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Neurodegenerative disorders often acquire due to genetic predispositions and genomic alterations after exposure to multiple risk factors. The most commonly found pathologies are variations of dementia, such as frontotemporal dementia and Lewy body dementia, as well as rare subtypes of cerebral and cerebellar atrophy-based syndromes. In an emerging era of biomedical advances, molecular–cellular studies offer an essential avenue for a thorough recognition of the underlying mechanisms and their possible implications in the patient’s symptomatology.
- neurodegenerative disorders
- frontotemporal dementia
- spinocerebellar ataxias
- Lewy body dementia
1. Frontotemporal Demetia (FTD)
Frontotemporal lobar degeneration (FTLD) syndromes exhibit a complex neuropathology characterized by heterogeneity. Two key forms are seen, known as FTLD-tau and TDP, distinguished by the presence of tau or TDP-43-positive inclusions, respectively [1]. Recently, FUS-positive inclusions have also been detected in some FTLD cases. Two rare neuropathological subtypes of FTLD exist. FTLD-UPS is characterized by inclusions positive for ubiquitin but negative for tau, TDP-43, and FUS. CHMP2B mutation cases tend to display this form, while FTLD-ni lacks discernable inclusions [2]. CHMP2B gene mutations were first identified in Danish kindred who suffered from frontotemporal dementia linked to chromosome 3 (FTD-3) [3]. This mutation alters the splice acceptor site for CHMP2B’s final exon, leading to the production of two novel transcripts known as CHMP2BIntron5 and CHMP2BDelta10. Furthermore, an autosomal dominant Belgian FTLD pedigree revealed another mutation known as CHMP2BQ165X, which causes premature stop codons, resulting in the protein lacking its final 49 amino acids, leading to its premature degradation [4].
Limited available data indicate that FTD occurs in approximately 11 cases per 100,000 individuals, with an incidence rate of 1.6 cases per 100,000 individuals. However, these figures appear to significantly increase from the fifth to seventh decades of life and likely underestimate actual prevalence due to misdiagnosis among older individuals. FTD accounts for 40% of dementia cases with early onset that have been confirmed through postmortem examination, although its onset typically begins between middle age and the ninth decade [5].
As serotonergic function is reduced in FTD, the use of serotonergic modulators is more apposite a priori, and modest behavioral benefit has been shown for trazodone and citalopram, though not for paroxetine [6]. Due to decreased serotonergic activity observed in FTD, serotonergic modulators appear more suitable as treatment options. Trazodone and citalopram have both demonstrated modest behavioral improvement; paroxetine did not achieve such benefits. If psychosis, aggression, or intrusive compulsions require management, then neuroleptic medications may be required, though care must be taken as individuals living with FTD can experience significant extrapyramidal side effects from even newer-generation antipsychotics. Therefore, in such instances, researchers suggest low-dose risperidone or quetiapine, with a strict clinical monitoring to avoid extrapyramidal side effects from antipsychotics [7].
Numerous potential strategies for treating FTD have been proposed. These include antitau antibodies and agents that stabilize microtubules, methods to increase the expression and release of progranulin, modulating autoimmunity and neuroinflammation (particularly applicable for GRN mutations), as well as using antisense oligonucleotides to silence toxic C9orf72 messenger RNA messengers—strategies which hold promise in targeting the root mechanisms while making advancements in FTD treatment [8].
GRN belongs to a family of growth factors with cysteine-rich polypeptides and can be found throughout various tissues. The GRN gene can be found 1.7 Mb upstream from MAPT’s microtubule-associated protein tau-encoding gene MAPT. GRN comprises 12 exons that code for its precursor glycoprotein of 68.5 kDa, divided into seven distinct granulins of 6 kDa each for secretion purposes by cells. GRN plays its role through cell signaling and signal transduction pathways [9].
Recent studies have demonstrated that mutations of the GRN gene are responsible for frontotemporal lobar degeneration, known as FTLD-U. This form is characterized by neuronal inclusions positive for ubiquitin but negative for tau. Mutations affecting GRN may lead to functional loss via an NMD process based on analysis of its cDNA both in brain cells and lymphoblastoid cells [10].
Frontotemporal dementia was initially clinically described by Arnold Pick in 1892. Later, Alois Alzheimer identified neuropathological lesions characteristic of Pick’s disease in 1911 [11]; these lesions, now known as Pick bodies, were later found in the 1960s to contain abnormal filaments made up of hyperphosphorylated microtubule-associated protein tau, and these neurofibrillary lesions closely resemble those described by Alzheimer in 1907, hence its naming after him [12].
In 1994, an autosomal dominant familial form of frontotemporal dementia with Parkinsonism was identified that was linked with chromosome 17q21.2. Missense mutations found in this form were thought to negatively impact how effectively tau protein interacts with microtubules; reduced interactions can be seen as partial loss of function, leading to destabilized microtubules that disrupt crucial cellular processes, such as rapid axonal transport [13].
Variants of FTD forms in other neurodegenerative disorders are as follows:
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PiD (Pick’s disease) typically presents as behavioral variant frontotemporal dementia (bvFTD) or nonfluent variant primary progressive aphasia (nfvPPA), with motor deficits being rare. Histological characteristics of PiD include neuronal loss and swelling known as Pick cells; distinct large spherical neuronal cytoplasmic inclusions called Pick bodies may also be observed in some individuals with the disorder [14].
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Progressive supranuclear palsy (PSP) typically presents as a movement disturbance characterized by early postural instability, axial rigidity, bradykinesia, and ophthalmoplegia. Cognitive impairment may be mild; however, some cases with PSP pathology show dementia similar to bvFTD or nfvPPA. PSP pathology also involves degeneration in multiple subcortical regions, including the striatum, globus pallidus, subthalamic nucleus, midbrain, tectum/tegmentum, substantia nigra, basis, pontis, cerebellar dentate nucleus, and cerebellar peduncles [15].
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Patients diagnosed with corticobasal degeneration (CBD) often display corticobasal syndrome (CBS), characterized by bradykinesia, rigidity, dystonia, apraxia, cortical sensory signs, alien limb phenomenon, and bradykinesia [16].
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They may also show features of FTD (bvFTD or nfvPPA), displaying depigmentation in the substantia nigra, atrophy of globus pallidus, as well as focal and asymmetric cerebral cortical atrophy—histopathological features that overlap between PSP and CBD such as tau-immunoreactive glial cells as well as NCI histopathological features of both syndromes [17].
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FTD caused by mutations of the MAPT gene is an autosomal dominant form linked to chromosome 17 (FTDP-17T) that accounts for roughly 10% of familial FTD cases. MAPT pathogenic mutations include missense or deletions in exons 1 and 9–13 or mutations after exon 10 that mainly manifest themselves through behavior changes, personality shifts, cognitive dysfunction, and atypical Parkinsonism, typically seen through behavior and personality alterations, cognitive deficits, and Parkinsonian-like symptoms as well as neuropathology featuring hyperphosphorylated tau deposits within gray and white matter structures [18].
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Mutations to the VCP gene (valosin-containing protein) cause a rare familial syndrome known as inclusion body myopathy, Paget’s disease of bone, and FTD with variable penetrance (IBMFD). VCP belongs to the AAA-ATPase gene superfamily and serves as a molecular chaperone involved in various cellular activities that are either directly or indirectly controlled by UPS (ubiquitin–proteasome system) [19].
This histological pattern has been observed frequently among cases associated with tau mutations in various exons, including exons 9 (K257T, L266V, and G272V), 10 and 11 (L315R and S320F), 12 (E342V K369I), and 13 (G389R). Notably, in cases of FTDP-17 linked to I260V mutation in exon 9, brain scans did not reveal typical pathological tau species such as Pick-like bodies and neurofibrillary tangles, whereas S352L mutation also did not lead to the deposition of insoluble tau adopting pathological forms [20].
Patients who carry mutations in exon 10 or intron 10 typically display neuronal and glial tau pathology with ribbon-like filaments primarily composed of 4R tau. On the other hand, missense mutations outside exon 10 tend to present selective neuronal pathology that includes all six isoforms deposited as either paired helical filaments (PHFs) or straight filaments (SFs) [21].
Studies of FTD linked to chromosome 17 have been complicated by genetic heterogeneity. Some families that clearly link with 17q21 have been found not positive for MAPT mutations despite extensive analysis of their coding regions. Those families without tau pathology might suggest the presence of another defective gene at 17q21; however, MAPT mutations or complex forms, such as chromosomal rearrangements, cannot be entirely excluded as causes. Investigating the disease mechanism in these tau-negative FTD families is of vital importance, given that most FTD patients do not exhibit tau pathology according to immunohistochemistry tests. Investigating both tau-positive and tau-negative families should contribute to researchers' knowledge about tau and related tauopathies, leading to more effective therapeutic approaches for this devastating disorder.
Targeting TDP-43 aggregates: One therapeutic strategy involves decreasing TDP-43 clearance or inhibiting their formation to help remove accumulations of toxic aggregates that accumulate soluble TDP-43 or toxic aggregates [22].
Targeting specific mutants: For specific mutations such as C9orf72, methods designed to decrease its transcript have shown promising results. Antisense oligonucleotides (ASOs) have been extensively researched and have proven successful at decreasing this mutated transcript.
FTD-FUS (FTD fused in sarcoma) and therapeutic strategies: Studies have demonstrated that treating cell cultures with methylation inhibitors may help decrease cytoplasmic mislocalization and aggregates associated with FUS mutants in FTD cases.
Mutations associated with FTD-UPS (ubiquitin–proteasome system): For therapeutic intervention, silencing the pathologically involved genes such as mutant CHMP2B by administering siRNA treatments has been observed to reverse cellular pathology in patient fibroblasts. FTD has several pathological conditions associated with it, yet no definitive mapping exists between these conditions and particular clinical presentations. One underlying condition often associated with FTD is “frontal lobe degeneration of the non-Alzheimer type,” or dementia lacking distinctive histopathology (DLDH), which helps distinguish its clinical presentation from any potential associated pathologies [23].
Human-induced pluripotent stem cells (iPSCs) are extensively employed in studies related to neurological and neurodegenerative conditions (Table 1). These iPSCs originate from specialized somatic cells, commonly from fibroblasts or peripheral blood mononuclear cells, through the heightened expression of the reprogramming agents Oct4, Klf4, Sox2, and c-Myc [24].
Table 1. Overview of targeted molecular therapies in frontotemporal dementia.
| Study Focus | Key Findings and Techniques | Citation |
|---|---|---|
| Origin and employment of iPSCs | Derived from somatic cells like fibroblasts. Uses agents Oct4, Klf4, Sox2, and c-Myc. | [22] |
| iPSC models for FTLD-tau | Focuses on fibroblasts from MAPT alterations. | [25] |
| Patient-sourced iPSCs with 10 + 16 mutation | Noted surge in 4R tau expression, leading to increased 4R:3R tau isoform ratio. | [26] |
| Tau pathology in N279K iPSC-derived neurons | Observed shifts in 4R:3R tau isoform balance, with increased 4R tau levels. | [27] |
| iPSCs from patients with N279K mutation | Differentiated into NPCs. Used CRISPR/Cas9 for isogenic controls. Differentiated into astrocytes using Sox10 and growth factors. | [27] |
A distinct study noted marked tau pathology in N279K iPSC-derived neurons. Here, the neurons displayed shifts in the 4R:3R tau isoform balance, showcasing increased 4R tau levels and augmented tau fragmentation as early as 28 days after the maturation process of iPSC-derived neural progenitor cells (NPCs) [25].
In an initial analysis of patient-sourced iPSCs possessing the 10 + 16 mutation, a significant surge in 4R tau expression was documented during neuronal development. This led to a heightened 4R:3R tau isoform proportion in these cells [26].
iPSCs from patients with the N279K mutation were differentiated into NPCs. Subsequently, CRISPR/Cas9 genome editing was utilized to produce isogenic control cells. These patient-derived and isogenic control cells underwent differentiation into astrocytes by amplifying the expression of Sox10 and introducing pro-astrocytic growth and neurotrophic factors, including ciliary neurotrophic factor [27].
2. Spinocerebellar Ataxias (SCA)
Autosomal dominant spinocerebellar ataxias (SCAs, or ADCAs) comprise an expansive group of inherited ataxias with symptoms usually appearing between 30 and 50 years of age, although specific subtypes of SCA can appear earlier or even after 60 years [28].
Recent epidemiological evidence indicates that SCAs may be more prevalent than previously estimated. Prevalence rates exceeding 5–7 in 100,000 have been documented across various geographical regions; Japan, in particular, has reported 18.5 cases per 100,000 when considering dominant, recessive, and sporadic SCAs plus familial spastic paraplegia [29]. These numbers are comparable with other less frequent motor neurodegenerative conditions like Huntington’s disease or motor neuron diseases [30].
At present, over 30 SCA genes or loci have been identified, each one contributing differently to spinocerebellar neurodegeneration. Polyglutamine expansions in specific genes (SCAs 1, 2, 3, 6, 7, 17, and DRPLA) cause abnormally long polyQ tracts in encoded proteins. Noncoding expansions contribute to SCA 10 and 12 cases. Conventional mutations affect genes encoding cytoskeletal proteins (bIII spectrin in SCA5), voltage-gated potassium channel Kv3.3 in SCA13), protein kinases (tau Tubulin Kinase 2, SCA11; protein Kinase C Gamma 14), intracellular calcium channels (Inositol 1,4,5-triphosphate receptor 1), and fibroblast growth factors (FGF14 and ATPases AFG3L2 in SCA27 and 28) [31] (Table 2).
Table 2. Molecular pathways useful in spinocerebellar ataxias treatment.
| Molecular Target | Pathway | SCA Subtype | Possible Medication |
|---|---|---|---|
| PP2 | PP2 | 1, 12 | PP2-mediated regulators |
| PRKC | PRCK | 1, 14 | PRKC-mediated regulators |
| Gene transcriptors | Multiple | 1–3, 6, 7 | HDACis |
| Aggregation | Autophagy Transglutaminase |
1–3, 6, 7, 17, DRLPA | Rapamycin Cystamine |
| Chaperons | HSR, UPR | 1–3, 6, 7, 17, DRLPA | Arimoclomol |
| Ubiquitin | UPS | 1–3, 6, 7, 17, DRLPA | UPS derivates |
| Mitochondrial approach | Multiple | Any | Coenzyme Q10 |
| Calcium activity | Calcium mechanisms | 1, 6 | Ca2+ blockers |
| Dopamine pathway | Dopamine | 1–3, 6, 17, 27 | Levodopa, anticholinergic, and dopaminergic pharmaceutical therapies |
| Neurotransmitters | GABA | Any | Glutamate inhibitors |
| Ataxins | RNAi | Any | RNAi |
| Caspases | Caspases | Any | Cystamine |
PP2—serine/threonine protein phosphatase 2; PRKC—protein kinase C; HDACis—histone deacetylase inhibitors; DRPLA—dentatorubral pallidoluysian atrophy; HSR—heat shock response; UPR—unfolded protein response; UPS—ubiquitin/proteasome system; GABA—gamma aminobutyric acid; RNAi—RNA interference.
Dysregulation of transcription and gene expression is seen in SCA1, where ataxin 1 interacts with various transcription factors involved in transcriptional regulation, such as Lanp/Anp32a, PQBP-1, Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT), Boat, Gfi-1/senseless, Capicua, and Tip60. Mutant forms of ataxin 1 disrupt these transcriptional regulators’ activity by disrupting gene expression levels, leading to changes in Wnt-receptor signaling and Retinoic Acid/Thyroid Hormone signaling, as well as nucleic acid binding [32].
Other SCAs such as SCA2, SCA3, SCA7, SCA17, and DRPLA, as well as atrophin 1 gene product, directly participate in transcription as components of transcriptional regulatory complexes. For example, ataxins 2, 3, and 7 interact with basal transcription factor TATA-binding protein while atrophin 1 interacts with various transcriptional regulators—such interactions interfere with CREB-dependent transcription, which has an effect on gene expression [33].
The balance between protein acetylation and deacetylation, essential to optimal cell functioning, can be disturbed when mutant proteins contain expanded polyglutamine repeats that cause pathogenesis of neurodegenerative diseases. Restoring this equilibrium through a genetic or pharmacological adjustment in histone deacetylases (HDACs) potentially offers therapeutic strategies using HDAC inhibitors against neurodegeneration [34].
Alterations of synaptic neurotransmission play an important part in the neurodegenerative mechanisms underlying SCAs. Motor dysfunction precedes neuronal death in SCA1 transgenic mice, leading to Purkinje cell dysfunction that compromises Purkinje cell functions as well as changes to synaptic plasticity [35].
SCA8 mice share similar symptoms to human patients of this disease, specifically a loss of GABAergic inhibition in the cerebellum and intranuclear inclusions with expanded polyglutamine content in Purkinje cells and other neurons [36]. This finding could provide one explanation for SCA8’s lack of disease penetrance; it has been associated with large CTG repeat expansion in an antisense RNA for KLHL1 gene antisense RNA, as well as neuropathological analysis showing degeneration of Purkinje cells, inferior olivary neurons, and nigral neurons [37].
Alterations of calcium homeostasis play an integral part in SCAs. For instance, SCA6 is caused by polyglutamine expansions in the CACNA1A gene that encodes the alpha (2.1) subunit of CaV2.1 voltage-dependent P/Q-type calcium channel [38], while mutations of the protein kinase C gamma (PKC gamma) gene affect the C1 domain, essential for translocation and regulation of PKC gamma kinase activity [39]. Mutations in the PRKCG gene, which codes PKC gamma, result in the dysfunction of calcium homeostasis [40]. Finally, SCA15 causes deletions or missense mutations within the ITPR1 gene that are involved with intracellular calcium release from the endoplasmic reticulum (Table 2).
These changes in neurotransmission and calcium homeostasis play a key role in the pathogenesis of SCAs, providing therapeutic targets for intervention.
Mitochondrial Stress and Apoptosis: Polyglutamine-expanded cellular death of cerebellar neurons by polyglutamine-expanded containing proteins is preceded by the recruitment of caspases into polyQ aggregates. This is followed by the activation of caspases 3 and 9 and of mitochondrial apoptotic pathways mediated by members of the Bcl-2 family, such as Bax and Bcl-x(L). Both factors are known key components of neuronal apoptosis by regulating the mitochondrial release of cytochrome-c and Smac/DIABLO [41].
A method that has proven effective in diminishing the expression of mutant ATXN1 in vivo involves introducing AAV vectors that carry an shRNA targeting ATXN1 to the cerebellum [42].
This results in a significant reduction in mutant ATXN1 expression, leading to considerable enhancement in motor function and normalization of the structure of Purkinje cells in the transformed cells. Even though this SCA1 research utilized an shRNA targeting both the wild-type and mutant ATXN1, strategies focusing specifically on the mutant allele are being devised for numerous polyQ disorders, SCA3 included [43]. (Table 3)
Table 3. Overview of targeted molecular therapies in spinocerebellar ataxias.
| Treatment/Research Focus | Research Focus | Citation |
|---|---|---|
| AAV vector method targeting ATXN1 | Introducing AAV vectors with shRNA targeting ATXN1 led to reduced mutant ATXN1 expression. This improved motor function and normalized Purkinje cells. Research now focuses on specifically targeting mutant alleles in polyQ disorders, including SCA3. | [42,43] |
| Research on polyQ expansion in SCA17 | PolyQ expansion in TBP affects its DNA binding and interactions with transcription regulators. This might reduce the expression of specific genes, impacting neuronal function. However, the majority of genes remain unaffected. | [44] |
In a sequence of research projects using a transgenic mouse model for SCA17, Xioa-Jiang Li and his team discovered indications suggesting that the polyQ expansion in TBP modifies its DNA-binding capacity and interaction with transcription regulators. This could potentially lead to the decreased expression of certain genes, such as HSPB1 and TrkA. Hence, for SCA7 and SCA17, the evidence suggests that polyQ expansion particularly affects these transcription regulators’ competency to manage the expression of certain key genes crucial for neuronal function, while not altering their regulation of the majority of other genes [44]. (Table 3)
3. Lewy Body Dementia (DLB)
Amyloid-beta protein has been implicated as an inducer of Lewy-type pathology, while mutations of alpha-synuclein can often result in cortical Lewy bodies as well as brainstem Lewy bodies; patients carrying these mutations frequently exhibit dementia symptoms. Other contributing factors of Lewy-type pathology include male gender, having late-onset Parkinson’s disease (PD), and carrying the CYP2D6*4 allele and specific alpha-synuclein haplotypes such as L478 and Rep1, among others. Mutations in the Parkin gene cause an early-onset autosomal recessive form of Parkinson’s disease characterized by changes to the substantia nigra without Lewy pathology development, suggesting that related metabolic pathways may influence vulnerable cell populations without leading to Lewy pathology development [45].
There may be an association between alpha-synuclein aggregation and Parkin mutations and proteasomal dysfunction and cell death pathways [46]; additionally, dementia found among DLB patients may be due to Alzheimer-type pathologies. Alpha-synuclein interacts with amyloid-beta protein through beta-amyloid’s ability to increase fibrillization and aggregation, leading to DLB pathology characterized by both Alzheimer-type pathology as well as alpha-synuclein pathology. Notably, alpha-synuclein aggregates may contribute to Parkinsonian features while amyloid-beta protein aggregates have been associated with Alzheimer’s disease (AD); hyperphosphorylated tau abnormalities may contribute to frontotemporal lobar degeneration [47].
Synucleinopathies are neurodegenerative conditions characterized by an accumulation of aggregated forms of the protein a-synuclein (a-syn) within various brain cells. Synucleinopathies, often associated with aging, are becoming increasingly prevalent due to extended life expectancy. Of all neurodegenerative conditions resulting in dementia, synucleinopathies rank second only to AD [48]. Most synucleinopathies fall under the category of Lewy body diseases (LBD), as they involve the build-up of aggregated a-syn in Lewy bodies within vulnerable neurons and Lewy neurites on neuronal processes. Parkinson’s disease, Parkinson’s disease dementia (PDD), and DLB are three of the more recognizable forms of Lewy body dementia; there may also be fewer common conditions [49].
Discovering a-syn as an essential component of LBD was made possible through findings of mutations of the SNCA gene (which encodes for a-syn) in familial forms of Parkinson’s disease and subsequent identification as one of the major components of Lewy bodies. Studies have demonstrated a strong link between mutations of SNCA and DLB occurrence sporadically. This association can be anticipated given that Lewy bodies contain a-syn, which has been implicated as playing an essential part in the pathophysiology of DLB, PD, and PDD. Unsurprisingly, research indicates a correlation between certain regions of the SNCA gene and different phenotypes of Parkinson’s disease and DLB; specifically, the 3′ region was linked with Parkinsonism while the 5′ region was linked with DLB pathology [50].
This may have an impact on the gene expression as well as brain distribution of Lewy body pathology. DLB has been linked with several genes, including SNCA, LRRK2, PSEN1, PSEN2, APP, SNCB MAPT SCARB2 GBA, and APOE. Noteworthy is the possibility that rare variants in AD-related genes (PSEN1, PSEN2, and APP) found in dementia cases could be misdiagnosed due to inadequate neuropathological assessment. Lewy body pathology is a relatively common feature of AD and may contribute to disease phenotype, leading to DLB. Recent genome-wide association studies have confirmed previously reported associations (APOE, SNCA, and GBA), and identified CNTN1 as an additional likely locus, providing an unbiased investigation of the genetics behind DLB [51].
APOE e4 allele and glucocerebrosidase (GBA) have emerged as two of the strongest genetic risk factors for DLB. APOE e4 allele is associated with an increased risk of DLB and is frequently found among individuals who exhibit mixed DLB-AD pathology, but is also overrepresented among cases of pure DLB and Parkinson’s disease dementia. Studies have established a correlation between APOE e4 and more severe Lewy body pathology, particularly among individuals with lower AD pathology [52].
GBA mutations are significantly more frequent among DLB patients compared to individuals without this condition. GBA mutations have been associated with early age of onset, higher disease severity, and faster disease progression in DLB cases. Similar to APOE, GBA may play an integral role in the formation and spread of Lewy body pathology, although its precise mechanisms have yet to be identified. Furthermore, an association was recently observed between DLB and SCARB2, a gene linked with Parkinson’s disease; this highlights lysosomal pathways as possible mediators of DLB development [53].
Studies conducted on DLB cases confirmed pathologically have revealed an association between GBA1 mutations and the condition. Initial investigations identified GBA1 mutations in an impressive percentage of DLB cases ranging from 3.5% to 28% depending on the specific research study conducted [54]. Subsequent multisite studies demonstrated GBA1 mutations in approximately 7.6% of DLB patients and 3.6% of individuals with both Lewy body disease and Alzheimer’s neuropathology [55]. These findings demonstrate that GBA1 mutations may be an influential risk factor for DLB and may impact disease development and progression. Furthermore, in a separate clinical study focused on Parkinson’s disease, GBA1 mutations had an enormous effect on its phenotype; specifically, the development of dementia symptoms in patients [56].
GBA1 mutations have been associated with earlier disease onset and death ages in DLB compared to noncarriers. DLB patients carrying GBA1 mutations generally experience disease onset approximately five years earlier compared to noncarriers, their median ages of disease onset being 63.5 and 68.9, respectively. The duration between diagnosis and death in cases carrying GBA1 mutations remains similar to noncarriers. Furthermore, they may demonstrate higher scores on the Hoehn Yahr scale and Unified Parkinson’s Disease Rating Scale than noncarriers, while E326K variant but not T369M has been associated with DLB and Parkinson’s disease dementia [57].
GBA1-associated Parkinsonism remains incompletely understood. Emerging evidence reveals that impaired lysosomal function, caused by deficient or mutant glucocerebrosidase enzyme, may impede alpha-synuclein degradation, an integral protein involved in DLB pathology [58].
Studies conducted using murine models and human neuronal cells demonstrate that dysfunctional glucocerebrosidase leads to accumulation and aggregation of alpha-synuclein, which, in turn, impairs trafficking and lysosomal activity of glucocerebrosidase activity, further worsening disease progression. Furthermore, autophagy disruption may contribute to its pathological mechanisms as part of DLB progression [59].
Recent biochemical studies have demonstrated similar levels of Ab40 and Ab42 in plaques between classic DLB and DLB with rapid progression (rpDLB), as well as abnormal solubility/aggregation of a-synuclein aggregates and increased binding to membranes of b-amyloid proteins in frontal cortex areas of both DLB and rpDLB cases [60].
Protein expression levels have been found to decrease significantly in DLB, with levels of NDUFA7, NDUFA10, NDUFB8, SDHB, UQCRC2, MTCO1, ATP5A, and ATP50 all showing significant reduction. No significant variations exist between rpDLB and DLB with respect to protein expression, with the exception of NDUFA7, which exhibits reduced expression even when normalized against VDAC expression levels, suggesting that rapid progression may have less of an impact on mitochondria compared to DLB [59].
Even though gene and protein expression vary significantly between DLB and rpDLB patients, the mitochondrial enzymatic activity of complexes I, II, III, and IV was significantly reduced in frontal cortex area 8 in both conditions, suggesting altered mitochondrial function as one major contributor to DLB and rpDLB pathogenesis in the frontal cortex [59].
Compared to DLB, three genes associated with purine metabolism (ENTPD2, NME3, and PRUNE) are significantly upregulated in rpDLB [59].
Additionally, reduced expression of NPM1 in the frontal cortex of DLB may indicate nucleolar stress linked to altered ribosomal biogenesis and protein expression of several transcription initiation factors at the ribosome, more so for rpDLB than DLB [61], while expression levels for elongation factors eEF1A and eEF2 were preserved across both types [62].
Notably, no significant variations were observed between DLB and controls in terms of gene expression for various cytokines and inflammatory mediators [63].
Genetic studies have identified variations in genes linked to other neurodegenerative disorders, including Parkinson’s disease (SNCA) and AD (APP, PSEN1, and PSEN2) among unrelated and sporadic DLB patients [64].
DLB was only recently recognized as a distinct disease entity, and research in molecular genetics of DLB lags behind that of Alzheimer’s and Parkinson’s diseases.
Rivastigmine, administered orally up to 12 mg/day, was the first to undergo a comprehensive evaluation in a large-scale (n = 120) randomized, double-blind, placebo-controlled international trial [65].
Remarkably, 63% of those treated with rivastigmine exhibited a 30% or greater enhancement on a digital cognitive assessment, contrasting with the placebo group, where only 30% exhibited improvement after 23 weeks. Rivastigmine-treated patients were observed to be less anxious and experienced fewer hallucinations. A comparable trend was detected with galantamine, given orally up to 24 mg/day, in a smaller (n = 50) open-label multi-center investigation on DLB patients. Here, a notable improvement from the starting point was seen on the Clinician’s Global Impression of Change (CGIC) scale (an increase of +0.5 out of 7 points; p = 0.01) after 24 weeks [66] Table 4.
Research using animal models for Parkinsonism and other neurodegenerative conditions has pointed towards excessive glutaminergic activity at cortical synapses. Memantine, an N-methyl d-aspartate (NMDA) receptor antagonist, benefits dementia patients by mitigating the harmful impacts of glutamate in their brains [67].
During the mild to intermediate stages of DLB, cholinesterase inhibitors such as rivastigmine, galantamine, and donepezil typically succeed in diminishing the frequency and intensity of hallucinations and delusions. Parkinsonian symptoms in DLB tend to be alleviated by the dopamine precursor levodopa, but its dosage must be moderated to prevent exacerbating visual hallucinations or the onset of unrest or excessive daytime drowsiness [68] Table 4.
Zonisamide, an anticonvulsant medication, obstructs sodium and T-type calcium channels and curtails the release of glutamate and carbonic anhydrase activity. It has secured approval in Japan for PD treatment. Its prevalent side effects involve weight reduction and diminished appetite, although these adverse reactions are infrequent [69].
Table 4. Overview of targeted molecular therapies in Lewy body dementia.
| Treatment/Drug | Key Details and Outcomes | Citation |
|---|---|---|
| Rivastigmine |
|
[65,66] |
| Galantamine |
|
[66,68] |
| Memantine |
|
[67] |
| Levodopa |
|
[68] |
| Zonisamide |
|
[69] |
This entry is adapted from the peer-reviewed paper 10.3390/ijms241613006
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