The behavioral variant of frontotemporal dementia (bvFTD) has a devastating effect on multiple domains of daily living. The purpose of this PRISMA-compliant systematic review is to summarize the most important factors associated with functional impairment in this clinical group by critically analyzing the existing literature spanning the period from 2000 to 2023. To be included in the review, the study had to investigate any kind of correlates of functional status in bvFTD patients, using a previously validated instrument of functional assessment. Out of 40 articles assessed for eligibility, 18 met the inclusion criteria. The anatomical pattern of cerebral atrophy at baseline appeared to be the strongest predictor of the rate of functional decline over time, with the frontal-dominant anatomical subtype being associated with a faster rate of functional impairment. Additionally, executive dysfunction as well as apathy appeared to contribute significantly to functional disability in bvFTD patients. A comparative examination of bvFTD in relation to other clinical subtypes of FTD and other types of dementia in general suggests that it’s the predominant atrophy of the frontal lobes along with the subsequent unique combination of cognitive and neuropsychiatric manifestations that account for the pronounced functional limitations observed in these individuals, even from the early stages of the disease.

The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter acetylcholine, is one of the first to degenerate in Alzheimer’s disease and is also affected in frontotemporal dementia. We developed a differentiation protocol to generate basal forebrain cholinergic neurons (BFCNs) from induced pluripotent stem cells (iPSCs) aided by the use of small molecule inhibitors and growth factors. Ten iPSC lines were successfully differentiated into BFCNs using this protocol. The neuronal cultures were characterised through RNA and protein expression, and functional analysis of neurons was confirmed by whole-cell patch clamp. We have developed a reliable protocol using only small molecule inhibitors and growth factors, while avoiding transfection or cell sorting methods, to achieve a BFCN culture that expresses the characteristic markers of cholinergic neurons.

Background. Amyotrophic Lateral Sclerosis (ALS) is a devastating disease involving motor neuron degeneration. The few drugs approved for treatment have at most a marginal benefit, and death usually occurs 2-5 years after diagnosis. Methods. A thorough manual examination of the relevant literature, covering over 35,000 papers. Results. Two major phenomena that are generally not known to clinicians were found. First, insulin signaling is impaired in ALS even in patients not diagnosed with diabetes (DB). Almost all studies that have explicitly tested insulin function in non-DB ALS patients using glucose tolerance tests (18 out of 20, 1964-2022, different groups) have found it to be impaired. Second, there is strong evidence for excessive insulin-independent glucose uptake (IIGU) in ALS. In addition, (i) early/late diabetes are associated with increased/decreased risk, respectively; (ii) insulin-based diabetes drugs are protective in ALS in large retrospective human studies; and (iii) strong animal and human evidence shows that insulin opposes all of the major pathological processes in ALS. Conclusion. Most ALS patients have insulin impairment, yet this is commonly not diagnosed, likely because excessive IIGU normalizes glucose levels. The impairment promotes disease progression. Late diabetes is associated with decreased risk because high glucose levels indicate non-excessive IIGU, and because diabetes drugs are protective. Insulin-based treatment (e.g., GLP1 agonists, insulin) is beneficial and can be disease-modifying in ALS and in frontotemporal dementia variants comorbid with ALS. ALS patients should be routinely tested for insulin function and treated if test results are positive.

Forensic hospitals throughout the country house individuals with severe mental illness and history of criminal violations. Insomnia affects 67.4% of hospitalized patients with chronic neuropsychiatric disorders, indicating that these conditions may hijack human somnogenic pathways. Conversely, somnolence is a common adverse effect of many antipsychotic drugs, further highlighting a common etiopathogenesis. The role of dysfunctional mitochondria in psychopathology is well-established, however, the association of these organelles with sleep physiology is novel. Indeed, reducing neuronal oxidative stress by importing mitochondria from astrocytes, may be the purpose of human slumber. This model may explain mitochondrial dysfunction during anesthesia as well as in the rare genetic disease, fatal familial insomnia. In this narrative review, we focus on the salience network of the brain, a common denominator for insomnia, neuropsychiatric and neurodegenerative disorders. We also discuss mitochondria-protecting strategies, including membrane lipid replacement, natural and synthetic phenazine and phenothiazine derivatives.

Intermediate CAG expansions in the gene ataxin-2 (ATXN2) are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different genetic background. The aim of this study was to assess the relationship of intermediate CAG expansions in ATXN2 with the risk and phenotype of ALS and FTD in the Spanish population. Repeat-Primed PCR was performed in 620 ALS and 137 FTD patients in three referral centers of Spain to determine the exact number of CAG repeats. In our cohort, ≥27 CAG repeats in ATXN2 was associated with a higher risk of developing ALS (odds ratio [OR] = 2.666 [1.471-4.882]; p = 0.0013), but not FTD (odds ratio [OR] = 1.446 [0.558-3.574]; p = 0.44). Moreover, ALS patients with ≥27 CAG repeats in ATXN2 showed shorter survival rate compared to those with <27 repeats (hazard ratio [HR] 1.74 [1.18, 2.56], p = 0.005), more frequent limb onset (odds ratio [OR] = 2.34 [1.093-4.936]; p = 0.028), as well as family history of ALS (odds ratio [OR] = 2.538 [1.375-4.634]; p = 0.002). Intermediate CAG expansions of ≥27 repeats in ATXN2 are associated with ALS risk, but not with FTD, in the Spanish population. ALS patients carrying an intermediate expansion in ATXN2 show more frequent limb onset, but worse prognosis than those without expansions. In patients carrying C9orf72 expansions, the intermediate ATXN2 expansion might increase the penetrance and modify the phenotype.

Frontotemporal lobar degeneration (FTLD) belongs to a heterogeneous group of highly complex neurodegenerative diseases and represents the second cause of presenile dementia in individuals under 65. Frontotemporal-TDP is a subgroup of frontotemporal dementia characterized by the aggregation of abnormal protein deposits, predominantly transactive response DNA-binding protein 43 (TDP-43), in the frontal and temporal brain regions. These deposits lead to progressive degeneration of neurons resulting in cognitive and behavioral impairments. Limbic age-related encephalopathy (LATE) pertains to age-related cognitive decline primarily affecting the limbic system which is crucial for memory, emotions, and learning. Though distinct, emerging research suggests a potential overlap in pathogenic processes, with some cases of limbic encephalopathy displaying TDP-43 pathology. Genetic factors play a pivotal role in both disorders. Mutations in various genes, such as progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72), have been identified as causative in frontotemporal-TDP. Similarly, specific genetic variants have been associated with an increased risk of developing LATE. Understanding these genetic links provides crucial insights into disease mechanisms and the potential for targeted therapies.

Patients with neurodegenerative diseases (NDDs) are rapidly increasing all over the world. Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease (HD), frontotemporal lobar degeneration (FTLD) and many other diseases are classified as NDDs, however, no therapeutic drugs have been developed against NDDs yet. As common phenomenon, protein oligomers and aggregates (inclusion bodies) are formed in neurons, and they trigger neuronal cell death and/or axonal degeneration. We have investigated the mechanisms of NDDs, and discovered several chemicals and peptides have potential to cure NDDs. Here, we show phorbol 12-myristate 13-acetate (PMA) significantly inhibits aggregate formation and promotes neurite regeneration in human neuronal cell culture model of NDDs, FTLD and AD. We expressed R406W mutant tau protein found in FTLD patients in human neuroblastoma SH-SY5Y cells as FTLD cell culture model. These FTLD neuronal cells showed intracellular aggregate formation and impaired neurite growth. Addition of PMA to culture medium 60% suppressed aggregate formation. PMA also enhanced neurite growth to the normal level at nanomolar concentration. We cultured SH-SY5Y cells in the medium containing -amyloid (1-42) as AD cell culture model. In these cells, neurite growth was limited to less than 50% of controls by the treatment of -amyloid (1-42). Surprisingly, addition of PMA increased the number of cells with >10-fold neurite extension to seven times even in -amyloid (1-42) contained medium. Also, PMA increased the expression of several genes and proteins important for cell survival in both cell culture models. These results suggest PMA has unexpected potential for the drug development against NDDs.

This article proposes the use of intranasal rifampin as a means to improve protein homeostasis and disaggregate misfolded proteins in the age-related neurodegenerative proteinopathies. Alzheimer’s disease, Parkinson’s disease, multi-system atrophy, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis and Huntington’s disease are all, at the core, proteinopathies. Although these diseases varying greatly in the specific disease-associated proteins, anatomic sites of the abnormal protein deposition and clinical presentations, what they have in common is disruption of normal “housekeeping” functions related to protein homeostasis, proteostasis. The prospect of pharmacologically augmenting autophagic capacity with a known drug repurposed to improve proteostasis is attractive; to accomplish these ends with an inexpensive drug with relative ease of delivery adds to the attractiveness. Rifampin can be delivered to the brain via the intranasal route. Rifampin has been used for decades primarily against mycobacterial infection; it has been given with intravenous, oral, intrathecal and topical routes including as eyedrops and nasal spray. Rifampin disaggregates toxic oligomers in vitro; given intranasally, rifampin improves memory and clears pathologic proteins in animal models of the proteinopathies. Rifampin acts as both a gatekeeper and a housekeeper against the abnormal proteins of these diseases. This article suggests the merit of a clinical trial with intranasal rifampin to boost protein homeostasis in the most common age-related neurodegenerative proteinopathy, Alzheimer’s disease. The primary outcome of such a trial is change in risk of Alzheimer’s pathology as measured by plasma-based amyloid peptide 42/40 testing pretreatment and follow-up testing after 6 months of intranasal rifampin.

Although originally multi-ethnic in its structure, nowadays the Calabria region of southern Italy represents an area with a low genetic heterogeneity and a high level of consanguinity that allows rare mutations to be maintained due to the founder effect. A complex research methodology ranging from clinical activity to genealogical reconstruction of families/populations along the centuries, creation of databases, and molecular/genetic research, has been modelled on the characteristics of the Calabrian population for more than three decades. This methodology allows to the identification of several novel genetic mutations or variants associated with neurodegenerative diseases. In addition, in this population it has been reported a higher prevalence of several hereditary neurodegenerative diseases such as Alzheimer’s disease, Frontotemporal dementia, Parkinson’s disease, Niemann Pick type C disease, Spino-cerebellar ataxia, Creutzfeldt–Jakob disease and Gerstmann Straussler Scheincker disease. Thus, Calabria constitutes a model for the study of neurodegenerative diseases, a sort of "outdoor laboratory" useful for the advancement of knowledge in this field. Here, we summarize and discuss some results of research data supporting the view that Calabria is a genetic isolate and could represent a useful model for the study and characterization of neurodegenerative diseases.