Per Borghammer

Bio: Per Borghammer is an academic researcher from Aarhus University Hospital. The author has contributed to research in topics: Parkinson's disease & Medicine. The author has an hindex of 35, co-authored 137 publications receiving 4279 citations. Previous affiliations of Per Borghammer include University of Copenhagen & Centre for Addiction and Mental Health.

Vagotomy and subsequent risk of Parkinson's disease

Abstract: Objective Parkinson's disease (PD) may be caused by an enteric neurotropic pathogen entering the brain through the vagal nerve, a process that may take over 20 years. We investigated the risk of PD in patients who underwent vagotomy and hypothesized that truncal vagotomy is associated with a protective effect, whereas superselective vagotomy has a minor effect. Methods We constructed cohorts of all patients in Denmark who underwent vagotomy during 1977–1995 and a matched general population cohort by linking Danish registries. We used Cox regression to compute hazard ratios (HRs) for PD and corresponding 95% confidence intervals (CIs), adjusting for potential confounders. Results Risk of PD was decreased in patients who underwent truncal (HR = 0.85; 95% CI = 0.56–1.27; follow-up of >20 years: HR = 0.58; 95% CI: 0.28–1.20) compared to superselective vagotomy. Risk of PD was also decreased after truncal vagotomy when compared to the general population cohort (overall adjusted HR = 0.85; 95% CI: 0.63–1.14; follow-up >20 years, adjusted HR = 0.53; 95% CI: 0.28–0.99). In patients who underwent superselective vagotomy, risk of PD was similar to the general population (HR = 1.09; 95% CI: 0.84–1.43; follow-up of >20 years: HR = 1.16; 95% CI: 0.80–1.70). Statistical precision of risk estimates was limited. Results were consistent after external adjustment for unmeasured confounding by smoking. Interpretation Full truncal vagotomy is associated with a decreased risk for subsequent PD, suggesting that the vagal nerve may be critically involved in the pathogenesis of PD. Ann Neurol 2015;78:522–529

Gastrointestinal Dysfunction in Parkinson’s Disease

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disease. Patients show deposits of pathological, aggregated α-synuclein not only in the brain but throughout almost the entire length of the digestive tract. This gives rise to non-motor symptoms particularly within the gastrointestinal tract and patients experience a wide range of frequent and burdensome symptoms such as dysphagia, bloating, and constipation. Recent evidence suggests that progressive accumulation of gastrointestinal pathology is underway several years before a clinical diagnosis of PD. Notably, constipation has been shown to increase the risk of developing PD and in contrast, truncal vagotomy seems to decrease the risk of PD. Animal models have demonstrated gut-to-brain spreading of pathological α-synuclein and it is currently being intensely studied whether PD begins in the gut of some patients. Gastrointestinal symptoms in PD have been investigated by the use of several different questionnaires. However, there is limited correspondence between subjective gastrointestinal symptoms and objective dysfunction along the gastrointestinal tract, and often the magnitude of dysfunction is underestimated by the use of questionnaires. Therefore, objective measures are important tools to clarify the degree of dysfunction in future studies of PD. Here, we summarize the types and prevalence of subjective gastrointestinal symptoms and objective dysfunction in PD. The potential importance of the gastrointestinal tract in the etiopathogenesis of PD is briefly discussed.

Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study

Abstract: Parkinson's disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner However, it remains uncertain where the initial α-synuclein aggregates originate We have hypothesized that Parkinson's disease comprises two subtypes A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups We included 37 consecutive de novo patients with Parkinson's disease into this case-control PET study Patients with Parkinson's disease were divided into 24 RBD-negative (PDRBD-) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity Colon volume and transit times were assessed with CT scans and radiopaque markers Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons The PDRBD- and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P < 10-13, ANOVA) When compared to the PDRBD- patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P < 10-5, ANOVA) and colon 11C-donepezil standard uptake values (P = 0008, ANOVA) The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD- (P = 007, t-test) In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P < 0001, ANOVA) and delayed colonic transit times (P = 001, Kruskal-Wallis) The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake In contrast, the PDRBD- data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal These findings support the existence of brain-first and body-first subtypes of Parkinson's disease

Pathological α-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients

Abstract: Objective It has been hypothesized that Lewy pathology initiates in the enteric nervous system years prior to debut of clinical motor symptoms in Parkinson disease patients. This study investigates whether Lewy pathology is present in various gastrointestinal tract tissues from Parkinson disease patients in the prodromal phase. Methods We used the Danish National Pathology Registry to identify archived paraffin-embedded tissue blocks from 57 Parkinson disease patients (98 blocks) and 90 control subjects (98 blocks). We employed 2 different immunohistochemistry techniques visualizing aggregated α-synuclein and phosphorylated α-synuclein. Results Thirty-nine Parkinson disease patients contributed tissues obtained in the prodromal disease phase, whereas 18 Parkinson disease patients contributed tissues obtained solely after Parkinson diagnosis. Prodromal tissues were obtained on average 7.0 years prior to diagnosis (range = 20 years to 4 months), and postdiagnosis tissue on average 2.8 years after diagnosis (range = 2 days to 18 years). Phosphorylated α-synuclein positivity was seen in 22 of 39 (56%) prodromal Parkinson disease subjects and 30 of 67 (45%) prodromal tissue blocks. These fractions were significantly higher compared to control subjects (p = 0.0001 and p = 0.0032, respectively). In contrast, no significant difference was seen in the positivity rate between prodromal Parkinson disease patients and controls when using the aggregated α-synuclein immunohistochemistry technique. Interpretation We detected Lewy pathology in the gastrointestinal tract of patients up to 20 years prior to their Parkinson disease diagnosis. These findings are in accordance with a hypothesized prodromal disease phase spanning 10 to 20 years. Ann Neurol 2016;79:940–949

In-vivo staging of pathology in REM sleep behaviour disorder: a multimodality imaging case-control study

Abstract: Summary Background Accumulating evidence suggests that α-synuclein aggregates—a defining pathology of Parkinson's disease—display cell-to-cell transmission. α-synuclein aggregation is hypothesised to start in autonomic nerve terminals years before the appearance of motor symptoms, and subsequently spread via autonomic nerves to the spinal cord and brainstem. To assess this hypothesis, we investigated sympathetic, parasympathetic, noradrenergic, and dopaminergic innervation in patients with idiopathic rapid eye movement (REM) sleep behaviour disorder, a prodromal phenotype of Parkinson's disease. Methods In this prospective, case-control study, we recruited patients with idiopathic REM sleep behaviour disorder, confirmed by polysomnography, without clinical signs of parkinsonism or dementia, via advertisement and through sleep clinics in Denmark. We used 11 C-donepezil PET and CT to assess cholinergic (parasympathetic) gut innervation, 123 I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure integrity of pigmented neurons of the locus coeruleus, 11 C-methylreboxetine (MeNER) PET to assess noradrenergic nerve terminals originating in the locus coeruleus, and 18 F-dihydroxyphenylalanine (DOPA) PET to assess nigrostriatal dopamine storage capacity. For each imaging modality, we compared patients with idiopathic REM sleep behaviour disorder with previously published reference data of controls without neurological disorders or cognitive impairment and with symptomatic patients with Parkinson's disease. We assessed imaging data using one-way ANOVA corrected for multiple comparisons. Findings Between June 3, 2016, and Dec 19, 2017, we recruited 22 consecutive patients with idiopathic REM sleep behaviour disorder to the study. Compared with controls, patients with idiopathic REM sleep behaviour disorder had decreased colonic 11 C-donepezil uptake (−0·322, 95% CI −0·112 to −0·531; p=0·0020), 123 I-MIBG heart:mediastinum ratio (−0·508, −0·353 to −0·664; p 18 F-DOPA uptake (Ki; −0·0023, −0·0009 to −0·0037; p=0·0013). No between-group differences were detected between idiopathic REM sleep behaviour disorder and Parkinson's disease groups with respect to 11 C-donepezil (p=0·39), 123 I-MIBG (p>0·99), neuromelanin-sensitive MRI (p=0·96), and 11 C-MeNER (p=0·56). By contrast, 15 (71%) of 21 patients with idiopathic REM sleep behaviour disorder had 18 F-DOPA Ki values within normal limits, whereas all patients with Parkinson's disease had significantly decreased 18 F-DOPA Ki values when compared with patients with idiopathic REM sleep behaviour disorder (p Interpretation Patients with idiopathic REM sleep behaviour disorder had fully developed pathology in the peripheral autonomic nervous system and the locus coeruleus, equal to that in diagnosed Parkinson's disease. These patients also showed noradrenergic thalamic denervation, but most had normal putaminal dopaminergic storage capacity. This caudorostral gradient of dysfunction supports the hypothesis that α-synuclein pathology in Parkinson's disease initially targets peripheral autonomic nerves and then spreads rostrally to the brainstem. Funding Lundbeck Foundation, Jascha Foundation, and the Swiss National Foundation.

NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease

Abstract: In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a "research framework" because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

Classification and diagnosis of diabetes

Abstract: 1. Type 1 diabetes (due to b-cell destruction, usually leading to absolute insulin deficiency) 2. Type 2 diabetes (due to a progressive insulin secretory defect on the background of insulin resistance) 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes) 4. Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exocrine pancreas (such as cystic fibrosis), and drugor chemical-induced diabetes (such as in the treatment of HIV/AIDS or after organ transplantation)