Wilma D.J. van de Berg

Longterm quiescent cells in the aged human subventricular neurogenic system specifically express GFAP-delta.

A main neurogenic niche in the adult human brain is the subventricular zone (SVZ). Recent data suggest that the progenitors that are born in the human SVZ migrate via the rostral migratory stream (RMS) towards the olfactory bulb (OB), similar to what has been observed in other mammals. A subpopulation of astrocytes in the SVZ specifically expresses an assembly‐compromised isoform of the intermediate filament protein glial fibrillary acidic protein (GFAP‐δ). To further define the phenotype of these GFAP‐δ expressing cells and to determine whether these cells are present throughout the human subventricular neurogenic system, we analysed SVZ, RMS and OB sections of 14 aged brain donors (ages 74‐93). GFAP‐δ was expressed in the SVZ along the ventricle, in the RMS and in the OB. The GFAP‐δ cells in the SVZ co‐expressed the neural stem cell (NSC) marker nestin and the cell proliferation markers proliferating cell nuclear antigen (PCNA) and Mcm2. Furthermore, BrdU retention was found in GFAP‐δ positive cells in the SVZ. In the RMS, GFAP‐δ was expressed in the glial net surrounding the neuroblasts. In the OB, GFAP‐δ positive cells co‐expressed PCNA. We also showed that GFAP‐δ cells are present in neurosphere cultures that were derived from SVZ precursors, isolated postmortem from four brain donors (ages 63‐91). Taken together, our findings show that GFAP‐δ is expressed in an astrocytic subpopulation in the SVZ, the RMS and the OB. Importantly, we provide the first evidence that GFAP‐δ is specifically expressed in longterm quiescent cells in the human SVZ, which are reminiscent of NSCs.

CSF α-Synuclein Does Not Discriminate Dementia with Lewy Bodies from Alzheimer's Disease

In this study, we assessed whether cerebrospinal fluid (CSF) levels of the biomarker α-synuclein have a diagnostic value in differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimers disease (AD). We also analyzed associations between CSF biomarkers and cognitive performance in DLB and in AD. We included 35 DLB patients, 63 AD patients, 18 patients with Parkinsons disease (PD), and 34 patients with subjective complaints (SC). Neuropsychological performance was measured by means of the Mini-Mental Status Examination (MMSE), Visual Association Test (VAT), VAT object-naming, Trail Making Test, and category fluency. In CSF, levels of α-synuclein, amyloid-β 1-42 (Aβ1-42), total tau (tau), and tau phosphorylated at threonine 181 (ptau-181) were measured. CSF α-synuclein levels did not differentiate between diagnostic groups (p=0.16). Higher ptau-181 and higher tau levels differentiated AD from DLB patients (p< 0.05). In DLB patients, lower Aβ1-42 and higher total tau levels were found than in SC and PD patients (p< 0.05). In DLB patients, linear regression analyses of CSF biomarkers showed that lower α-synuclein was related to lower MMSE-scores (β (SE) = 6(2) and p< 0.05) and fluency (β (SE) = 4(2), p< 0.05). Ultimately, CSF α-synuclein was not a useful diagnostic biomarker to differentiate DLB and/or PD (α-synucleinopathies) from AD or SC. In DLB patients maybe lower CSF α-synuclein levels are related to worse cognitive performance.

Clusterin Levels in Plasma Predict Cognitive Decline and Progression to Alzheimer’s Disease

BACKGROUND Increased clusterin levels have been reported in brain, cerebrospinal fluid (CSF), and plasma of Alzheimers disease (AD) patients. Because changes are also observed in mild cognitive impairment (MCI), a possible relationship between clusterin levels and early neurodegenerative changes in AD was suggested. OBJECTIVES To determine whether clusterin concentrations could 1) serve as a diagnostic marker for AD, 2) predict disease progression in MCI, and 3) correlate with AD-biomarkers. METHODS Clusterin levels in CSF and plasma, as well as AD biomarker levels of Aβ42, Tau, and pTau in CSF and Mini-Mental State Examination scores (MMSE) were determined in 67 controls, 50 MCI, and 107 AD patients. Repeated MMSE was obtained for 44 MCI and 72 AD patients after, on average, 2.7 years. RESULTS Elevated clusterin concentrations in plasma, but not in CSF, were a risk factor for AD (HR 18.6; 95% CI 2.8-122), and related to cognitive decline in MCI (r =-0.38; p <  0.01). An inverse relation between plasma clusterin levels and cognitive decline was observed in AD patients (r = 0.23; p≤0.05). In CSF, but not in plasma, clusterin levels correlated with Tau and pTau in all groups. CONCLUSION Elevated plasma clusterin levels in MCI confer an increased risk for progression to AD, and more rapid cognitive decline. We speculate that clusterin levels in CSF may reflect its involvement in the earliest neurodegenerative processes associated with AD pathology. Whereas neither clusterin levels in CSF nor in plasma had diagnostic value, plasma clusterin levels may serve as a prognostic marker for AD.

Morphometric Changes in the Cortical Microvascular Network in Alzheimer's Disease

Alzheimers disease (AD) pathology is accompanied by abnormalities of the microvasculature. Despite the potential importance of morphometric changes in the cortical capillary network on neuronal dysfunction and cognitive impairment, few autopsy studies have addressed this issue. In the present study, we investigated morphological microvascular changes and capillary length density (CLD) in ten well-characterized AD patients compared to ten age-matched controls using virtual isotropic hemispheres. The CLD in the temporal cortex was increased by 33% in AD patients compared to controls (p=0.04), whereas CLD in the occipital cortex was unchanged. An increase of CLD was correlated to a decrease of cortical diameter in the temporal cortex (Pearsons r -0.62, p=0.003), suggesting that the increase in temporal CLD results from, or contributes to cortical atrophy. In the occipital cortex, more string vessels, probably remnants of degenerated capillaries, were observed in AD patients than in controls (p=0.004). An exploratory analysis suggests co-localization of Aβ and string vessels. Our data indicate that morphometric changes in the cortical capillary network occur in AD in a region-specific manner and may be related to cortical atrophy in the affected regions.

An update on the genetics of dementia with Lewy bodies

The genetic architecture of dementia with Lewy bodies (DLB) is increasingly taking shape. Initially, genetic research focused mainly on linkage and candidate gene studies in small series of DLB patients. More recently, association and exome sequencing studies in larger groups have been conducted, and have shown that several variants in GBA and the APOE ε4 allele are important genetic risk factors for DLB. However, genetic research in DLB is still in its infancy. So far, many genetic studies have been biased and performed in clinically and pathologically heterogeneous populations. Therefore, it is likely that multiple DLB-specific genetic determinants still have to be identified. To further our understanding of the role of genetics in DLB, future genetic studies should be unbiased and performed in large series of DLB patients, ideally with both a clinical diagnosis and pathological confirmation. The combination of genomic techniques with other research modalities, such as proteomic research, is a promising approach to identify novel genetic determinants. More knowledge about the genetics of DLB will increase our understanding of the pathophysiology of the disease and its relation with Parkinsons Disease and Alzheimers Disease, and may eventually lead to the development of disease modifying treatments.

Loss of Functional Connectivity in Patients with Parkinson Disease and Visual Hallucinations

Purpose To gain more insight into the pathophysiological mechanisms of visual hallucinations (VHs) in patients with Parkinson disease (PD) by analyzing whole-brain resting-state functional connectivity in PD patients with VH (hereafter, referred to as PD + VH patients) and without VH (hereafter, referred to as PD - VH patients) and control participants. Materials and Methods For this retrospective study, 15 PD + VH patients, 40 PD - VH patients, and 15 control participants from a prospective cohort study were included, which was approved by the local ethics board and written informed consent was obtained from all participants. Functional connectivity was calculated between 47 regions of interests, of which whole-brain and region-specific means were compared by using a general linear model with false discovery rate control for multiple comparisons. Results Whole-brain mean functional connectivity was significantly lower in PD patients compared with control participants, with regional decreases involving paracentral and occipital regions in both PD + VH and PD - VH patients (mean whole-brain functional connectivity in PD + VH vs PD - VH, 0.12 ± 0.01 [standard deviation] vs 0.14 ± 0.03, respectively; control participants, 0.15 ± 0.04; P < .05, corrected). In PD + VH patients, nine additional frontal, temporal, occipital, and striatal regions showed decreased functional connectivity compared with control participants (mean of these nine regions in PD + VH, PD - VH, and control participants: 0.12 ± 0.02, 0.14 ± 0.03, and 0.16 ± 0.04, respectively; P < .05, corrected). Resting-state functional connectivity was unrelated to motor performance (r = 0.182; P = .184) and related to cognitive deficits such as attention and perception (ρ, -0.555 and -0.558, respectively; P < .05). Conclusion The findings show a PD-related effect on resting-state functional connectivity of posterior and paracentral brain regions, whereas the presence of VH is associated with a more global loss of connectivity, related to attention and perception. These findings suggest that the pathophysiological mechanisms of VH in PD may include a global loss of network efficiency, which could drive disturbed attentional and visual processing.

LOWER STRUCTURAL DEGREE AND HIGHER LOCAL EFFICIENCY RELATED TO DIFFUSE AMYLOID-BETA LOAD IN CORTEX OF NON-NEUROLOGICAL AGED DONORS

investigate the extent to which plaque formation interferes with the expression and polarisation of this channel. Conclusions:These preliminary findings in the J20 mouse suggest that early plaque formation has limited impact on these dynamic MRI measures of glymphatic inflow, in the absence of observable neurodegeneration. Comparison of the current data to quantification of glymphatic function in other mouse models of amyloid pathology (the APP/ PS1 mouse [Peng et.al.,NuerB.ofDis.,2016]) suggests that amyloid induced glymphatic changes may differ between genetic strain and harbouring mutations. Together our data suggest that glymphatic impairment during early disease development warrants further investigation.

ALPHA-SYNUCLEIN SPECIES AS POTENTIAL CSF BIOMARKERS FOR DEMENTIA WITH LEWY BODIES

Background: The discovery of alpha-synuclein (a-syn) as a major component of Lewy bodies lead to the idea that a-syn could be a potential cerebrospinal fluid (CSF) biomarker for dementia with Lewy bodies (DLB). So far, studies measuring CSF total a-syn have yielded conflicting results. However, recent studies showed that a combination of CSF a-syn species may improve the diagnostic value of a-syn in synucleinopathies. In this study we assessed the diagnostic value of different CSF a-syn species (total-, oligomericand pS129-a-syn) for DLB. Methods:We measured the levels of CSF a-syn species in DLB (n=42), Alzheimers disease (AD) (n=39), Parkinsons disease (PD) (n=46), subjective cognitive decline (SCD) (n=31) and healthy controls (HC) (n=48) using newly developed ELISAs (Majbour et al., 2016). Linear regression analysis corrected for age and gender were performed to assess differences in a-syn levels between diagnostic groups. In addition, we used receiver operation characteristic (ROC) analysis and logistic regression analysis to determine the diagnostic accuracy between DLB and AD and between DLB and controls (SCD + HC) of (the combination of) the a-syn biomarker(s). Results: The levels of total- a-syn in CSF were decreased in DLB (1.48+/-0.08ng/ml) and PD (1.41+/-0.05ng/ml) compared to AD (2.14+/-0.14ng/ml, p

DIFFERENT PATHOLOGICAL DISTRIBUTION PATTERN OF PHOSPHORYLATED TAU AND MICROGLIA IN AMNESTIC AND NON-AMNESTIC ALZHEIMER’S DISEASE

have higher dementia prevalence, different genetic markers and higher vascular risk factors. However, pathological underpinnings are unknown. Methods:We included 111 AA demented autopsies and 444 random Caucasians autopsies and compared the two groups regarding demographics, cognition, apolipoprotein E (ApoE), comorbidities including cerebrovascular pathology and Lewy body disease (LBD), clinical and pathological diagnoses, neuropathological Alzheimer disease (AD) criteria, quantitative Ab and tau scales, neuropathological vascular findings and nonAlzheimer diseases. Results:When comparing AA and Caucasians the primary clinical diagnoses differed but the primary pathological diagnoses did not. Importantly, there is evidence that AA had more AD-related pathology, measured as meeting the NIA/Reagan and CERAD criteria and throughAD neuropathological features (Braak Stage, CERAD neuritic and diffuse plaque scores). ApoE 4 was more common in AA than Caucasians. There were significant differences vascular, LBD and TDP pathology. Conclusions: Primary pathological diagnosis does not differ between groups however AD, LBD and vascular pathology are more common in AA and TDP and Tau less common. ApoE accounts for most of the AD pathology scales differences. These similarities and differences are important in public policy.