The effects of cerebrospinal fluid tap-test on idiopathic normal pressure hydrocephalus: an inertial sensors based assessment.

BACKGROUND: Gait disturbances are typical of persons with idiopathic normal pressure hydrocephalus (iNPH) without signs distinctive from other neurodegenerative and vascular conditions. Cerebrospinal fluid tap-test (CSF-TT) is expected to improve the motor performance of iNPH patients and is a prognostic indicator in their surgical management. This observational prospective study aims to determine which spatio-temporal gait parameter(s), measured during instrumented motor tests, and clinical scale(s) may provide a relevant contribution in the evaluation of motor performance pre vs. post CSF-TT on iNPH patients with and without important vascular encephalopathy. METHODS: Seventy-six patients (20 with an associated vascular encephalopathy) were assessed before, and 24 and 72 h after the CSF-TT by a timed up and go test (TUG) and an 18 m walking test (18 mW) instrumented using inertial sensors. Tinetti Gait, Tinetti Balance, Gait Status Scale, and Grading Scale were fulfilled before and 72 h after the CSF-TT. Stride length, cadence and total time were selected as the outcome measures. Statistical models with mixed effects were implemented to determine the relevant contribution to response variables of each quantitative gait parameter and clinical scales. RESULTS AND CONCLUSION: From baseline to 72 h post CSF-TT patients improved significantly by increasing cadence in 18 mW and TUG (on average of 1.7 and 2.4 strides/min respectively) and stride length in 18 mW (on average of 3.1 cm). A significant reduction of gait apraxia was reflected by modifications in double support duration and in coordination index. Tinetti Gait, Tinetti Balance and Gait Status Scale were able to explain part of the variability of response variables not covered by instrumental data, especially in TUG. Grading Scale revealed the highest affinity with TUG total time and cadence when considering clinical scales alone. Patients with iNPH and an associated vascular encephalopathy showed worst performances compared to pure iNPH but without statistical significance. Gait improvement following CSF-TT was comparable in the two groups. Overall these results suggest that, in order to augment CSF-TT accuracy, is key to assess the gait pattern by analyzing the main spatio-temporal parameters and set post evaluation at 72 h. TRIAL REGISTRATION: Approved by ethics committee: CE 14131 23/02/2015.

Effects on cognition of 20-day anodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex in patients affected by mild cognitive impairment: a case-control study.

BACKGROUND: Mild cognitive impairment (MCI) is a common disorder affecting as much as 15% of the elderly population. Transcranial direct current stimulation (tDCS) is a non-invasive technique of neuromodulation that has proven to influence performance in different cognitive domains. OBJECTIVE/HYPOTHESIS: We investigated the effects on cognition of 20-day anodal tDCS in 17 MCI patients compared with 17 matched MCI patients. METHODS: Patients underwent neuropsychological evaluation at baseline and then were randomly assigned to the anodal or sham group. The tDCS protocol consisted in 20 min, 5 days per week (up to a total of 20 days), of 2-mA anodal stimulation over the left dorsolateral prefrontal cortex (DLPFC). The location of anodal electrode was chosen in accordance with previous reports which relate anodal stimulation of this site with cognitive enhancement. At the end of the last day of stimulation, a second neuropsychological evaluation was performed. We compared baseline and post-stimulation neuropsychological results in the anodal vs sham group using repeated measures ANOVA as a statistical analysis test. RESULTS: At follow-up, patients exposed to anodal stimulation showed improvement in episodic verbal memory (p < 0.001) and figure naming test (p < 0.01), in a general index of cognitive function (Brief Mental Deterioration Battery) (p < 0.0001) and in a mood measurement test (Beck Depression Inventory) (p < 0.01). CONCLUSION: Anodal tDCS could be a useful tool to improve cognitive symptoms in MCI although more evidence is needed to understand the exact underlying mechanisms. Confirmation of its potential benefits in MCI would be significant.

Human figure drawing distinguishes Alzheimer's patients: a cognitive screening test study.

To study human figure drawing in a group of Alzheimer's disease (AD) patients and compare it with a group of patients with mild cognitive impairment (MCI) and controls. We evaluated consecutive outpatients over a one-year period. Patients were classified as affected by AD or by MCI. All patients and controls underwent a simplified version of the human-figure drawing test and MMSE. A qualitative and quantitative analysis of all human figures was obtained. 112 AD, 100 MCI patients and 104 controls were enrolled. AD patients drew human figures poor in details and globally smaller than MCI patients and controls. Human figures drawn by MCI patients are intermediate in body height between those of the AD patients and the healthy subjects. The head-to-body ratio of human figures drawn by AD patients is greater than controls and MCI patients, while the human figure size-relative-to-page space index is significantly smaller. Body height is an independent predictor of cognitive impairment correlating with its severity and with the number of the figure's details. Human figures drawn by AD patients are different from those drawn by healthy subjects and MCI patients. Human figure drawing test is a useful tool for orienting cognitive impairment's diagnosis.

Superficial siderosis associated with peripheral autonomic failure and tetraventricular hydrocephalus: a case report.

We describe the case of a man whose initial clinical presentation included sensorineural hearing loss and orthostatic hypotension. The patient was diagnosed with superficial siderosis associated with peripheral autonomic failure and tetraventricular hydrocephalus.

Precuneal Thickness and Depression in Parkinson Disease.

BACKGROUND: Depression-related gray matter changes in Parkinson disease (PD) patients have been reported, although studies investigating cortical thickness in early-stage disease are lacking. OBJECTIVE: We aimed to evaluate cortical changes related to depression in early-stage PD patients with an extensive neuropsychological evaluation. METHODS: 17 PD patients and 22 healthy controls underwent a 1.5-T brain MR protocol, and voxel-wise differences in cortical thickness among patients with (n = 6) and without (n = 11) depression and controls were evaluated using FreeSurfer software. RESULTS: Cortical thickness was increased in the precuneus bilaterally in PD patients with depression compared to the other groups (number of vertices >100; p < 0.001, uncorrected) with a direct correlation with the Beck Depression Inventory score (p < 0.001, uncorrected). CONCLUSION: Precuneal cortical thickening is evident in PD patients with mild-moderate depression even in the early stages of the disease. This finding may reflect the early involvement of this region in the development of PD-related depression.

Cognitive and sleep features of multiple system atrophy: review and prospective study.

BACKGROUND: The profile and degree of cognitive impairment in Multiple System Atrophy (MSA) and the impact of sleep disorders, REM sleep behavior disorder (RBD) in particular, in parkinsonism-related cognitive deficits are currently being debated. SUMMARY: We reviewed the cognitive, affective and sleep findings in MSA and also carried out a longitudinal investigation of 10 MSA patients. At the first evaluation, 3 patients showed isolated cognitive deficits. After a mean of 16 months, these patients remained unchanged, while 1 patient worsened from a normal condition. No significant differences emerged when the cognitive, affective and video-polysomnographic findings of MSA-P and MSA-C were compared. Depression was present in half of the patients, although it did not influence their cognitive performance. Comparisons between the first and second evaluation data showed significant worsening in visual attention and in ADL/IADL and UMSARS. KEY MESSAGES: Isolated cognitive deficits are evidenced in a minority of MSA patients with the absence of a clear-cut diagnosis of dementia in the early stages of the disease. Attention and executive functions are often impaired. This study with a short follow-up period showed that RBD, although present in almost all patients affected by MSA, does not appear a clear early marker of cognitive impairment. Future longer-term studies with a larger patient sample are thus encouraged.

Simple verbal analogies test: normative data on a short task exploring abstract thinking.

BACKGROUND AND AIMS: The simple verbal analogies test (SVAT) is a short neuropsychological task requiring few minutes of administration that explores inductive verbal abstract thinking. It already showed a good specificity and sensitivity in discriminating normal controls from probable Alzheimer's disease patients. Verbal working memory, semantic knowledge and memory and word-finding ability are also involved in performing analogies. The aim of this study is to provide the normative values of this test in a sample of normal controls and corrections of raw scores and equivalent scores. METHODS AND RESULTS: We determined the normative values of SVAT in a sample of 424 normal controls to provide corrections of raw scores and equivalent scores. CONCLUSIONS: SVAT is a useful test to assess executive functions, working memory and to discriminate between cognitive deterioration and normal aging.

The Role of Simultaneous Medical Conditions in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a chronic neurologic syndrome that affects the elderly population in a context of concomitant medical conditions. The aim of this study was to understand the significance of comorbidities using 4 validated and specific clinical scores: Cumulative Illness Rating Scale (CIRS), American Society of Anesthesiologists (ASA) score, Comorbidity Index (CMI), and Charlson Comorbidity Index (CCI). METHODS: From 2015 until 2019, the Bologna PRO-Hydro multidisciplinary team selected 63 patients for shunt surgery. All comorbidity scores were collected during preoperative anesthesia evaluation. Positive shunt response was defined as an improvement in overall disability (assessed with modified Rankin Scale [mRS]), in risk of fall (assessed with Tinetti Permormance Orientated Mobility Assessment, Tinetti) and in INPH specific symptoms (assessed with INPH Grading Scale, INPHGS). RESULTS: Patients with elevated values of CIRS had worse performance in gait and balance at Tinetti scale, both before (P = 0.039) and after surgery (P = 0.005); patients with high values of CMI had inferior values of Tinetti at baseline (P = 0.027) and higher mRS after surgery (P = 0.009); ASA 2 patients had better postoperative Tinetti scores than ASA 3 patients (P = 0.027). A positive or negative shunt response was not significantly correlated with patients' preoperative comorbidity scores. CONCLUSIONS: Patients with multiple comorbidities have a worse preoperative condition compared to patients with less concomitant diseases, and the proposed comorbidity scores, CIRS in particular, are useful clinical tools for the anesthesiologist. Comorbidities, though, do not impact overall postoperative outcome.

Accelerated long-term forgetting in temporal lobe epilepsy: evidence of improvement after left temporal pole lobectomy.

Accelerated long term forgetting (ALF) is a characteristic cognitive aspect in patients affected by temporal lobe epilepsy that is probably due to an impairment of memory consolidation and retrieval caused by epileptic activity in hippocampal and parahippocampal regions. We describe a case of a patient with TLE who showed improvement in ALF and in remote memory impairment after an anterior left temporal pole lobectomy including the uncus and amygdala. Our findings confirm that impairment of hippocampal functioning leads to pathological ALF, whereas restoration of hippocampal functioning brings ALF to a level comparable to that of controls.

The Combination of Metabolic Posterior Cingulate Cortical Abnormalities and Structural Asymmetries Improves the Differential Diagnosis Between Primary Progressive Aphasia and Alzheimer's Disease.

Differential diagnosis between primary progressive aphasia (PPA) and Alzheimer's disease (AD) could be difficult if based on clinical grounds alone. We evaluated the combination of proton MR spectroscopy of posterior cingulate cortex (PCC) and quantitative structural imaging asymmetries to differentiate PPA from AD patients. A greater left-lateralized temporo-parietal atrophy (higher accuracy for the PCC, 81.4%) and metabolic neurodegenerative changes in PCC (accuracy 76.8%) was demonstrated in PPA versus AD. The combined multiparametric approach increased the accuracy to 94%in the differential diagnosis between these two neurodegenerative diseases.

Targeted sequencing panels in Italian ALS patients support different etiologies in the ALS/FTD continuum.

BACKGROUND: 5-10% of amyotrophic lateral sclerosis (ALS) patients presented a positive family history (fALS). More than 30 genes have been identified in association with ALS/frontotemporal dementia (FTD) spectrum, with four major genes accounting for 60-70% of fALS. In this paper, we aimed to assess the contribution to the pathogenesis of major and rare ALS/FTD genes in ALS patients. METHODS: We analyzed ALS and ALS/FTD associated genes by direct sequencing or next-generation sequencing multigene panels in ALS patients. RESULTS: Genetic abnormalities in ALS major genes included repeated expansions of hexanucleotide in C9orf72 gene (7.3%), mutations in SOD1 (4.9%), FUS (2.1%), and TARDBP (2.4%), whereas variants in rare ALS/FTD genes affected 15.5% of subjects overall, most frequently involving SQSTM1 (3.4%), and CHMP2B (1.9%). We found clustering of variants in ALS major genes in patients with a family history for "pure" ALS, while ALS/FTD related genes mainly occurred in patients with a family history for other neurodegenerative diseases (dementia and/or parkinsonism). CONCLUSIONS: Our data support the presence of two different genetic components underlying ALS pathogenesis, related to the presence of a family history for ALS or other neurodegenerative diseases. Thus, family history may help in optimizing the genetic screening protocol to be applied.

Are subjective cognitive complaints a risk factor for dementia?

UNLABELLED: The objective is to evaluate the prognosis of subjective cognitive complaints (SCC) patients during 4-year follow-up. A prospective study on 92 SCC patients investigating their cognitive, affective and behavioural aspects. SCC patients were classified as having no objective cognitive impairment (NOCI), mild cognitive impairment (MCI), or subtypes of MCI. RESULTS: 43 patients were found to have NOCI and 49 MCI. During the follow-up, 45.5% of NOCI patients remained unchanged, 13.9% were diagnosed as MCI and only one progressed to dementia. Of the MCI patients, 32.3% remained stable, 18.4% became demented and 4% reverted to NOCI. Visual attention, behavioural memory, long-term verbal memory, apathy and caregiver distress, provided independent predictors of progression to dementia.

Cognitive Profile and Its Evolution in a Cohort of Multiple System Atrophy Patients.

Introduction: Cognitive decline is not a characteristic feature of multiple system atrophy (MSA), but recent evidence suggests cognitive impairment as an integral part of the disease. We aim to describe the cognitive profile and its progression in a cohort of patients with MSA. Methods: We retrospectively selected patients referred to our department with a clinical diagnosis of MSA who were evaluated at least once a year during the course of the disease and underwent a comprehensive neuropsychological evaluation. Results: At the first evaluation (T0), 37 out of 60 patients (62%) were cognitively impaired, mainly (76%) in attention and executive functioning. Thirteen patients were impaired in one cognitive domain and 24 in more than one cognitive domain. Six out of the 24 had dementia. Twenty patients underwent a follow-up evaluation (T1) after a mean of 16.6 ± 9.3 months from the first evaluation (T0). Eight out of 20 patients were cognitively normal at both T0 and T1. Seven out of 12 patients presented with stable cognitive impairment at T1, while cognitive decline progressed in five patients. Patients with progression in cognitive decline performed significantly worse at T0 than cognitively stable patients. Education was significantly different between patients with and without cognitive impairment. No other differences in demographic and clinical variables and autonomic or sleep disturbances were found. Patients with dementia were older at disease onset and at T0 and had lower education and disease duration at T0 compared to those in other groups. Conclusions: In patients with MSA, we observed three different cognitive profiles: normal cognition, stable selective attention-executive deficits, and progressive cognitive deficits evolving to dementia. The detection of cognitive impairment in patients with suspected MSA suggests the need for comprehensive and longitudinal neuropsychological evaluation.

Anterior Callosal Angle: A New Marker of Idiopathic Normal Pressure Hydrocephalus?

OBJECTIVE: Diagnosing idiopathic normal pressure hydrocephalus (iNPH) still remains a clinical challenge. The callosal angle (CA) is a widely used neuroradiologic marker for iNPH. However, the relationship of the CA to clinical features has not been well investigated. We hypothesize that iNPH symptoms might better correlate with a variant of the CA (anterior callosal angle [ACA]). We aim to establish the validity of the ACA measurement for the diagnosis of iNPH and compare it with current radiologic parameters. METHODS: The multidisciplinary BOLOGNA PRO-HYDRO Study Group performed a retrospective review of consecutive iNPH patients. Magnetic resonance imaging studies for these patients were collected, as well as magnetic resonance imaging studies from Alzheimer disease and healthy control patients. The CA, ACA, and Evans Index were measured by 2 blinded members of the study team based on magnetic resonance images for each of these populations. RESULTS: The ACA shows high accuracy, sensitivity, and specificity in distinguishing iNPH patients from healthy control and Alzheimer disease patients. The optimal pathologic diagnostic cut-off value for the ACA is 119 degrees. The diagnostic accuracy of the ACA is not significantly different from the CA. CONCLUSIONS: The ACA could be a valid radiologic parameter in the diagnostic armamentarium for iNPH.

Color Choice Preference in Cognitively Impaired Patients: A Look Inside Alzheimer's Disease Through the Use of Lüscher Color Diagnostic.

OBJECTIVE: To study the emotional state of cognitively impaired patients through the color choice preference in a group of Alzheimer's disease (AD) patients and compare it with a group of Mild Cognitive Impairment (MCI) patients and a matched control group. METHODS: A total of 71 AD, 50 MCI and 68 controls were consecutively evaluated. All patients and controls underwent the Mini Mental State Evaluation (MMSE) and the Lüscher color test. RESULTS: Cognitively impaired patients mainly chose auxiliary colors, in particular violet and brown, and rejected black and gray. AD patients predominantly chose forms corresponding to auxiliary colors. The auxiliary color choice negatively correlated with the MMSE score. MCI patients and controls had a higher presence of anxiety on gray table and controls had higher frustration and ambivalence, i.e., psychic complexity, on basic color tables.Data globally suggest that AD patients live with a feeling of personal change due to instability and emotional insecurity, experiencing physical discomfort and a bodily need of being welcomed in a favorable environment. They aspire to a sensitive understanding by someone with whom they can be identified. Differently, MCI patients have less of these needs; however, they feel more anxious. CONCLUSION: The comprehension of the inner emotional state of cognitively impaired patients allows us to better communicate with them and effectively approach their behavioral disorders. Like other projective techniques, such as the tree-drawing test and the human figure-drawing test, Lüscher color test is proposed as a simple and unconventional approach to understand the emotional life of AD patients. The awareness of clinicians about the existential fragility and insecurity of such type of patients allows us not only to better manage their behavioral disturbances but also to improve their quality of life and that of their caregivers.

A prospective evaluation of clinical and instrumental features before and after ventriculo-peritoneal shunt in patients with idiopathic Normal pressure hydrocephalus: The Bologna PRO-Hydro study.

INTRODUCTION: Idiopathic Normal Pressure Hydrocephalus (iNPH) is a complex and often misdiagnosed syndrome, whose major challenge is to identify which patients will benefit from surgery. Previous studies reported a variability in positive surgery response. The role of tap test(TT) in screening patients suitable for shunting is controversial. The primary aim of this study was to describe the clinical/instrumental features and their longitudinal progression after surgery in iNPH patients. Secondarily, we aimed to investigate the response of the three iNPH domains and the best time of outcome assessment after TT. METHODS: Patients compatible with iNPH underwent a 3-T-MRI and an inpatients program with TT including standardized clinical evaluations, neuropsychological assessments and instrumental gait analysis pre- and after-(24-h and 72-h) TT. The multidisciplinary team selected candidates for surgery. Patients were evaluated 6- and 12-months after surgery. RESULTS: A total of 154 consecutive patients were included from 2015 to 2018, 76 with an iNPH diagnosis (43 underwent surgery, 35 were evaluated after 6-months). Clinical and instrumented quantitative gait measures and urinary symptoms improved over time along with some neuropsychological functions. Concerning pre- and post-TT analyses, the three iNPH domains showed a different response after TT, the delayed motor assessment was more appropriate than the early one and the instrumental measures highlighted the motor improvement. CONCLUSION: iNPH patients improved after surgery, when accurately selected. A multidisciplinary team focused on this disease and a standardized protocol helped in achieving a correct diagnosis and management of iNPH. Our results could impact the management of this disease.

Revisiting the Cerebrospinal Fluid Biomarker Profile in Idiopathic Normal Pressure Hydrocephalus: The Bologna Pro-Hydro Study.

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in idiopathic normal pressure hydrocephalus (iNPH) with the aim of a better differential diagnosis, but the pathophysiological mechanisms underlying CSF biomarker changes and the relationship between biomarker levels and clinical variables are still a matter of debate. We evaluated CSF amyloid-ß (Aß)42 and Aß40, total (t)-tau, phosphorylated (p)-tau, total prion protein (t-PrP), and neurofilament light chain protein (NfL) in healthy controls (n = 50) and subjects with iNPH (n = 71), Alzheimer's disease (AD) (n = 60), and several other subtypes of dementia (n = 145). Patients with iNPH showed significantly lower levels of Aß42, Aß40, t-tau, and p-tau compared to controls. Similarly, t-PrP values showed a trend toward lower levels in iNPH patients than in controls. At variance, NfL levels were increased in iNPH as in all other neurodegenerative dementias, with no significant difference between "pure" iNPH cases and those with vascular or AD comorbidities. The Aß42/Aß40 ratio showed higher diagnostic value than Aß42 alone in the differential diagnosis between iNPH and AD. There were no clinically relevant associations between neuroimaging markers, scores at clinical and cognitive scales/tests, or rates of response at tap test and CSF biomarker results. In summary, the CSF biomarker signature in patients with iNPH is mainly characterized by reduced CSF concentrations of Aß- and tau-related proteins. The assessment of CSF neurodegenerative biomarker profile in iNPH, including the Aß42/Aß40 ratio, contributes to the differential diagnosis with AD and other dementias but shows poor associations with clinical variables.

Predicting conversion from mild cognitive impairment to Alzheimer's disease using brain 1H-MRS and volumetric changes: A two- year retrospective follow-up study.

This study investigated the ability of magnetic resonance spectroscopy (1H-MRS) of posterior cingulate cortex (PCC) and brain volumetry to predict the progression from mild cognitive impairment (MCI) to Alzheimer's Disease (AD) on the basis of clinical classification at 2 years follow-up. Thirty-eight MCI patients, eighteen healthy older adults and twenty-three AD patients were included in this study. All participants underwent a brain-MR protocol (1.5 T GE scanner) including high-resolution T1-weighted volumetric sequence (isotropic 1mm3). Voxel-wise differences in brain volumetry were evaluated using FreeSurfer software and all volumes were normalized by the total intracranial volume (TIV). Careful localization of 1H-MRS volume of PCC was performed and data were processed with the LCModel program. MCI patients underwent a complete neuropsychological assessment at baseline and were clinically re-evaluated after a mean of 28 months; twenty-six MCI patients (68.4%) converted to AD and twelve remained stable. At baseline these two MCI subgroups did not differ in the global cognitive level (Mini Mental State Examination, MMSE) or in any of the other cognitive domains; the NAA/ mI ratio in the PCC was able to differentiate MCI converters from those MCI that did not develop AD (p = 0.022) with a level of accuracy (AUC area) of 0.779. A significantly reduced volume of parahippocampal gyrus (p = 0.010) and fusiform gyrus (p = 0.026) were found in the converter MCI subgroup compared to the stable MCI subgroup. The combined use of both N- acetyl-aspartate (NAA)/myo-Inositol (mI) ratio and volume of parahippocampal gyrus, increases the overall accuracy (AUC = 0.910) in predicting the conversion to AD two years before the development of clinical symptoms. Additional longitudinal studies with a broader representative sample of MCI patients and longer follow-up might be helpful to confirm these results and to elucidate the role of each parameter in predicting the possible progression to AD, and also to all the other non-AD dementia subtypes.