Alexander Gerhard

A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD

The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

Evolution of microglial activation in patients after ischemic stroke: A [11C](R)-PK11195 PET study

We obtained [11C](R)-PK11195 PET scans in six patients at different time points between 3 and 150 days after onset of ischemic stroke in order to measure the time course of microglial activation. Increased [11C](R)-PK11195 binding around the lesion was observed as early as 3 days. Scans at later time points showed ongoing changes in the distribution of the [11C](R)-PK11195 signal, involving the area of the primary lesion and areas distant from the primary lesion site. Our data suggest that [11C](R)-PK11195 PET can be used to investigate both the primary lesion and remote pathological changes following Wallerian degeneration.

[11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy

Microglia, the brain’s intrinsic macrophages, bind (R)-PK11195 when activated by neuronal injury. The authors used [11C](R)-PK11195 PET to localize in vivo microglial activation in patients with multiple system atrophy (MSA). Increased [11C](R)-PK11195 binding was primarily found in the dorsolateral prefrontal cortex, putamen, pallidum, pons, and substantia nigra, reflecting the known distribution of neuropathologic changes in MSA. Providing an indicator of disease activity, [11C](R)-PK11195 PET can thus be used to characterize the in vivo neuropathology of MSA.

Brain inflammation is induced by co-morbidities and risk factors for stroke

Highlights ► Risk factors for stroke include atherosclerosis, obesity, diabetes and hypertension. ► Stroke risk factors are associated with peripheral inflammation. ► Corpulent rats and atherogenic mice show increased inflammation in the brain. ► Pilot data show that patients at risk of stroke may also develop brain inflammation. ► Chronic peripheral inflammation can drive inflammatory changes in the brain.

In vivo imaging of activated microglia using [11C]PK11195 and positron emission tomography in patients after ischemic stroke.

Neuroprotective strategies are currently being developed for stroke patients. Although the focus is on the development of early treatment the importance of late pathogenetic events is increasingly recognized. To investigate the microglial reaction in stroke we used a marker for activated microglia, [11C]PK11195, and PET in five patients with ischemic stroke 5–53 days after infarction. In one patient serial measurements were made. We demonstrated in each individual and at each point in time that a microglial reaction takes place in the area where T1 weighted MRI (magnetic resonance imaging) shows intensity changes. We consider this PET method as a promising tool to study the late pathogenetic consequences of cerebral infarction and to evaluate neuroprotective strategies with respect to the consequences of the microglial activation.

Minocycline 1‐year therapy in multiple‐system‐atrophy: Effect on clinical symptoms and [11C] (R)‐PK11195 PET (MEMSA‐trial)

The aim of the study was to investigate the efficacy of the antibiotic minocycline as a drug treatment in patients with Multiple‐System‐Atrophy Parkinson‐type (MSA‐P). Sixty‐three patients were randomized to minocycline 200 mg/d (n = 32) or a matching placebo (n = 31). The primary outcome variable was the change in the value of the motor score of the Unified Multiple‐System‐Atrophy Rating‐Scale (UMSARSII) from baseline to 48 weeks. Secondary outcome variables included subscores and individual Parkinsonian symptoms as determined by the UMSARS and the Unified‐Parkinsons‐Disease Rating‐Scale (UPDRS). Health‐related quality of life (HrQoL) was assessed using the EQ‐5D and SF‐12. “Progression rate” was assumed to be reflected in the change in motor function over 48 weeks. At 24 weeks and 48 weeks of follow‐up, there was a significant deterioration in motor scores in both groups, but neither the change in UMSARSII nor in UPDRSIII differed significantly between treatment groups, i.e. “progression rate” was considered to be similar in both treatment arms. HrQoL did not differ among the two treatment arms. In a small subgroup of patients (n = 8; minocycline = 3, placebo = 5)[11C](R)‐PK11195‐PET was performed. The three patients in the minocycline group had an attenuated mean increase in microglial activation as compared to the placebo group (P = 0.07) and in two of them individually showed decreased [11C](R)‐PK11195 binding actually decreased. These preliminary PET‐data suggest that minocycline may interfere with microglial activation. The relevance of this observation requires further investigation. This prospective, 48 week, randomized, double‐blind, multinational study failed to show a clinical effect of minocycline on symptom severity as assessed by clinical motor function.

Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients

Background: An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive dystonia (DRD). A classic phenotype of young-onset lower-limb dystonia, diurnal fluctuations and excellent response to levodopa has been well recognised in association with GCH1 mutations, and rare atypical presentations have been reported. However, a number of clinical issues remain unresolved including phenotypic variability, long-term response to levodopa and associated non-motor symptoms, and there are limited data on long-term follow-up of genetically proven cases. Methods: A detailed clinical evaluation of 34 patients (19 women, 15 men), with confirmed mutations in the GCH1 gene, is presented. Results and conclusions: The classic phenotype was most frequent (n = 23), with female predominance (F:M = 16:7), and early onset (mean 4.5 years) with involvement of legs. However, a surprisingly large number of patients developed craniocervical dystonia, with spasmodic dysphonia being the predominant symptom in two subjects. A subset of patients, mainly men, presented with either a young-onset (mean 6.8 years) mild DRD variant not requiring treatment (n = 4), or with an adult-onset (mean 37 years) Parkinson disease-like phenotype (n = 4). Two siblings were severely affected with early hypotonia and delay in motor development, associated with compound heterozygous GCH1 gene mutations. The study also describes a number of supplementary features including restless-legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder and specific levodopa-resistant symptoms (writer’s cramp, dysphonia, truncal dystonia). Levodopa was used effectively and safely in 20 pregnancies, and did not cause any fetal abnormalities.

Progression of multiple system atrophy (MSA): A prospective natural history study by the European MSA study group (EMSA SG)

The disease‐specific Unified Multiple System Atrophy Rating Scale (UMSARS) has been developed recently and validated for assessing disease severity in multiple system atrophy (MSA). Here, we aimed at (1) assessing rates of disease progression in MSA and (2) validating UMSARS for sensitivity to change over time. Impairment was assessed at two time points 12 months apart using UMSARS Part I (historical review), UMSARS Part II (motor examination), as well as measures of global disease severity, including UMSARS Part IV, Hoehn and Yahr (HY) Parkinsons disease staging, Schwab England Activities of Daily Living (SE ADL), and a three‐point global Severity Scale (SS3). Fifty patients (male:female ratio, 1:0.9; possible MSA, 16%; probable MSA, 84%; MSA‐parkinsonian, 58%; MSA‐cerebellar, 42%) were assessed twice with an interval of 12.3 months. UMSARS II scores progressed by 57.3% (P < 0.0001) and UMSARS I scores by 35.6% (P < 0.0001) in relation to the respective baseline scores with no differences between motor subtypes, diagnostic categories and gender. Significant inverse correlations between (1) UMSARS I or UMSARS II progression and (2) baseline disability measures (i.e., the respective UMSARS or SS3 scores) and disease duration were found. Furthermore, the increases in HY staging, SE ADL and SS3 correlated significantly with UMSARS I, UMSARS II, and UMSARS IV progression. This report is the first prospective study showing rapid annual UMSARS rates of decline in MSA. Our data contribute to the ongoing validation process of UMSARS, and they facilitate the planning and implementation of future neuroprotective intervention trials.

In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease presenting with voluntary gaze difficulties, early falls, and Parkinsonism. Neuronal loss, associated with intracellular neurofibrillary tangles and activated microglia, is found targeting the basal ganglia, brainstem nuclei, and frontal cortex. [11C](R)‐PK11195 PET is a marker of peripheral benzodiazepine binding sites (PBBS) expressed by activated microglia. We have used [11C](R)‐PK11195 PET to demonstrate in vivo the degree and distribution of the glial response to the degenerative process in four patients with PSP. Compared to normal age‐matched controls, the PSP patient group showed significantly increased mean [11C](R)‐PK11195 binding in the basal ganglia, midbrain, the frontal lobe, and the cerebellum. Two of the patients were rescanned after 6 to 10 months and during that time the level of microglial activation remained stable. [11C](R)‐PK11195 PET reveals a pattern of increased microglial activation in PSP patients involving cortical and subcortical regions that corresponds well with the known distribution of neuropathological changes. [11C](R)‐PK11195 PET, therefore, may help in characterizing in vivo the underlying disease activity in PSP.

Imaging microglial activation in Huntington's disease

Activated microglia have been proposed to play a major role in the pathogenesis of Huntingtons Disease (HD). PK11195 is a ligand which binds selectively to peripheral benzodiazepine binding sites, a type of receptor selectively expressed by activated microglia in the central nervous system. Using (11)C-(R)-PK11195 positron emission tomography (PET), we have recently shown in vivo evidence of increased microglial activation in both symptomatic and presymptomatic HD gene carriers and that the degree of microglial activation in the striatum correlates with the severity of striatal dopamine D2 receptor dysfunction measured with (11)C-raclopride PET. Our findings indicate that microglial activation is an early process in the HD pathology, occurring before the onset of symptoms. The close spatial and temporal relationship between microglial activation and neuronal dysfunction lends further support to the pathogenic link between the two processes in HD. Further longitudinal studies are needed to fully elucidate this link.