Subcortical tau is linked to hypoperfusion in connected cortical regions in 4-repeat tauopathies.

Four-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R tauopathies are progressive supranuclear palsy (PSP) and corticobasal degeneration characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction, and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces remote neuronal dysfunction in functionally connected cortical regions to test a pathophysiological model that mechanistically links subcortical tau accumulation to cortical neuronal dysfunction in 4R tauopathies. We included 51 Aß-negative patients with clinically diagnosed PSP variants (n = 26) or corticobasal syndrome (n = 25) who underwent structural MRI and 18F-PI-2620 tau-PET. 18F-PI-2620 tau-PET was recorded using a dynamic one-stop-shop acquisition protocol to determine an early 0.5-2.5 min post tracer-injection perfusion window for assessing cortical neuronal dysfunction, as well as a 20-40 min post tracer-injection window to determine 4R-tau load. Perfusion-PET (i.e. early window) was assessed in 200 cortical regions, and tau-PET was assessed in 32 subcortical regions of established functional brain atlases. We determined tau epicentres as subcortical regions with the highest 18F-PI-2620 tau-PET signal and assessed the connectivity of tau epicentres to cortical regions of interest using a resting-state functional MRI-based functional connectivity template derived from 69 healthy elderly controls from the ADNI cohort. Using linear regression, we assessed whether: (i) higher subcortical tau-PET was associated with reduced cortical perfusion; and (ii) cortical perfusion reductions were observed preferentially in regions closely connected to subcortical tau epicentres. As hypothesized, higher subcortical tau-PET was associated with overall lower cortical perfusion, which remained consistent when controlling for cortical tau-PET. Using group-average and subject-level PET data, we found that the seed-based connectivity pattern of subcortical tau epicentres aligned with cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicentre showed lower perfusion. Together, subcortical tau-accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions in 4R-tauopathies. This suggests that subcortical tau pathology may induce cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.

Vestibular contribution to spatial orientation and navigation.

PURPOSE OF REVIEW: The vestibular system provides three-dimensional idiothetic cues for updating of one's position in space during head and body movement. Ascending vestibular signals reach entorhinal and hippocampal networks via head-direction pathways, where they converge with multisensory information to tune the place and grid cell code. RECENT FINDINGS: Animal models have provided insight to neurobiological consequences of vestibular lesions for cerebral networks controlling spatial cognition. Multimodal cerebral imaging combined with behavioural testing of spatial orientation and navigation performance as well as strategy in the last years helped to decipher vestibular-cognitive interactions also in humans. SUMMARY: This review will update the current knowledge on the anatomical and cellular basis of vestibular contributions to spatial orientation and navigation from a translational perspective (animal and human studies), delineate the behavioural and functional consequences of different vestibular pathologies on these cognitive domains, and will lastly speculate on a potential role of vestibular dysfunction for cognitive aging and impeding cognitive impairment in analogy to the well known effects of hearing loss.

Network Architecture of Verticality Processing in the Human Thalamus.

OBJECTIVE: Thalamic dysfunction in lesions or neurodegeneration may alter verticality perception and lead to postural imbalance and falls. The aim of the current study was to delineate the structural and functional connectivity network architecture of the vestibular representations in the thalamus by multimodal magnetic resonance imaging. METHODS: Seventy-four patients with acute unilateral isolated thalamic infarcts were studied prospectively with emphasis on the perception of verticality (tilts of the subjective visual vertical [SVV]). We used multivariate lesion-symptom mapping based on support-vector regression to determine the thalamic nuclei associated with ipsiversive and contraversive tilts of the SVV. The lesion maps were used to evaluate the white matter disconnection and whole brain functional connectivity in healthy subjects. RESULTS: Contraversive SVV tilts were associated with lesions of the ventral posterior lateral/medial, ventral lateral, medial pulvinar, and medial central/parafascicular nuclei. Clusters associated with ipsiversive tilts were located inferiorly (ventral posterior inferior nucleus) and laterally (ventral lateral, ventral posterior lateral, and reticular nucleus) to these areas. Distinct ascending vestibular brainstem pathways terminated in the subnuclei for ipsi- or contraversive verticality processing. The functional connectivity analysis showed specific patterns of cortical connections with the somatomotor network for lesions with contraversive tilts, and with the core multisensory vestibular representations (areas Ri, OP2-3, Ig, 3av, 2v) for lesions with ipsiversive tilts. INTERPRETATION: The functional specialization may allow both a stable representation of verticality for sensorimotor integration and flexible adaption to sudden changes in the environment. A targeted modulation of this circuitry could be a novel therapeutic strategy for higher level balance disorders of thalamocortical origin. ANN NEUROL 2023;94:133-145.

Precision Balance Assessment in Parkinson's Disease: Utilizing Vision-Based 3D Pose Tracking for Pull Test Analysis.

Postural instability is a common complication in advanced Parkinson's disease (PD) associated with recurrent falls and fall-related injuries. The test of retropulsion, consisting of a rapid balance perturbation by a pull in the backward direction, is regarded as the gold standard for evaluating postural instability in PD and is a key component of the neurological examination and clinical rating in PD (e.g., MDS-UPDRS). However, significant variability in test execution and interpretation contributes to a low intra- and inter-rater test reliability. Here, we explore the potential for objective, vision-based assessment of the pull test (vPull) using 3D pose tracking applied to single-sensor RGB-Depth recordings of clinical assessments. The initial results in a cohort of healthy individuals (n = 15) demonstrate overall excellent agreement of vPull-derived metrics with the gold standard marker-based motion capture. Subsequently, in a cohort of PD patients and controls (n = 15 each), we assessed the inter-rater reliability of vPull and analyzed PD-related impairments in postural response (including pull-to-step latency, number of steps, retropulsion angle). These quantitative metrics effectively distinguish healthy performance from and within varying degrees of postural impairment in PD. vPull shows promise for straightforward clinical implementation with the potential to enhance the sensitivity and specificity of postural instability assessment and fall risk prediction in PD.

[The six most frequent peripheral vestibular syndromes]. / Die sechs häufigsten peripheren vestibulären Syndrome.

Three forms of peripheral vestibular disorders, each with its typical symptoms and clinical signs, can be differentiated functionally, anatomically and pathophysiologically: 1. inadequate unilateral paroxysmal stimulation or rarely inhibition of the peripheral vestibular system, e. g., BPPV, Menière's disease, vestibular paroxysmia or syndrome of the third mobile windows; 2. acute unilateral vestibulopathy leading to an acute vestibular tone imbalance manifesting as an acute peripheral vestibular syndrome; and 3. loss or impairment of function of the vestibular nerve and/or labyrinth: bilateral vestibulopathy. For all of these diseases, current diagnostic criteria by the Bárány-Society are available with a high clinical and scientific impact, also for clinical trials. The treatment depends on the underlying disease. It basically consists of 5 principles: 1. Explaining the symptoms and signs, pathophysiology, aetiology and treatment options to the patient; this is important for compliance, adherence and persistence. 2. Physical therapy: A) For BPPV specific liberatory maneuvers, depending on canal involved. Posterior canal: The new SémontPLUS maneuver is superior to the regular Sémont and Epley maneuvers; horizontal canal: the modified roll-maneuver; anterior canal the modified Yacovino-maneuver; 3. Symptomatic or causative drug therapy. There is still a deficit of placebo-controlled clinical trials so that the level of evidence for pharmacotherapy is most often low. 4. Surgery, mainly for the syndrome of the third mobile windows. 5. Psychotherapeutic measures for secondary functional dizziness.

Additive value of [18F]PI-2620 perfusion imaging in progressive supranuclear palsy and corticobasal syndrome.

PURPOSE: Early after [18F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [18F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [18F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs. METHODS: Seventy-eight patients with 4RTs (71 ± 7 years, 39 female), 79 patients with other neurodegenerative diseases (67 ± 12 years, 35 female) and twelve age-matched controls (69 ± 8 years, 8 female) underwent dynamic (0-60 min) [18F]PI-2620 PET imaging. Regional perfusion (0.5-2.5 min p.i.) and tau load (20-40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value ratios (SUVr), cerebellar reference]. Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p < 0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value - 2SD threshold). Additionally, perfusion and tau pattern expression levels were explored regarding their potential discriminatory value of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset (n = 37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living). RESULTS: Patients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression showed promise for discrimination of patients with 4RTs from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was replicated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale (R = 0.402; p = 0.0012) and activities of daily living (R = - 0.431; p = 0.0005). CONCLUSION: [18F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression may provide an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression.

Impact of episodic and chronic vestibular disorders on health-related quality of life and functioning-results from the DizzyReg patient registry.

PURPOSE: Vertigo and dizziness belong to the most frequent syndromes in the primary, secondary and tertiary setting and can be divided into vertigo with episodic or chronic persistent complaints. Episodic vertigo (EVS) is characterized by recurrent attacks of vertigo or dizziness with intermittent symptom-free periods, while chronic vertigo (CVS) presents with persistent vertigo. It is still not completely understood how EVS or CVS affect health-related quality of life (HRQoL) and functioning. METHODS: Data originates from the DizzyReg patient registry, an ongoing prospective clinical patient registry situated at tertiary clinic at the university hospital, Munich. HRQoL and functioning was measured by self-report. CVS and EVS was categorized after comprehensive neuro-otological work-up in line with the diagnostic guidelines. Association of CVS and EVS was assessed with multivariable linear regression models adjusting for potential risk factors and confounders. RESULTS: The study included 548 patients (57% female, mean age 51.35). Patients with EVS were significantly younger (48.5 vs. 59.6 years) and were more often female (60 vs. 49%). EVS patients reported significantly better functioning (42.1 vs. 47.8) and HRQoL (63.87 vs. 58.08) than CVS patients. The effect was stable after adjusting for potential confounders. CONCLUSION: This is the first study to show worse HRQoL in patients with CVS compared to EVS. The results of the study underpin the experience from clinical practice that mobility and balance control are especially important for patients with CVS.

In vivo neuroplasticity in vestibular animal models.

An acute unilateral vestibulopathy leads to symptoms of vestibular tone imbalance, which gradually decrease over days to weeks due to central vestibular compensation. Animal models of acute peripheral vestibular lesions are optimally suited to investigate the mechanisms underlying this lesion-induced adaptive neuroplasticity. Previous studies applied ex vivo histochemical techniques or local in vivo electrophysiological recordings mostly in the vestibular nucleus complex to delineate the mechanisms involved. Recently, the use of imaging methods, such as positron emission tomography (PET) or magnetic resonance imaging (MRI), in vestibular animal models have opened a complementary perspective by depicting whole-brain structure and network changes of neuronal activity over time and in correlation to behaviour. Here, we review recent multimodal imaging studies in vestibular animal models with a focus on PET-based measurements of glucose metabolism, glial activation and synaptic plasticity. [18F]-FDG-PET studies indicate dynamic alterations of regional glucose metabolism in brainstem-cerebellar, thalamic, cortical sensory and motor, as well as limbic areas starting early after unilateral labyrinthectomy (UL) in the rat. Sequential whole-brain analysis of the metabolic connectome during vestibular compensation shows a significant increase of connections mostly in the contralesional hemisphere after UL, which reaches a maximum at day 3 and thereby parallels the course of vestibular recovery. Glial activation in the ipsilesional vestibular nerve and nucleus peak between days 7 and 15 after UL. Synaptic density in brainstem-cerebellar circuits decreases until 8 weeks after UL, while it increases in frontal, motor and sensory cortical areas. We finally report how pharmacological compounds modulate the functional and structural plasticity mechanisms during vestibular compensation.

Vestibular syndromes after COVID-19 vaccination: A prospective cohort study.

BACKGROUND AND PURPOSE: Dizziness and vertigo are common symptoms after COVID-19-vaccination. We aimed to prospectively evaluate objective central or peripheral vestibular function in patients with dizziness, vertigo, and postural symptoms that started or worsened after COVID-19-vaccination. METHODS: Of 4137 patients who presented between January 2021 and April 2022 at the German Center for Vertigo and Balance Disorders, Ludwig Maximilian University of Munich, we identified 72 patients (mean age = 47 years) with enduring vestibular symptoms following COVID-19 vaccination. All underwent medical history-taking, and neurological and neuro-otological workup with bithermal caloric test, video head-impulse test, orthoptics, and audiometry. Diagnoses were based on international criteria. The distribution of diagnoses was compared to a cohort of 39,964 patients seen before the COVID-19 pandemic. RESULTS: Symptom onset was within the first 4 weeks postvaccination. The most prevalent diagnoses were somatoform vestibular disorders (34.7%), vestibular migraine (19.4%), and overlap syndromes of both (18.1%). These disorders were significantly overrepresented compared to the prepandemic control cohort. Thirty-six percent of patients with somatoform complaints reported a positive history of depressive or anxiety disorders. Nine patients presented with benign paroxysmal positional vertigo, three with acute unilateral vestibulopathy, and seven with different entities (vestibular paroxysmia, Ménière disease, polyneuropathy, ocular muscular paresis). Causally related central vestibular deficits were lacking. Novel peripheral vestibular deficits were found in four patients. CONCLUSIONS: Newly induced persistent vestibular deficits following COVID-19 vaccination were rare. The predominant causes of prolonged vestibular complaints were somatoform vestibular disorders and vestibular migraine, possibly triggered or aggravated by stress-related circumstances due to the COVID-19 pandemic or vaccination. An increase of other central or peripheral vestibular syndromes after COVID-19 vaccination was not observed.

Validation of a comprehensive diagnostic algorithm for patients with acute vertigo and dizziness.

BACKGROUND AND PURPOSE: Vertigo and dizziness are common complaints in emergency departments and primary care, and pose major diagnostic challenges due to their various underlying etiologies. Most supportive diagnostic algorithms concentrate on either identifying cerebrovascular events (CVEs) or diagnosing specific vestibular disorders or are restricted to specific patient subgroups. The aim of the present study was to develop and validate a comprehenisve algorithm for identifying patients with CVE and classifying the most common vestibular disorders. METHODS: The study was conducted within the scope of the "PoiSe" project (Prevention, Online feedback, and Interdisciplinary Therapy of Acute Vestibular Syndromes by e-health). A three-level algorithm was developed according to international guidelines and scientific evidence, addressing both the detection of CVEs and the classification of non-vascular vestibular disorders (unilateral vestibulopathy, benign paroxysmal positional vertigo, vestibular paroxysmia, Menière's disease, vestibular migraine, functional dizziness). The algorithm was validated in a prospectively collected dataset of 407 patients with acute vertigo and dizziness presenting to the Emergency Department at the Ludwig-Maximilian University of Munich. RESULTS: The algorithm assigned 287 of 407 patients to the correct diagnosis, corresponding to an overall accuracy of 71%. CVEs were identified with high sensitivity of 94%. The six most common vestibular disorders were classified with high specificity, above 95%. Random forest identified presence of a paresis, sensory loss, central ocular motor and vestibular signs (HINTS [head impulse test, nystagmus assessment, and test of skew deviation]), and older age as the most important variables indicating a cerebrovascular event. CONCLUSIONS: The proposed diagnostic algorithm can correctly classify the most common vestibular disorders based on a comprehensive set of key questions and clinical examinations. It is easily applied, not limited to subgroups, and might therefore be transferred to broad clinical settings such as primary healthcare.

Current-dependent ocular tilt reaction in deep brain stimulation of the subthalamic nucleus: Evidence for an incerto-interstitial pathway?

BACKGROUND AND PURPOSE: The aim was to characterize a combined vestibular, ocular motor and postural syndrome induced by deep brain stimulation (DBS) of the subthalamic nucleus in a patient with Parkinson's disease. METHODS: In a systematic DBS programming session, eye, head and trunk position in roll and pitch plane were documented as a function of stimulation amplitude and field direction. Repeat ocular coherence tomography was used to estimate ocular torsion. The interstitial nucleus of Cajal (INC), zona incerta (ZI) and ascending vestibular fibre tracts were segmented on magnetic resonance imaging using both individual and normative structural connectomic data. Thresholded symptom-associated volumes of tissue activated (VTA) were calculated based on documented stimulation parameters. RESULTS: Ipsilateral ocular tilt reaction and body lateropulsion as well as contralateral torsional nystagmus were elicited by the right electrode in a current-dependent manner and subsided after DBS deactivation. With increasing currents, binocular tonic upgaze and body retropulsion were observed. Symptoms were consistent with an irritative effect on the INC. Symptom-associated VTA was found to overlap with the dorsal ZI and the ipsilateral vestibulothalamic tract, while lying rather distant to the INC proper. A ZI-to-INC 'incerto-interstitial' tract with contact to the medial-uppermost portion of the VTA could be traced. CONCLUSION: Unilateral stimulation of INC-related circuitry induces an ipsilateral vestibular, ocular motor and postural roll-plane syndrome, which converts into a pitch-plane syndrome when functional activation expands bilaterally. In this case, tractography points to an incerto-interstitial pathway, a tract previously only characterized in non-human primates. Directional current steering proved useful in managing this rare side effect.

Dynamic whole-brain metabolic connectivity during vestibular compensation in the rat.

Unilateral damage to the inner ear results in an acute vestibular syndrome, which is compensated within days to weeks due to adaptive cerebral plasticity. This process, called central vestibular compensation (VC), involves a wide range of functional and structural mechanisms at the cellular and network level. The short-term dynamics of whole-brain functional network recruitment and recalibration during VC has not been depicted in vivo. The purpose of this study was to investigate the interplay of separate and distinct brain regions and in vivo networks in the course of VC by sequential [18F]-FDG-PET-based statistical and graph theoretical analysis with the aim of revealing the metabolic connectome before and 1, 3, 7, and 15 days post unilateral labyrinthectomy (UL) in the rat. Temporal changes in metabolic brain connectivity were determined by Pearson's correlation (|r| > 0.5, p < 0.001) of regional cerebral glucose metabolism (rCGM) in 57 segmented brain regions. Metabolic connectivity analysis was compared to univariate voxel-wise statistical analysis of rCGM over time and to behavioral scores of static and dynamic sensorimotor recovery. Univariate statistical analysis revealed an ipsilesional relative rCGM decrease (compared to baseline) and a contralesional rCGM increase in vestibular and limbic networks and an increase in bilateral cerebellar and sensorimotor networks. Quantitative analysis of the metabolic connections showed a maximal increase from baseline to day 3 post UL (interhemispheric: 2-fold, ipsilesional: 3-fold, contralesional: 12-fold) and a gradual decline until day 15 post UL, which paralleled the dynamics of vestibular symptoms. In graph theoretical analysis, an increase in connectivity occurred especially within brain regions associated with brainstem-cerebellar and thalamocortical vestibular networks and cortical sensorimotor networks. At the symptom peak (day 3 post UL), brain networks were found to be organized in large ensembles of distinct and highly connected hubs of brain regions, which separated again with progressing VC. Thus, we found rapid changes in network organization at the subcortical and cortical level and in both hemispheres, which may indicate an initial functional substitution of vestibular loss and subsequent recalibration and reorganization of sensorimotor networks during VC.

Metabolic connectivity-based single subject classification by multi-regional linear approximation in the rat.

Metabolic connectivity patterns on the basis of [18F]-FDG positron emission tomography (PET) are used to depict complex cerebral network alterations in different neurological disorders and therefore may have the potential to support diagnostic decisions. In this study, we established a novel statistical classification method taking advantage of differential time-dependent states of whole-brain metabolic connectivity following unilateral labyrinthectomy (UL) in the rat and explored its classification accuracy. The dataset consisted of repeated [18F]-FDG PET measurements at baseline and 1, 3, 7, and 15 days (= maximum of 5 classes) after UL with 17 rats per measurement day. Classification in different stages after UL was performed by determining connectivity patterns for the different classes by Pearson's correlation between uptake values in atlas-based segmented brain regions. Connections were fitted with a linear function, with which different thresholds on the correlation coefficient (r = [0.5, 0.85]) were investigated. Rats were classified by determining the congruence of their PET uptake pattern with the fitted connectivity patterns in the classes. Overall, the classification accuracy with this method was 84.3% for 3 classes, 75.0% for 4 classes, and 54.1% for 5 classes and outperformed random classification as well as machine learning classification on the same dataset. The optimal classification thresholds of the correlation coefficient and distance-to-fit were found to be |r| > 0.65 and d = 4 when using Siegel's slope estimator for fitting. This connectivity-based classification method can compete with machine learning classification and may have methodological advantages when applied to support PET-based diagnostic decisions in neurological network disorders (such as neurodegenerative syndromes).

[Diagnosis and Differential Diagnosis of Peripheral and Central Vestibular Disorders]. / Diagnose und Differenzialdiagnose von peripheren und zentralen Schwindelsyndromen.

The diagnosis of the various peripheral and central vestibular disorders is mainly based on the patient history (time course, type of symptoms, modulating factors, and accompanying symptoms) and a systematic clinical examination of the vestibular, ocular motor, and cerebellar systems (examination for nystagmus, head impulse test, positional maneuvers, Romberg test and examination for central ocular motor signs). The two most important laboratory tests are the "video-head impulse test" and caloric irrigation. Fortunately, the diagnosis of vestibular disorders has become easier and more precise as a result of the very clinically oriented diagnostic criteria of the Bárány Society (www.jvr-web.org/ICVD.html).

[Update on diagnosis and therapy in frequent vestibular and balance disorders]. / Aktuelles zu den häufigen Schwindelsyndromen: Diagnostik und Therapie.

The 8 most frequent vestibular disorders account for more than 70% of all presentations of vertigo, dizziness, and imbalance. In acute (and mostly non-repetitive) vestibular disorders acute unilateral vestibulopathy and vestibular stroke are most important, in episodic vestibulopathies benign paroxysmal positional vertigo (BPPV), Menière's disease and vestibular migraine, and in chronic vestibular disorders bilateral vestibulopathy/presbyvestibulopathy, functional dizziness and cerebellar dizziness. In the last decade, internationally consented diagnostic criteria and nomenclature were established for the most frequent vestibular disorders, which can be easily applied in clinical practice. The diagnostic guidelines are based on history taking (including onset, duration, course, triggers, accomanying symptoms), clinical examination, and only a few apparative tests (by videooculography and audiometry) for securing the diagnosis. Treatment of vestibular disorders includes physical training (repositioning maneuvers, multimodal balance training) and pharmacological approaches (e.g., corticosteroids, antiepileptics, antidepressants, potassium-canal-blockers, drugs enhancing neuroplasticity). For most drugs, high-level evidence from prospective controlled trials is lacking. In clinical practice, the most frequent vestibular disorders can be treated effectively, thus avoiding chronicity and secondary comorbidity (by immobility, falls or psychiatric disorders such as anxiety or depression).

Vertigo and dizziness in the emergency room.

PURPOSE OF REVIEW: To provide an update on diagnostic algorithms for differential diagnosis of acute vertigo and dizziness and swift identification of potentially harmful causes. RECENT FINDINGS: About 25% of patients with acute vertigo and dizziness have a potentially life-threatening diagnosis, including stroke in 4-15%. Diagnostic work-up relies on the combination of symptom features (triggers, duration, history of vertigo/dizziness, accompanying symptoms) and a comprehensive vestibular, ocular motor, and balance exam. The latter includes head impulse, head-shaking nystagmus, positional nystagmus, gaze-holding, smooth pursuit, skew deviation, and Romberg's test. Recent standardized diagnostic algorithms (e.g., HINTS, TriAGe+) suggest the combination of several elements to achieve a good diagnostic accuracy in differentiation of central and peripheral vestibular causes. Neuroimaging with MRI must be applied and interpreted with caution, as small strokes are frequently overlooked, especially in the acute setting (false-negative rate of up to 50%). SUMMARY: Diagnostic differentiation of acute vertigo and dizziness remains a complex task, which can be tackled by a structured clinical assessment focusing on symptom characteristics and constellations of ocular motor and vestibular findings. Specific challenges arise in cases of transient or atypical vestibular syndromes.

Longitudinal TSPO expression in tau transgenic P301S mice predicts increased tau accumulation and deteriorated spatial learning.

BACKGROUND: P301S tau transgenic mice show age-dependent accumulation of neurofibrillary tangles in the brainstem, hippocampus, and neocortex, leading to neuronal loss and cognitive deterioration. However, there is hitherto only sparse documentation of the role of neuroinflammation in tau mouse models. Thus, we analyzed longitudinal microglial activation by small animal 18 kDa translocator protein positron-emission-tomography (TSPO µPET) imaging in vivo, in conjunction with terminal assessment of tau pathology, spatial learning, and cerebral glucose metabolism. METHODS: Transgenic P301S (n = 33) and wild-type (n = 18) female mice were imaged by 18F-GE-180 TSPO µPET at the ages of 1.9, 3.9, and 6.4 months. We conducted behavioral testing in the Morris water maze, 18F-fluordesoxyglucose (18F-FDG) µPET, and AT8 tau immunohistochemistry at 6.3-6.7 months. Terminal microglial immunohistochemistry served for validation of TSPO µPET results in vivo, applying target regions in the brainstem, cortex, cerebellum, and hippocampus. We compared the results with our historical data in amyloid-ß mouse models. RESULTS: TSPO expression in all target regions of P301S mice increased exponentially from 1.9 to 6.4 months, leading to significant differences in the contrasts with wild-type mice at 6.4 months (+ 11-23%, all p < 0.001), but the apparent microgliosis proceeded more slowly than in our experience in amyloid-ß mouse models. Spatial learning and glucose metabolism of AT8-positive P301S mice were significantly impaired at 6.3-6.5 months compared to the wild-type group. Longitudinal increases in TSPO expression predicted greater tau accumulation and lesser spatial learning performance at 6.3-6.7 months. CONCLUSIONS: Monitoring of TSPO expression as a surrogate of microglial activation in P301S tau transgenic mice by µPET indicates a delayed time course when compared to amyloid-ß mouse models. Detrimental associations of microglial activation with outcome parameters are opposite to earlier data in amyloid-ß mouse models. The contribution of microglial response to pathology accompanying amyloid-ß and tau over-expression merits further investigation.

Cerebellar Dizziness and Vertigo: Etiologies, Diagnostic Assessment, and Treatment.

Cerebellar dizziness and vertigo account for approximately 10% of diagnoses in a tertiary dizziness center. This term summarizes a large group of disorders with chronic (degenerative, hereditary, acquired cerebellar ataxias), recurrent (episodic ataxias), or acute (stroke, inflammation) presentations. Key to the diagnosis is a comprehensive examination of central ocular motor and vestibular function. Patients with cerebellar dizziness and vertigo usually show a pattern of deficits in smooth pursuit, gaze-holding, saccade accuracy, or fixation-suppression of the vestibulo-ocular reflex. Central fixation nystagmus (e.g., downbeat nystagmus), gaze-evoked nystagmus, central positional nystagmus, or head-shaking nystagmus with cross-coupling (i.e., horizontal head shaking causing inappropriate vertical nystagmus) occurs frequently. Overlap syndromes with peripheral vestibular disorders, such as cerebellar ataxia, neuropathy, and vestibular areflexia, exist rarely. Posturography and gait analysis can contribute to diagnostic differentiation, estimation of the risk of falls, as well as quantification of progression and treatment effects. Patients with cerebellar dizziness and vertigo should receive multimodal treatment, including balance training, occupational therapy, and medication.

What Is Behind Cerebellar Vertigo and Dizziness?

The differential diagnosis of vertigo or dizziness as a result of cerebellar disorders can be difficult as many patients with a cerebellar pathology do not present with the full spectrum of cerebellar signs. The main goal of this study was to describe the typical clinical features of these patients with vertigo or dizziness of a cerebellar origin. We reviewed the medical records of 5400 patients with vertigo and dizziness from our tertiary outpatient clinic for vertigo and balance disorders. In 459 the diagnosis of "cerebellar vertigo or dizziness" was made; 90 patients were excluded from further analysis due to evident structural changes in MRI. Of the remaining 369 patients (67.0 ± 15.1, 54% female, symptom duration until diagnosis 5.5 ± 6.9 years), 81% suffered from persistent vertigo or dizziness, 31% from attacks of vertigo and dizziness and 21% from both. Neuro-ophthalmologically, 95% had saccadic smooth pursuit, 80% gaze-holding deficits, 64% a pathological fixation suppression of the VOR, 24% central fixation nystagmus (in 64% of these cases downbeat nystagmus (DBN)), 23% rebound nystagmus, and an ocular misalignment in 84% in near view and 50% in distance view. Eleven percent had isolated mild to moderate cerebellar ocular motor disturbances without any other typical cerebellar signs. The most common diagnoses were sporadic adult-onset degenerative ataxia in 26%; idiopathic DBN syndrome in 20%; cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in 10%; episodic ataxia type 2 in 7%; and multiple system atrophy cerebellar type in 6%. In posturography, a typical cerebellar 3-Hz sway was found in 16%. The diagnostic key to patients with cerebellar vertigo or dizziness is a careful examination of eye movements since practically all of them have cerebellar ocular disturbances.

Coupling between physiological TSPO expression in brain and myocardium allows stabilization of late-phase cerebral [18F]GE180 PET quantification.

OBJECTIVES: PET imaging of the 18 kDa translocator protein (TSPO), a biomarker of microglial activity, receives growing interest in clinical and preclinical applications of neuroinflammatory and neurodegenerative brain diseases. In globally affected brains, intra-cerebral pseudo reference regions are not feasible. Consequently, many brain-independent approaches have been attempted, including SUV analysis and normalization to muscle- or heart uptake, aiming to stabilize quantitative analysis. In this study, we systematically compared different image normalization methods for static late phase TSPO-PET imaging of rodent brain. METHODS: We first obtained gamma counter measurements for gold standard quantitation of [18F]GE180 uptake in brain of C57Bl/6 mice (N = 10) after PET, aiming to identify factors contributing significantly to the quantitative results. Subsequently, data from a large cohort of C57Bl/6 mice (N = 79) were compiled to precisely determine the weighted influence and variance attributable these factors by regression analysis. Scan-rescan variability and agreement with histology were used to validate the tested normalization methods in an Alzheimer's disease (AD) mouse model with pathologically increased TSPO expression (PS2APP; N = 24). Longitudinal data from AD model mice (N = 10) scanned at four different ages were used to challenge and validate the different normalization methods in a practical application. RESULTS: Gamma counter results revealed that injected dose, body weight and PET-measured radioactivity concentration in the ventral myocardium all significantly accounted for [18F]GE180 activity in the brain. Skeletal muscle activity had high test-retest variance in this PET only application and was therefore pursued no further. Regression analysis of the large scale evaluation showed that scaling to injected dose or SUV analysis accounted for little variance in brain activity (R2 < 0.5), but inclusion of myocardial activity together with injected dose and body weight in the regression model accounted for most of the variance in brain uptake (R2 = 0.94). Scan-rescan stability, correlation with histology and applicability for longitudinal examination in the disease model were also significantly improved by inclusion of myocadial uptake in the quantitative model. CONCLUSION: Cerebral and myocardial TSPO expression are highly coupled under physiological conditions. Myocardial uptake has great potential for stabilization of static late phase [18F]GE180 quantification in brain in the absence of a valid intra-cerebral pseudo-reference region.