Bernhard Landwehrmeyer

• MD, FRCP
• Ulm University

Accurate diagnosis and monitoring of neurodegenerative diseases require reliable biomarkers. Cerebrospinal fluid (CSF) proteins are promising candidates for reflecting brain pathology; however, their diagnostic utility may be compromised by natural variability between individuals, weakening their association with disease. Here, we measured the leve...

Background Understanding quality of life (QoL) is important in diseases for which there is no cure to date, such as Huntington’s disease (HD). A deeper level of understanding is, however, compromised by the lack of studies examining QoL from the perspectives of HD gene expansion carriers (HDGECs). Only a few qualitative studies on QoL in HD have be...

Introduction eHealth seems promising in addressing challenges in the provision of care for Huntington’s disease (HD) across Europe. By harnessing information and communication technologies, eHealth can partially relocate care from specialized centers to the patients’ home, thereby increasing the availability and accessibility of specialty care serv...

Huntington's disease (HD), due to expansion of a CAG repeat in HTT , is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the...

INTRODUCTION Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross‐validated fluid biomarkers and neuroimaging. METHODS Seven fluid biomarkers from cerebrospinal fluid and serum we...

Background Accurate diagnosis and monitoring of neurodegenerative diseases requires reliable biomarkers. Cerebrospinal fluid (CSF) proteins hold promise for reflecting brain pathology, yet their utility may be compromised by natural variability between individuals, weakening their association with disease and impacting their diagnostic accuracy. M...

Background The disease-causing mutation in Huntington disease (HD) is a CAG trinucleotide expansion in the huntingtin ( HTT ) gene. The mutated CAG tract results in the production of a small RNA, HTT1a , coding for only exon 1 of HTT. HTT1a is generated by a block in the splicing reaction of HTT exon 1 to exon 2 followed by cleavage in intron 1 and...

Transition from child-centered to adult-centered healthcare is a gradual process that addresses the medical, psychological, and educational needs of young people in the management of their autonomy in making decisions about their health and their future clinical assistance. This transfer is challenging across all chronic diseases but can be particu...

Cortical cell loss is a core feature of Huntington Disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate this using cell-specific...

Background A declining cognitive performance is a hallmark of Huntington’s disease (HD). The neuropsychological battery of the Unified HD Rating Scale (UHDRS'99) is commonly used for assessing cognition. However, there is a need to identify and minimize the impact of confounding factors, such as language, gender, age, and education level on cogniti...

Understanding the relationships between brain structure and language behavior in primary progressive aphasia provides crucial information about these diseases’ pathomechanisms. However, previous investigations have been limited from providing a statistically reliable view of broad language abilities by sample size, variant focus, and task focus. In...

Background: Whole-brain longitudinal diffusion studies are crucial to examine changes in structural connectivity in neurodegeneration. Here, we investigated the longitudinal alterations in white matter (WM) microstructure across the time course of Huntington’s disease (HD). Methods: We examined changes in WM microstructure from premanifest to early...

Background: Motor speech alterations are a prominent feature of clinically manifest Huntington disease (HD). Objective acoustic analysis of speech can quantify speech alterations. It is currently unknown, however, at what stage of HD speech alterations can be reliably detected. Aim: We explored patterns and extent of speech alterations using obj...

Background Huntington’s disease (HD) is a genetic, neurodegenerative disease. Due to the progressive nature of HD and the absence of a cure, (health-related) quality of life ((HR)QoL) is an important topic. Several studies have investigated (HR)QoL in HD, yet a clear synthesis of the existing literature is lacking to date. We performed a systematic...

Background: Recent data support beta-synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD). Methods: We provide a detailed comparison of serum beta-synuclein immunoprecipitation - mass spectrometry (IP-MS) with the established blood markers phosphorylated tau 181 (p-tau181) (Simoa) and neurofilament light (NfL...

Background A declining cognitive performance is a hallmark of Huntington Disease (HD). A battery of neuropsychological assessments (Symbol Digit Modalities Test, Stroop Word Reading, Stroop Color Naming and Stroop Interference Test, Trail Making Test A and B, Categorial and Letter Fluency) is part of the standardized assessment for HD. However, the...

A promising approach to treat HD is the reduction of the disease-causing mutated form of the Huntingtin (HTT) protein and mRNA in the patient’s brain by antisense oligonucleotides (ASO). One of the main difficulties in current clinical trials it to assess the direct target engagement of these drugs. Extracellular vesicles in the cerebrospinal fluid...

Background In patients with Huntington disease (HD), subtle alterations in speech rate and timing may precede the more characteristic motor signs, such as chorea. Aims We studied oral diadochokinesis (DDK) using alternating (AMR) and sequential (SMR) syllable repetition tasks in manifest HD patients and explored the effect of antidopaminergic medi...

Background In Huntington disease (HD), inflammatory markers were found to be elevated. HD monocytes reportedly are hyperreactive in vitro. Aim To explore autoimmune disease (AID) frequency in HD mutations carriers (HD+) as marker for immune dysfunction and whether AIDs and immunomodulatory/anti-inflammatory drugs (IM/AID) affect HD progression. M...

Background Respiratory function deteriorates markedly in patients with Huntington disease (HD) over the course of the disease. However, it remains unclear, how early the first breathing abnormalities become apparent. Aims This study aimed to investigate breathing patterns during speech in early and moderate HD. Methods Different measures of respi...

Background Besides motor and behavioural disturbances, HD patients also develop cognitive deficits. Different speech and language impairments have been described, but there is no evidence of progredient semantic deficits as seen in a semantic variant of the primary progressive aphasia (svPPA) which is characterized by loss of semantic knowledge, se...

Huntington disease (HD) is an inherited neurodegenerative disease. The stability of the proteome – proteostasis – is crucial for cellular integrity. Proteins are synthesized by ribosomes consisting of ribosomal proteins and catalytic active ribosomal-RNA (rRNA). rRNA is encoded by the rDNA and transcribed by the RNA-polymerase I transcription machi...

Huntington’s disease is caused by an expanded CAG tract in HTT . The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously...

Huntington's disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously...

Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. Objective: To use machine learning to compare the expression of structural magnetic resona...

Since the discovery of the mutation causing Huntington’s disease (HD) in 1993, it has been debated whether an expanded polyglutamine (polyQ) stretch affects the properties of the huntingtin (HTT) protein and thus contributes to the pathological mechanisms responsible for HD. Here we review the current knowledge about the structure of HTT, alone (ap...

Background: Proenkephalin (PENK) and prodynorphin (PDYN) are peptides mainly produced by the striatal medium spiny projection neurons (MSNs) under dopaminergic signaling. Therefore, they may represent candidate biomarkers in Huntington's disease (HD) and Parkinson's disease (PD), two neurodegenerative diseases characterized by striatal atrophy and...

Introduction While physical activity (PA) is recognized as important in Huntington's disease (HD) disease management, there has been no long-term evaluation undertaken. We aimed to evaluate the feasibility of a nested (within cohort) randomized controlled trial (RCT) of a physical therapist-led PA intervention. Methods Participants were recruited...

Catatonia is a complex neuropsychiatric disorder with motor, affective and cognitive-behavioural manifestations. Understanding the relationships between these features has proven to be a challenge for psychiatrists and neurologists alike. Here we look back at the history of catatonia but also provide a modern perspective on how to understand the co...

Intrathecal administration involves the introduction of a drug substance into the subarachnoid space of the spinal column through a needle inserted into the lower back via lumbar puncture (LP) or via a special device. This procedure is used when drugs cannot cross the blood-brain barrier. Once injected, drugs are distributed within the cerebrospina...

The age at onset of motor symptoms in Huntington’s disease (HD) is driven by HTT CAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants i...

[This corrects the article DOI: 10.3389/fneur.2022.817753.].

Genome-wide association studies (GWASs) of Huntington disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage. The largest studies have been limited to HD individuals w...

One percent of patients with a Huntington's disease (HD) phenotype do not have the Huntington (HTT) gene mutation. These are known as HD phenocopies. Their diagnosis is still a challenge. Our objective is to provide a diagnostic approach to HD phenocopies based on medical expertise and a review of the literature. We employed two complementary appro...

Background: Primary progressive aphasia (PPA) may present with three distinct clinical sybtypes: semantic variant PPA (svPPA), nonfluent/agrammatic variant PPA (nfvPPA), and logopenic variant PPA (lvPPA). Objective: The aim was to examine the utility of the German version of the Repeat and Point (R&P) Test for subtyping patients with PPA. Metho...

Genome-wide association studies (GWAS) of Huntington’s disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage. The largest studies have been limited to HD individuals...

Introduction: The behavioral variant of frontotemporal dementia (bvFTD) is a rare neurodegenerative disease. Reliable predictors of disease progression have not been sufficiently identified. We investigated multivariate magnetic resonance imaging (MRI) biomarker profiles for their predictive value of individual decline. Methods: One hundred five...

Background Patient involvement in research increases the impact of research and the likelihood of adoption in clinical practice. A first step is to know which research themes are important for patients. We distributed a survey on research priorities to ERN-RND members, both patient representatives and healthcare professionals, asking them to priori...

Background Primary progressive aphasia (PPA) is a rare primarily language‐related neurodegenerative disorder that subdivides into the non‐fluent (nfvPPA) and the semantic variant (svPPA). Atrophy progression shows variant‐specific patterns, however, its extent seems highly individual and thus difficult to predict. Method We investigated volumetric...

Zusammenfassung Die Huntington-Krankheit (HK) ist die häufigste monogenetische neurodegenerative Erkrankung und kann bereits im präklinischen Stadium zweifelsfrei diagnostiziert werden, zumindest in allen Fällen, bei denen die CAG-Expansionsmutation im Huntingtin-Gen ( HTT ) im Bereich der vollen Penetranz liegt. Wichtige Voraussetzungen für eine f...

Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for H...

Background Huntington’s disease is caused by an expanded CAG tract in HTT . The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene,...

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD...

Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that affects the quality of life (QoL) of HD gene expansion carriers (HDGECs) and their partners. Although HD expertise centers have been emerging across Europe, there are still some important barriers to care provision for those affected by this rare disease,...

Background In Germany at least 8000 people suffer from clinically manifest HD, ultimately resulting in patients dependent on care. There are no defined pathways for multidisciplinary HD care in Germany. While slowing down the progression of HD may be available in the future, optimized care is needed now. Aims Jointly defined activities aim to prov...

Background The huntingtin-associated protein 40 (HAP40) is an abundant interactor of huntingtin (HTT). In a complex of the two proteins, HAP40 tightly binds to HTT in a cleft formed by two larger domains, rich in HEAT repeats, and a smaller bridge domain that connects the two. When generating HEK293-based cell lines for producing the HTT-HAP40 comp...

Background Body composition is a strong indicator of nutritional and health status. Dual energy X-ray absorptiometry (DXA), multifrecuency bioelectrical impedance analysis (BIA), anthropometry and, skinfolds are non invasive methods to assess body composition with different levels of reliability. The validity of anthropometric and skinfolds to esti...

Background The course of Huntington’s disease (HD) is believed to be modulated by lifestyle and genetic factors. However, we do not understand how the interplay of these affects disease progression. An efficient method of measuring lifestyle factors involves the use of digital monitoring devices, but their long-term use in clinical HD populations h...

Established in July 2012, Enroll-HD is both an integrated clinical research platform and a worldwide observational study designed to meet the clinical research requirements necessary to develop therapeutics for Huntington's disease (HD). The platform offers participants a low-burden entry into HD research, providing a large, well-characterized, res...

The huntingtin-associated protein 40 (HAP40) is an abundant interactor of huntingtin (HTT). In complexes of these proteins, HAP40 tightly binds to HTT in a cleft formed by two larger domains rich in HEAT repeats, and a smaller bridge domain connecting the two. We show that HAP40 steady-state protein levels are directly dependent on HTT (both normal...

Objective Weight loss is associated with clinical progression in Huntington disease (HD), but whether body weight causally affects disease onset or progression is unknown. Therefore, we aimed to assess whether genetically determined variations in body weight are causally related to age at onset in HD. Methods Using data from different recent genom...

Background Longitudinal brain MRI monitoring in neurodegeneration potentially provides substantial insights into the temporal dynamics of the underlying biological process, but is time- and cost-intensive and may be a burden to patients with disabling neurological diseases. Thus, the conceptualization of follow-up time-intervals in longitudinal MRI...

Introduction Clinical diagnosis of Parkinsonism is still challenging, and the diagnostic biomarkers of Multiple System Atrophy (MSA) are scarce. This study aimed to investigate the diagnostic value of the combined eye movement tests in patients with Parkinson's disease (PD) and those with MSA. Methods We enrolled 96 PD patients, 33 MSA patients (1...

Background: Neuroimaging shows considerable promise in generating sensitive and objective outcome measures for therapeutic trials across a range of neurodegenerative conditions. For volumetric measures the current gold standard is manual delineation, which is unfeasible for samples sizes required for large clinical trials. Methods: Using a cohort o...

The age at onset of motor symptoms in Huntington disease (HD) is driven by HTT CAG repeat length but modified by other genes. We used exome sequencing of 683 HD patients with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We identified damaging coding variants in candidate modifier g...

Objective Motor speech disorders (MSDs) are characteristic for nonfluent primary progressive aphasia (nfvPPA). In PPA of the semantic (svPPA) and of the logopenic type (lvPPA), speech motor function is considered typically intact. However, knowledge on the prevalence of MSDs in svPPA and lvPPA is mainly based on studies with a priori knowledge of P...

Introduction: The term primary progressive aphasia (PPA) sums up the non-fluent (nfv), the semantic (sv), and the logopenic (lv) variant. Up to now, there is only limited data available concerning magnetic resonance imaging volumetry to monitor disease progression. Methods: Structural brain imaging and an extensive assessment were applied at bas...

Objective To assess the prevalence, timing and functional impact of psychiatric, cognitive and motor abnormalities in Huntington’s disease (HD) gene carriers, we analysed retrospective clinical data from individuals with manifest HD. Methods Clinical features of HD patients were analysed for 6316 individuals in the European REGISTRY study from 161...

While rare diseases (RDs) are by definition of low prevalence, the total number of patients suffering from an RD is high, and the majority of them have neurologic manifestations, involving central, peripheral nerve, and muscle. In 2017, 24 European Reference Networks (ERNs), each focusing on a specific group of rare or low-prevalence complex diseas...

Background: Besides cognitive and psychiatric abnormalities, motor symptoms are the most prominent in Huntington's disease. The manifest disease is preceded by a prodromal phase with subtle changes such as fine motor disturbances or concentration problems. Objective: Movement disorders show a high variation in their clinical manifestation depend...

Diminished glutamate (Glu) uptake via the excitatory amino acid transporter EAAT2, which normally accounts for ~90% of total forebrain EAAT activity, may contribute to neurodegeneration via Glu‐mediated excitotoxicity. C‐terminal cleavage by caspase‐3 (C3) was reported to mediate EAAT2 inactivation and down‐regulation in the context of neurodegener...

Background: Patient involvement in research increases the impact of research and the likelihood of adoption in clinical practice. A first step is to know which research themes are important for patients. We distributed a survey on research priorities to ERN-RND members, both patient representatives and health care professionals, asking them to prio...

Background: Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by a selective loss of striatal medium spiny projection neurons (MSNs). Prodynorphin (PDYN) is enriched in a subpopulation of striatal MSNs. Postmortem brains of HD patients and rodent models have been demonstrated to have reduced levels of PDYN transcr...

Objective: Cognitive decline is a key characteristic of Huntington's disease (HD). This study aimed to investigate the diagnostic accuracy of a cognitive battery with six tests used by most HD research centers to assess cognitive impairment in HD. Method: In total, 106 HD patients in different disease stages with more (HD-CD, N = 30) and less co...

Objective To assess the prevalence, timing and functional impact of psychiatric, cognitive and motor manifestations of Huntington’s disease (HD), we analysed retrospective clinical data from individuals with manifest HD. Methods The clinical manifestations of HD were analysed for 6316 individuals in the European REGISTRY study from 161 sites acros...

Zusammenfassung In Deutschland leiden derzeit mindestens 8000, vermutlich aber sogar bis zu ca. 14.000 Menschen an einer klinisch apparenten („manifesten“) Huntington-Krankheit (HK). Zudem tragen schätzungsweise 24.000 Deutsche die der HK zugrunde liegende Mutation im Huntingtin -( HTT )-Gen und werden im Laufe ihres Lebens an der HK erkranken. Obw...

Objectives The hexanucleotide repeat expansion in the C9orf72 gene is the most common mutation associated with amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD). Until now, it is unknown which factors define whether C9orf72 mutation carriers develop ALS or FTD. Our aim was to identify protein biomarker candidates in the ce...

Background: Changes in phosphodiesterase 10A enzyme levels may be a suitable biomarker of disease progression in Huntington's disease. Objectives: To evaluate phosphodiesterase 10A PET imaging as a biomarker of HD progression using the radioligand, [18 F]MNI-659. Methods: The cross-sectional study (NCT02061722) included 45 Huntington's disease...

Background Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, a...

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death,...

Background: Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized examination of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor sy...

Background Olfactory testing is a useful tool in the differential diagnosis of Parkinson’s Disease (PD). Although fast and easy to use, the high intercultural variability of odor detection limits the world-wide use of the most common test sets. Objective The aim of this study was to test one of the most commonly used olfactory tests (Sniffin’ Stic...

Importance In Huntington disease (HD), mutation severity is defined by the length of the CAG trinucleotide sequence, a well-known predictor of clinical onset age. The association with disease trajectory is less well characterized. Quantifiable summary measures of trajectory applicable over decades of early disease progression are lacking. An accura...

Variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from the length of huntingtin's polyglutamine segment, dictates the rate at which Huntington's disease (HD) develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in...

Family carers of individuals living with Huntington’s disease (HD) manage a distinct and unique series of difficulties arising from the complex nature of HD. This paper presents the validation of the definitive measure of quality of life (QoL) for this group. The Huntington’s Disease Quality of Life Battery for Carers (HDQoL-C) was expanded (n = 47...

Family carers of individuals living with Huntington's disease (HD) manage a distinct and unique series of difficulties arising from the complex nature of HD. This paper presents the validation of the definitive measure of quality of life (QoL) for this group. The Huntington's Disease Quality of Life Battery for Carers (HDQoL-C) was expanded (n = 47...

Background Although health-related quality of life is key for patients with long-term neurodegenerative conditions, measuring this is less straightforward and complex in Huntington’s disease (HD). Objectives To refine and validate a fully patient-derived instrument, the Huntington’s Disease health-related Quality of Life questionnaire (HDQoL), and...

Huntingtons disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in HTT. It is diagnosed following a standardized exam of motor control and often presents with cognitive decline and neuropsychiatric signs and symptoms. Recent studies have indicated genetic loci modifying the age at onset of motor symptoms, and it...

Background Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin. Methods We con...

BACKGROUND: Huntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin. METHODS: We co...

Studying individuals with extreme phenotypes could facilitate the understanding of disease modification by genetic or environmental factors. Our aim was to identify Huntington's disease (HD) patients with extreme symbol digit modality test (SDMT) scores. We first examined in HD the contribution of cognitive measures of the Unified Huntington's Dise...

Introduction: A volumetric MRI analysis of longitudinal regional cerebral atrophy in Huntington's disease (HD) was performed as a read-out of disease progression to calculate sample sizes for future clinical trials. Methods: This study was based on MRI data of 59 patients with HD and 40 controls recruited within the framework of the PADDINGTON s...

Alien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one’s limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia,...