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1.
Neuropathol Appl Neurobiol ; 44(7): 722-736, 2018 12.
Article in English | MEDLINE | ID: mdl-29676021

ABSTRACT

AIMS: Gastrointestinal (GI) α-synuclein (aSyn) detection as a potential biomarker of Parkinson's disease (PD) is challenged by conflicting results of recent studies. To increase sensitivity and specificity, we applied three techniques to detect different conformations of aSyn in GI biopsies obtained from a longitudinal, clinically well-characterized cohort of PD patients and healthy controls (HC). METHODS: With immunohistochemistry (IHC), we used antibodies reactive for total, phosphorylated and oligomeric aSyn; with aSyn proximity ligation assay (AS-PLA), we targeted oligomeric aSyn species specifically; and with paraffin-embedded tissue blot (AS-PET-blot) we aimed to detect fibrillary, synaptic aSyn. RESULTS: A total of 163 tissue blocks were collected from 51 PD patients (113 blocks) and 21 HC (50 blocks). In 31 PD patients, biopsies were taken before the PD diagnosis (Prodromal); while in 20 PD patients biopsies were obtained after diagnosis (Manifest). The majority of tissues blocks were from large intestine (62%), followed by small intestine (21%), stomach (10%) and oesophagus (7%). With IHC, four staining patterns were detected (neuritic, ganglionic, epithelial and cellular), while two distinct staining patterns were detected both with AS-PLA (cellular and diffuse signal) and with AS-PET-blot (aSyn-localized and pericrypt signal). The level of agreement between different techniques was low and no single technique or staining pattern reliably distinguished PD patients (Prodromal or Manifest) from HC. CONCLUSIONS: Our study suggests that detection of aSyn conformational variants currently considered pathological is not adequate for the diagnosis or prediction of PD. Future studies utilizing novel ultrasensitive amyloid aggregation assays may increase sensitivity and specificity.


Subject(s)
Esophagus/metabolism , Gastric Mucosa/metabolism , Intestinal Mucosa/metabolism , Parkinson Disease/diagnosis , alpha-Synuclein/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers/metabolism , Biopsy , Esophagus/pathology , Female , Gastric Mucosa/pathology , Humans , Intestinal Mucosa/pathology , Male , Middle Aged , Parkinson Disease/metabolism , Parkinson Disease/pathology , Phosphorylation , Protein Conformation
2.
NMR Biomed ; 31(4): e3900, 2018 04.
Article in English | MEDLINE | ID: mdl-29436039

ABSTRACT

Magnetic resonance imaging (MRI) studies in early Parkinson's disease (PD) have shown promise in the detection of disease-related brain changes in the white and deep grey matter. We set out to establish whether intrinsic cortical involvement in early PD can be detected with quantitative MRI. We collected a rich, multi-modal dataset, including diffusion MRI, T1 relaxometry and cortical morphometry, in 20 patients with early PD (disease duration, 1.9 ± 0.97 years, Hoehn & Yahr 1-2) and in 19 matched controls. The cortex was reconstructed using FreeSurfer. Data analysis employed linked independent component analysis (ICA), a novel data-driven technique that allows for data fusion and extraction of multi-modal components before further analysis. For comparison, we performed standard uni-modal analysis with a general linear model (GLM). Linked ICA detected multi-modal cortical changes in early PD (p = 0.015). These comprised fractional anisotropy reduction in dorsolateral prefrontal, cingulate and premotor cortex and the superior parietal lobule, mean diffusivity increase in the mesolimbic, somatosensory and superior parietal cortex, sparse diffusivity decrease in lateral parietal and right prefrontal cortex, and sparse changes to the cortex area. In PD, the amount of cortical dysintegrity correlated with diminished cognitive performance. Importantly, uni-modal analysis detected no significant group difference on any imaging modality. We detected microstructural cortical pathology in early PD using a data-driven, multi-modal approach. This pathology is correlated with diminished cognitive performance. Our results indicate that early degenerative processes leave an MRI signature in the cortex of patients with early PD. The cortical imaging findings are behaviourally meaningful and provide a link between cognitive status and microstructural cortical pathology in patients with early PD.


Subject(s)
Cerebral Cortex/pathology , Cerebral Cortex/physiopathology , Cognitive Dysfunction/physiopathology , Parkinson Disease/pathology , Parkinson Disease/physiopathology , Aging/pathology , Female , Humans , Male , Middle Aged
3.
Neuropathol Appl Neurobiol ; 42(5): 436-50, 2016 08.
Article in English | MEDLINE | ID: mdl-26527105

ABSTRACT

AIMS: Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. METHODS: One hundred and twenty-one cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Aß plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. RESULTS: The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, P < 0.001). The total cortical Aß plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (P = 0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE ϵ4 allele was associated with a higher cortical LB burden (P = 0.02), particularly in the neocortical frontal, parietal and temporal regions. CONCLUSIONS: High CLB burden is a key neuropathological substrate of dementia in LBD. Elevated cortical LB pathology and Aß plaque deposition are both correlated with a faster progression to dementia. The higher CLB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be mediated by the APOE ϵ4 allele.


Subject(s)
Cerebral Cortex/pathology , Dementia/epidemiology , Lewy Bodies/pathology , Lewy Body Disease/pathology , Parkinson Disease/pathology , Adult , Aged , Aged, 80 and over , Amyloid beta-Peptides/metabolism , Dementia/etiology , Dementia/pathology , Female , Humans , Lewy Body Disease/complications , Male , Middle Aged , Parkinson Disease/complications , Prevalence
6.
J Neurol Sci ; 253(1-2): 88-9, 2007 Feb 15.
Article in English | MEDLINE | ID: mdl-17217966

ABSTRACT

Sjogren's syndrome (SS) is a systemic autoimmune disorder, and neurological involvement may frequently occur. Here we describe a 79-year-old woman who came to our attention for a sudden right incomplete 3rd cranial nerve palsy. Following extensive investigations, a diagnosis of primary SS was reached, and the patient recovered after treatment with ev Ig and steroids. Therefore, we suggest that SS should be considered in apparently idiopathic 3rd cranial nerve palsies, since, with the appropriate treatment, they might be transient and reversible.


Subject(s)
Oculomotor Nerve Diseases/diagnosis , Oculomotor Nerve Diseases/etiology , Sjogren's Syndrome/complications , Sjogren's Syndrome/diagnosis , Aged , Diplopia/diagnosis , Diplopia/etiology , Early Diagnosis , Female , Humans
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