Alzheimer's disease (AD) has a devastating impact on aged people worldwide. Although sophisticated and advanced molecular methods have been developed for its diagnosis since early phases, pharmacological treatment still represents an unresolved topic. The more the disease progresses, the more the uneffectiveness of antidementia drugs emerges. New and encouraging results from experimental works indicate that glutamate pathway may play a substantial role in the pathogenesis since early stages of the disease. Several experimental data together with the clinical use of the uncompetitive N-methyl-d-aspartate (NMDA) antagonist memantine strengthen this idea. Unfortunately, definitive data on the glutamatergic transmission involvement in AD are still incomplete. Moreover, clinical results indicate only temporarily limited effects of memantine. Currently, memantine is indicated for moderate-to-severe cases of AD, an indication that may limit its efficacy and impact on Alzheimer's dementia. The association of memantine with the acetylcholinesterase inhibitor drugs used to treat dementia symptoms appears to be beneficial, in both experimental and clinical studies. Because cholinergic and glutamatergic dysfunction occurs early in AD, the coadministration of appropriate treatment in early stages of the disease might represent a valid option from the beginning of cognitive decline. Moreover, to better evaluate drug efficacy, the association of the recently introduced biomarkers with a clinical AD profile should be considered an aim to pursue.

People with Alzheimer’s disease (AD) have significantly higher rates of subclinical and overt epileptiform activity. In animal models, oligomeric Aβ amyloid is able to induce neuronal hyperexcitability even in the early phases of the disease. Such aberrant activity subsequently leads to downstream accumulation of toxic proteins, and ultimately to further neurodegeneration and neuronal silencing mediated by concomitant tau accumulation. Several neurotransmitters participate in the initial hyperexcitable state, with increased synaptic glutamatergic tone and decreased GABAergic inhibition. These changes appear to activate excitotoxic pathways and, ultimately, cause reduced long-term potentiation, increased long-term depression, and increased GABAergic inhibitory remodelling at the network level. Brain hyperexcitability has therefore been identified as a potential target for therapeutic interventions aimed at enhancing cognition, and, possibly, disease modification in the longer term. Clinical trials are ongoing to evaluate the potential efficacy in targeting hyperexcitability in AD, with levetiracetam showing some encouraging effects. Newer compounds and techniques, such as gene editing via viral vectors or brain stimulation, also show promise. Diagnostic challenges include identifying best biomarkers for measuring sub-clinical epileptiform discharges. Determining the timing of any intervention is critical and future trials will need to carefully stratify participants with respect to the phase of disease pathology.

Cognitive impairment following SARS-CoV-2 infection is being increasingly recognized as an acute and possibly also long-term sequela of the disease. Direct viral entry as well as systemic mechanisms such as cytokine storm are thought to contribute to neuroinflammation in these patients. Biomarkers of COVID-19-induced cognitive impairment are currently lacking, but there is some limited evidence that SARS-CoV-2 could preferentially target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET. Possible confounders include cognitive impairment due to hypoxia and mechanical ventilation and post-traumatic stress disorder. Conversely, patients already suffering from dementia, as well as their caregivers, have been greatly impacted by the disruption of their care caused by COVID-19. Patients with dementia have experienced worsening of cognitive, behavioral, and psychological symptoms, and the rate of COVID-19-related deaths is disproportionately high among cognitively impaired people. Multiple factors, such as difficulties in remembering and executing safeguarding procedures, age, comorbidities, residing in care homes, and poorer access to hospital standard of care play a role in the increased morbidity and mortality. Non-pharmacological interventions and new technologies have shown a potential for the management of patients with dementia, and for the support of their caregivers.

Acute delirium and other neuropsychiatric symptoms have frequently been reported in COVID-19 patients and are variably referred to as acute encephalopathy, COVID-19 encephalopathy, SARS-CoV-2 encephalitis, or steroid-responsive encephalitis. COVID-19 specific biomarkers of cognitive impairment are currently lacking, but there is some evidence that SARS-CoV-2 could preferentially and directly target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET imaging. We suggest that an inflammatory parainfectious process targeting preferentially the frontal lobes (and/or frontal networks) could be the underlying cause of these shared clinical, neurophysiological, and imaging findings in COVID-19 patients. We explore the biological mechanisms and the clinical biomarkers that might underlie such disruption of frontal circuits and highlight the need of standardized diagnostic procedures to be applied when investigating patients with these clinical findings. We also suggest the use of a unique label, to increase comparability across studies.

In Alzheimer’s disease (AD) patients, apopoliprotein (APOE) polymorphism is the main genetic factor associated with more aggressive clinical course. However, the interaction between cerebrospinal fluid (CSF) tau protein levels and APOE genotype has been scarcely investigated. A possible key mechanism invokes the dysfunction of synaptic plasticity. We investigated how CSF tau interacts with APOE genotype in AD patients. We firstly explored whether CSF tau levels and APOE genotype influence disease progression and long-term potentiation (LTP)-like cortical plasticity as measured by transcranial magnetic stimulation (TMS) in AD patients. Then, we incubated normal human astrocytes (NHAs) with CSF collected from sub-groups of AD patients to determine whether APOE genotype and CSF biomarkers influence astrocytes survival. LTP-like cortical plasticity differed between AD patients with apolipoprotein E4 (APOE4) and apolipoprotein E3 (APOE3) genotype. Higher CSF tau levels were associated with more impaired LTP-like cortical plasticity and faster disease progression in AD patients with APOE4 but not APOE3 genotype. Apoptotic activity was higher when cells were incubated with CSF from AD patients with APOE4 and high tau levels. CSF tau is detrimental on cortical plasticity, disease progression and astrocyte survival only when associated with APOE4 genotype. This is relevant for new therapeutic approaches targeting tau.

The role of the cerebellum in cognitive function has been broadly investigated in the last decades from an anatomical, clinical, and functional point of view and new evidence points toward a significant contribution of the posterior lobes of the cerebellum in cognition in Alzheimer’s disease (AD). In the present work we used SUIT-VBM (spatially unbiased infratentorial template, voxel-based morphometry) to perform an analysis of the pattern of cerebellar gray matter (GM) atrophy in amnestic mild cognitive impairment (a-MCI) and AD dementia patients compared to healthy subjects (HS), in order to follow the changes of non-motor features of cerebellar degeneration throughout disease progression. This template has been validated to guarantee a significant improvement in voxel-to-voxel alignment of the individual fissures and the deep cerebellar nuclei compared to Montreal Neurological Institute (MNI) whole-brain template. Our analysis shows a progression of cerebellar GM volume changes throughout a continuous spectrum from early to late clinical stages of AD. In particular vermis and paravermian areas of the anterior (I-V) and posterior (VI) lobes are involved since the a-MCI stage, with a later involvement of the hemispheric part of the posterior lobes (VI lobule) and Crus I in AD dementia patients only. These findings support the role of the cerebellum in higher-level functions, and whilst confirming previous data on the involvement of Crus I in AD dementia, provide new evidence of an involvement of the vermis in the early stages of the disease.

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Background/Aims: To investigate the differences in brain glucose consumption between patients with early onset of Alzheimer's disease (EOAD, aged ≤65 years) and patients with late onset of Alzheimer's disease (LOAD, aged >65 years). Methods: Differences in brain glucose consumption between the groups have been evaluated by means of Statistical Parametric Mapping version 8, with the use of age, sex, Mini-Mental State Examination and cerebrospinal fluid values of Aβ_1-42, phosphorylated Tau and total Tau as covariates in the comparison between EOAD and LOAD. Results: As compared to LOAD, EOAD patients showed a significant decrease in glucose consumption in a wide portion of the left parietal lobe (BA7, BA31 and BA40). No significant differences were obtained when subtracting the EOAD from the LOAD group. Conclusions: The results of our study show that patients with EOAD show a different metabolic pattern as compared to those with LOAD that mainly involves the left parietal lobe.