Abstract Body

MCI in Parkinson's disease (PD) has been a heterogeneous clinical entity caused by various brain pathologies. According to cross-sectional studies, it is present in approximately 25% of all PD patients; attention/executive function deficits seem to be most prevalent. Early cognitive deficits predominantly affect attention and executive functions and result particularly from dopamine depletion in the basal ganglia. The cholinergic system has been implicated in cognitive dysfunction and in PD dementia in particular; serotonergic, glutamatergic, and noradrenergic systems could also be involved. Recent studies have pointed out the impact of metabolic syndrome and its treatment potential in decreasing the risk of cognitive decline in PD. Recommendations for symptomatic treatment with acetylcholinesterase inhibitors and memantine in PD-dementia have been published. Several drugs (e.g. rivastigmine, rasagiline, atomotoxetine) have been tested also in MCI-PD populations in small randomized placebo-controlled studies, however, without any conclusive positive results. Future studies should use specific biomarkers to help to identify distinct PD subgroups that might benefit from potential novel therapies. Non-pharmacological interventions may be beneficial in distinct patient subgroups, including exercise, cognitive training, non-invasive brain stimulation methods, and other techniques to enhance angiogenesis, synaptic plasticity, and neurogenesis. Neuroprotective or disease-modifying drugs for treatment of mild cognitive impairment in PD or even for preclinical stages are awaited.

Aims

To conduct a data-driven exploration of distinct cognitive profiles among patients with Parkinson’s disease dementia (PDD), and characterize these cognitive subtypes with respect to clinical and genetic characteristics as well as biomarkers of Alzheimer’s disease (AD).

Methods

From the Parkinson’s Progression Markers Initiative (PPMI) cohort we identified all individuals with Parkinson’s disease and dementia (N=74). Of these, 51 (69%) were initially enrolled as de novo idiopathic PD and 23 (31%) had a confirmed LRRK2, GBA, or SNCA mutation. Ward’s hierarchical clustering was applied to domain-specific neuropsychological test data, and the derived PDD subgroups were then compared on clinical characteristics, prevalence of genetic mutations, as well as APOE4 genotype and CSF AD biomarkers (available for 44 and 59 patients, respectively).

Results

Clustering identified two distinct PDD subgroups with differing cognitive profiles (Fig. 1). Subgroups did not differ in overall dementia severity (MoCA: 19.7 vs 21.4, p=0.15) and were equally impaired in attention/executive functions, but Cluster-A (N=52, 70%) showed a more pronounced memory impairment, whereas Cluster-B (N=22, 30%) was more selectively impaired in visuospatial skills. Subgroups did not differ in duration or severity of motor symptoms, but Cluster-B trended towards an earlier age at PD onset (60.5 vs 65.3 years, p=0.07) and had a higher proportion of GBA mutation carriers (27% vs 4%, p=0.007). Subgroups did not differ in APOE4 prevalence or CSF amyloid-β or tau levels.

Conclusions

We identified distinct memory-predominant and visuospatial-predominant dementia presentations among PDD patients. These distinct cognitive profiles do not appear to be driven by comorbid AD pathology.

Aims

Parkinson's disease (PD) is a neurodegenerative disease causing deficits in decision‐making. However, the mechanism by which PD affects decisions remains unknown. Computational modeling has been used to study perceptual decisions that are based on sensory evidence and value-based decisions that depend on internal preferences in healthy controls (HCs). Our experiments aimed to characterize decision behavior in PD patients in an on and off dopaminergic state using computational modeling.

Methods

PD patients on and off dopaminergic medication and age‐matched HCs performed a value‐based decision task and made choices between pairs of familiar food items. The value of each item was determined in advance using a separate food‐rating task. The same participants also made perceptual decisions about the color of random dynamic dots with different color coherence. The reaction time (RT) and choice performance in both tasks were measured and fitted with a drift‐diffusion model (DDM).

Results

Our results revealed that patients off‐medication showed similar accuracies to HCs in making value‐based and perceptual decisions but were faster than HCs. Furthermore, patients’ RTs were significantly longer when they were on‐medication and were making value-based decisions but not when making perceptual decisions.

Conclusions

We conclude that the threshold for decision-making is less in patients than HCs, indicating a less deliberative decision process. Moreover, the decision threshold is less when patients are off‐medication than when they are on‐medication, showing that dopaminergic medication increases the decision threshold to allow more deliberation. We propose that dopaminergic medication affects deliberation process by strengthening frontostriatal and hippocampal-striatal connections.

Aims

The relationship between brain atrophy in Parkinson’s disease (PD) and specific CNS cell type distribution is unclear. This study aims to determine whether specific cell type distributions are related to atrophy progression after two and four years in patients enrolled with de novo PD.

Methods

Deformation-based morphometry (DBM) maps computed from 74 PD patients (50 men) T1-weighted MRI at baseline, two and four years, and 157 healthy control (115 men) at baseline in the PPMI database were used as atrophy maps. Then, W-score maps were computed to regress out the expected effect of age and sex. Atrophy differences between time points were compared with rANOVA and the pTFCE approach (p_FWE<.05). To investigate the relationship between regional cell density and atrophy progression, a virtual histology approach with seven cell-class gene expression maps from Seidlitz et al. (2019) were used.

Results

Small clusters of atrophy progression were found after two years in the bilateral temporal gyrus, white matter (WM), left precuneus and right caudate. The progression was more widespread after four years and overlapped with the bilateral WM, temporal, parietal and occipital cortex in addition to the caudate and putamen. Significant correlations were found between the density of endothelial cells and the regional atrophy progression after two (r=-.15, p_spin=.04) and four years (r=-.19, p_spin=.01). The atrophy progression was also significantly correlated with oligodendrocyte density after two (r=-.11, p_spin=.04) and four years (r=-.11, p_spin=.049).

Conclusions

The atrophy in brain regions with higher density of endothelial cells or oligodendrocytes progresses more slowly in de novo Parkinson’s disease.

Abstract Body

Huntington’s disease (HD) has historically been conceptualized as eminently a subcortical dementia due to basal ganglia degeneration. Accordingly, the cognitive domains assumed to be prototypically affected in HD are frontal-executive functions, attention and psychomotor speed. However, compelling evidence proves that, from the early stages of the disease, the pattern of brain atrophy characterising HD extends beyond the basal ganglia and also involves posterior-cortical and temporal regions. Thus, in HD, accurate neuropsychological examination reveals a complex cognitive phenotype not limited to frontal-striatal functions.

In addition to frontal-executive, attention and psychomotor speed disturbances, deficits of different severity at level of visuomotor integration, episodic and autobiographical memory, visual perception, mental rotation, arithmetic reasoning, social cognition and language can be also detected decades before the diagnosis of the disease.

The time of presentation and the pattern of progression of cognitive changes in HD show a relation with the disease burden. However, a marked heterogeneity is also frequently observed between patients sharing equivalent CAG repeat length, education and age. It suggest, that additional mechanisms rather than those driven by disease burden may also contribute to the complex cognitive picture of HD. Ultimately; the progression of cognitive deterioration along HD always associates a significant impact on functional independence to the point of dementia.

Here we review the cognitive aspects of HD, emphasising on the neural substrates of general-to-specific cognitive changes, the affected cognitive domains and processes, the neuropsychological assessment approaches, and the possible mechanisms participating in the differential expression of cognitive deterioration in the HD population.

Aims

Previous MRI studies reported iron accumulation within the striatum of Huntington’s disease (HD). However, the pattern and origin of iron accumulation is poorly understood. This study characterized the histopathological correlates of iron-sensitive ex vivo MRI in HD brains. We delineated the pattern and co-localization of iron with specific cells such as microglia and astrocytes.

Methods

T2*-weighted 7T MRI was performed on postmortem tissue of the striatum of three controls and 10 HD patients followed by histology. In addition, tissue of three controls and 14 HD patients was selected to identify the cellular localization of iron using stainings for iron, myelin, microglia and astrocytes.

Results

Compared to controls, the striatum of HD patients was more hypointense on MRI and showed a more intense histopathological staining for iron. T2*-weighted MRI also identified large focal hypointensities (arrows) within the striatum of HD patients which frequently co-localized with enlarged perivascular spaces (fig1). Microscopically, iron was predominantly found within reactive astrocytes (fig2).

Fig1. Representative T2*-weighted MRI of striatal tissue of two controls and four HD cases. Scale=1cm.

Fig2. Histological examples in two control and three HD striata. The iron staining showed a very similar pattern as the staining for astrocytes.

Scale= 50µm; Scale zoom=25µm.

Conclusions

Ex vivo MRI showed that the HD striatum was characterized by large focal hypointensities that co-localized with enlarged perivascular spaces. Histopathology showed reactive astrocytes as the predominant source of the increase of iron within the striatum. These results are important for the interpretation and understanding of underlying mechanisms of T2*-weighted MRI in HD.

Aims

Background: Pridopidine is a well-tolerated, potent, selective sigma-1 receptor (S1R) agonist. The S1R regulates key cellular processes implicated in neurodegeneration including reducing ER stress and enhancing mitochondrial function. Pridopidine is the first drug to find a beneficial effect on TFC, a validated scale measuring functional capacity that is relevant to both patients and clinicians, in long-term HD trials. In post-hoc analysis of the PRIDE-HD trial, pridopidine 45mg bid had improved TFC scores vs placebo in early HD participants (HD 1+2) at 52 weeks (change from placebo 1.16, nominal p=0.0003). Responder analysis shows that pridopidine reduced the probability of TFC decline (1 or more points) by 80% (nominal p=0.02, week 52). Exploratory endpoints cUHDRS (combined score of cognitive, motor and function; nominal p=0.04) and Q-Motor assessment measuring motor function at 26 and 52 weeks (nominal p=0.02, p=0.195, respectively) also suggest beneficial effects.

Aim: To assess the effect of pridopidine 45mg bid on TFC in patients with early stage HD.

Methods

Design: PROOF-HD is a Phase 3, 65-week, randomized, double-blind, placebo-controlled trial. The primary endpoint is the mean change from baseline to week 65 in TFC. Secondary endpoints include change from baseline in Total Motor Score (TMS), cUHDRS, and Q-Motor to week 65.

Results

The target population is early HD (TFC≥7) participants with an expected TFC decline of -0.8 to -1 points/year.

Conclusions

We use data from prior trials where pridopidine has showed clinically meaningful and nominally significant benefit on endpoints to maximize likelihood of success in the design of the PROOF-HD trial.

Aims

Semaphorin 4D (SEMA4D) is upregulated in neurons and triggers activation of inflammatory glial cells in Huntington’s Disease (HD) and Alzheimer’s Disease (AD). Antibody neutralization of SEMA4D ameliorates neurodegenerative processes in preclinical models, and, in a Phase 2 HD trial, clinical benefit was evaluated.

Objectives: Blocking SEMA4D-induced inflammation to restore normal astrocytic and neuronal function and to delay cognitive deterioration and brain atrophy.

Methods

Preclinical studies investigate effects of SEMA4D on reactive transformation of astrocytes. A randomized placebo-controlled study (SIGNAL) of pepinemab (VX15/2503) in subjects with HD evaluated Clinical Global Impression of Change (CGIC), cognitive and imaging endpoints.

Results

Antibody blockade inhibited reactive astrocyte phenotype and showed beneficial effects on synaptic activity and behavior in a mouse AD model. While the SIGNAL trial did not meet pre-specified endpoints, exploratory analyses revealed a treatment benefit of pepinemab on the HD-Cognitive Assessment Battery Composite Score (p=0.007) in patients with early manifest (EM) disease and, among patients with more advanced disease (total functional capacity=11), treatment reduced deteriorating CGIC status (p=0.04). Finally, volumetric MRI and FDG-PET imaging analysis in EM patients demonstrated reduction in disease-associated atrophy and loss of brain metabolic activity in multiple brain regions.

Conclusions

The mechanism of action of pepinemab in slowing neurodegeneration is believed to be equally applicable to HD and AD. Based on mouse AD model data and exploratory clinical findings in SIGNAL-HD, initiation of a Phase 1b study of pepinemab in AD is planned with partial funding support from the Alzheimer’s Association and from the Alzheimer’s Drug Discovery Foundation.