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In Parkinson’s disease (PD), α-synuclein aggregation in striatal synapses is hypothesised to trigger a cascade of events leading to synaptic loss and cortical Lewy body (LB) pathology. Using multiplex immunofluorescence and confocal microscopy on 69 brains spanning Braak stages 0–6—including controls, incidental LB disease (iLBD), and PD—we show that phosphorylated (pSer129) α-synuclein is enriched in putaminal dopaminergic synapses already in early disease stages, and associates with dopaminergic terminal loss. C-terminally truncated (CTT122) α-synuclein shows a similar trend in later stages. Enrichment of pSer129 and CTT122 α-synuclein in cortical glutamatergic synapses in the putamen occurs prior to LB appearance in cortical regions, supporting the theory of α-synuclein retrograde transport from synapse to cell body. Using AlphaLISA, we confirm that isolated PD putaminal synaptosomes contain higher pSer129 α-synuclein protein levels compared to controls. These findings suggest that synaptic enrichment of pSer129 α-synuclein occurs in early PD, possibly contributing to dopaminergic denervation and cortical LB pathology. α-Synuclein accumulation in putaminal synapses is hypothesised to drive Parkinson’s disease progression. This study demonstrates synaptic pSer129 α-synuclein enrichment in early-stage Parkinson’s disease, and its link with dopaminergic denervation and cortical Lewy body pathology.

Background Degeneration of the locus coeruleus (LC) noradrenergic system contributes to clinical symptoms in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Diffusion magnetic resonance imaging (MRI) has the potential to evaluate the integrity of the LC noradrenergic system. The aim of the current study was to determine whether the diffusion MRI-measured integrity of the LC and its tracts are sensitive to noradrenergic degeneration in AD and PD. Methods Post-mortem in situ T1-weighted and multi-shell diffusion MRI was performed for 9 AD, 14 PD, and 8 control brain donors. Fractional anisotropy (FA) and mean diffusivity were derived from the LC, and from tracts between the LC and the anterior cingulate cortex, the dorsolateral prefrontal cortex (DLPFC), the primary motor cortex (M1) or the hippocampus. Brain tissue sections of the LC and cortical regions were obtained and immunostained for dopamine-beta hydroxylase (DBH) to quantify noradrenergic cell density and fiber load. Group comparisons and correlations between outcome measures were performed using linear regression and partial correlations. Results The AD and PD cases showed loss of LC noradrenergic cells and fibers. In the cortex, the AD cases showed increased DBH + immunoreactivity in the DLPFC compared to PD cases and controls, while PD cases showed reduced DBH + immunoreactivity in the M1 compared to controls. Higher FA within the LC was found for AD, which was correlated with loss of noradrenergic cells and fibers in the LC. Increased FA of the LC-DLPFC tract was correlated with LC noradrenergic fiber loss in the combined AD and control group, whereas the increased FA of the LC-M1 tract was correlated with LC noradrenergic neuronal loss in the combined PD and control group. The tract alterations were not correlated with cortical DBH + immunoreactivity. Conclusions In AD and PD, the diffusion MRI-detected alterations within the LC and its tracts to the DLPFC and the M1 were associated with local noradrenergic neuronal loss within the LC, rather than noradrenergic changes in the cortex.

Regional differences in synaptic degeneration may underlie differences in clinical presentation and neuropathological disease progression in Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB). Here, we mapped and quantified synaptic degeneration in cortical brain regions in PD, PD with dementia (PDD) and DLB, and assessed whether regional differences in synaptic loss are linked to axonal degeneration and neuropathological burden. We included a total of 47 brain donors, 9 PD, 12 PDD, 6 DLB and 20 non-neurological controls. Synaptophysin + and SV2A + puncta were quantified in eight cortical regions using a high throughput microscopy approach. Neurofilament light chain (NfL) immunoreactivity, Lewy body (LB) density, phosphorylated-tau and amyloid-β load were also quantified. Group differences in synaptic density, and associations with neuropathological markers and Clinical Dementia Rating (CDR) scores, were investigated using linear mixed models. We found significantly decreased synaptophysin and SV2A densities in the cortex of PD, PDD and DLB cases compared to controls. Specifically, synaptic density was decreased in cortical regions affected at Braak α-synuclein stage 5 in PD (middle temporal gyrus, anterior cingulate and insula), and was additionally decreased in cortical regions affected at Braak α-synuclein stage 4 in PDD and DLB compared to controls (entorhinal cortex, parahippocampal gyrus and fusiform gyrus). Synaptic loss associated with higher NfL immunoreactivity and LB density. Global synaptophysin loss associated with longer disease duration and higher CDR scores. Synaptic neurodegeneration occurred in temporal, cingulate and insular cortices in PD, as well as in parahippocampal regions in PDD and DLB. In addition, synaptic loss was linked to axonal damage and severe α-synuclein burden. These results, together with the association between synaptic loss and disease progression and cognitive impairment, indicate that regional synaptic loss may underlie clinical differences between PD and PDD/DLB. Our results might provide useful information for the interpretation of synaptic biomarkers in vivo.

The abnormal accumulation of alpha-Synuclein (αSyn) within neurons is a hallmark of synucleinopathies, such as Parkinson's disease (PD), and could stem from impaired protein degradation. Genetic, in vitro, and post-mortem studies have suggested that lysosomal dysfunction and impaired proteolytic activity play important roles in the pathogenesis of PD. Lysosomes have been proposed as key sites for αSyn degradation, but direct evidence of the lysosomal localization of endogenous αSyn in the human brain is limited. This study aimed to investigate the localization of αSyn proteoforms, including different post-translational modifications (PTMs), within lysosomes of post-mortem human nigral neurons. We analyzed formalin-fixed, paraffin-embedded brain tissue from donors diagnosed with PD, PD with Dementia (PDD) or incidental Lewy body disease (iLBD). Substantia nigra sections were assessed using an extensive panel of αSyn-specific antibodies, including PTM-specific antibodies, and selected lysosomal markers via multiplex immunofluorescence, confocal and stimulated emission depletion (STED) microscopy. Here, we demonstrate widespread accumulation of αSyn within lysosomes in nigral dopaminergic neuron somas of donors with PD/PDD and iLBD. This lysosomal αSyn appeared morphologically distinct from cytosolic inclusions such as Lewy bodies (LBs) and related macro-aggregates, and was present both in cells with and without these larger αSyn deposits. When present, macro-aggregates were consistently accompanied by ring-shaped lysosomal structures. Compared to other neuronal morphologies, lysosomal αSyn was the most frequent morphology at early Braak stages (1–4), with a decline at later stages (5–6). Interestingly, lysosomal αSyn was detected solely by targeting the N-terminus or the NAC domain of αSyn, and not with antibodies targeting Serine 129-phosphorylated αSyn or other epitopes at the C-terminus (CT), suggesting that lysosome-associated αSyn lacks the CT. Our findings reveal two co-existing pools of neuronal somatic αSyn: a CT-negative lysosome-associated form, and a primarily non-lysosomal CT-positive form. Overall, we provide direct evidence of lysosomal involvement in cellular αSyn metabolism in post-mortem human PD brain.

Background The hippocampus is highly affected in neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). The relationship between neuropathology and atrophy in hippocampal subfields is complex due to differences in the selective neuronal vulnerability to distinct protein aggregates that underlie cognitive impairment. The aim of the current study was to investigate the relation between hippocampal subfield volumes, neuropathological burden (amyloid-β, p-tau and α-synuclein) and cognitive performance in AD, PD and control brain donors, using a cross-disease and within-subject post-mortem in situ MRI and neuropathology approach. Methods A total of 60 brain donors, including 14 non-neurological controls, 27 AD and 19 PD, underwent post-mortem in situ MRI. From 3D-T1 images hippocampal subfield and entorhinal cortex volumes were derived using FreeSurfer-based subfield segmentation. Hippocampal tissue was obtained at subsequent autopsy, fixed and immunostained for amyloid-β, p-tau and pSer129-αSyn. Immunoreactivity in hippocampal subfields was quantified as area% load using QuPath. Clinical Dementia Rating scores were extracted from the clinical files when available. Results AD showed atrophy and increased p-tau, but not amyloid-β, burden in the CA1, subiculum and entorhinal cortex compared to controls, however MRI and neuropathology did not correlate. Controls and PD had similar hippocampal subfield volumes and pathology load. In PD, p-tau pathology, rather than pSer129-αSyn, was associated with lower total hippocampal volume ( r =-0.68, p  = 0.045), predominantly in PD with dementia (PDD) ( r =-0.99, p  = 0.013). Cross-disease, volume loss of the subiculum ( r=- 0.68, p =  0.001) and entorhinal cortex ( r=- 0.73, p =  0.004) strongly associated with cognitive impairment. Moreover, p-tau pathology had the strongest effect on subfield atrophy, most pronounced in the subiculum ( β=-0.570 , p  < 0.001), but could only explain 22–44% of the volumetric variance. Conclusions Even though p-tau was the strongest predictor of hippocampal subfield atrophy, AD-pathology (p-tau and amyloid-β) only partially accounted for volumetric differences in hippocampal subfields, highlighting the significance of other pathologies or mechanisms. The increased sensitivity of subicular and entorhinal cortical atrophy compared to total hippocampal atrophy highlights the potential clinical value of incorporating hippocampal subfield atrophy in monitoring disease progression.

Background Increased neurofilament levels in biofluids are commonly used as a proxy for neurodegeneration in several neurodegenerative disorders. In this study, we aimed to investigate the distribution of neurofilaments in the cerebral cortex of Parkinson’s disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) donors, and its association with pathology load and MRI measures of atrophy and diffusivity. Methods Using a within-subject post-mortem MRI-pathology approach, we included 9 PD, 12 PDD/DLB and 18 age-matched control donors. Cortical thickness and mean diffusivity (MD) metrics were extracted respectively from 3DT1 and DTI at 3T in-situ MRI. After autopsy, pathological hallmarks (pSer129-αSyn, p-tau and amyloid-β load) together with neurofilament light-chain (NfL) and phosphorylated-neurofilament medium- and heavy-chain (p-NfM/H) immunoreactivity were quantified in seven cortical regions, and studied in detail with confocal-laser scanning microscopy. The correlations between MRI and pathological measures were studied using linear mixed models. Results Compared to controls, p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB, whereas NfL immunoreactivity was increased in the parahippocampal and entorhinal cortex in PDD/DLB. NfL-positive neurons showed degenerative morphological features and axonal fragmentation. The increased p-NfM/H correlated with p-tau load, and NfL correlated with pSer129-αSyn but more strongly with p-tau load in PDD/DLB. Lastly, neurofilament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB. Conclusions Taken together, increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increased pathological burden. Importantly, we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process.

Background The hippocampus is highly vulnerable to amyloid‐b (Aβ) and phosphorylated tau (p‐tau), and shows synaptic loss in Alzheimer’s disease (AD). Moreover, the loss of synapses correlates strongly with cognitive decline and leads to neuronal network dysfunction. Here, we aim to map the selective synaptic loss in hippocampal and parahippocampal subregions in AD and its association to the severity of neuropathology, axonal damage and cognitive decline. Method We included (para)hippocampal tissue of 26 AD and 17 age‐matched control donors. Synaptophysin puncta was measured using multiple measurements per subregion, distinguishing superficial and deep cortical layers in the parahippocampus. Aβ and p‐tau load, and NfL immunoreactivity were quantified in manually segmented hippocampal and parahippocampal subregions. Clinical Dementia Rating (CDR) scores were retrieved from the clinical reports. Group differences were analysed using linear mixed models and correlations between synaptic and pathological measures and cognitive scores were studied using linear regression, correcting for age, sex and post‐mortem delay. Result The AD (para)hippocampus tended to have a lower synaptic density compared to controls (‐5.6%, p = 0.270). Within hippocampal and parahippocampal subregions, we observed synaptic loss in the entorhinal cortex in AD vs controls (‐8.9%, p = 0.028) and a trend for the subiculum (‐8.8%, p = 0.069) (Fig. 1). Synaptic degeneration was most pronounced in the deeper layers of the enthorinal cortex (layer V‐VI) (Fig. 2). Synaptic loss was not correlated with Aβ and p‐tau load, however higher NfL immunoreactivity associated with synapse loss in the fusiform gyrus (r = ‐0.467, p = 0.008). Synaptic degeneration in the CA1 (r = ‐0.769, p = 0.023), entorhinal cortex (r = ‐0.700, p = 0.035) and fusiform gyrus (r = ‐0.762, p = 0.014) was strongly correlated with higher CDR scores (Fig. 3). Conclusion The entorhinal cortex is vulnerable to synapse degeneration in AD. Moreover, our results confirm the strong relation between (para)hippocampal synaptic loss, axonal damage and cognitive decline in AD, while neuropathological load (Aβ and p‐tau) could not explain differences in vulnerability across donors. These results suggest that the synaptic integrity in these regions seem to be important for cognitive function. A better understanding of the selective vulnerability of hippocampal subregions would provide insight into their intricate connections and functions, underpunning their involvement in cognitive decline.

The hippocampus is highly vulnerable to amyloid-b (Aβ) and phosphorylated tau (p-tau), and shows synaptic loss in Alzheimer's disease (AD). Moreover, the loss of synapses correlates strongly with cognitive decline and leads to neuronal network dysfunction. Here, we aim to map the selective synaptic loss in hippocampal and parahippocampal subregions in AD and its association to the severity of neuropathology, axonal damage and cognitive decline. We included (para)hippocampal tissue of 26 AD and 17 age-matched control donors. Synaptophysin puncta was measured using multiple measurements per subregion, distinguishing superficial and deep cortical layers in the parahippocampus. Aβ and p-tau load, and NfL immunoreactivity were quantified in manually segmented hippocampal and parahippocampal subregions. Clinical Dementia Rating (CDR) scores were retrieved from the clinical reports. Group differences were analysed using linear mixed models and correlations between synaptic and pathological measures and cognitive scores were studied using linear regression, correcting for age, sex and post-mortem delay. The AD (para)hippocampus tended to have a lower synaptic density compared to controls (-5.6%, p = 0.270). Within hippocampal and parahippocampal subregions, we observed synaptic loss in the entorhinal cortex in AD vs controls (-8.9%, p = 0.028) and a trend for the subiculum (-8.8%, p = 0.069) (Fig. 1). Synaptic degeneration was most pronounced in the deeper layers of the enthorinal cortex (layer V-VI) (Fig. 2). Synaptic loss was not correlated with Aβ and p-tau load, however higher NfL immunoreactivity associated with synapse loss in the fusiform gyrus (r = -0.467, p = 0.008). Synaptic degeneration in the CA1 (r = -0.769, p = 0.023), entorhinal cortex (r = -0.700, p = 0.035) and fusiform gyrus (r = -0.762, p = 0.014) was strongly correlated with higher CDR scores (Fig. 3). The entorhinal cortex is vulnerable to synapse degeneration in AD. Moreover, our results confirm the strong relation between (para)hippocampal synaptic loss, axonal damage and cognitive decline in AD, while neuropathological load (Aβ and p-tau) could not explain differences in vulnerability across donors. These results suggest that the synaptic integrity in these regions seem to be important for cognitive function. A better understanding of the selective vulnerability of hippocampal subregions would provide insight into their intricate connections and functions, underpunning their involvement in cognitive decline.

Background Recent studies highlight distinct patterns of cortical atrophy between amnestic (typical) and non‐amnestic (atypical, with subtypes: behavioural, dysexecutive, logopenic and visuospatial) clinical phenotypes of Alzheimer’s disease (AD). The current study aimed to assess regional MRI patterns of cortical atrophy across AD phenotypes, and their association with amyloid‐beta (Aß), phosphorylated tau (pTau), axonal degeneration (NfL) and microvascular deterioration (COLIV). Method Postmortem In‐situ 3DT1 3T‐MRI data was collected for 33 AD (17 typical, 16 atypical) and 16 control brain donors. Images were segmented and AAL3 atlas regional volumes were obtained using QyScore®. At subsequent autopsy, eight brain regions were selected, immunostained for Aß (4G8), pTau (AT8), Neurofilament‐light (NFL), and Collagen‐IV (COLIV), and quantified using qupath. Group comparisons and volume‐pathology associations were analyzed using linear models and partial correlations with covariates age, sex, postmortem delay, and intracranial volume. Results Compared to controls, AD phenotype groups showed overall lower cortical volume, while only minor volume differences were observed between AD phenotype groups, observed primarily in limbic regions (Figure 1). Across pathological markers, AD phenotype groups showed consistently higher immunoreactivity than controls, while atypical AD showed consistently higher immunoreactivity than typical AD (Figure 2). Moreover, different patterns of pathology could be observed between atypical subtypes (e.g. distinctly higher pTau load in the occipital gyrus of the visuospatial subtype). In typical AD, global volume loss was associated with lower Aß and higher pTau, NFL and COLIV immunoreactivity, while in atypical AD, global volume loss was primarily associated with higher NFL immunoreactivity (Figure 3a). Regionally, AD phenotype differences in atrophy‐pathology association were most pronounced in the (para)hippocampal regions. This distinction was mainly characterized by negative associations for NFL and COLIV, which was only observed in typical AD (Figure 3b‐c). Conclusion Atrophy patterns between AD phenotypes showed only minor differences, potentially attributable to the on average later disease stage of the study cohort. The higher immunoreactivity for pathological markers found in atypical AD might suggest a more severe disease burden. (Para)hippocampal volume decline was associated with axonal and microvascular deterioration in typical AD, but not in the higher pathologically burdened atypical AD group, suggesting a differential susceptibility between AD phenotypes.

Background Recent studies highlight distinct patterns of cortical atrophy between amnestic (typical) and non‐amnestic (atypical, with subtypes: behavioural, dysexecutive, logopenic and visuospatial) clinical phenotypes of Alzheimer’s disease (AD). The current study aimed to assess regional MRI patterns of cortical atrophy across AD phenotypes, and their association with amyloid‐beta (Aβ), phosphorylated tau (pTau), axonal degeneration (NfL) and microvascular deterioration (COLIV). Method Postmortem In‐situ 3DT1 3T‐MRI data was collected for 33 AD (17 typical, 16 atypical) and 16 control brain donors. Images were segmented and AAL3 atlas regional volumes were obtained using QyScore®. At subsequent autopsy, eight brain regions were selected, immunostained for Aβ (4G8), pTau (AT8), Neurofilament‐light (NFL), and Collagen‐IV (COLIV), and quantified using qupath. Group comparisons and volume‐pathology associations were analyzed using linear models and partial correlations with covariates age, sex, postmortem delay, and intracranial volume. Results Compared to controls, AD phenotype groups showed overall lower cortical volume, while only minor volume differences were observed between AD phenotype groups, observed primarily in limbic regions (Fig. 1). Across pathological markers, AD phenotype groups showed consistently higher immunoreactivity than controls, while atypical AD showed consistently higher immunoreactivity than typical AD (Fig. 2). Moreover, different patterns of pathology could be observed between atypical subtypes (e.g. distinctly higher pTau load in the occipital gyrus of the visuospatial subtype). In typical AD, global volume loss was associated with lower Aβ and higher pTau, NFL and COLIV immunoreactivity, while in atypical AD, global volume loss was primarily associated with higher NFL immunoreactivity (Fig. 3a). Regionally, AD phenotype differences in atrophy‐pathology association were most pronounced in the (para) hippocampal regions. This distinction was mainly characterized by negative associations for NFL and COLIV, which was only observed in typical AD (Fig. 3b‐c). Conclusion Atrophy patterns between AD phenotypes showed only minor differences, potentially attributable to the on average later disease stage of the study cohort. The higher immunoreactivity for pathological markers found in atypical AD might suggest a more severe disease burden. (Para) hippocampal volume decline was associated with axonal and microvascular deterioration in typical AD, but not in the higher pathologically burdened atypical AD group, suggesting a differential susceptibility between AD phenotypes.