We have not heard much about synaptophysin but now in the primate study, there was a clear finding that synaptophysin increased by ATH434 at the same time when iron content was down and when motor activity improved.

This new paper from Netherlands looks at cadaver population differences in synaptic density in PD, PD with dementia, and dementia with Lewy bodies in comparison to controls.

In their conclusion, they say: "Synaptic neurodegeneration occurs 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 of synaptic loss with disease progression and cognitive impairment, indicate that regional synaptic loss may underlie clinical heterogeneity in PD(D) and DLB".

Seems that the primate study results could offer some future help not only in PD but also in Lewy body disease, A lot of new clinical studies are needed after ATH434 is on the market.

Acta Neuropathol Commun

. 2024 Jan 3;12(1):4.

doi: 10.1186/s40478-023-01711-w.

Regional differences in synaptic degeneration are linked to alpha-synuclein burden and axonal damage in Parkinson's disease and dementia with Lewy bodies

Irene Frigerio ^{1 2 3}, Maud M A Bouwman ^{4 5 6}, Ruby T G M M Noordermeer ⁴, Ema Podobnik ⁴, Marko Popovic ⁷, Evelien Timmermans ⁴, Annemieke J M Rozemuller ⁸, Wilma D J van de Berg ^{4 5}, Laura E Jonkman ^{4 5 6}

Affiliations expand

• PMID: 38173031

PMCID: PMC10765668 DOI: 10.1186/s40478-023-01711-wFree PMC article

Abstract

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.