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BACKGROUND: Observations in people with cerebral cavernous malformations, and in preclinical models of this disorder, suggest that the β-blocker propranolol might reduce the risk of intracerebral haemorrhage. We aimed to evaluate the safety and efficacy of prolonged treatment with propranolol to reduce the incidence of symptomatic intracerebral haemorrhage or focal neurological deficit in people with familial cerebral cavernous malformations.METHODS: We conducted a randomised, open-label, blinded-endpoint, phase 2 pilot trial (Treat_CCM) at six national reference centres for rare diseases in Italy. People aged 18 years or older with symptomatic familial cerebral cavernous malformation were eligible for enrolment. Participants were randomly assigned (2:1) to receive either oral propranolol (20-320 mg daily) plus standard care (intervention group), or standard care alone (control group), for 24 months. Participants, caregivers, and investigators were aware of treatment group assignment. Participants had clinical assessments and 3 T brain MRI at baseline and at 12 and 24 months. The primary outcome was new occurrence of symptomatic intracerebral haemorrhage or focal neurological deficit attributable to cerebral cavernous malformation over 24 months. Outcome assessors were masked to treatment group assignment. The primary analysis was done in the intention-to-treat population. Because of the pilot study design, we chose a one-sided 80% CI, which could either exclude a clinically meaningful effect or show a signal of efficacy. This trial is registered with EudraCT, 2017-003595-30, and ClinicalTrials.gov, NCT03589014, and is closed to recruitment.FINDINGS: Between April 11, 2018, and Dec 5, 2019, 95 people were assessed for eligibility and 83 were enrolled, of whom 57 were assigned to the propranolol plus standard care group and 26 to the standard care alone group. The mean age of participants was 46 years (SD 15); 48 (58%) were female and 35 (42%) were male. The incidence of symptomatic intracerebral haemorrhage or focal neurological deficit was 1·7 (95% CI 1·4-2·0) cases per 100 person-years (two [4%] of 57 participants) in the propranolol plus standard care group and 3·9 (3·1-4·7) per 100 person-years (two [8%] of 26) in the standard care alone group (univariable hazard ratio [HR] 0·43, 80% CI 0·18-0·98). The univariable HR showed a signal of efficacy, according to predefined criteria. The incidence of hospitalisation did not differ between groups (8·2 cases [95% CI 7·5-8·9] per 100 person-years in the propranolol plus standard care group vs 8·2 [95% CI 7·1-9·3] per 100 person-years in the standard care alone group). One participant in the standard care alone group died of sepsis. Three participants in the propranolol plus standard care group discontinued propranolol due to side-effects (two reported hypotension and one reported weakness).INTERPRETATION: Propranolol was safe and well tolerated in this population. Propranolol might be beneficial for reducing the incidence of clinical events in people with symptomatic familial cerebral cavernous malformations, although this trial was not designed to be adequately powered to investigate efficacy. A definitive phase 3 trial of propranolol in people with symptomatic familial cerebral cavernous malformations is justified.FUNDING: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro, Swedish Science Council, Knut and Alice Wallenberg Foundation, CARIPLO Foundation, Italian Ministry of Health.

Background: For a long time, surgery of insular gliomas was considered at high risk for postoperative cognitive deficits, but recent studies highlighted the feasibility of the surgical approach. The aims of our study were to investigate the presence of language impairment before and after surgery and the relationship between language impairment and tumor volume preoperatively and extent of resection (EOR) 3 months after surgery. Methods: Thirty-five patients with insular gliomas underwent an extensive language assessment before and few days after surgery, and after 3 months. Intraoperative neurophysiological monitoring (IOM) and brain mapping with direct electrical stimulation (DES) were used in all the cases; 8 patients underwent awake craniotomy. Statistical analysis was performed on the language tests administered. Results: Patients with pure left insular lesion showed language impairment before and after surgery. Overall, patients with a left lesion showed a drop of performance after surgery followed by a partial recovery. Moreover, when the tumor involved the insula and adjacent networks, we observed a more severe deficit. No correlations were found between tumor volume, EOR, and language impairment. Conclusions: Left insular lobe is an important hub in language networks; its involvement determines pre- and postsurgical deficits, together with the involvement of white matter connections. Tumor volume and EOR are not risk factors per se directly related to language functioning. Surgery of insular gliomas is possible with a pre- and intraoperative extensive study of the patient with IOM and awake surgery, and encouraged by the trend of cognitive recovery highlighted.

OBJECTIVESome studies have highlighted psychological and neuropsychological difficulties and a potential reduction in health-related quality of life (HRQOL) in patients with pituitary tumors, despite hormone deficits or excess. To the authors’ knowledge, this study is the first prospective longitudinal case-control study with the aim of simultaneously testing whether HRQOL and psychiatric and neuropsychological disabilities are related to neural dysfunction due to hypercortisolism per se, or tumor mass and/or surgery in patients with Cushing’s disease (CD). The authors evaluated a homogeneous cohort of patients with CD and nonfunctioning pituitary adenomas (NFPAs) before and after neurosurgery and compared these patients with healthy controls.METHODSTwenty patients (10 with NFPA and 10 with CD) were evaluated using 3 validated questionnaires (SF-36, Beck Depression Inventory–II [BDI-II], and Minnesota Multiphasic Personality Inventory–II [MMPI-II]) to assess HRQOL and psychological status preoperatively and 12 months after neurosurgery. Neuropsychological tests were assessed preoperatively, 3–7 days postoperatively, and 12 months postoperatively. Twenty healthy matched controls were recruited.RESULTSPreoperatively, the NFPA and CD subgroups had worse HRQOL scores than controls on the basis of SF-36 scores, although the NFPA subgroup experienced significant recovery 12 months postoperatively. Preoperatively, CD patients had depressive symptoms according to the BDI-II and MMPI-II that persisted 12 months postoperatively, together with social introversion and hypochondriasis; NFPA patients were similar to controls except for hypochondriasis scores that were clinically significant at all timepoints. Preoperatively and 3–7 days postoperatively, both subgroups showed significant neuropsychological disabilities compared with controls, but only the CD subgroup did not completely recover over time.CONCLUSIONSHRQOL and neuropsychological impairments were observed in all patients at early timepoints, independent of hypercortisolism, tumor mass, and successful surgery. Over time, CD patients showed persistent changes in HRQOL, in particular in social activities. In this light, CD seems to have a strong impact on HRQOL and to be associated with more psychological and neuropsychological comorbidities than NFPA.

Introduction: Verbs and nouns can be selectively impaired, suggesting that they are processed, at least in part, by distinct neural structures. While several tests of object naming are available, tasks involving action verb naming with normative data are lacking. We report the construction and standardization of a new test for the assessment of picture naming of actions. Material and methods: The test includes 50 stimuli, strictly controlled for several confounding variables. Normative data on 290 Italian subjects pooled across homogenous subgroups for age, sex, and education are reported. Results: Multiple regression analyses revealed that age and education significantly correlated with the subject’s score. In particular, increasing age negatively affected performance, while the performance increased with a higher education. Conclusions: In the clinical practice, the availability of equivalent scores will help the comparison with performance in the picture naming of objects. This test allows investigating action naming deficits in aphasic patients, in Parkinson’s disease patients and in further neurodegenerative disorders, in which a specific impairment of action verbs is expected, filling a gap in the clinical neuropsychological assessment.

Patients affected by a high-grade glioma (HGG) have a poor prognosis with a median survival of 12–16 months. Such poor prognosis affects the perception of the remaining life by patients and the neuropsychological status can strongly affect every-day functioning of these patients. Monitoring changes of neuropsychological functioning (NPF) overtime may provide better clinical information and optimize the neuro-oncological management. The aims of our work were (1) to investigate the feasibility of a complex neuropsychological battery in HGG patients before and during follow-up after surgery; (2) to study the neuropsychological profile of patients affected by HGGs and their relation with the disease status (relapse/death) across time after surgery. One hundred two patients who received surgery for HGG between 2011 and 2017 were studied. All clinical data were prospectively recorded. NPF was assessed during the neuro-oncological follow-up through the Milano-Bicocca Battery (MIBIB). Statistical analysis was performed on the neuropsychological results of the tests administered. First, MIBIB proved to be suitable for patients with HGG tumors before and after surgery, and during long-term follow-up; it also showed a cluster structure representative of the principal cognitive domains. Second, we found a steep decline in the neuropsychological profile before death and/or tumor relapse for the 52% of the neuropsychological tests administered. Complex neuropsychological batteries can be administered to HGG patients before and during follow-up after surgery. There is a correlation between neuropsychological deterioration and tumor relapse and/or death, which may reflect a progressive damage to cognitive functions due to tumor infiltration and progression.

Patients affected by a high-grade glioma (HGG) have a poor prognosis with a median survival of 12-16 months. Such poor prognosis affects the perception of the remaining life by patients and the neuropsychological status can strongly affect every-day functioning of these patients. Monitoring changes of neuropsychological functioning (NPF) overtime may provide better clinical information and optimize the neuro-oncological management. The aims of our work were (1) to investigate the feasibility of a complex neuropsychological battery in HGG patients before and during follow-up after surgery; (2) to study the neuropsychological profile of patients affected by HGGs and their relation with the disease status (relapse/death) across time after surgery.One hundred two patients who received surgery for HGG between 2011 and 2017 were studied. All clinical data were prospectively recorded. NPF was assessed during the neuro-oncological follow-up through the Milano-Bicocca Battery (MIBIB). Statistical analysis was performed on the neuropsychological results of the tests administered.First, MIBIB proved to be suitable for patients with HGG tumors before and after surgery, and during long-term follow-up; it also showed a cluster structure representative of the principal cognitive domains. Second, we found a steep decline in the neuropsychological profile before death and/or tumor relapse for the 52% of the neuropsychological tests administered.Complex neuropsychological batteries can be administered to HGG patients before and during follow-up after surgery. There is a correlation between neuropsychological deterioration and tumor relapse and/or death, which may reflect a progressive damage to cognitive functions due to tumor infiltration and progression.

Personalized medicine (PM) aims to optimize patient management, taking into account the individual traits of each patient. The main purpose of PM is to obtain the best response, improving health care and lowering costs. Extending traditional approaches, PM introduces novel patient-specific paradigms from diagnosis to treatment, with greater precision. In neuro-oncology, the concept of PM is well established. Indeed, every neurosurgical intervention for brain tumors has always been highly personalized. In recent years, PM has been introduced in neuro-oncology also to design and prescribe specific therapies for the patient and the patient's tumor. The huge advances in basic and translational research in the fields of genetics, molecular and cellular biology, transcriptomics, proteomics, and metabolomics have led to the introduction of PM into clinical practice. The identification of a patient's individual variation map may allow to design selected therapeutic protocols that ensure successful outcomes and minimize harmful side effects. Thus, clinicians can switch from the "one-size-fits-all" approach to PM, ensuring better patient care and high safety margin. Here, we review emerging trends and the current literature about the development of PM in neuro-oncology, considering the positive impact of innovative advanced researches conducted by a neurosurgical laboratory.

Background Constructional apraxia (CA) is a neuropsychological impairment of either basic perceptual and motor abilities or executive functions, in the absence of any kind of motor or perceptual deficit. Considering patients with focal brain tumors, CA is common in left or right parietal and parieto-occipital lesions. In neuropsychology, the Rey-Osterrieth Complex Figure Test (ROCFT; or parallel forms) is commonly used for the assessment of CA. This study stems from a clinical observation of a difficulty with CA tests for the majority of older neurosurgical patients without occipitoparietal lesions. Methods Patients were tested at 3 points: before surgery, 3 months after surgery, and 12 months after surgery. Thirty patients (15 meningiomas and 15 glioblastomas) were studied retrospectively. Results Older patients with focal brain lesions, regardless of the nature of the tumor, performed poorly at CA tests. More than 50% of patients obtained pathologic results at all 3 times considered. Conclusions Our findings suggest that as CA complex tests involve multiple domains, poor results in copy task may reflect a global cognitive deficit of older patients with tumors, without a specific constructional praxis deficit. CA complex tests (such as the ROCFT) do not give significant informations about visuo-constructional abilities.

Surgical treatment of elderly patients with meningioma is has proved to be safe, especially when patients are selected using dedicated surgical scores. These scores take into account tumor size, edema, location and patient's co-morbidities. Neuropsychological functioning (NPF) of this kind of patients has been poorly studied in literature and it is not taken into account by these scores. Aim of our study was to describe the long-term outcome in terms of NPF of elderly patients undergoing surgery. Patients older than 70 years of age affected by intracranial meningioma and selected with the Clinical-Radiological Grading Score were included in our study. Neuropsychological testing was performed using a dedicated battery of tests before surgery, 3 and 12 months after surgery. Clinical, neurological and radiological outcomes were studied as well. Forty-one patients with a median age of 74 years were included in this study. Preoperatively only 1/41 patients showed a normal NPF with all tests scoring normally. Four out of 39 patients showed a complete neuropsychological recovery after 3 months; while 10/37 patients had a complete recovery after 12 months. NPF showed a trend of progressive improvement after surgery. Our study is the first experience reported in literature describing a long term follow-up in elderly patients after surgery for intracranial meningioma. In our series, surgery determined an improvement of NPF over time; especially with a low complication rate related to the selection of patients obtained through the CRGS. Further studies need to be performed in order to understand how brain edema, tumor size, volume and tumor location affect NPF in both short and long term.

High grade gliomas (HGG) are tumors with a rapidly progressive course and the standard of care consists of surgery and chemo-radiotherapy. Elderly patients with HGG usually have a worse prognosis due to their comorbidities and difficulties in accessing or completing adjuvant treatments. The purpose of our study was to assess the influence of pre-operative factors (MMSE, age, sex, KPS, tumor volume) on the post-operative access to chemo-radiotherapy in the elderly population. In addition, the influence of the access to adjuvant therapies on overall survival (OS) was assessed. We retrospectively reviewed our consecutive case series of 117 elderly patients (≥65 years) with HGG treated in our Institution. All the clinical records regarding age, sex, tumor location, MMSE, KPS, access to adjuvant treatments and OS were analyzed. 72 males and 45 females with a median age of 71 years were analyzed. Adjuvant therapies were considered; concomitant chemo-radiotherapy with standard radiotherapy or hypofractionated radiation regimen. 84 patients had access to adjuvant therapies. Access to therapies was associated with a median age of 71(range 66–80) years, a median MMSE of 26(range 5–30), and a median tumor volume of 24 cm3(range 1–140). The median OS was 13 months for patients who had access to adjuvant therapies and 5 months for patients who did not. In the elderly patients with HGG, the MMSE, age and tumor volume were predictive of post-surgery access to adjuvant treatments. OS was significantly longer in elderly patients with HGG who had access to post-surgery chemo-radiotherapy.

Semantic verbal fluency test is frequently used in clinical practice to assess lexical retrieval and production in neurological and psychiatric diseases. Semantic category is a crucial variable to consider in patients with language disorders. Norms for this task were collected from a population of 290 Italian healthy participants with age ranging from 18 to 98 years. The aim was to provide normative data both for the global score and for each semantic category (animals, fruits, brands of cars). Multiple regression analysis revealed that age and education significantly correlated with the global score and with single semantic categories. In particular, increasing age negatively affected performance, whereas the performance increased with a higher education. Statistically significant differences between men and women were found only for brands of cars. The availability of equivalent scores for the single semantic categories will prove useful in clinical practice since it allows the comparison of single semantic categories in patients with language disorders.

Background The lumbar infusion test (LIT) and tap test (TT) have previously been described for the diagnosis and selection of appropriate surgical candidates in idiopathic normal pressure hydrocephalus (iNPH). Methods We retrospectively reviewed 81 consecutive patients with a clinical diagnosis of iNPH selected for supplementary testing. Clinical evaluation was scored with the Japanese Grading Scale for Normal Pressure Hydrocephalus, the Global Deterioration Score, and the modified Rankin Scale (mRS). The test protocol included a cerebrospinal fluid pressure monitoring (PMi), an LIT, and a TT. Patients were selected for surgery if outflow resistance was ≥14 mm Hg/mL/minute or if a clinical improvement was recorded after TT. Results Sixty-eight patients were selected for ventriculoperitoneal shunting; 72.8% had a positive PMi or LIT, 74.1% had a positive TT, and 63.0% were positive to both tests. Complications were all transient. Clinical evaluation at 12 months after shunting showed a global improvement in 60 patients (88.2%). Overall, 75.0% of patients had no significant disability (mRS score, 1 and 2), 20.6% had an mRS score of 3 or 4, and 4.4% had severe disability after surgery. The positive predictive value of PMi/LIT, TT, or both combined was similar (89.8, 90.0, and 88.2%); however, 21.7% of patients who improved after surgery were selected with either a positive LIT or TT alone. Conclusions LIT and TT are complementary and they can easily be combined in sequence with a low complication rate and high probability of selecting patients with iNPH who may benefit from ventriculoperitoneal shunt surgery.

Background The thalamus is a deep-seated and crucial structure for the sensorimotor system. It has been long considered a surgically inaccessible area because of the morbidity associated with surgical resections. Astrocytomas of the thalamus are usually treated with bioptic procedures followed by adjuvant treatments. Intraoperative neurophysiologic monitoring (IONM) allows safe and satisfactory resections of lobar gliomas, but few data are available for thalamic lesions. The aim of this study was to review the outcome of a small series of patients with thalamic astrocytomas that were treated with surgical resection with the aid of IONM. Methods Surgical resection with IONM was performed in 5 patients with thalamic astrocytomas (1 grade I, 1 grade II, 2 grade III, 1 grade IV). Two astrocytomas were in the dominant hemisphere. Preoperative and postoperative neuropsychological assessments were performed in 3 patients. IONM was tailored to the individual patient and consisted of transcranial motor evoked potential monitoring, cortical motor evoked potential monitoring, somatosensory evoked potential monitoring, direct electrical stimulation, electroencephalography, and electrocorticography. Results None of the patients experienced permanent motor deficits; 2 patients had a transient hemiparesis requiring rehabilitation; 1 patient had a transient aphasia, and 1 patient had permanent aphasia. None of the patients had intraoperative seizures, but 1 patient experienced postoperative transient status epilepticus. The extent of resection on postoperative volumetric magnetic resonance imaging was >70% in all cases. Conclusions Surgical resection of thalamic astrocytomas appeared to be effective and relatively safe when guided by IONM. Larger series of patients are required to confirm these preliminary data.

INTRODUCTION: Intra-operative neurophysiological monitoring and brain mapping techniques represent nowadays the gold standard for surgical resection of brain tumors. Brain mapping usually requires the exposure of a large area of brain cortex in order to identify the different eloquent sites (e.g. primary motor strip, speech arrest sites). Thus, relatively large classic fronto-temporal craniotomies are generally performed. Nevertheless, in recent years the use of small craniotomies targeted on the tumor has gained popularity thanks to Neuronavigation systems and to the low morbidity rates associated with shorter surgical procedures and reduced anesthestic drug administration. Aim of this study was to review our experience which combines extensive neurophysiological monitoring and small craniotomies. Length of surgical time, intra-operative and post-operative complications, length of stay, extent of resection rate and the neurological outcomes were assessed. PATIENTS AND METHODS: Eighty-five consecutive patients (54 Males, 31 Females; Median Age 55 years, range 12-77) underwent surgery with brain mapping and intra-operative neurophysiological monitoring for resection of a brain tumor in eloquent location under asleep-asleep (62 patients) or asleep-awake (23 patients) anesthesia. Pre- and post-operative assessment included in-depth neuropsychological evaluation and MRI. Tumor histologies were the following: 74 gliomas (60 HGG, 14 LGG), 6 metastases and 5 other tumor histologies (2 cavernomas, 2, meningiomas, 1 AVM). The bone flap was tailored to the size of the tumor; no cortex other than that which was strictly necessary for tumor resection was exposed. The intra-operative neurophysiological monitoring included: EEG, SSEP, transcranial MEP and/or cortical MEP, ECoG; direct electrical stimulation (DES) was performed using bipolar and monopolar probes. RESULTS: Median surgical time was 230 minutes (range 90-390). Intra-operative complications included 9 seizures (3 requiring pharmacological treatment, 6 regressing after cold irrigation) and 5 electrical seizure. Post-operative neurosurgical complications were the following: 8 seizures and 4 re-operation for hematoma. Seventy-three patients (86%) could be discharged home while 12 (14%) were transferred to rehabilitation. In only 3 patients (3.5%) a permanent new neurological deficit could be noted at 3-month follow-up. Median post-operative stay was 7 days (range 3-45). CONCLUSIONS: In our experience a small craniotomy supported by extensive neurophysiological monitoring and brain mapping permitted to achieve satisfactory results in terms of complications, hospitalization, and neurological outcomes.

Based on a retrospective study, in a previous report we developed a grading system, called ‘Clinical Radiological Grading System’ (CRGS), in order to standardise surgical indications in patients older than 70 years affected by intracranial meningiomas. Various prognostic factors were taken into consideration: clinical conditions, comorbidities, neurological status, size and size of the lesion and peritumoral edema. We then performed a prospective cross-sectional study including 90 consecutively recruited patients (from 1990 to 2000), 70 years of age or older, affected by meningiomas in whom the decision whether to operate was based on the CRGS score. Our findings showed that patients with a score lower than 10 had a poor prognosis regardless of surgical treatment, those with a score between 10 and 12 had a prognosis positively influenced by surgery, and those with a score higher than 12 had a good prognosis regardless of surgical treatment. A further validation of our scale has been made in a second prospective study, which is discussed in the present chapter. We also analyzed similar studies performed by other authors and compare our grading system to alternative scores which have been created afterwards.

Data for copying and delayed recall (after a 15-min delay) of the Modified Taylor Complex Figure (MTCF), an alternative form of the Rey-Osterrieth Complex Figure (ROCF), were collected from 290 healthy participants. Normative data are provided. Age and education were significantly correlated with MTCF scores and must be corrected for to interpret results accurately. More specifically, increasing age adversely affected performance, whereas a higher education resulted in a better performance. Twenty-five participants were tested with both complex figures (MTCF and ROCF) in two separate sessions to assess correlation, which proved to be high. The collected data allow using the MTCF as a valid alternative material for testing visual long-term memory avoiding implicit learning that can occur when the same version of the ROCF is used for repeated testing sessions.

Early and delayed cognitive dysfunctions are an understudied issue after aneurysmal subarachnoid hemorrhage (aSAH), irrespective of neurological outcome. The aim of this study was to describe early and delayed changes of cognitive functions, activities of everyday life, and quality of life in aSAH patients.

INTRODUCTION: The thalamus is a deep-seated and crucial structure for the sensory-motor system. It has been longly considered a surgically inaccessible area due to the morbidity associated with surgical resections. In fact, astrocytomas of the thalamus usually undergo bioptic procedures followed by adjuvant treatments (if indicated). Intra-operative neurophysiological monitoring (IONM) allows safe and satisfactory resections of lobar gliomas. Considering the need of reliable specimens for the pathological diagnosis and that the extent of resection is positively associated with overall survival, aim of this study was to review the feasibility and outcome of a small series of patients with thalamic astrocytomas operated with the aid of IONM. PATIENTS AND METHODS: Five patients with thalamic astrocytomas (1 grade I, 3 grade III, 1 grade IV) underwent surgical resection with IONM. Two astrocytomas were in the dominant hemisphere. All patients performed pre-operative and post-operative neuropsychological assessment. IONM consisted in transcranial MEP monitoring (4 patients), cortical MEP monitoring (2 patients), direct electrical stimulation (5 patients), EEG (5 patients) and ECoG monitoring (2 patients). Anesthesia was totally intra-venous (propofol + remifentanyl) for all patients; 1 patients was operated following an asleep-awake protocol, 4 following an asleep-asleep protocol. RESULTS: None of patients suffered from permanent motor deficits; 2 patients had a transient hemiparesis requiring rehabilitation; 1 patient suffered a transient aphasia, and 1 patient had permanent aphasia. None of the patients had intraoperative seizures, but 1 patient had a post-operative transient status epilepticus. Resection was total or subtotal in 3 cases and partial (with resection between 50 and 80% of the tumor volume) in the other 2 cases. CONCLUSIONS: Surgical resection of thalamic astrocytomas could be meaningful and relatively safe when guided by IONM. Larger series of patients are required to confirm this preliminary data.

Introduction Although it was a giant leap forward when it was introduced, the classic approach to the norming of neuropsychological tests (Capitani, 1987) has two main limitations: (i) it doesn’t consider possible interactions between covariates (e.g., age and education); (ii) working on by–subject percentages of correct responses, it cannot consider item covariates (e.g., frequency, length, imageability) that are known to affect performance substantially. Here we show how to overcome these limitations, and how this improves our diagnosis. Methods As a test case, we used the action–naming task devised by Crepaldi et al. (2006). 290 healthy Italian speakers (148 F and 142 M) made up our norming sample. They ranged 18 to 98 years in age (M=54.1) and 3 to 23 years in education (M=12.3). The test was standardized: (i) following the classic Capitani approach, based on regressing by–subject mean accuracy on gender, age and education; (ii) adding interactions between gender, age and education to the classic approach; (iii) using raw correct/incorrect scores thanks to mixed–effect models, thus being able to take under control also item variables (e.g., frequency, imageability) and any additional item– or subject–specific random variability (mixed–effects norming; Jaeger, 2008). Results We first contrasted the three approaches in terms of their amount of explained variance in the computation of expected scores, that is, their ability to “wash out” unwanted effects from expected scores. The classic Capitani norming explained 34.7% of the total variance; interaction norming went up to 43.7%; and mixed–effects norming ensured 73% of explained variance. A comparison between expected scores according to Capitani and mixed–effects norming in 2,600 combinations of age (20–85) and education values (3-22) revealed an overall correlation of .81. Differences were generally bigger with young age and low education, and with old age and high education; and typically showed higher expected scores by mixed–effects than Capitani norming (see Figure 1). Equivalent Scores (ES) were then computed for a simulated sample of around 80,000 patients ranging in age (20–85 years), education (3–22 years), gender (M–F) and raw scores (20–50 correct responses). They disagree 28% of the times according to the two approaches. The difference (in either direction) is 1.28 in mean, and ranges from 1 to 4. Mixed–effects ES is lower than Capitani ES in 61% of the cases. Among the 45070 simulated patients that would be classified as impaired at naming verbs (ES=0) according to Capitani norming, 5% would not be classified as such (ES>0) according to mixed–effects norming. These figures are closely replicated in a sample of 69 unselected aphasic patients. Discussion The data indicate that using a better statistical model to calculate expected scores is highly beneficial in terms of amount of explained variance, that is, we can gauge the true effects of subject (e.g., age) and item variables (e.g., frequency) much more precisely, thus enjoying higher–quality corrected scores. Critically, this reflects substantially into how (simulated and actual) patients are classified.

BACKGROUND: Patients with high grade gliomas (HGG) have a poor prognosis and experience cognitive deficits which depend on location, size, mass effect and edema of the tumor. Neuropsychological functioning (NPF) can be assessed by a battery of tests which objectivise the cognitive status of the patients. These tests are time-consuming and fatiguing for the patients, nevertheless could give relevant information about the course of the disease. Aim of our work was to describe overtime the NPF of patients affected by HGG and to correlate the NPF scores with tumor recurrence and survival. MATERIAL AND METHODS: We examined the NPF in 102 patients operated for HGG. Patients were followed longitudinally with the Milano-Bicocca Battery for neuropsychological assessment of low grade gliomas. Patients were evaluated before surgery and few days after surgery. Then, neuropsychological and neuro-oncological follow-up were performed every three months. We first explored the correlational structure of our neuropsychological variables through hierarchical clustering in the R package Hmisc. We then investigated the impact on patients’ outcome of the variables selected through hierarchical clustering via non-linear regression, with fixed/random effects. Time to tumor recurrence/death was selected as the main dependent variable. RESULTS: Sixty-seven males and 35 females (median age 59, range 18–81) were included. Starting from a battery of 27 neuropsychological tests, 10 tests could be selected from the statistical analysis (cluster structure, condition number K of 51.16) since they were strictly correlated with the other tests; thus, these 10 tests were used for the further statistical analysis. Pitting patients’ neuropsychological profiles against tumor relapse/death, 5 cognitive tests showed a significant correlation: Token test (p=0.003), Object Naming test (p=0.02), Digit Memory Span (p=0.001), Corsi Block test (p=0.004), Semantic Fluency test (p=0.003). A steep decline for all these tests emerged a few weeks before tumor relapse/death. Analyzing the NPF overtime, all the tests worsened immediately after surgery, recovered steadily within 2–3 months and then remained stable until progression. CONCLUSION: The tests which showed to be more informative about the patients NPF were Token test, Object Naming test, Digit Memory Span, Corsi Block test, Semantic Fluency test. These tests showed a significant decline few weeks before tumor relapse/death.