Towards a Novel Treatment of Huntington´s Disease

The function of the human brain is based on complex interactions between billions of neurons. The brain function declines as a result of normal aging, but is also disturbed in neuropsychiatric and neurodegenerative disorders. Huntington’s disease is a hereditary autosomal-dominant neurodegenerative disorder that manifests with a complex range of symptoms resulting in severe motor deficiencies, cognitive decline, behavioral disturbances, and premature death. To date, no preventive, disease-modifying, or even symptomatic therapy exists. Normal function of the brain is maintained by different neurotransmitters, which act through their receptors. One such example is the monoamine neurotransmitter dopamine, which plays a central role in normal brain function. The dopamine system is involved in a wide range of functions such as motor function, reward, cognition and emotion, and is importantly connected to the modulation of glutamate functions in the brain. There is evidence that dopaminergic systems are disturbed in Huntington’s disease, and that the delicate balance between dopamine and glutamate interplay is disrupted in the disorder. Dopaminergic stabilizers belong to a novel class of CNS compounds that can both enhance and counteract psychomotor activity depending on the initial level. Such effects are believed to be mediated by state dependent modulation of monoaminergic and glutamatergic functions. One such compound, pridopidine (ACR16), is currently in development for the treatment of Huntington’s disease. The aim of this thesis was to better understand the physiopharmacology of dopaminergic stabilizers and to investigate their effects in healthy subjects and patients with Huntington’s disease. To explore the possibilities for this therapy in Huntington’s disease, three experimental studies using positron emission tomography were undertaken. These studies yielded a number of findings. It could be shown that the extrastriatal density of dopamine D2 receptors is well preserved in patients with Huntington’s disease. This finding has implications for pridopidine therapy since the D2 receptor is believed to be the primary target receptor for the compound. In addition, it was shown that in patients with Huntington’s disease, pridopidine treatment induced general state dependent changes in cerebral metabolic activity, and increases in cerebral metabolic activity in brain regions believed to be important for mediating compensatory mechanisms in the disorder. In another study elucidating the mechanisms of action of dopaminergic stabilizers in healthy subjects, it could be shown that a single dose of the compound produced modest reductions in the availability of striatal dopamine D2 receptors, and more marked fluctuations in the availability of cortical and striatal dopamine D1 receptors. The results from this mechanistic study suggest that dopaminergic stabilizers exert their glutamate modulating properties via indirect effects of dopamine D1 receptors. Moreover, in the framework of this thesis, an overview of available imaging biomarkers to study the progression of Huntington’s disease is presented, providing guidance for methods to be applied in studies aimed at modifying disease progressio

High seroprevalence of SARS-CoV-2 in elderly care employees in Sweden

The COVID-19 pandemic is growing and spread in the Swedish elderly care system during April 2020. The increasing number of employees on sick-leave due to COVID-19 created severe logistic problems. Some elderly care homes therefore started to screen their personnel to secure the safety of the elderly and to avoid unnecessary quarantine of potentially immune employees. Secondary data from a screening with a COVID-19 rapid test for detection of SARS-CoV-2-specific IgM and IgG of 1,005 employees in 22 elderly care homes in Stockholm, Sweden, were analyzed. Seropositive employees were found in 21 out of the 22 care homes. In total, 23% (231/1,005) of the employees tested positive for antibodies against SARS-CoV-2, and 14.3% (144/1,005) were found positive for IgM (either alone or combined with IgG), indicating recent or present infection. Of those that tested seropositive, 46.5% did not report any clinical symptoms, indicating pre- or asymptomatic infections. Reported symptoms with the highest correlation with seropositivity were fever and loss of smell and taste. These results suggest that antibody testing of employees in elderly care homes is valuable for surveillance of disease development and a crucial screening tool in the effort to decrease the death toll in this pandemic

Evaluation of a COVID-19 IgM and IgG rapid test; an efficient tool for 4 assessment of past exposure to SARS-CoV-2

COVID-19 is the most rapidly growing pandemic in modern time, and the need for 21 serological testing is most urgent. Although the diagnostics of acute patients by RT-PCR is 22 both efficient and specific, we are also crucially in need of serological tools for investigating 23 antibody responses and assessing individual and potential herd immunity. We evaluated a 24 commercially available test developed for rapid (within 15 minutes) detection of SARS-CoV-25 2-specific IgM and IgG by 29 PCR-confirmed COVID-19 cases and 124 negative controls. 26 The results revealed a sensitivity of 69.0 % and 93.1 % for IgM and IgG, respectively, based 27 solely on PCR-positivity due to the absence of a serological gold standard. The assay 28 specificities were shown to be 100 % for IgM and 99.2 % for IgG. This indicates that the test 29 is suitable for assessing previous virus exposure, although negative results may be unreliable 30 during the first weeks after infection. More detailed studies on antibody responses during and 31 post infection are urgently needed

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P <.001). Overall motor and cognitive performance (P <.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P <.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P <.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P <.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients