The relationship between aging, mitochondrial dysfunction, neurodegeneration, and the onset of Alzheimer’s disease (AD) is a complex area of study. Aging is the primary risk factor for AD, and it is associated with a decline in mitochondrial function. This mitochondrial dysfunction is believed to contribute to the neurodegenerative processes observed in AD. Neurodegeneration in AD is characterized by the progressive loss of synapses and neurons, particularly in regions of the brain involved in memory and cognition. It is hypothesized that mitochondrial dysfunction plays a pivotal role by disrupting cellular energy metabolism and increasing the production of reactive oxygen species (ROS), which can damage cellular components and exacerbate neuronal loss. Despite extensive research, the precise molecular pathways linking mitochondrial dysfunction to AD pathology are not fully understood. Various hypotheses have been proposed, including the mitochondrial cascade hypothesis, which suggests that mitochondrial dysfunction is an early event in AD pathogenesis that triggers a cascade of cellular events leading to neurodegeneration. With this narrative review, we aim to summarize some specific issues in the literature on mitochondria and their involvement in AD onset, with a focus on the development of therapeutical strategies targeting the mitochondria environment and their potential application for the treatment of AD itself.

Here, we aim to describe COVID-19 pathology across different tissues to clarify the disease’s pathophysiology. Lungs, kidneys, hearts, and brains from nine COVID-19 autopsies were compared by using antibodies against SARS-CoV-2, macrophages-microglia, T-lymphocytes, B-lymphocytes, and activated platelets. Alzheimer’s Disease pathology was also assessed. PCR techniques were used to verify the presence of viral RNA. COVID-19 cases had a short clinical course (0–32 days) and their mean age was 77.4 y/o. Hypoxic changes and inflammatory infiltrates were present across all tissues. The lymphocytic component in the lungs and kidneys was predominant over that of other tissues (p < 0.001), with a significantly greater presence of T-lymphocytes in the lungs (p = 0.020), which showed the greatest presence of viral antigens. The heart showed scant SARS-CoV-2 traces in the endothelium–endocardium, foci of activated macrophages, and rare lymphocytes. The brain showed scarce SARS-CoV-2 traces, prominent microglial activation, and rare lymphocytes. The pons exhibited the highest microglial activation (p = 0.017). Microthrombosis was significantly higher in COVID-19 lungs (p = 0.023) compared with controls. The most characteristic pathological features of COVID-19 were an abundance of T-lymphocytes and microthrombosis in the lung and relevant microglial hyperactivation in the brainstem. This study suggests that the long-term sequelae of COVID-19 derive from persistent inflammation, rather than persistent viral replication.

Alzheimer’s disease (AD), the leading cause of dementia, is expected to markedly increase in prevalence in the coming decades. Beyond amyloid and tau pathologies, accumulating evidence suggests that mitochondrial dysfunction and impaired protein homeostasis play crucial roles in AD onset and progression. Building on our previous identification of molecular signatures associated with disease progression, this study investigated whether epigenetic alterations of mitochondrial DNA (mtDNA) contribute to cognitive decline. Specifically, we analyzed the methylation status of the mtDNA regulatory D-loop region and mtDNA copy number in blood-derived DNA samples from 75 participants who we followed longitudinally over eight years. Subjects were classified into four groups according to clinical progression from healthy cognition to mild cognitive impairment (MCI) and AD. Using a linear mixed-effects model, we observed significant differences in methylation dynamics and mtDNA copy number across groups and time points. Healthy controls showed a progressive increase in D-loop methylation, whereas individuals converting to AD exhibited a marked decrease in its level. An opposite trend was evidenced for mtDNA copy number. These findings suggest that reduced D-loop methylation and increased mtDNA are associated with mitochondrial dysfunction and disease progression, whereas increased methylation may represent a possible protective mechanism.

Neuropathological examination of the brain and its biochemical analyses are fundamental to neuroscience studies and public health decisions, but are dependent on the effectiveness of regulations and operational protocols. The article discusses opportunities and limits of Italian regulation on body donation in relation to the specific requirements of neuropathology and brain sciences, in comparison with the regulations of other countries. Some crucial issues emerge, widely shared in the various regulatory contexts. The main aspect is the willingness to donate, consciously expressed by the subject by signing an informed consent or through the formulation of advanced directives. The donation of a single organ, the brain in particular, does not necessarily imply the donation of the entire body, which should be considered separately. In the specific case of the brain, particular attention is given to reducing the post-mortem interval, in order to obtain tissues suitable for research. Consequently, the centres that deal with the brain and brain banking must have experience and expertise in handling nervous tissue, and do not necessarily have to deal with the management of the entire body. These aspects, still little addressed in Italy, are the basis to develop an effective brain banking activity, which can only develop by integrating post-mortem body donation with specific rules for brain banking without which Italian neuroscience will be penalised in the coming years.

Background: Aging is often characterized by a progressive loss of cognitive abilities due to the onset of Alzheimer Disease (AD). In recent years, ‐omic sciences have allowed us to begin to shed light on its molecular pathways in order to speculate about new and attractive hypothesis on AD pathogenesis.Method: In this study, a whole transcriptome analysis and a Gene Set Enrichment Analysis (GSEA) have been carried out on brain samples from hippocampus (HI), temporal and parietal cortex (TC, PC), cingulate cortex (CG), and substantia nigra (SN) from the Abbiategrasso Brain Bank (ABB) of 6 subjects with clinical and neuropathological diagnosis of AD and 3 healthy age‐matched controls in duplicate. Clinical and neuropsychological profile were obtained through serial evaluations, made at the baseline and in the following years. According to the ABB protocol, the neuropathological diagnosis was based on a complete histological characterization, including all the main proteinopathies and vascular scoring.Result: Transcriptomic results showed a greater number of differentially expressed genes (DEGs) in TC (1571) and CG (1210) and a least amount of DEGs in HI (206), PC (109) and SN (60). Furthermore, the GSEA showed a difference between the group of early affected brain areas (HI, TC) and the group of the subsequently involved areas (PC, CG, SN). Notably, in HI and TC there was a significant down‐regulation of shared DEGs primarily involved in the synaptic transmission and in the development of the central nervous system (CDK5R1, KCNC1, KCNC2, BSN), while in PC, CG and SN there was a significant down‐regulation of genes primarily involved in the proper protein folding and trafficking and inflammation (HSPA1B, HSPA1A, DNAJB1, FKBP4, CHORDC1, STIP1).Conclusion: The course of AD could follow a definite time and severity‐related pattern that arises from inflammatory processes and protein misfolding, observed in PC, CG and SN, and leads to synaptic impairment, observed in HI and TC. Therefore, we can relate neurobiological processes to clinical manifestations and outline a clearer picture of AD neuropathology and pathogenesis. This could help to discover novel biological targets in order to develop effective and well‐timed therapeutical approaches.

Background: Few studies investigate the correlation between the quantitative EEG (QEEG) and the neuropathological picture. The purpose of this study is to explore how QEEG can recognize the type and extent of neuropathological changes.Method: The EEG traces and brains belonging to 14 donors of the Abbiategrasso Brain Bank were analyzed. The subjects suffered from neurocognitive disorders due to AD, LBD or AD/vascular lesions (mixed dementia‐MD), with different stages of clinical and neuropathological severity. Clinical and neuropathological characterization was performed according to our protocol; biochemical measurements to determine the amount of proteinopathies are in runtime on frozen samples. QEEG analysis considered the relative power distribution (RPD) of the frequency bands (β, α, θ, δ) and the peak frequency (PF), i.e. the most represented frequency considering all the leads. The PF was measured every 2 seconds for 200‐400 samples, and then averaged. The Kruskall‐Wallis test was used for the comparison between groups.Result: The clinical diagnosis included: 2 MCI, 4 AD, 6 MD, and 2 LBD. The neuropathological definite diagnosis demonstrated frequent co‐pathologies, and some discrepancies compared to the clinical diagnosis. The neuropathological characterization identified 2 cases with low AD pathology (corresponding to the 2 MCI), 8 cases with intermediate or high AD pathology (4 MD with concomitant cerebrovascular disease), and 4 cases with prevalent LBD pathology. Considering both clinical and neuropathological diagnoses, the comparison between groups revealed no significant differences in QEEG parameters. Nonetheless, a trend emerges towards a lower β‐RPD and a higher θ‐RPD in cases with prevalent LBD pathology. Grouping based on the severity of AD pathology (2 low, 4 intermediate, 4 high) demonstrated significant differences depending upon the neuropathological scoring with a progressive decrease of α‐RPD (p = 0.029) and PF (p = 0.019), and an increase of δ‐RPD (p = 0.020).Conclusion: RPD and PF show low discriminatory capacity on etiology. Nonetheless, the presence of LBD seems to boost the EEG slowing. The PF slowing down parallels the increase of AD pathology, representing an indicator for the degenerative load. PF is a simple QEEG parameter, easily obtainable through standard digital EEG; it can be useful for monitoring neurodegenerative burden and disease evolution.