Expanding SPG18 clinical spectrum: autosomal dominant mutation causes complicated hereditary spastic paraplegia in a large family.

BACKGROUND: SPG18 is caused by mutations in the endoplasmic reticulum lipid raft associated 2 (ERLIN2) gene. Autosomal recessive (AR) mutations are usually associated with complicated hereditary spastic paraplegia (HSP), while autosomal dominant (AD) mutations use to cause pure SPG18. AIM: To define the variegate clinical spectrum of the SPG18 and to evaluate a dominant negative effect of erlin2 (encoded by ERLIN2) on oligomerization as causing differences between AR and AD phenotypes. METHODS: In a four-generation pedigree with an AD pattern, a spastic paraplegia multigene panel test was performed. Oligomerization of erlin2 was analyzed with velocity gradient assay in fibroblasts of the proband and healthy subjects. RESULTS: Despite the common p.V168M mutation identified in ERLIN2, a phenoconversion to amyotrophic lateral sclerosis (ALS) was observed in the second generation, pure HSP in the third generation, and a complicated form with psychomotor delay and epilepsy in the fourth generation. Erlin2 oligomerization was found to be normal. DISCUSSION: We report the first AD SPG18 family with a complicated phenotype, and we ruled out a dominant negative effect of V168M on erlin2 oligomerization. Therefore, our data do not support the hypothesis of a relationship between the mode of inheritance and the phenotype, but confirm the multifaceted nature of SPG18 on both genetic and clinical point of view. Clinicians should be aware of the importance of conducting an in-depth clinical evaluation to unmask all the possible manifestations associated to an only apparently pure SPG18 phenotype. We confirm the genotype-phenotype correlation between V168M and ALS emphasizing the value of close follow-up.

Incidence and Prevalence of Dementia: A 2015-2020 Population-Based Study in the Campania Region of Italy.

OBJECTIVE: The aims of this study were to provide population-based estimates of prevalence and incidence of any dementia and Alzheimer's dementia (AD) in the Campania region (South Italy) and to validate towards a clinical registry. METHODS: This was a population-based study, using routinely collected healthcare data of individuals living in the Campania region (South Italy) from 2015 to 2020. We included individuals aged ≥65 years alive at the prevalence day (January 1, 2021) who had at least one administrative record for dementia and/or AD from 2015 to 2020. Age-and sex-standardised prevalence rates were calculated using direct standardisation method (European population in 2020 as the reference population). To estimate the incidence, we tested three possible algorithms, which differed for the duration of the time interval between study baseline (January 1, 2015) and index date (first record for dementia and/or AD in administrative databases). We employed a clinical database for the validation of our algorithms towards neuropsychological test results. RESULTS: Among individuals aged over 65 years, 80,392 had dementia, of which 35,748 had AD. The age- and sex-standardised prevalence rates per 1,000 individuals for any dementia and AD were 77.64 (95% confidence interval [CI] = 77.57; 77.68) and 34.05 (95% CI = 34.01; 34.09), respectively. There were 82.10 incident cases of any dementia per 100,000 per year (0.79 sensitivity and 0.62 specificity) and 59.89 incident cases of AD per 100,000 per year (0.80 sensitivity and 0.59 specificity). The capture-recapture method showed a very low number of undetected cases (1.7% for any dementia and 3.0% for AD). Our algorithms showed acceptable performance with the area under the curve ranging from 0.59 to 0.72 and a double likelihood ratio of correctly identifying individuals above and below mini-mental status examination (MMSE) standard cut-offs (24 and 26). CONCLUSIONS: Prevalence and incidence of any dementia and AD in the Campania region (South Italy) from 2015 to 2020 are in line with previous estimates from other countries. Our algorithm, integrating administrative and clinical data, holds potential for assessing dementia's epidemiological burden, identifying risk factors, planning healthcare access, and developing prevention strategies.

Measuring cognitive impairment and monitoring cognitive decline in Huntington's disease: a comparison of assessment instruments.

BACKGROUND: Progressive cognitive decline is an inevitable feature of Huntington's disease (HD) but specific criteria and instruments are still insufficiently developed to reliably classify patients into categories of cognitive severity and to monitor the progression of cognitive impairment. METHODS: We collected data from a cohort of 180 positive gene-carriers: 33 with premanifest HD and 147 with manifest HD. Using a specifically developed gold-standard for cognitive status we classified participants into those with normal cognition, those with mild cognitive impairment, and those with dementia. We administered the Parkinson's Disease-Cognitive Rating Scale (PD-CRS), the MMSE and the UHDRS cogscore at baseline, and at 6-month and 12-month follow-up visits. Cutoff scores discriminating between the three cognitive categories were calculated for each instrument. For each cognitive group and instrument we addressed cognitive progression, sensitivity to change, and the minimally clinical important difference corresponding to conversion from one category to another. RESULTS: The PD-CRS cutoff scores for MCI and dementia showed excellent sensitivity and specificity ratios that were not achieved with the other instruments. Throughout follow-up, in all cognitive groups, PD-CRS captured the rate of conversion from one cognitive category to another and also the different patterns in terms of cognitive trajectories. CONCLUSION: The PD-CRS is a valid and reliable instrument to capture MCI and dementia syndromes in HD. It captures the different trajectories of cognitive progression as a function of cognitive status and shows sensitivity to change in MCI and dementia.

Cognitive impairment is associated with gait variability and fall risk in amyotrophic lateral sclerosis.

BACKGROUND: In amyotrophic lateral sclerosis (ALS), gait abnormalities contribute to poor mobility and represent a relevant risk for falls. To date, gait studies in ALS patients have focused on the motor dimension of the disease, underestimating the cognitive aspects. METHODS: Using a wearable gait analysis device, we compared gait patterns in ambulatory ALS patients with mild cognitive impairment (ALS MCI+; n = 18), and without MCI (ALS MCI-; n = 24), and healthy subjects (HS; n = 16) under two conditions: (1) normal gait (single task) and (2) walking while counting backward (dual task). Finally, we examined if the occurrence and number of falls in the 3 months following the baseline test were related to cognition. RESULTS: In the single task condition, ALS patients, regardless of cognition, displayed higher gait variability than HS, especially for stance and swing time (p < 0.001). The dual task condition revealed additional differences in gait variability parameters between ALS MCI+ and ALS MCI- for cadence (p = 0.005), stance time (p = 0.04), swing time (p = 0.04) and stability index (p = 0.02). Moreover, ALS MCI+ showed a higher occurrence (p = 0.001) and number of falls (p < 0.001) at the follow-up. Regression analyses demonstrated that MCI condition predicted the occurrence of future falls (ß = 3.649; p = 0.01) and, together with executive dysfunction, was associated with the number of falls (cognitive impairment: ß = 0.63; p < 0.001; executive dysfunction: ß = 0.39; p = 0.03), regardless of motor impairment at clinical examination. CONCLUSION: In ALS, MCI is associated with exaggerated gait variability and predicts the occurrence and number of short-term falls.

Corrigendum: A two-year longitudinal study of retinal vascular impairment in patients with amnestic mild cognitive impairment.

[This corrects the article DOI: 10.3389/fnagi.2022.993621.].

Digital Health Service for Identification of Frailty Risk Factors in Community-Dwelling Older Adults: The SUNFRAIL+ Study Protocol.

This article reports the study protocol of a nationwide multicentric study in seven Italian regions aimed at assessing the effectiveness of a digitally supported approach for the early screening of frailty risk factors in community-dwelling older adults. SUNFRAIL+ is a prospective observational cohort study aimed at carrying out a multidimensional assessment of community-dwelling older adults through an IT platform, which allows to connect the items of the SUNFRAIL frailty assessment tool with a cascading multidimensional in-depth assessment of the bio-psycho-social domains of frailty. Seven centers in seven Italian regions will administer the SUNFRAIL questionnaire to 100 older adults. According to the answers provided by older adults, they will be subjected to one or more validated in-depth scale tests in order to perform further diagnostic or dimensional evaluations. The study aims to contribute to the implementation and validation of a multiprofessional and multistakeholder service model for the screening of frailty in community-dwelling older adult population.

Innovative approaches to service integration addressing the unmet needs of irritable bowel syndrome patients and new approaches for the needs of IBS patients.

Background: Irritable bowel syndrome (IBS) is a common multifactorial condition that affects the large intestine and is characterized by chronic and relapsing abdominal pain and altered bowel habit. IBS is due to a combination of genetic, environmental and dietary factors. It's usually a lifelong problem very frustrating to live with and can have a big impact on quality of life, as single-agent therapy ra. Objective: To analyze the approaches and solutions that address the social and health unmet needs of patients with IBS. Design: A quantitative-qualitative approach was adopted in the current study to identify and specify key digital solution and high impact user scenarios applied to IBS patients, through an adaptation of the "Blueprint on Digital Transformation in Health and Care in an Ageing Society" persona methodology. Settings: Digital health solutions bring the potential of supporting health interventions through mobile apps, wearable devices, telemedicine. Patients: A Survey was administered to a group of patients in an anonymous form, and no need for Medical Ethical Committee approval was identified. Interventions: The theoretical elaboration IBS personas was developed through an interdisciplinary Focus Group, which also mapped the pathway for the patient's management. Main outcome: Three main needs were identified to be met to improve IBS patient's lifestyle: access to psychological support, mHealth solutions supporting diet and adapted physical activity, and home-based digital health support. mHealth intervention has been identified for diet adherence, physical exercise and psychological well-being. The process has been mapped and adapted to integrate the new solutions into the care pathway. Limitation: Further research is needed to evaluate how mHealth services enable IBS patients to manage their conditions and improve their quality of life. Conclusion: The person-centered approach was implemented through a multidisciplinary Focus group that enabled the identification of the need for a mHealth intervention.

Assessment Tools of Biopsychosocial Frailty Dimensions in Community-Dwelling Older Adults: A Narrative Review.

Frailty is a complex interplay between several factors, including physiological changes in ageing, multimorbidities, malnutrition, living environment, genetics, and lifestyle. Early screening for frailty risk factors in community-dwelling older people allows for preventive interventions on the clinical and social determinants of frailty, which allows adverse events to be avoided. By conducting a narrative review of the literature employing the International Narrative Systematic Assessment tool, the authors aimed to develop an updated framework for the main measurement tools to assess frailty risks in older adults, paying attention to use in the community and primary care settings. This search focused on the biopsychosocial domains of frailty that are covered in the SUNFRAIL tool. The study selected 178 reviews (polypharmacy: 20; nutrition: 13; physical activity: 74; medical visits: 0; falls: 39; cognitive decline: 12; loneliness: 15; social support: 5; economic constraints: 0) published between January 2010 and December 2021. Within the selected reviews, 123 assessment tools were identified (polypharmacy: 15; nutrition: 15; physical activity: 25; medical visits: 0; falls: 26; cognitive decline: 18; loneliness: 9; social support: 15; economic constraints: 0). The narrative review allowed us to evaluate assessment tools of frailty domains to be adopted for multidimensional health promotion and prevention interventions in community and primary care.

Proposal for innovative and integrated approaches to the unmet needs of patients with irritable bowel syndrome. Preliminary Vigour report.

Irritable bowel syndrome (IBS) is a common multifactorial condition that affects the large intestine and is characterized by chronic and relapsing abdominal pain and altered bowel habit. IBS is due to a combination of genetic, environmental and dietary factors. It's usually a lifelong problem very frustrating to live with and can have a big impact on quality of life, as single-agent therapy rarely relieves bothersome symptoms for all patients. The objective of this study was to analyze the approaches and solutions that address the social and health unmet needs of patients with IBS. A qualitative approach was adopted in the current study to identify and specify key digital solution and high impact user scenarios applied to IBS patients, through an adaptation of the "Blueprint on Digital Transformation in Health and Care in an Ageing Society" persona methodology. A Survey was administered to a group of patients in anonymous form. The theoretical elaboration IBS personas was developed through an interdisciplinary Focus Group, which also mapped the pathway for the patient's management. Three main needs were identified to be met to improve IBS patient's lifestyle: access to psychological support, mHealth solutions supporting diet and adapted physical activity, and homebased digital health support. mHealth intervention has been identified for diet adherence, physical exercise and psychological well-being. The process has been mapped and adapted to integrate the new solutions into the care pathway. Further research is needed to evaluate how mHealth services enable IBS patients to manage their conditions and improve their quality of life. KEY WORDS: Digital Health, Irritable bowel syndrome, mHealth, Nutrition, Physical activity, Psychological support.

Alteration of interoceptive sensitivity: expanding the spectrum of behavioural disorders in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with progressive loss of upper and lower motor neurons. Non-motor-symptoms, such as cognitive, emotional, autonomic, and somatosensory alterations, have been also described. Interoception represents the link between the body and brain, since it refers to the ability to consciously perceive the physical condition of the inner body, including one's heartbeat (i.e., interoceptive sensitivity, IS). OBJECTIVES: To evaluate IS in ALS patients by means of a well-established task: the heartbeat perception task. Moreover, we evaluated possible correlations between IS and neuropsychological, affective, and disease-related characteristics. METHODS: Fifty-five ALS patients (mean-age = 60.3 ± 12.5 years; mean disease-duration = 20.9 ± 18.8 months) and 41 caregivers (CG) underwent the heartbeat perception task and an extensive evaluation of motor, cognitive, body awareness, affective, and emotion domains. RESULTS: ALS patients showed lower IS than CG (0.68 ± 0.24 vs 0.82 ± 0.16; p = 0.003). Significant correlations were found between IS and self-reported measures of alexithymia (subscale of Toronto Alexithymia scale-20 "difficulties in describing feelings"; rho = - .391, p = .003) and interoceptive awareness (subscale of Multidimensional assessment of interoceptive awareness "not worrying about pain"; rho = .405, p = .002). No significant differences were found on questionnaires for depression and anxiety between patients with ALS and their caregivers (p > .05). CONCLUSIONS: ALS patients show reduced interoceptive sensitivity that is associated with poorer ability to describe feelings and with lower focalization on pain, regardless of cognitive and motor impairment. Alteration of interoception may represent a specific behavioural sign within the spectrum of emotion processing deficits described in ALS patients.

Lower Prevalence of Chronic Pain in Manifest Huntington's Disease: A Pilot Observational Study.

Pain is a minor problem compared with other Huntington Disease (HD) symptoms. Nevertheless, in HD it is poorly recognized and underestimated. So far, no study evaluated the presence of chronic pain in HD. The aim of this pilot study was to evaluate the presence and features of chronic pain in a cohort of HD gene carriers. An observational cross-sectional study was conducted in a cohort of HD gene carriers compared to not gene carriers (n.134 HD subjects, n.74 not gene mutation carriers). A specific pain interview, alongside a neurological, cognitive and behavioural examination, was performed in order to classify the type of pain, subjective intensity. A significant prevalence of "no Pain" in HD was found, which tended to increase with HD progression and a reduced frequency of pain in the last 3 months. A clear difference was found between manifest and premanifest HD in terms of intensity of pain, which did not change significantly with HD progression; however, a tendency emerges to a progressive reduction. No significant group difference was present in analgesic use, type and the site of pain. These findings could support a lower prevalence of chronic pain in manifest HD. Prevalence and intensity of chronic pain seem directly influenced by the process of neurodegeneration rather than by an incorrect cognitive and emotional functioning.

Radial peripapillary vessel density as early biomarker in preperimetric glaucoma and amnestic mild cognitive impairment.

PURPOSE: To investigate the vessel density (VD) of the radial peripapillary capillary (RPC) plexus in patients affected by preperimetric glaucoma (PPG), amnestic mild cognitive impairment (aMCI) and in a healthy control group using optical coherence tomography angiography (OCTA) in order to clarify the pathogenetic mechanisms of these neurodegenerative diseases. METHODS: In this prospective study, we studied 54 eyes of 54 patients with PPG, 54 eyes of 54 patients with aMCI and 54 healthy controls. All subjects underwent structural spectral domain optical coherence tomography (SD)-OCT to assess the ganglion cell complex (GCC) and the retinal nerve fibre layer (RNFL). OCTA was used to evaluate the VD of the RPC in different regions (whole image, inside disc and peripapillary). RESULTS: The PPG and aMCI groups showed a statistically significant reduction in SD-OCT and parameters with respect to controls (p < 0.001). No statistically significant difference was found in GCC and RNFL parameters between the two study groups (p > 0.05). At OCTA examination, PPG and aMCI patients exhibited a statistically significant reduction in the VD of the RPC in whole image, inside and peripapillary regions compared to healthy controls (p < 0.001). When comparing the two study groups, the OCTA parameters were significantly impaired in PPG with respect to aMCI patients. Significant correlations were found between structural OCT and OCTA parameters in PPG and aMCI groups (p < 0.05). CONCLUSIONS: RPC vessel density could represent a helpful and sensible biomarker to identify early retinal microvascular changes in PPG and MCI in order to better understand the vascular pathophysiological mechanisms involved in these neurodegenerative diseases.

Autonomic disorders and myocardial 123I-metaiodobenzylguanidine scintigraphy in Huntington's disease.

BACKGROUND: Huntington's disease (HD) patients often present with abnormal modulation of blood pressure and heart rate. We investigated whether cardiac autonomic innervation assessed by 123I-metaiodobenzylguanidine (MIBG) imaging is impaired in HD patients, in comparison with controls (Ctrl). METHODS: Fifteen patients (6 F and 9 M) were assessed by the motor section of the Unified HD Rating Scale, the Total Function Capacity, and the scale for outcomes in Parkinson's disease-autonomic (SCOPA-AUT) questionnaire. All patients and 10 Ctrl (5 F and 5 M) underwent 123I-MIBG imaging. From planar images, the early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates (WR) were calculated. RESULTS: We did not find significant differences in early and late H/M ratios and WR between the two groups. At individual level, three patients showed reduced early and/or late H/M ratios. The most common autonomic complaints were gastrointestinal and genitourinary disorders. SCOPA-AUT questionnaire score results positively correlated with the disease duration and WR. CONCLUSIONS: Our study indicates that myocardial postganglionic sympathetic innervation is essentially preserved or only minimally involved in HD. These findings suggest that the cardiovascular dysfunction might be mainly due to the impairment of brain areas associated with the regulation and modulation of the heart function.

Arithmetic Word-Problem Solving as Cognitive Marker of Progression in Pre-Manifest and Manifest Huntington's Disease.

BACKGROUND: Arithmetic word-problem solving depends on the interaction of several cognitive processes that may be affected early in the disease in gene-mutation carriers for Huntington's disease (HD). OBJECTIVE: Our goal was to examine the pattern of performance of arithmetic tasks in premanifest and manifest HD, and to examine correlations between arithmetic task performance and other neuropsychological tasks. METHODS: We collected data from a multicenter cohort of 165 HD gene-mutation carriers. The sample consisted of 31 premanifest participants: 16 far-from (>12 years estimated time to diagnosis; preHD-A) and 15 close-to (≤12 years estimated time to diagnosis; preHD-B), 134 symptomatic patients (early-mild HD), and 37 healthy controls (HC). We compared performance between groups and explored the associations between arithmetic word-problem solving and neuropsychological and clinical variables. RESULTS: Total arithmetic word-problem solving scores were lower in preHD-B patients than in preHD-A (p < 0.05) patients and HC (p < 0.01). Early-mild HD patients had lower scores than preHD patients (p < 0.001) and HC (p < 0.001). Compared to HC, preHD and early-mild HD participants made more errors as trial complexity increased. Moreover, arithmetic word-problem solving scores were significantly associated with measures of global cognition (p < 0.001), frontal-executive functions (p < 0.001), attention (p < 0.001) visual working memory (p < 0.001), mental rotation (p < 0.001), and confrontation naming (p < 0.05). CONCLUSION: Arithmetic word-problem solving is affected early in the course of HD and is related to deficient processes in frontal-executive and mentalizing-related processes.

Optical coherence tomography angiography findings in Huntington's disease.

OBJECTIVES: To evaluate the retinal and choriocapillaris vascular networks in macular region and the central choroidal thickness (CCT) in patients affected by Huntington disease (HD), using optical coherence tomography angiography (OCTA) and enhanced depth imaging spectral-domain OCT (EDI SD-OCT). METHODS: We assessed the vessel density (VD) in superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC) using OCTA, while CCT was measured by EDI SD-OCT. RESULTS: Sixteen HD patients (32 eyes) and thirteen healthy controls (26 eyes) were enrolled in this prospective study. No significant difference in retinal and choriocapillaris VD was found between HD patients and controls while CCT turned to be thinner in patients respect to controls. There were no significant relationships between OCTA findings and neurological parameters. CONCLUSION: The changes in choroidal structure provide useful information regarding the possible neurovascular involvement in the physiopathology of HD. Choroidal vascular network could be a useful parameter to evaluate the vascular impairment that occurs in this neurodegenerative disease.

[18F]FDG uptake of the normal spinal cord in PET/MR imaging: comparison with PET/CT imaging.

BACKGROUND: The lack of visualization of the spinal cord hinders the evaluation of [18F]Fluoro-deoxy-glucose (FDG) uptake of the spinal cord in PET/CT. By exploiting the capability of MRI to precisely outline the spinal cord, we performed a retrospective study aimed to define normal pattern of spinal cord [18F]FDG uptake in PET/MRI. METHODS: Forty-one patients with lymphoma without clinical or MRI signs of spinal cord or bone marrow involvement underwent simultaneous PET and MRI acquisition using Siemens Biograph mMR after injection of 3.5 MBq/kg body weight of [18F]FDG for staging purposes. Using a custom-made software, we placed ROIs of 3 and 9 mm in diameter in the spinal cord, lumbar CSF, and vertebral marrow that were identified on MRI at 5 levels (C2, C5, T6, T12, and L3). The SUVmax, SUVmean, and the SUVmax and SUVmean normalized (NSUVmax and NSUVmean) to the liver were measured. For comparison, the same ROIs were placed in PET-CT images obtained immediately before the PET-MRI acquisition following the same tracer injection. RESULTS: On PET/MRI using the 3 mm ROI, the following average (all level excluding L3) spinal cord median (1st and 3rd quartile) values were measured: SUVmean, 1.68 (1.39 and 1.83); SUVmax, 1.92 (1.60 and 2.14); NSUVmean, 1.18 (0.93 and 1.36); and NSUVmax, 1.27 (1.01 and 1.33). Using the 9 mm ROI, the corresponding values were SUVmean, 1.41 (1.25-1.55); SUVmax, 2.41 (2.08 and 2.61); NSUVmean, 0.93 (0.79 and 1.04); and NSUVmax, 1.28 (1.02 and 1.39). Using the 3 mm ROI, the highest values of PET-MRI SUVmax, SUVmean, NSUVmax, and NSUVmean were consistently observed at C5 and the lowest at T6. Using a 9 mm ROI, the highest values were consistently observed at C5 and the lowest at T12 or T6. The spinal cord [18F]FDG-uptake values correlated with the bone marrow uptake at the same level, especially in case of NSUVmax. Comparison with PET-CT data revealed that the average SUVmax and SUVmean of the spinal cord were similar in PET-MRI and PET-CT. However, the average NSUVmax and NSUVmean of the spinal cord were higher (range 21-47%) in PET-MRI than in PET-CT. CONCLUSIONS: Using a whole-body protocol, we defined the maximum and mean [18F]FDG uptake of the normal spinal cord in PET/MRI. While the observed values show the expected longitudinal distribution, they appear to be higher than those measured in PET/CT. Normalization of the SUVmax and SUVmean of the spinal cord to the liver radiotracer uptake could help in multi-institutional comparisons and studies.

Surface-enhanced Raman spectroscopy of tears: toward a diagnostic tool for neurodegenerative disease identification.

SIGNIFICANCE: A noninvasive method based on surface-enhanced Raman spectroscopy (SERS) of tears was proposed as a support for diagnosing neurodegenerative pathologies, including different forms of dementia and Alzheimer's disease (AD). In this field, timely and reliable discrimination and diagnosis are critical aspects for choosing a valid medical therapy, and new methods are highly required. AIM: The aim is to evince spectral differences in SERS response of human tears from AD affected, mild cognitive impaired (MCI), and healthy control (Ctr) subjects. APPROACH: Human tears were characterized by SERS coupled with multivariate data analysis. Thirty-one informed subjects (Ctr, MCI, and AD) were considered. RESULTS: Average SERS spectra from Ctr, MCI, and AD subjects evidenced differences related to lactoferrin and lysozyme protein components. Quantitative changes were also observed by determining the intensity ratio between selected bands. We also constructed a classification model that discriminated among AD, MCI, and Ctr subjects. The model was built using the scores obtained by performing principal component analysis on specific spectral regions (i-PCA). CONCLUSIONS: The results are very encouraging with interesting perspectives for medical applications as support of clinical diagnosis and discrimination of AD from other forms of dementia.