Plasma neurofilament light chain predicts Alzheimer's disease in patients with subjective cognitive decline and mild cognitive impairment: A cross-sectional and longitudinal study.

BACKGROUND AND PURPOSE: We aimed to evaluate the accuracy of plasma neurofilament light chain (NfL) in predicting Alzheimer's disease (AD) and the progression of cognitive decline in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). METHODS: This longitudinal cohort study involved 140 patients (45 with SCD, 73 with MCI, and 22 with AD dementia [AD-D]) who underwent plasma NfL and AD biomarker assessments (cerebrospinal fluid, amyloid positron emission tomography [PET], and 18 F-fluorodeoxyglucose-PET) at baseline. The patients were rated according to the amyloid/tau/neurodegeneration (A/T/N) system and followed up for a mean time of 2.72 ± 0.95 years to detect progression from SCD to MCI and from MCI to AD. Forty-eight patients (19 SCD, 29 MCI) also underwent plasma NfL measurements 2 years after baseline. RESULTS: At baseline, plasma NfL detected patients with biomarker profiles consistent with AD (A+/T+/N+ or A+/T+/N-) with high accuracy (area under the curve [AUC] 0.82). We identified cut-off values of 19.45 pg/mL for SCD and 20.45 pg/mL for MCI. During follow-up, nine SCD patients progressed to MCI (progressive SCD [p-SCD]), and 14 MCI patients developed AD dementia (progressive MCI [p-MCI]). The previously identified cut-off values provided good accuracy in identifying p-SCD (80% [95% confidence interval 65.69: 94.31]). The rate of NfL change was higher in p-MCI (3.52 ± 4.06 pg/mL) compared to non-progressive SCD (0.81 ± 1.25 pg/mL) and non-progressive MCI (-0.13 ± 3.24 pg/mL) patients. A rate of change lower than 1.64 pg/mL per year accurately excluded progression from MCI to AD (AUC 0.954). CONCLUSION: Plasma NfL concentration and change over time may be a reliable, non-invasive tool to detect AD and the progression of cognitive decline at the earliest stages of the disease.

Depressive Symptoms Moderate the Association Between Functional Level at Admission to Intensive Post-Stroke Rehabilitation and Effectiveness of the Intervention.

INTRODUCTION: Previous studies showed that depression acts as an independent factor in functional recovery after stroke. In a prospective cohort of patients admitted to intensive inpatient rehabilitation after a stroke, we aimed to test depression as a moderator of the relationship between the functional level at admission and the effectiveness of rehabilitation at discharge. METHODS: All patients admitted to within 30 days from an ischemic or hemorrhagic stroke to 4 intensive rehabilitation units were prospectively screened for eligibility to a multicenter prospective observational study. Enrolled patients underwent an evidence-based rehabilitation pathway. We used clinical data collected at admission (T0) and discharge (T1). The outcome was the effectiveness of recovery at T1 on the modified Barthel Index (proportion of achieved over potential functional improvement). Moderation analysis was performed by using the PROCESS macro for SPSS using the bootstrapping procedure. RESULTS: Of 278 evaluated patients, 234 were eligible and consented to enrolment; 81 patients were able to answer to the Hospital Anxiety and Depression Scale (HADS) and were included in this analysis. The relationship between the functional status at admission and rehabilitation effectiveness was significant only in persons with fewer depressive symptoms; depression (HADS cut-off score: 5.9) moderated this relationship (P = .047), independent from age and neurological impairment. CONCLUSIONS: Our results suggest that depression moderates between the functional status at admission and the functional recovery after post-stroke rehabilitation. This approach facilitates the identification of subgroups of individuals who may respond differently to stroke rehabilitation based on depression.

The role of plasma neurofilament light chain and glial fibrillary acidic protein in subjective cognitive decline and mild cognitive impairment.

INTRODUCTION AND AIM: NfL and GFAP are promising blood-based biomarkers for Alzheimer's disease. However, few studies have explored plasma GFAP in the prodromal and preclinical stages of AD. In our cross-sectional study, our aim is to investigate the role of these biomarkers in the earliest stages of AD. MATERIALS AND METHODS: We enrolled 40 patients (11 SCD, 21 MCI, 8 AD dementia). All patients underwent neurological and neuropsychological examinations, analysis of CSF biomarkers (Aß42, Aß42/Aß40, p-tau, t-tau), Apolipoprotein E (APOE) genotype analysis and measurement of plasma GFAP and NfL concentrations. Patients were categorized according to the ATN system as follows: normal AD biomarkers (NB), carriers of non-Alzheimer's pathology (non-AD), prodromal AD, or AD with dementia (AD-D). RESULTS: GFAP was lower in NB compared to prodromal AD (p = 0.003, d = 1.463) and AD-D (p = 0.002, d = 1.695). NfL was lower in NB patients than in AD-D (p = 0.011, d = 1.474). NfL demonstrated fair accuracy (AUC = 0.718) in differentiating between NB and prodromal AD, with a cut-off value of 11.65 pg/mL. GFAP showed excellent accuracy in differentiating NB from prodromal AD (AUC = 0.901) with a cut-off level of 198.13 pg/mL. CONCLUSIONS: GFAP exhibited excellent accuracy in distinguishing patients with normal CSF biomarkers from those with prodromal AD. Our results support the use of this peripheral biomarker for detecting AD in patients with subjective and objective cognitive decline.

PRedicting the EVolution of SubjectIvE Cognitive Decline to Alzheimer's Disease With machine learning: the PREVIEW study protocol.

BACKGROUND: As disease-modifying therapies (DMTs) for Alzheimer's disease (AD) are becoming a reality, there is an urgent need to select cost-effective tools that can accurately identify patients in the earliest stages of the disease. Subjective Cognitive Decline (SCD) is a condition in which individuals complain of cognitive decline with normal performances on neuropsychological evaluation. Many studies demonstrated a higher prevalence of Alzheimer's pathology in patients diagnosed with SCD as compared to the general population. Consequently, SCD was suggested as an early symptomatic phase of AD. We will describe the study protocol of a prospective cohort study (PREVIEW) that aim to identify features derived from easily accessible, cost-effective and non-invasive assessment to accurately detect SCD patients who will progress to AD dementia. METHODS: We will include patients who self-referred to our memory clinic and are diagnosed with SCD. Participants will undergo: clinical, neurologic and neuropsychological examination, estimation of cognitive reserve and depression, evaluation of personality traits, APOE and BDNF genotyping, electroencephalography and event-related potential recording, lumbar puncture for measurement of Aß42, t-tau, and p-tau concentration and Aß42/Aß40 ratio. Recruited patients will have follow-up neuropsychological examinations every two years. Collected data will be used to train a machine learning algorithm to define the risk of being carriers of AD and progress to dementia in patients with SCD. DISCUSSION: This is the first study to investigate the application of machine learning to predict AD in patients with SCD. Since all the features we will consider can be derived from non-invasive and easily accessible assessments, our expected results may provide evidence for defining cost-effective and globally scalable tools to estimate the risk of AD and address the needs of patients with memory complaints. In the era of DMTs, this will have crucial implications for the early identification of patients suitable for treatment in the initial stages of AD. TRIAL REGISTRATION NUMBER (TRN): NCT05569083.

Huntingtin gene intermediate alleles influence the progression from subjective cognitive decline to mild cognitive impairment: A 14-year follow-up study.

BACKGROUND AND PURPOSE: Huntingtin (HTT) is a gene containing a key region of CAG repeats. HTT alleles containing from 27 to 35 CAG repeats are termed intermediate alleles (IAs). We aimed to assess the effect of IAs on progression of cognitive impairment in patients with subjective cognitive decline (SCD). METHODS: We included 106 patients with SCD. All the patients underwent neuropsychological assessments and blood sample collection at baseline. Patients were followed up for a median (interquartile range) time of 13.75 (8.17) years. We genotyped APOE and HTT at the end of the follow-up. RESULTS: Eleven out of 106 patients (10.38%, 95% confidence interval [CI] 4.57-16.18) were carriers of IAs (IA+ ). During the follow-up, 44 patients (41.51%, 95% CI 32.13-50.89) progressed to mild cognitive impairment (MCI; p-SCD group), while 62 patients (58.49%, 95% CI 49.11-67.87) did not (np-SCD group). Rate of progression to MCI was associated with IAs, age at baseline, and APOE ɛ4. We dichotomized age at baseline (<60 years = younger patients [YP], >60 years = older patients [OP]) and then classified patients into four groups: YP/IA- , YP/IA+ , OP/IA-  and OP/IA+ . The OP/IA+  group had a higher proportion of patients with progression from SCD to MCI (85.71%, 95% CI 59.79-100) as compared to the YP/IA-  group (28.57%, 95% CI 13.60-43.54, χ2  = 15.25; p < 0.001) and the OP/IA-  group (45.00%, 95% CI 32.41-57.59, χ2  = 7.903; p = 0.005). We classified patients according to APOE and IA as: ɛ4- /IA- , ɛ4- /IA+ , ɛ4+ /IA- , ɛ4+ /IA+ . The proportion of patients with progression in the ɛ4+ /IA+  group (100%) was higher as compared to the ɛ4- /IA-  group (33.33%, 95% CI 21.96-44.71, χ2  = 14.43; p < 0.001) and ɛ4+ /IA-  (55.56%, 95% CI 36.81-74.30, χ2  = 4.60; p = 0.032). CONCLUSIONS: Intermediate alleles interact with age and APOE ɛ4, increasing the risk of progression to MCI in SCD patients.

Gender differences in cognitive reserve: implication for subjective cognitive decline in women.

BACKGROUND: Subjective Cognitive Decline (SCD) is a self-experienced decline in cognitive capacity with normal performance on standardized cognitive tests, showing to increase risk of Alzheimer's Disease (AD). Cognitive reserve seems to influence the progression from SCD to Mild Cognitive Impairment (MCI) and to AD. The aim of our study was to investigate gender differences in cognitive reserve evaluating how sex might modulate the role of cognitive reserve on SCD. METHODS: We included 381 SCD patients who underwent clinical evaluation, neuropsychological assessment, evaluation of premorbid intelligence by the Test di Intelligenza Breve (TIB), cognitive complaints by the Memory Assessment Clinics Questionnaire (MAC-Q), and apolipoprotein E (APOE) genotyping. RESULTS: The proportion between women and men was significantly different (68.7% [95% CI 63.9-73.4 vs 31.4%, 95% CI 26.6-36.0]). Women were younger than men at onset of SCD and at the baseline visit (p = 0.021), had lower years of education (p = 0.007), lower TIB scores (p < 0.001), and higher MAC-Q scores (p = 0.012). TIB was directly associated with age at onset of SCD in both women and men, while years of education was inversely associated with age at onset only in women. Multivariate analysis showed that sex influences TIB independently from years of education. TIB was directly associated with MAC-Q in men. CONCLUSIONS: Sex interacts with premorbid intelligence and education level in influencing the age at onset and the severity of SCD. As the effect of education was different between men and women, we speculated that education might act as a minor contributor of cognitive reserve in women.

Cerebral amyloid load determination in a clinical setting: interpretation of amyloid biomarker discordances aided by tau and neurodegeneration measurements.

BACKGROUND: Alzheimer's disease (AD) diagnosis can be hindered by amyloid biomarkers discordances. OBJECTIVE: We aim to interpret discordances between amyloid positron emission tomography (Amy-PET) and cerebrospinal fluid (CSF) (Aß42 and Aß42/40), using Amy-PET semiquantitative analysis, [18F]fluorodeoxyglucose (FDG)-PET pattern, and CSF assays. METHOD: Thirty-six subjects with dementia or mild cognitive impairment, assessed by neuropsychological tests, structural and functional imaging, and CSF assays (Aß42, Aß42/40, p-tau, t-tau), were retrospectively examined. Amy-PET and FDG-PET scans were analyzed by visual assessment and voxel-based analysis. SUVR were calculated on Amy-PET scans. RESULTS: Groups were defined basing on the agreement among CSF Aß42 (A), CSF Aß42/40 Ratio (R), and Amy-PET (P) dichotomic results ( ±). In discordant groups, CSF assays, Amy-PET semiquantification, and FDG-PET patterns supported the diagnosis suggested by any two agreeing amyloid biomarkers. In groups with discordant CSF Aß42, the ratio always agrees with Amy-PET results, solving both false-negative and false-positive Aß42 results, with Aß42 levels close to the cut-off in A + R-P- subjects. The A + R + P- group presented high amyloid deposition in relevant areas, such as precuneus, posterior cingulate cortex (PCC) and dorsolateral frontal inferior cortex at semiquantitative analysis. CONCLUSION: The amyloid discordant cases could be overcome by combining CSF Aß42, CSF ratio, and Amy-PET results. The concordance of any 2 out of the 3 biomarkers seems to reveal the remaining one as a false result. A cut-off point review could avoid CSF Aß42 false-negative results. The regional semiquantitative Amy-PET analysis in AD areas, such as precuneus and PCC, could increase the accuracy in AD diagnosis.

The implication of BDNF Val66Met polymorphism in progression from subjective cognitive decline to mild cognitive impairment and Alzheimer's disease: a 9-year follow-up study.

Brain-derived natriuretic factor (BDNF) Val66Met polymorphism has been frequently reported to be associated with Alzheimer's disease (AD) with contrasting results. Numerous studies showed that Met allele increased the risk of AD only in women, while other studies have found worse cognitive performance in Val/Val carriers. We aimed to inquire the effects of Val66Met polymorphism on the progression from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) and from MCI to AD and to ascertain if this effect is modulated by demographic and cognitive variables. For this purpose, we followed up 74 subjects (48 SCD, 26 MCI) for a mean time of 9 years. All participants underwent extensive neuropsychological assessment, cognitive reserve estimation, BDNF and apolipoprotein E (ApoE) genotype analysis at baseline. Personality traits and leisure activities were assessed in a subgroup. Each patient underwent clinical-neuropsychological follow-up, during which 18 out of 48 SCD subjects progressed to MCI and 14 out of 26 MCI subjects progressed to AD. We found that Val66Met increased the risk of progression from SCD to MCI and from MCI to AD only in women. Nevertheless, Val/Val carriers who progressed from SCD to MCI had a shorter conversion time compared to Met carriers. We concluded that Val66Met polymorphism might play different roles depending on sex and stage of the disease.

Comparison between radioiodine therapy and single-session radiofrequency ablation of autonomously functioning thyroid nodules: A retrospective study.

OBJECTIVE: To compare the efficacy of Radioiodine (RI) and Radiofrequency ablation (RFA) in the treatment of autonomously functioning thyroid nodules (AFTNs). End-points: nodule volume reduction (NVR) and thyroid function normalization. DESIGN, PATIENTS AND MEASUREMENTS: Twenty-two patients (2:20 M:F; 51.9 ± 13.9 years) affected by 25 AFTNs, treated by RFA were retrospectively compared with 25 patients (8:17 M:F; 57.2 ± 12.8 years) affected by a single AFTN treated by RI. Both group showed analogous characteristics as to age, gender, toxic/pretoxic phase and pretreatment nodule volume (calculated by the ellipsoid formula). Thyroid hormone levels and autoimmune thyroid profile were assessed before treatment. A fixed RI activity of 555 MBq (15 mCi) was administered. RFA was performed with an 18G, single-tipped electrode, by the "modified moving shot technique." Thyroid hormones were assessed and the nodule post-treatment volume calculated 12 months after treatment. RESULTS: No statistical difference was found between the post-treatment NVR by comparing RI and RFA (P = 0.69). The volume reduction rates were 68.4 ± 28.9% and 76.4 ± 16.9% after RI and RFA, respectively. As to the thyroid function, 5/25 patients developed clinical hypothyroidism after RI. After RFA, all the 22 patients silenced their AFTN and normalized the thyroid hormones. Subclinical hypothyroidism was recorded in two patients after both RI and RFA. Thus, the functional therapeutic success, defined as the restoration of euthyroidism, was achieved in 18/25 (72%) patients treated by RI and in 20/22 (90.9%) treated by RFA. CONCLUSIONS: No statistical difference in NVR was found between RI and RFA. All patients responded to RI but 5/25 were "over-treated" developing hypothyroidism. RFA was effective in all patients with no case of post-treatment clinical hypothyroidism. No radiation exposure and lower risk of post-treatment hypothyroidism might make RFA the favourite option especially for young patients.

KIBRA T allele influences memory performance and progression of cognitive decline: a 7-year follow-up study in subjective cognitive decline and mild cognitive impairment.

KIBRA is a signal transducer protein, mainly expressed in the kidney and brain. A single-nucleotide polymorphism (SNP rs17070145, T → C exchange) has been linked to different cognitive function. In 2008, we studied 70 subjects who complained of subjective cognitive decline (SCD) and found that CT/TT carriers performed worse than CC carriers on a long-term memory test. We followed up the 70 SCD subjects and also 31 subjects affected by mild cognitive impairment (MCI) for a mean follow-up time of 7 years, during which 16 SCD subjects progressed to MCI and 14 MCI subjects progressed to Alzheimer's disease (AD). Carrying the T allele was associated with MCI and with a two times-higher risk of developing MCI than CC carriers. In the SCD sample, CT/TT carriers showed a greater worsening on Rivermead Behavioral Memory Test (RBMT) compared to CC carriers. In the MCI sample, CT/TT carriers performed worse than CC carriers on RBMT. There is a lack of consensus on the effect of KIBRA gene variants on cognitive performances in episodic memory and on the risk of AD. Our results confirm a role of T allele on progression of cognitive decline.

Management of pregnancy-associated pancreatic cystic tumors: Review of the literature and results of a Pancreas Club Inc. Survey.

BACKGROUND/OBJECTIVES: Management of patients with pregnancy-associated cyst pancreatic cystic tumors (PA-PCT) is complicated by lack of large series. METHODS: A systematic literature review was conducted to extrapolate data on management of PA-PCT, and make a questionnaire on pending issues to be administered to the members of the Pancreas Club Inc. RESULTS: The literature review demonstrated a total of 35 PA-PCT in 34 women, described exclusively in the form of case reports, and permitted the identification of eleven key questions to be addressed in the survey. The combined analysis of literature review and survery responses provided several information. First, PA-PCT are predominantly located in the body-tail of the pancreas, cause non-specific symptoms, are of large size (mean size: 11.2 ±â€¯4.5 cm), and are nearly always malignant or premalignant, making timing of surgery, and not indication for surgery, the main issue in the management of these tumors. Second, there is a risk of PA-PCT rupture during pregnancy. Ruptured PA-PCT had a mean size 13.5 ±â€¯4.9 cm, but no prognostic factor could be identified. Survey opinions suggested that this occurrence is quite rare, even for large tumors. Third, most pregnancies were conducted to term (mean gestational age: 40.5 ±â€¯0.7 weeks), with a vaginal delivery. Fourth, all procedures were carried out through an open approach and the spleen was rarely preserved. Survey indicated instead that laparoscopy could play a role, and that the spleen should be preserved when feasible. CONCLUSIONS: PA-PCT require individualized treatment. The definition of a management algorithm requires the implementation of an International Registry.

Radiofrequency Ablation in the Treatment of Benign Thyroid Nodules: An Efficient and Safe Alternative to Surgery.

PURPOSE: To evaluate the efficacy and safety of radiofrequency (RF) ablation in the treatment of benign thyroid nodules (BTNs) by applying a modification of the moving-shot technique. MATERIALS AND METHODS: Fifty-one BTNs in 46 patients for whom surgery was contraindicated or who refused surgery were treated with RF ablation: 31 had lesion volumes < 20 cm3 (group A) and 20 had volumes ≥ 20 cm3 (group B). The solid component percentage of each lesion was assessed, and any present fluid component was aspirated. Symptomatic scores and cosmetic scores (CSs) were assessed. All RF ablations were performed under ultrasound (US) guidance with an 18-gauge electrode. Treatment response was evaluated by contrast-enhanced US at 6-month intervals for 18 months in group A. In group B, after the 6- and 12-month follow-up assessments, a second treatment was performed in selected cases, and the 6-month contrast-enhanced US follow-up was started again. Volume reduction rate (VRR) was evaluated at each follow-up examination. RESULTS: No permanent paralysis of the laryngeal nerve was observed; 2 patients experienced transient hoarseness. In all nodules treated with a single RF ablation session, the VRRs at 6, 12, and 18 months were 69.4%, 78.7%, and 84% in group A, respectively, and 66.6%, 79.4%, and 81.5% in group B, respectively. The VRRs of group B nodules treated with a second RF ablation procedure (n = 6) were 86.4% and 88.2% at 6 and 12 mo after the second treatment, respectively. All patients reported symptom relief and CS improvement. CONCLUSIONS: RF ablation is a reliable alternative to surgery in patients affected by BTNs and can be safely repeated in selected cases.

Contrast enhancement pattern on multidetector CT predicts malignancy in pancreatic endocrine tumours.

OBJECTIVES: Preoperative suspicion of malignancy in pancreatic neuroendocrine tumours (pNETs) is mostly based on tumour size. We retrospectively reviewed the contrast enhancement pattern (CEP) of a series of pNETs on multiphasic multidetector computed tomography (MDCT), to identify further imaging features predictive of lesion aggressiveness. METHODS: Sixty pNETs, diagnosed in 52 patients, were classified based on CEP as: type A showing early contrast enhancement and rapid wash-out; type B presenting even (B1) or only (B2) late enhancement. All tumours were resected allowing pathologic correlations. RESULTS: Nineteen pNETs showed type A CEP (5-20 mm), 29 type B1 CEP (5-80 mm) and 12 type B2 (15-100 mm). All tumours were classified as well differentiated tumours, 19 were benign (WDt-b), 15 with uncertain behaviour (WDt-u) and 26 carcinomas (WDC). None of A lesions were malignant (12 WDt-b; 7 WDt-u), all B2 lesions were WDC, 7 B1 lesions were WDt-b, 8 WDt-u and 14 WDC; 4/34 (12 %) lesions ≤2cm were WDC. CEP showed correlation with all histological prognostic indicators. CONCLUSIONS: Correlating with the lesion grading and other histological prognostic predictors, CEP may preoperatively suggest the behaviour of pNETs, assisting decisions about treatment. Moreover CEP allows recognition of malignant small tumours, incorrectly classified on the basis of their dimension.

Plasma GFAP, NfL and pTau 181 detect preclinical stages of dementia.

Background: Plasma biomarkers are preferable to invasive and expensive diagnostic tools, such as neuroimaging and lumbar puncture that are gold standard in the clinical management of Alzheimer's Disease (AD). Here, we investigated plasma Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light Chain (NfL) and Phosphorylated-tau-181 (pTau 181) in AD and in its early stages: Subjective cognitive decline (SCD) and Mild cognitive impairment (MCI). Material and methods: This study included 152 patients (42 SCD, 74 MCI and 36 AD). All patients underwent comprehensive clinical and neurological assessment. Blood samples were collected for Apolipoprotein E (APOE) genotyping and plasma biomarker (GFAP, NfL, and pTau 181) measurements. Forty-three patients (7 SCD, 27 MCI, and 9 AD) underwent a follow-up (FU) visit after 2 years, and a second plasma sample was collected. Plasma biomarker levels were detected using the Simoa SR-X technology (Quanterix Corp.). Statistical analysis was performed using SPSS software version 28 (IBM SPSS Statistics). Statistical significance was set at p < 0.05. Results: GFAP, NfL and pTau 181 levels in plasma were lower in SCD and MCI than in AD patients. In particular, plasma GFAP levels were statistically significant different between SCD and AD (p=0.003), and between MCI and AD (p=0.032). Plasma NfL was different in SCD vs MCI (p=0.026), SCD vs AD (p<0.001), SCD vs AD FU (p<0.001), SCD FU vs AD (p=0.033), SCD FU vs AD FU (p=0.011), MCI vs AD (p=0.002), MCI FU vs AD (p=0.003), MCI FU vs AD FU (p=0.003) and MCI vs AD FU (p=0.003). Plasma pTau 181 concentration was significantly different between SCD and AD (p=0.001), MCI and AD (p=0.026), MCI FU and AD (p=0.020). In APOE ϵ4 carriers, a statistically significant increase in plasma NfL (p<0.001) and pTau 181 levels was found (p=0.014). Moreover, an association emerged between age at disease onset and plasma GFAP (p = 0.021) and pTau181 (p < 0.001) levels. Discussion and conclusions: Plasma GFAP, NfL and pTau 181 are promising biomarkers in the diagnosis of the prodromic stages and prognosis of dementia.

Primary progressive aphasia: six questions in search of an answer.

Here, we review recent progress in the diagnosis and management of primary progressive aphasia-the language-led dementias. We pose six key unanswered questions that challenge current assumptions and highlight the unresolved difficulties that surround these diseases. How many syndromes of primary progressive aphasia are there-and is syndromic diagnosis even useful? Are these truly 'language-led' dementias? How can we diagnose (and track) primary progressive aphasia better? Can brain pathology be predicted in these diseases? What is their core pathophysiology? In addition, how can primary progressive aphasia best be treated? We propose that pathophysiological mechanisms linking proteinopathies to phenotypes may help resolve the clinical complexity of primary progressive aphasia, and may suggest novel diagnostic tools and markers and guide the deployment of effective therapies.

Heterogeneity and overlap in the continuum of linguistic profile of logopenic and semantic variants of primary progressive aphasia: a Profile Analysis based on Multidimensional Scaling study.

BACKGROUND: Primary progressive aphasia (PPA) diagnostic criteria underestimate the complex presentation of semantic (sv) and logopenic (lv) variants, in which symptoms partially overlap, and mixed clinical presentation (mixed-PPA) and heterogenous profile (lvPPA +) are frequent. Conceptualization of similarities and differences of these clinical conditions is still scarce. METHODS: Lexical, semantic, phonological, and working memory errors from nine language tasks of sixty-seven PPA were analyzed using Profile Analysis based on Multidimensional Scaling, which allowed us to create a distributed representation of patients' linguistic performance in a shared space. Patients had been studied with [18F] FDG-PET. Correlations were performed between metabolic and behavioral data. RESULTS: Patients' profiles were distributed across a continuum. All PPA, but two, presented a lexical retrieval impairment, in terms of reduced production of verbs and nouns. svPPA patients occupied a fairly clumped space along the continuum, showing a preponderant semantic deficit, which correlated to fusiform gyrus hypometabolism, while only few presented working memory deficits. Adjacently, lvPPA + presented a semantic impairment combined with phonological deficits, which correlated with metabolism in the anterior fusiform gyrus and posterior middle temporal gyrus. Starting from the shared phonological deficit side, a large portion of the space was occupied by all lvPPA, showing a combination of phonological, lexical, and working memory deficits, with the latter correlating with posterior temporo-parietal hypometabolism. Mixed PPA did not show unique profile, distributing across the space. DISCUSSION: Different clinical PPA entities exist but overlaps are frequent. Identifying shared and unique clinical markers is critical for research and clinical practice. Further research is needed to identify the role of genetic and pathological factors in such distribution, including also higher sample size of less represented groups.

Personalized modeling of Alzheimer's disease progression estimates neurodegeneration severity from EEG recordings.

INTRODUCTION: Early identification of Alzheimer's disease (AD) is necessary for a timely onset of therapeutic care. However, cortical structural alterations associated with AD are difficult to discern. METHODS: We developed a cortical model of AD-related neurodegeneration accounting for slowing of local dynamics and global connectivity degradation. In a monocentric study we collected electroencephalography (EEG) recordings at rest from participants in healthy (HC, n = 17), subjective cognitive decline (SCD, n = 58), and mild cognitive impairment (MCI, n = 44) conditions. For each patient, we estimated neurodegeneration model parameters based on individual EEG recordings. RESULTS: Our model outperformed standard EEG analysis not only in discriminating between HC and MCI conditions (F1 score 0.95 vs 0.75) but also in identifying SCD patients with biological hallmarks of AD in the cerebrospinal fluid (recall 0.87 vs 0.50). DISCUSSION: Personalized models could (1) support classification of MCI, (2) assess the presence of AD pathology, and (3) estimate the risk of cognitive decline progression, based only on economical and non-invasive EEG recordings. Highlights: Personalized cortical model estimating structural alterations from EEG recordings.Discrimination of Mild Cognitive Impairment (MCI) and Healthy (HC) subjects (95%)Prediction of biological markers of Alzheimer's in Subjective Decline (SCD) Subjects (87%)Transition correctly predicted for 3/3 subjects that converted from SCD to MCI after 1y.

Disentangling empathy impairment along Alzheimer's disease continuum: From subjective cognitive decline to Alzheimer's dementia.

Little is known about empathy changes from the early stages of Alzheimer's Disease (AD) continuum. The aim of this study is to investigate empathy across AD spectrum from Subjective Cognitive Decline (SCD) to Mild Cognitive Impairment (MCI) and AD dementia (AD-d). Forty-five SCD, 83 MCI and 80 AD-d patients were included. Empathy was assessed by Interpersonal Reactivity Index (IRI) (Perspective Taking - PT, Fantasy - FT, Empathic Concern - EC, and Personal Distress - PD), rated by caregivers before (T0) and after (T1) cognitive symptoms' onset. IRI was also administered to SCD patients to have a self-reported empathy evaluation. Facial emotion recognition was assessed by Ekman-60 Faces Test. Twenty-two SCD, 54 MCI and 62 AD-d patients underwent CSF biomarkers analysis and were classified as carriers of AD pathology (AP+) when they were A+/T+ (regardless of N), or non-carriers (AP-) when they were A- (regardless of T and N), or A+/T-/N-, or A+/T-/N+ according to the A/T(N) system. Cerebral FDG-PET SPM analysis was used to explore neural correlates underlying empathy deficits. PD scores significantly increased from T0 to T1 in SCD, MCI and AD-d (p < .001), while PT scores decreased in MCI and in AD-d (p < .001). SCD AP+ showed a greater increase in PD scores over time (ΔPD T0 - T1) than SCD AP- (p < .001). SCD self-reported PT scores were lower than those of general Italian population (14.94 ± 3.94, 95% C.I. [13.68-16.20] vs 17.70 ± 4.36, 95% C.I. [17.30-18.10]). In AD continuum (SCD AP+, MCI AP+, AD-d), a positive correlation was detected between PT-T1 and brain metabolism in left posterior cingulate gyrus, precuneus and right frontal gyri; a negative correlation was found between ΔPT and brain metabolism in bilateral posterior cingulate gyri. PT may be subtly involved since the preclinical phase of AD. Changes over time of PD are influenced by the underlying Alzheimer's pathology and could potentially serve as an early AD neuropsychological marker.

Future perspective and clinical applicability of the combined use of plasma phosphorylated tau 181 and neurofilament light chain in Subjective Cognitive Decline and Mild Cognitive Impairment.

We aimed to assess diagnostic accuracy of plasma p-tau181 and NfL separately and in combination in discriminating Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) patients carrying Alzheimer's Disease (AD) pathology from non-carriers; to propose a flowchart for the interpretation of the results of plasma p-tau181 and NfL. We included 43 SCD, 41 MCI and 21 AD-demented (AD-d) patients, who underwent plasma p-tau181 and NfL analysis. Twenty-eight SCD, 41 MCI and 21 AD-d patients underwent CSF biomarkers analysis (Aß1-42, Aß1-42/1-40, p-tau, t-tau) and were classified as carriers of AD pathology (AP+) it they were A+/T+ , or non-carriers (AP-) when they were A-, A+/T-/N-, or A+/T-/N+ according to the A/T(N) system. Plasma p-tau181 and NfL separately showed a good accuracy (AUC = 0.88), while the combined model (NfL + p-tau181) showed an excellent accuracy (AUC = 0.92) in discriminating AP+ from AP- patients. Plasma p-tau181 and NfL results were moderately concordant (Coehn's k = 0.50, p < 0.001). Based on a logistic regression model, we estimated the risk of AD pathology considering the two biomarkers: 10.91% if both p-tau181 and NfL were negative; 41.10 and 76.49% if only one biomarker was positive (respectively p-tau18 and NfL); 94.88% if both p-tau181 and NfL were positive. Considering the moderate concordance and the risk of presenting an underlying AD pathology according to the positivity of plasma p-tau181 and NfL, we proposed a flow chart to guide the combined use of plasma p-tau181 and NfL and the interpretation of biomarker results to detect AD pathology.