Thalamic pathology in frontotemporal dementia: Predilection for specific nuclei, phenotype-specific signatures, clinical correlates, and practical relevance.

BACKGROUND: Frontotemporal dementia (FTD) phenotypes are classically associated with distinctive cortical atrophy patterns and regional hypometabolism. However, the spectrum of cognitive and behavioral manifestations in FTD arises from multisynaptic network dysfunction. The thalamus is a key hub of several corticobasal and corticocortical circuits. The main circuits relayed via the thalamic nuclei include the dorsolateral prefrontal circuit, the anterior cingulate circuit, and the orbitofrontal circuit. METHODS: In this paper, we have reviewed evidence for thalamic pathology in FTD based on radiological and postmortem studies. Original research papers were systematically reviewed for preferential involvement of specific thalamic regions, for phenotype-associated thalamic disease burden patterns, characteristic longitudinal changes, and genotype-associated thalamic signatures. Moreover, evidence for presymptomatic thalamic pathology was also reviewed. Identified papers were systematically scrutinized for imaging methods, cohort sizes, clinical profiles, clinicoradiological associations, and main anatomical findings. The findings of individual research papers were amalgamated for consensus observations and their study designs further evaluated for stereotyped shortcomings. Based on the limitations of existing studies and conflicting reports in low-incidence FTD variants, we sought to outline future research directions and pressing research priorities. RESULTS: FTD is associated with focal thalamic degeneration. Phenotype-specific thalamic traits mirror established cortical vulnerability patterns. Thalamic nuclei mediating behavioral and language functions are preferentially involved. Given the compelling evidence for considerable thalamic disease burden early in the course of most FTD subtypes, we also reflect on the practical relevance, diagnostic role, prognostic significance, and monitoring potential of thalamic metrics in FTD. CONCLUSIONS: Cardinal manifestations of FTD phenotypes are likely to stem from thalamocortical circuitry dysfunction and are not exclusively driven by focal cortical changes.

Unique Subtype of Microglia in Degenerative Thalamus After Cortical Stroke.

BACKGROUND AND PURPOSE: Stroke disrupts neuronal functions in both local and remotely connected regions, leading to network-wide deficits that can hinder recovery. The thalamus is particularly affected, with progressive development of neurodegeneration accompanied by inflammatory responses. However, the complexity of the involved inflammatory responses is poorly understood. Herein we investigated the spatiotemporal changes in the secondary degenerative thalamus after cortical stroke, using targeted transcriptome approach in conjunction with histology and flow cytometry. METHODS: Cortical ischemic stroke was generated by permanent occlusion of the left middle cerebral artery in male C57BL6J mice. Neurodegeneration, neuroinflammatory responses, and microglial activation were examined in naive and stroke mice at from poststroke days (PD) 1 to 84, in both ipsilesional somatosensory cortex and ipsilesional thalamus. NanoString neuropathology panel (780 genes) was used to examine transcriptome changes at PD7 and PD28. Fluorescence activated cell sorting was used to collect CD11c+ microglia from ipsilesional thalamus, and gene expressions were validated by quantitative real-time polymerase chain reaction. RESULTS: Neurodegeneration in the thalamus was detected at PD7 and progressively worsened by PD28. This was accompanied by rapid microglial activation detected as early as PD1, which preceded the neurodegenerative changes. Transcriptome analysis showed higher number of differentially expressed genes in ipsilesional thalamus at PD28. Notably, neuroinflammation was the top activated pathway, and microglia was the most enriched cell type. Itgax (CD11c) was the most significantly increased gene, and its expression was highly detected in microglia. Flow-sorted CD11c+ microglia from degenerative thalamus indicated molecular signatures similar to neurodegenerative disease-associated microglia; these included downregulated Tmem119 and CX3CR1 and upregulated ApoE, Axl, LpL, CSF1, and Cst7. CONCLUSIONS: Our findings demonstrate the dynamic changes of microglia after stroke and highlight the importance of investigating stroke network-wide deficits. Importantly, we report the existence of a unique subtype of microglia (CD11c+) with neurodegenerative disease-associated microglia features in the degenerative thalamus after stroke.

Robot-assisted stereotactic biopsy of pediatric brainstem and thalamic lesions.

OBJECTIVE: Biopsies of tumors located in deep midline structures require highly accurate stereotaxy to safely obtain lesional tissue suitable for molecular and histological analysis. Versatile platforms are needed to meet a broad range of technical requirements and surgeon preferences. The authors present their institutional experience with the robotic stereotactic assistance (ROSA) system in a series of robot-assisted biopsies of pediatric brainstem and thalamic tumors. METHODS: A retrospective analysis was performed of 22 consecutive patients who underwent 23 stereotactic biopsies of brainstem or thalamic lesions using the ROSA platform at Rady Children's Hospital in San Diego between December 2015 and January 2020. RESULTS: The ROSA platform enabled rapid acquisition of lesional tissue across various combinations of approaches, registration techniques, and positioning. No permanent deficits, major adverse outcomes, or deaths were encountered. One patient experienced temporary cranial neuropathy, and 3 developed small asymptomatic hematomas. The diagnostic success rate of the ROSA system was 91.3%. CONCLUSIONS: Robot-assisted stereotactic biopsy of these lesions may be safely performed using the ROSA platform. This experience comprises the largest clinical series to date dedicated to robot-assisted biopsies of brainstem and diencephalic tumors.

Osteopontin Attenuates Secondary Neurodegeneration in the Thalamus after Experimental Stroke.

Cortical cerebral ischemia elicits neuroinflammation as well as secondary neuronal degeneration in remote areas. Locally distinct and specific secondary neurodegeneration affecting thalamic nuclei connected to cortical areas highlights such processes. Osteopontin (OPN) is a cytokine-like glycoprotein that is excreted in high amounts after cerebral ischemia and exerts various immunomodulatory functions. We here examined putative protective effects of OPN in secondary thalamic degeneration. We subjected male Wistar rats to photothrombosis and subsequently injected OPN or placebo intracerebroventricularly. Immunohistochemical and fluorescence staining was used to detect the extent of neuronal degeneration and microglia activation. Ex vivo autoradiography with radiotracers available for human in vivo PET studies, i.e., CIS-4-[18F]Fluor-D-Proline (D-cis-[18F]FPRO), and [6-3H]thymidine ([3H]thymidine), confirmed degeneration and proliferation, respectively. We found secondary neurodegeneration in the thalamus characterized by microglial activation and neuronal loss. Neuronal loss was restricted to areas of microglial infiltration. Treatment with OPN significantly decreased neurodegeneration, inflammation and microglial proliferation. Microglia displayed morphological signs of activation without expressing markers of M1 or M2 polarization. D-CIS-[18F]FPRO-uptake mirrored attenuated degeneration in OPN-treated animals. Notably, [3H]thymidine and BrdU-staining revealed increased stem cell proliferation after treatment with OPN. The data suggest that OPN is able to ameliorate secondary neurodegeneration in thalamic nuclei. These effects can be visualized by radiotracers D-CIS-[18F]FPRO and [3H]thymidine, opening new vistas for translational studies. Graphical Abstract Intracerebroventricular injection of osteopontin attenuates thalamic degeneration after cortical ischemia (pink area). Disruption of thalamocortical connections (blue) and degeneration of thalamic nuclei (encircled) leads to microglia activation. Osteopontin protects from both neurodegeneration and microglia activation as assessed by histological analysis and autoradiograpic studies.

Delayed-onset central poststroke pain due to degeneration of the spinothalamic tract following thalamic hemorrhage: A case report.

RATIONALE: Recent studies have used diffusion tensor tractography (DTT) to demonstrate that central poststroke pain (CPSP) was related to spinothalamic tract (STT) injury in patients with stroke. However, few studies have been reported about delayed-onset CPSP due to degeneration of the STT following a stroke. PATIENT'S CONCERNS: A 57-year-old female patient presented with right hemiparesis after stroke. Two weeks after onset, she did not report any pain. At approximately 6 months after onset, she reported pain in the right arm and leg, and the pain slowly intensified with the passage of time. At 14 months after onset, the characteristics and severity of her pain were assessed to be continuous pain without allodynia or hyperalgesia; tingling and cold-sensational pain in her right whole arm and leg (visual analog scale score: 5). DIAGNOSES: The patient was diagnosed as the right hemiparesis due to spontaneous thalamic hemorrhage. INTERVENTIONS: Clinical assessment and diffusion tensor imaging (DTI) were performed 2 weeks and 14 months after onset. OUTCOMES: She suffered continuous pain in her right whole arm and leg (visual analog scale score: 5). On DTT of the 2-week postonset DTI scans, the configuration of the STT was well-preserved in both hemispheres. However, in contrast to those 2-week postonset results, the 14-month postonset DTT results showed partial tearing and thinning in the left STT. Regardless, both the 2-week and 14-month postonset DTT showed that the left STT passed through the vicinity of the thalamic lesion. LESSONS: Diagnostic importance of performing a DTT-based evaluation of the STT in patients exhibiting delayed-onset CPSP following intracerebral hemorrhage.

Persistent anterograde amnesia due to the artery of Percheron occlusion: a case report.

Bilateral thalamic infarction involving the artery of Percheron (AOP) can cause diagnostic difficulties due to the varying clinical presentations. AOP infarcts presented with isolated memory impairment are not common and the factors affecting the persistence of memory disorders are still unknown. A 41-year-old male patient was hospitalized with acute unconsciousness. MRI disclosed bilateral paramedian thalamic infarction The patient had isolated memory deficit and his anterograde amnesia continued without any change in the past decade. More cases might answer the questions concerning the intra- and extra-thalamic structures responsible for the amnesic syndrome and the factors affecting the persistence of the symptoms.

Clinical and Neuroimaging Findings in Thalamic Territory Infarctions: A Review.

The thalamus is a part of the diencephalon, containing numerous connections between the forebrain and subcortical structures. It serves an important function as a relay center between the cerebral cortex and the subcortical regions, particularly with sensory information. The thalamus also plays a major role in regulating arousal and the levels of awareness. Distinct vascular distribution of the thalamus give rises to different syndromic presentation of thalamic nuclei infarcts. The clinical records and available imaging studies of patients with confirmed thalamic territory infarcts on magnetic resonance imaging (MRI) at the University Hospital of Rochester were reviewed and analyzed. This analysis was then used to provide an effective summary of thalamic vascular anatomy, the clinical symptoms, and syndromes associated with strokes in the affected territories. Specifically, we review the syndromes associated with classic vascular territories, including the anterior, paramedian, inferolateral, and posterior thalamic nuclei, that are supplied by the polar (tuberothalamic), paramedian, inferolateral (thalamogeniculate), and posterior choroidal arteries, respectively. In addition, we will also review the variant thalamic territories and associated infarction syndromes of the anteromedian, central, and posterolateral territories. This review article is aimed to better the clinical and radiologic understanding as well as the diagnosis of classic and variant thalamic territory infarcts. This article will also briefly touch on the recovery of function after thalamic infarcts.

Degeneration of paramedian nuclei in the thalamus induces Holmes tremor in a case of artery of Percheron infarction.

RATIONALE: Holmes' tremor is an uncommon neurologic disorder following brain insults, and its pathogenesis is undefined. The interruption of the dento-rubro-thalamic tract and secondary deterioration of the nigrostriatal pathway are both required to initiate Holmes' tremor. We used nuclear medicine imaging tools to analyze a patient with concurrent infarction in different zones of each side of the thalamus. Finding whether the paramedian nuclear groups of the thalamus were injured was a decisive element for developing Holmes' tremor. PATIENT CONCERNS: A 36-year-old woman was admitted to our department due to a bilateral paramedian thalamic infarction. Seven months after the stroke, a unilaterally involuntary trembling with irregularly wavering motions occurring in both her left hand and forearm. DIAGNOSIS: Based on the distinct features of the unilateral coarse tremor and the locations of the lesions on the magnetic resonance imaging (MRI), the patient was diagnosed with bilateral paramedian thalamic infarction complicated with a unilateral Holmes' tremor. INTERVENTIONS: The patient refused our recommendation of pharmacological treatment with levodopa and other dopamine agonists based on personal reasons and was only willing to accept physical and occupational training programs at our outpatient clinic. OUTCOMES: We utilized serial anatomic and functional neuroimaging of the brain to survey the neurologic deficit. A brain magnetic resonance imaging showed unequal recovery on each side of the thalamus. The residual lesion appeared larger in the right-side thalamus and had gathered in the paramedian area. A brain perfusion single-photon emission computed tomography (SPECT) revealed that the post-stroke hypometabolic changes were not only in the right-side thalamus but also in the right basal ganglion, which was anatomically intact. Furthermore, the brain Technetium-99m-labeled tropanes as a dopamine transporter imaging agents scan ( Tc-TRODAT-1) displayed a secondary reduction of dopamine transporters in the right nigrostriatal pathway which had resulted from the damage on the paramedian nuclear groups of the right-side thalamus. LESSONS: Based on the functional images, we illustrated that a retrograde degeneration originating from the thalamic paramedian nuclear groups, and extending forward along the direct innervating fibers of the mesothalamic pathway, played an essential role towards initiating Holmes' tremor.

Pediatric Thalamic Gliomas: An Updated Review.

CONTEXT: - Neoplasms originating in the thalamus are rare overall (1% of all brain tumors); however, they comprise approximately 5% of pediatric intracranial tumors and approach 15% of all malignant pediatric intracranial tumors in some series. OBJECTIVE: - To update readers about the current understanding of the diverse histology, biology, and behavior of pediatric thalamic tumors. Histologic verification is now thought to be critical for planning treatment, and, as a result, biopsy and total/subtotal resections are much more common today than in the past. DATA SOURCES: - A PubMed search using the keywords "pediatric + thalamic + glioma" yielded 45 publications with a total of 445 cases of thalamic gliomas in patients less than 18 years of age. We found only 9 substantial institutional series tabulating all encountered thalamic histologic types in children. This survey confirmed a high proportion of astrocytomas, 81% (214 of 265), of which approximately two-thirds were diffuse astrocytomas (146 of 214) and one-third were pilocytic astrocytomas (68 of 214). Of the diffuse astrocytomas, 34% (49 of 146) were low grade (World Health Organization grade II) and 55% (81 of 146) were high grade (World Health Organization grade III or IV), making the latter subgroup the largest single category of all pediatric thalamic tumors. Oligodendrogliomas and ependymomas (mostly anaplastic in both cases) comprised 10% and 3% of all pediatric thalamic tumors, respectively. CONCLUSIONS: - Tissue diagnosis is now thought crucial for prognostication and treatment, particularly as more potentially therapeutic molecular targets are discovered. Secure diagnosis allows identification of tumors for which resection is more feasible and beneficial.

Third Ventricular Cerebrospinal Fluid Cysts of Thalamic Origin: Review of Embryologic Origin, Presentation, and Management Strategies with a Case Series.

OBJECTIVE: Third ventricular cerebrospinal fluid (CSF) cysts of thalamic origin are rare. The objective of this study is to review their possible pathogenesis, clinical presentation, and management strategies with a case series describing management via an endoscopic approach with fenestration using a single burr-hole technique. METHODS: A systematic literature review of reported cases of thalamic cysts was conducted with further meta-analysis of CSF cysts that involve the third ventricle. The mode of presentation, pathologic analysis, surgical management, and outcomes were analyzed. RESULTS: Twenty-two studies reported between 1990 and 2013 described 42 cases of thalamic cyst. Of those cases, 13 were consistent with CSF cyst that originated in the thalamus and involved the third ventricle. Eight cases (61.5%) were treated via endoscopic fenestration, 2 cases (15.4%) were surgically drained, 2 cases (15.4%) were stereotactically aspirated, and 1 case (7.69%) was observed. The most common presenting symptoms were gait disturbance (26.3%) and headaches (26.3%) followed by tremors (15.8%) and weakness (15.8%). In our series, a single burr-hole technique was a successful definitive treatment, with an average period of 23 months. CONCLUSIONS: Third ventricular CSF cysts of thalamic origin most commonly present with hydrocephalus. They can be safely definitively treated via endoscopic fenestration to the CSF circulation using a single burr-hole technique. Long-term follow-up shows lasting improvement in symptoms without reaccumulation of the cyst.

Distant recurrences limit the survival of patients with thalamic high-grade gliomas after successful resection.

The indications of surgery for thalamic high-grade gliomas are not well established. The present study investigated the outcome of 21 patients treated by surgery and reports the high incidence of distant recurrences including disseminations after successful removal. Twenty-one patients with thalamic high-grade gliomas not invading the pyramidal tract or midbrain underwent cytoreductive surgery at our institute from June 1997 to August 2015. Surgery was performed with the aid of a neuronavigation system, electrophysiological monitoring, and fluorescence navigation. Tumor histology included 12 cases of the World Health Organization grade III and nine cases of grade IV. Gross total resection was achieved in six cases, subtotal in 13, and partial in two. Motor weakness accompanied by sensory disturbance deteriorated immediately after surgery in 13 patients. However, five patients were determined to show deterioration at 2 months after surgery. Postoperative radiation and chemotherapy were given to every patient, and median progression-free survival of patients with grade III and IV tumors was 12.1 and 7.0 months, respectively. Median overall survival of patients with grade III and IV tumors was 25.6 and 12.6 months, respectively. High incidence of distant recurrences was found, with distant lesions at recurrence in 13 of 19 patients with recurrence, suggesting the life-restricting factor in these patients. Thalamic high-grade glioma without invasion into the pyramidal tract and brainstem can be considered as a candidate for surgical resection. Distant lesion limits the survival of patients after successful resection.

High-Definition Fiber Tractography in Evaluation and Surgical Planning of Thalamopeduncular Pilocytic Astrocytomas in Pediatric Population: Case Series and Review of Literature.

OBJECTIVE: Thalamopeduncular tumors (TPTs) of childhood present a challenge for neurosurgeons due to their eloquent location. Preoperative fiber tracking provides total or near-total resection, without additional neurologic deficit. High-definition fiber tractography (HDFT) is an advanced white matter imaging technique derived from magnetic resonance imaging diffusion data, shown to overcome the limitations of diffusion tensor imaging. We aimed to investigate alterations of corticospinal tract (CST) and medial lemniscus (ML) caused by TPTs and to demonstrate the application of HDFT in preoperative planning. METHODS: Three pediatric patients with TPTs were enrolled. CSTs and MLs were evaluated for displacement, infiltration, and disruption. The relationship of these tracts to tumors was identified and guided surgical planning. Literature was reviewed for publications on pediatric thalamic and TPTs that used diffusion imaging. RESULTS: Two patients had histologic diagnosis of pilocytic astrocytoma. One patient whose imaging suggested a low-grade glioma was managed conservatively. All tracts were displaced (1 CST anteriorly, 2 CSTs, 1 ML anteromedially, 1 ML medially, and 1 ML posteromedially). Literature review revealed 2 publications with 15 pilocytic astrocytoma cases, which investigated CST only. The condition of sensory pathway or anteromedial displacement of the CST in these tumors was not reported previously. CONCLUSIONS: Displacement patterns of the perilesional fiber bundles by TPTs are not predictable. Fiber tracking, preferably HDFT, should be part of preoperative planning to achieve maximal extent of resection for longer survival rates in this young group of patients, while preserving white matter tracts and thus quality of life.

Bilateral Thalamic Glioma: Case Report and Review of the Literature.

Bilateral thalamic glioma is extremely rare and the incidence cannot be adequately expressed. We present the case of a 72 years old male suffering from the rapid deterioration of cognitive function to moderately severe dementia in a short period of time. Magnetic resonance studies demonstrated a bilateral thalamic glioma with a minimal focal gadolinium uptake in the left thalamus. Biopsy was performed and pathology report was of anaplastic astrocytoma, WHO grade III. Radiotherapy was proposed but was rejected by the patient's relatives. The patient deceased 57 days later. We performed an extensive review of the literature and by updating the previous described series we can state that to the best of our knowledge this is the 60th case described in the literature and the second eldest patient presented. Patients suffering from this disease present a poor prognosis, the longest survival described being of 3 years in patients diagnosed with grade II bilateral thalamic glioma. Adjuvant therapy in form of radiotherapy to the thalami is most commonly used but the benefits are unclear. The natural progression of WHO grade III bilateral thalamic glioma left untreated, as can be seen from our case, has an even poorer outcome.

A case report on 1-year follow-up of bilateral thalamic glioma.

Bilateral thalamic glioma is one of the rarest tumor occurrences, representing a small fraction of thalamic gliomas, which only accounts for 1-1.5% of all brain tumors. It is usually a diffuse, low-grade astrocytoma (WHO grade II), seen mainly in adults, with approximately 25% of them involving children under the age of 15. Radiotherapy is the main mode of treatment since surgical intervention is limited to a role of biopsy and management of secondary effects, due to the deep brain location of the lesion and the complexity of the involved structures. We report a 1-year follow-up of a 55-year-old female patient with bilateral WHO grade II thalamic astrocytoma. Following histological and neuroradiological consensus regarding the diagnosis, the patient was referred for radiotherapy. The effectiveness of available therapy and long-term neuroradiological follow-up is not reliably established due to rapid fatal evolution following diagnosis. Contrary to the norm, our patient showed stable disease with radiotherapy for a 1-year period.

Repeated head trauma is associated with smaller thalamic volumes and slower processing speed: the Professional Fighters' Brain Health Study.

OBJECTIVES: Cumulative head trauma may alter brain structure and function. We explored the relationship between exposure variables, cognition and MRI brain structural measures in a cohort of professional combatants. METHODS: 224 fighters (131 mixed martial arts fighters and 93 boxers) participating in the Professional Fighters Brain Health Study, a longitudinal cohort study of licensed professional combatants, were recruited, as were 22 controls. Each participant underwent computerised cognitive testing and volumetric brain MRI. Fighting history including years of fighting and fights per year was obtained from self-report and published records. Statistical analyses of the baseline evaluations were applied cross-sectionally to determine the relationship between fight exposure variables and volumes of the hippocampus, amygdala, thalamus, caudate, putamen. Moreover, the relationship between exposure and brain volumes with cognitive function was assessed. RESULTS: Increasing exposure to repetitive head trauma measured by number of professional fights, years of fighting, or a Fight Exposure Score (FES) was associated with lower brain volumes, particularly the thalamus and caudate. In addition, speed of processing decreased with decreased thalamic volumes and with increasing fight exposure. Higher scores on a FES used to reflect exposure to repetitive head trauma were associated with greater likelihood of having cognitive impairment. CONCLUSIONS: Greater exposure to repetitive head trauma is associated with lower brain volumes and lower processing speed in active professional fighters.

Anomalous Origin of Left Vertebral Artery from Carotid Bulb Seen as "Trifurcation" of Left Common Carotid Artery with Acute Infarct in Ipsilateral Thalamus: A Case Report.

Anomalous origin of vertebral arteries is not common and usually seen as an incidental finding on imaging. We report a case of anomalous origin of left vertebral artery from left carotid bulb ("trifurcation" of left common carotid artery) on magnetic resonance angiography in a 64-year old male who also had ipsilateral thalamic acute infarct.