Nicolaas Paul L.G. Verhoeff

Effect of subthalamic stimulation on mood state in Parkinson’s disease: evaluation of previous facts and problems

In an attempt to clarify the effect of deep brain stimulation (DBS) to the subthalamic nucleus (STN) on mood state, previous evidence and problems were evaluated through a systematic literature search. Twenty three articles reported the effect of STN DBS on mood state in Parkinson’s disease (PD), and antidepressant, depressant, and mania-induced effects were reported in 16.7–76%, 2–33.3%, and 4.2–8.1% of the patients treated with STN DBS, respectively. Most articles reported larger subgroups showing antidepressant effects than those showing depressant effects. The average depression scale score of all subjects was improved or unchanged after STN DBS. Although there was a limitation due to the varied results, it was suggested that, in general, STN DBS had an antidepressant effect in PD. However, the studies reporting severe depressant symptoms, such as suicidal attempts, after STN DBS indicated the importance of careful attention to mood state as well as to motor symptoms after STN DBS. It may be crucial to reduce the variation in the results by, for example, the use of standardized protocols and the precise verification of the stimulated region in further investigations to address this issue.

Alzheimer's Disease, Cerebrovascular Disease, and the β-amyloid Cascade

Alzheimer’s disease (AD), considered the commonest neurodegenerative cause of dementia, is associated with hallmark pathologies including extracellular amyloid-β protein (Aβ) deposition in extracellular senile plaques and vessels, and intraneuronal tau deposition as neurofibrillary tangles. Although AD is usually categorized as neurodegeneration distinct from cerebrovascular disease (CVD), studies have shown strong links between AD and CVD. There is evidence that vascular risk factors and CVD may accelerate Aβ 40-42 production/ aggregation/deposition and contribute to the pathology and symptomatology of AD. Aβ deposited along vessels also causes cerebral amyloid angiopathy. Amyloid imaging allows in vivo detection of AD pathology, opening the way for prevention and early treatment, if disease-modifying therapies in the pipeline show safety and efficacy. In this review, we review the role of vascular factors and Aβ, underlining that vascular risk factor management may be important for AD prevention and treatment.

Acetylcholinergic neurotransmission and the β-amyloid cascade: implications for Alzheimer’s disease

Alzheimer’s disease is characterized by both decreases in acetylcholinergic neurotransmission and increases in β-amyloid accumulation. Currently, available clinical psychopharmacologic treatment is focused on increasing acetylcholinergic neurotransmission, whereas no clinical treatments to directly reduce β-amyloid accumulation are available. Cholinesterase inhibitors improve cognition, certain neuropsychiatric symptoms and functional impairment in patients with mild-to-moderate Alzheimer’s disease, and it is believed that this is mainly symptomatic treatment. However, this review discusses various levels of interaction between acetylcholinergic neurotransmission and the β-amyloid cascade, which suggest that some specific acetylcholinergic treatments may reduce β-amyloid accumulation, and therefore may slow disease progression over the long term. Various suggestions are made on how such potential disease-modifying effects could be studied in the future.

Quantitative imaging of neuroinflammation in human white matter: A positron emission tomography study with translocator protein 18 kDa radioligand, [18F]‐FEPPA

The ability to quantify translocator protein 18 kDa (TSPO) in white matter (WM) is important to understand the role of neuroinflammation in neurological disorders with WM involvement. This article aims to extend the utility of TSPO imaging in WM using a second‐generation radioligand, [18F]‐FEPPA, and high‐resolution research tomograph (HRRT) positron emission tomography (PET) camera system. Four WM regions of interests (WM‐ROI), relevant to the study of aging and neuroinflammatory diseases, were examined. The corpus callosum, cingulum bundle, superior longitudinal fasciculus, and posterior limb of internal capsule were delineated automatically onto subjects T1‐weighted magnetic resonance image using a diffusion tensor imaging‐based WM template. The TSPO polymorphism (rs6971) stratified individuals to three genetic groups: high‐affinity binders (HAB), mixed‐affinity binders (MAB), and low‐affinity binders. [18F]‐FEPPA PET scans were acquired on 32 healthy subjects and analyzed using a full kinetic compartment analysis. The two‐tissue compartment model showed moderate identifiability (coefficient of variation 15–19%) for [18F]‐FEPPA total volume distribution (VT) in WM‐ROIs. Noise affects VT variability, although its effect on bias was small (6%). In a worst‐case scenario, ≤6% of simulated data did not fit reliably. A simulation of increased TSPO density exposed minimal effect on variability and identifiability of [18F]‐FEPPA VT in WM‐ROIs. We found no association between age and [18F]‐FEPPA VT in WM‐ROIs. The VT values were 15% higher in HAB than in MAB, although the difference was not statistically significant. This study provides evidence for the utility and limitations of [18F]‐FEPPA PET to measure TSPO expression in WM. Synapse 68:536–547, 2014.

Small vessel disease is linked to disrupted structural network covariance in Alzheimer's disease

Cerebral small vessel disease (SVD) is thought to contribute to Alzheimers disease (AD) through abnormalities in white matter networks. Gray matter (GM) hub covariance networks share only partial overlap with white matter connectivity, and their relationship with SVD has not been examined in AD.

Functional outcome in delusional Alzheimer disease patients. A systematic review.

Background: In spite of the prevalence of delusions in Alzheimer’s disease (AD) and their association with poor outcomes, there has been little study of the impact of delusions on real-world functioning. Method: A number of databases, including Psychlit and Medline, were searched using the keywords: delusions, functional outcomes, activities of daily living, dementia, and Alzheimer’s disease. Studies were included in the review if they were in English, restricted to patients with AD, and addressed delusions and function. Results: The review yielded a total of 6 studies, 3 of which showed a correlation between delusions and real-world functioning and 3 of which did not. Conclusion: A critical analysis of the existing studies suggests that there may be an association between delusions and impaired real-world functioning. We believe that 2 of the 3 negative studies did not show an association due to issues relating to study design and the use of measures insensitive to executive impairment. This review highlights the future need for more scientifically rigorous studies to clarify this association, so as to ultimately improve treatment outcomes for patients.

Amyloid deposition in semantic dementia: a positron emission tomography study

Pittsburgh compound B ([11C]‐PIB) identifies amyloid‐β (Aβ) deposition in vivo. Asymptomatic Aβ deposition has been reported consistently in some healthy older subjects. Of patients with frontotemporal dementia, those who have later onset have a higher potential for Aβ deposition.

Imaging microglial activation and amyloid burden in amnestic mild cognitive impairment

Amnestic mild cognitive impairment (aMCI) is defined as a transitional state between normal aging and Alzheimer’s disease (AD). Given the replicated finding of increased microglial activation in AD, we sought to investigate whether microglial activation is also elevated in aMCI and whether it is related to amyloid beta (Aβ) burden in-vivo. Eleven aMCI participants and 14 healthy volunteers completed positron emission tomography (PET) scans with [18F]-FEPPA and [11C]-PIB. Given the known sensitivity in affinity of second-generation TSPO radioligands, participants were genotyped for the TSPO polymorphism and only high-affinity binders were included. Dynamic [18F]-FEPPA PET images were analyzed using the 2-tissue compartment model with arterial plasma input function. Additionally, a supplementary method, the standardized uptake value ratio (SUVR), was explored. [11C]-PIB PET images were analyzed using the Logan graphical method. aMCI participants had significantly higher [11C]-PIB binding in the cortical regions. No significant differences in [18F]-FEPPA binding were observed between aMCI participants and healthy volunteers. In the aMCI group, [18F]-FEPPA and [11C]-PIB bindings were correlated in the hippocampus. There were no correlations between our PET measures and cognition. Our findings demonstrate that while Aβ burden is evident in the aMCI stage, microglial activation may not be present.

Radiotracer imaging of dopamine transporters and presynaptic dopamine synthesis in parkinsonian syndromes

Both figures increase with age. These figu-res show that IPD is and will be one of the major neurologicalcauses of morbidity, especially with an increasing mean age ofthe population. The development of possible pharmacologicaltreatments to retard the progression of IPD, such as selegilineand dopamine (DA) agonists rather than L-DOPA, has increasedthe need for a reliable outcome measure to assess progressiveloss of the dopaminergic (DAergic) system, to monitor theefficacy of treatment and to diagnose the disease during thepreclinical phase so that treatments can be implemented beforeirreversible loss of DAergic neurons occurs.

INVESTIGATING BIOMARKERS OF AGITATION IN MODERATE-TO-SEVERE ALZHEIMER’S DISEASE PATIENTS ENROLLED IN A RANDOMIZED CONTROLLED TRIAL WITH NABILONE

neuropathological AD lesions leading to their inclusion into AD criteria. However, these biomarkers are costly and invasive and new simple biomarkers are needed. Several studies have established a link between morphological and functional changes occurring in the monoaminergic ascending system and the physiopathology of AD. Noradrenaline (NA)-containing neurons in the locus coerulus (LC) are the main source of noradrenergic inputs to numerous regions throughout the brain. Due to its widespread efferent inervation, the LC projection system plays a pivotal regulatory role in processes such as stress and maintenance of cognitive performance. Gannon et al. have reported that a significant loss and damage of noradrenergic neurons in LC occurs in AD. Furthermore, O’Bryant et al. have suggested an important contribution of noradrenergic LC dysfunction in AD pathogenesis. In this work we present our preliminary results demonstrating that the simultaneous quantitation of 3 catecholamines (CAs) could be a potential new plasma AD biomarkers.Methods:In this retrospective study, we quantified epinephrine, norepinephrine (NE) and dopamine (DA) levels in plasma from patients investigated for neurocognitive disorders (NC), other neurological diseases without dementia (CON), and healthy controls (HC) (Montpellier, Paris). All diagnoses were performed according to current diagnostic criteria including neurological examination, neuropsychological tests, brain MRI and CSF biomarkers. CAs quantifications were performed by HPLC coupled with electrochemical detection. A mathematical model was developed to discriminate AD from other neurocognitive diseases, CON and HC. Results: Plasma from 202 participants, including 30 AD, were analyzed. A distinctive CAs signature in AD patients was observed comparatively to NC and CON groups. Significant lower levels in epinephrine and NE were observed, whereas DA was increased. A positive correlation between MMSE score and noradrenaline concentrations was observed. This method displays a good discrimination power regarding AD patients with 80 % in sensitivity and 97 % in specificity. Conclusions:Mathematical scores based on plasma CAs quantitation allowed us to clearly distinguish AD patients from NC and CON. Large prospective studies are needed to confirm that CAs are blood biomarkers for the screening of AD. 1. Simic G, Stanic G,Mladinov M, Jovanov-Milosevic N, Kostovic I, Hof PR. Does Alzheimer’s disease begin in the brainstem?: Annotation. Neuropathol Appl Neurobiol. 2009;35(6):532-554. https://doi.org/10.1111/j. l365-2990.2009.01038.x. 2. Trillo L, Das D, Hsieh W, et al. Ascending monoaminergic systems alterations in Alzheimer’s disease. Translating basic science into clinical care. Neurosci Biobehav Rev. 2013;37(8):1363-1379. https://doi.org/10.1016/j.neubiorev. 2013.05.008. 3. Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci. 2009;10(3):211-223. https:// doi.org/10.1038/nrn2573. 4. Gannon M, Che P, Chen Y, Jiao K, Roberson ED, Wang Q. Noradrenergic dysfunction in Alzheimer’s disease. Front Neurosci. 2015;9(JUN):1-12. https://doi.org/10.3389/ fnins.2015.00220. 5. O’Bryant SE, Edwards M, Johnson L, et al. A blood screening test for Alzheimer’s disease. Alzheimer’s Dement Diagnosis, Assess Dis Monit. 2016;3:83-90. https://doi.org/10.1016/ J.DADM.2016.06.004. P3-250 INVESTIGATING BIOMARKERS OF AGITATION IN MODERATE-TO-SEVERE ALZHEIMER’S DISEASE PATIENTS ENROLLED IN A RANDOMIZED CONTROLLED TRIALWITH NABILONE Myuri Ruthirakuhan, Nathan Herrmann, Ana C. Andreazza, Nicolaas Paul L. G. Verhoeff, Damien Gallagher, Sandra E. Black, Krista L. Lanctot, Sunnybrook Research Institute, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada; Neuropsychopharmacology Research Group, Toronto, ON, Canada; Baycrest Hospital, Toronto, ON, Canada; Sunnybrook Health Sciences Centre, Toronto, ON, Canada. Contact e-mail: rutmyuri@sri.utoronto.ca