patlak slopes indicating dopamine synthesis capacity were calculated. All participants completed the QUIP-RS questionnaire, a well validated test to quantify severity of impulsive-compulsive behaviour in Parkinson's disease. A voxel-wise correlation analysis between dopamine synthesis capacity and QUIP-RS score was calculated for striatal regions. To investigate the relationship between symptom severity and functional connectivity, voxel-wise correlations were performed. A negative correlation was found between dopamine synthesis capacity and QUIP-RS score in the nucleus accumbens (r = -0.57, P = 0.001), a region functionally connected to the rostral anterior cingulate cortex. The connectivity strength was modulated by QUIP-RS, i.e. patients with more severe impulsive-compulsive behaviours had a weaker functional connectivity between rostral anterior cingulate cortex and the nucleus accumbens. In addition, cortical thickness and severity of impulsive-compulsive behaviour were positively correlated in the subgenual rostral anterior cingulate cortex. We found three factors to be associated with severity of impulsive-compulsive behaviour: (i) decreased dopamine synthesis capacity in the nucleus accumbens; (ii) decreased functional connectivity of the rostral anterior cingulate cortex with the nucleus accumbens; and (iii) increased cortical thickness of the subgenual rostral anterior cingulate cortex. Rather than a downregulation of dopamine transporters, a reduction of mesolimbic dopaminergic projections in conjunction with a dysfunctional rostral anterior cingulate cortexa region known to play a key role in impulse control-could be the most crucial neurobiological risk factor for the development of impulsive-compulsive behaviours in patients with Parkinson's disease under dopamine replacement therapy

Level of education mitigates the impact of tau pathology on neuronal function

PurposeUsing PET imaging in a group of patients with Alzheimer's disease (AD), we investigated whether level of education, a proxy for resilience, mitigates the harmful impact of tau pathology on neuronal function.MethodsWe included 38 patients with mild-to-moderate AD (mean age 677years, mean MMSE score 244, mean years of education 14 +/- 4; 20 men, 18 women) in whom a [F-18]AV-1451 scan (a measure of tau pathology) and an [F-18]FDG scan (a measure of neuronal function) were available. The preprocessed PET scans were z-transformed using templates for [F-18]AV-1451 and [F-18]FDG from healthy controls, and subsequently thresholded at a z-score of >= 3.0, representing an one-tailed p value of 0.001. Next, three volumes were computed in each patient: the tau-specific volume (tau pathology without neuronal dysfunction), the FDG-specific volume (neuronal dysfunction without tau pathology), and the overlap volume (tau pathology and neuronal dysfunction). Mean z-scores and volumes were extracted and used as dependent variables in regression analysis with years of education as predictor, and age and MMSE score as covariates.Results Years of education were positively associated with tau-specific volume (beta=0.362, p=0.022), suggesting a lower impact of tau pathology on neuronal function in patients with higher levels of education. Concomitantly, level of education was positively related to tau burden in the overlap volume (beta=0.303, p=0.036) implying that with higher levels of education more tau pathology is necessary to induce neuronal dysfunction.Conclusion In patients with higher levels of education, tau pathology is less paralleled by regional and remote neuronal dysfunction. The data suggest that early life-time factors such as level of education support resilience mechanisms, which ameliorate AD-related effects later in life