Background and Aims:

Growing body of evidence supports that patients with Alzheimer’s disease have a higher occurrence of epileptic seizures. Recent experiments also postulated that epileptiform discharges might contribute to the pathogenesis of cognitive decline. The aim of our study was to analyze the impact of epileptic activity on the cognitive performance and on the progression of cognitive decline in clinical and prodromal Alzheimer patients.

Methods:

We investigated 50 mild Alzheimer patients and 30 patients with mild cognitive impairment (MCI) with no history of epileptic seizures. All participants underwent a 24-hour electroencephalography, neurology, neuroimaging (structural and resting state functional MRI) and neuropsychology examination. Patients were enrolled in a 1-year follow-up study with repeated examination protocol.

Results:

Subclinical epileptiform discharges were recorded in 48% of Alzheimer and 33% of MCI patients. Epileptiform discharges were associated with lower performance scores in memory (p<0.001). Epileptic activity also associated with lower hippocampal volumes (p:0.012) and larger extent of disconnection between default mode network and temporal brain structures (p:0.034). Patients with spikes showed 1.3-times faster decline in global cognitive scores than patients without (p<0.001) and higher conversion rate into dementia by MCI patients (p<0.001).

Conclusions:

Epileptiform activity occurs in half of Alzheimer and third of MCI patients who have never suffered epileptic seizures. Epileptic activity associates with lower cognitive performance and impaired structural and functional organization of brain structures. Epileptic discharges accelerate the progression of cognitive decline. Our findings suggest the prominent role of epileptiform discharges in the pathomechanism of cognitive decline in Alzheimer pathology.

Background and Aims:

Lecanemab (BAN2401) preferentially targets soluble aggregated amyloid beta (Aβ). Herein, we provide updated efficacy, safety and pharmacokinetic/dynamic data from a phase 2 trial (Core) and an open-label extension (OLE) assessing lecanemab in early Alzheimer’s disease (AD).

Methods:

This trial utilized a Bayesian design with response-adaptive randomization to assess 6 lecanemab dosing regimens versus placebo in early AD, defined as mild cognitive impairment due to AD and mild AD dementia. The primary endpoint was Bayesian analysis at 12-months on the Alzheimer’s Disease Composite Score (ADCOMS). Secondary endpoints included 18-month analyses of PET brain amyloid reduction; clinical decline on ADCOMS, CDR-SB, & ADAS-cog14. An ongoing OLE was initiated following the Core study where consenting subjects receive 10 mg/kg biweekly for up to 60 months.

Results:

854 randomized subjects were treated (lecanemab:609; placebo:245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (-0.306 SUVr units) while improving ADCOMS (30%), ADAS-cog14 (26%), and CDR-SB (26%) versus placebo. Lecanemab was well-tolerated with <10% incidence of ARIA-E at 10-mg/kg biweekly. A similar profile has been observed in 180 subjects who have been dosed in the OLE.

Conclusions:

Lecanemab was well tolerated and demonstrated reduction in brain amyloid along with consistent reduction of clinical decline across several endpoints in the Core study and a similar profile in the ongoing OLE. A Phase 3 study (ClarityAD) is underway.

Background and Aims:

To investigate the relationship between emotion processing and resting state-functional connectivty (RS-FC) in healthy controls and in patients with frontotemporal lobar degeneration (FTLD).

Methods:

We recruited 80 FTLD (26 bvFTD, 10 PSP, 12 PPA, and 32 ALS) and 65 healthy controls. Participants underwent a RS-functional MRI (RS-fMRI) and the Comprehensive Affect Testing System. In each group, correlation models were performed between each emotion construct and RS-FC changes.

Results:

A high performance at the emotion naming was related in healthy controls with decreased RS-FC of the right inferior temporal gyrus within the right frontoparietal-network; and in FTLD patients with increased RS-FC of the frontal regions within salience, frontoparietal and executive-control networks. Furthermore, a high performance at the emotion differentiation was related in healthy controls with decreased RS-FC of the right middle temporal gyrus within the salience-network; and in FTLD patients with increased RS-FC of the left inferior and medial-orbitofrontal gyri, and right thalamus within the subcortical-network. Finally, a high performance at the emotion matching was related in both healthy controls and FTLD groups with increased RS-FC of precuneus and vermis within the visual-network, and with further increased RS-FC of bilateral lingual, middle temporal and calcarine gyri in FTLD group only.

Conclusions:

In FTLD compared to healthy controls, RS-FC associated with emotional performance involves a larger number of brain regions, which are linked to the disease development and progression. These findings offer new potential markers for detecting functional vulnerability linked to social interactions.

Funding: Italian Ministry of Health (GR-2013-02357415); European Research Council (StG-2016_714388_NeuroTRACK).

Background and Aims:

The thalamus is a strategic hub for cognition. We hypothesize that subjects with Mild Cognitive Impairment (MCI) are characterized by an adaptive functional reorganization of the thalamic networks and that this process is influenced by the hierarchical topographic distribution of the tau pathology in the thalamus.

Methods:

Magnetic resonance imaging patterns of thalamic functional connectivity were assessed on Alzheimer's Disease Neuroimaging Initiative data set that included healthy controls (n=39), subjects with mild cognitive impairment (MCI, n=59), and patients with Alzheimer's Disease (AD, n=18). The MCI group was divided, by through a clinical follow-up of 24 months, into individuals remaining cognitively or clinically stable who either did (ncMCI^AD-, n=21) or did not (ncMCI^AD+, n=25) show the presence of AD-related alterations in the liquor, and individuals who showed the presence of AD-related alterations in the liquor and who convert (c-MCI^AD+, n=11) to AD. Thalami were subdivided, according with theoretical distribution of tau-pathology, in: i) a limbic subfield that is severely affected; ii) a subfield integrated into the associative networks that is middy affected; iii) a sensory-motor subfield that is spared.

Results:

Nc-MCI^AD- subjects showed functional hyper-connectivity of all thalamic subfields with rest of the brain. MCI^AD+ groups exhibited a tau-dependent hierarchical lack of hyper-connectivity. The phenomenon is particularly exacerbated in c-MCI^AD+ subjects who show, like in AD patients, a peculiar patterns of disconnection between the limbic subfield and subcortical structures.

Conclusions:

Thalamic hyper-connectivity may represent a compensatory strategy against the progression of cognitive impairment.

Background and Aims:

Locus Coeruleus (LC) is the main noradrenergic nucleus in the brain; it is involved in several physiological functions and modulates cell survival in its target regions. Post-mortem studies show that LC significantly degenerates in Alzheimer’s disease (AD). We assessed the association between LC-MRI and [¹⁸F]Fluorodeoxyglucose (FDG) PET uptake in amnestic Mild Cognitive Impairment (aMCI) and AD dementia (ADD) patients.

Methods:

30 aMCI,14 ADD, and 16 healthy controls (HC) underwent LC-MRI measurement through 2DFast-Spin-Echo T1-weighted sequence; a template-based approach was then used to extrapolate LC contrast-ratio (LC_CR) and LC volume (LC_vol). MCI and ADD underwent also FDG-PET scan acquired in three-dimensional list mode. Voxel-wise regression analysis was applied to investigate the association between metabolic activity in brain regions-of-interest (ROI) and the LC MRI-signal.

Results:

LC_vol and LC_CR were significantly reduced in HC when compared to patients. We observed that in aMCI and AD patients, left LC_vol was positively associated with FDG uptake in the left superior and middle frontal gyrus, while left LC_CR correlated with frontal regions with explicit left hemispheric dominance. Right LC_vol was associated with the left frontal-parietal-occipital regions, and right LC_CR with the right middle frontal and left superior frontal and parietal regions.

Conclusions:

LC parameters assessed by MRI correlate with FDG uptake measured by Brain PET in MCI and ADD patients. In particular, the reduction of LC_vol and LC_CR corresponded to cortical hypometabolism, in line with current literature on LC involvement in AD and its role in both cortical degeneration and brain metabolism.

This work is supported by the Italian Ministry of Health -Ministero della Salute, Ricerca Finalizzata #PE- 2013-02359574 (P.I.: FSG).

Background and Aims:

Primary Progressive Aphasia (PPA) represents an atypical presentation of Alzheimer’s Disease (AD). Factors associated with different trajectories of linguistic and functional deficit progression have been poorly investigated. We aimed to identify prognostic factors of progression to total language loss (TLL) and loss of functional autonomy (LoFA) by multifactorial approach.

Methods:

23 consecutive patients diagnosed with Alzheimer-related PPA were included. All patients underwent neuropsychological evaluation, [18]F-Fludeoxyglucose-PET brain scan, CSF biomarkers measurement and Apolipoprotein E genotype analysis at baseline and underwent neurological follow-up every 6 months for a mean time of 2.42 years. All patients had positive amyloid-β biomarkers.

Results:

During follow-up, 11 patients progressed to TLL (TLL⁺). Greater impairment in Writing (p=0.017,Figure 1.A) and higher t-tau (p=0.028, Figure 2) were detected as risk factors for progression to TLL. A cut-off value of 955 pg/ml for t-tau was found to distinguish the two groups (accuracy=76.19%[95%C.I.=59.15%-93.23%]). TLL⁺ had hypometabolism in middle and superior temporal gyrus, paracentral lobule and precuneus (Figure 3.A), while TLL^– had hypometabolism in inferior and middle temporal gyrus and fusiform gyrus (Figure 3.B). 12 patients progressed to LoFA (LoFA⁺). Impairment in Single-Word Comprehension influenced the risk of progression to LoFA (p=0.031,Figure 1.B). LoFA⁺ patients showed hypometabolism in left superior and middle temporal gyrus, left supramarginal gyrus, left postcentral gyrus and left fusiform gyrus while LoFA- patients had hypometabolism in left middle and inferior temporal gyrus and left fusiform gyrus.

Conclusions:

Linguistic features, t-tau and brain hypometabolic patterns could be considered as predictive factors for progression to TLL and LoFA in patients with Alzheimer-related PPA.

Background and Aims:

Mild cognitive impairment (MCI) is an heterogenous condition that can identify patients with prodromal Alzheimer disease (AD), but differential diagnosis may be challenging at this stage. REM sleep behavior disorder (RBD) is often associated with MCI and is considered a prodromal synucleinopathy. Aim of the study was to investigate neuropsychological and brain metabolism characteristics of MCI due to AD (MCI-AD) and MCI with RBD (MCI-RBD).

Methods:

Fifty-one MCI patients, including 17 MCI-RBD (age 73.6±6.5 years) and 34 MCI-AD (age 74.8±4.4 years) were enrolled. MCI-RBD patients underwent ¹²³I-FP-CIT-SPECT and video-polysomnography while MCI-AD patients had a positive amyloidosis biomarker. All patients underwent brain ¹⁸F-FDG-PET and a comprehensive neuropsychological assessment. ¹⁸F-FDG-PET data were compared (SPM-12) between groups. Subsequently, two forward stepwise linear regression analyses were performed using the neuropsychological tests scores as independent variables. The dependent variable was the hypometabolic MCI-RBD-VOI in MCI-RBD patients and the hypometabolic MCI-AD-VOI in MCI-AD patients. Years of age and education were used as nuisance.

Results:

Compared with MCI-AD, MCI-RBD patients showed relative hypometabolism in bilateral cuneus and occipital cortex (height threshold p<0.0001 at voxel level). Compared with MCI-RBD, MCI-AD patients showed relative hypometabolism in left hippocampus (height threshold p<0.0001 at voxel level). MCI-RBD-VOI was significantly correlated with executive function and visuospatial ability scores in MCI-RBD patients (p<0.05), whereas MCI-AD-VOI was significantly correlated with verbal memory scores in MCI-AD patients (p<0.0001).

Conclusions:

MCI-RBD and MCI-AD are distinct phenotypes, with specific neuropsychological and brain metabolism characteristics, well detectable already in these prodromal stages.

Background and Aims:

Correlation between CSF-Aβ₄₂ and amyloid-PET is inconstant across the AD spectrum. However, they are considered interchangeable, along with Aβ_42/40 ratio, for defining ‘Alzheimer’s Disease pathologic change’ (A+). We aimed at further unravelling the association between amyloid-PET and CSF biomarkers of AD in patients with low CSF-Aβ₄₂.

Methods:

We included 23 patients who underwent ¹⁸F-Florbetaben-PET scan, MRI and CSF analysis showing reduced levels of Aβ₄₂ within a 365 days interval. Thresholds used for dichotomization were: Aβ₄₂<640 pg/mL (A+); pTau>61 pg/mL (T+); Aβ_42/40<0.069 (AD_ratio). Amyloid-PET scans were visually classified as positive/negative and processed by four pipelines (SPM_CL, SPM_AAL, FS_GM, FS_WC). Transformation to Centiloid units was performed, setting threshold for PET-positivity to 20.1.

Results:

Different pipelines gave highly intercorrelated SUVRs (rho 0.93-0.99). The most significant findings were: pTau positive correlation with SPM_CL and SPM_AAL SUVRs (rho 0.56, p 0.0063; rho 0.51, p 0.0148 respectively) and Aβ_42/40 negative correlation with SPM_CL and SPM_AAL SUVRs (rho -0.56, p 0.0058; rho -0.52, p 0.0117 respectively). In subregion analysis, SUVRs of precuneus, posterior cingulate and anterior cingulate cortices showed the highest correlation with pTau, while Aβ_42/40 ratio best correlated with posterior cingulate SUVR. SUVRs were significantly higher in A+/T+ than in A+/T- (p 0.0018-0.0059) and in AD_ratio versus non AD_ratio subjects (p 0.0002). Combining either pTau or Aβ₄₀ with Aβ₄₂ significantly increased concordance with PET-status.

Conclusions:

Our data confirm that correlation between Aβ₄₂ and PET SUVR does not hold after CSF-Aβ₄₂ positivity has been reached and that PET measures show a stronger association with pTau and Aβ_42/40 at this stage.