RARE DISEASE
Posterior cortical atrophy
Posterior cortical atrophy
Posterior cortical atrophy
Synonyms: Benson syndrome, Biparietal Alzheimer disease, PCA
Synonyms: Benson syndrome, Biparietal Alzheimer disease, PCA
Synonyms: Benson syndrome, Biparietal Alzheimer disease, PCA
Drug discovery
135
papers
On emerging therapies
Overview
Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome characterized by progressive visuospatial and visuoperceptual deficits due to posterior brain atrophy. Most cases (70–94%) are linked to Alzheimer’s pathology, though Lewy body disease or corticobasal degeneration may also underlie it [1][5][7][12]. Symptoms include simultanagnosia, optic ataxia, alexia, and apraxia, with onset typically between ages 50–65 [2][7][12]. Diagnosis relies on neuroimaging (posterior-predominant atrophy/hypometabolism) and exclusion of ocular pathology [5][10][16].
Therapies
Categories: rare genetic diseases, rare neurological diseases
Research Papers
135 drug discovery papers about Posterior cortical atrophy, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
135 drug discovery papers about Posterior cortical atrophy, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-02-06 | Pharmacological interventions in patients with posterior cortical atrophy: a systematic review
Background: Posterior Cortical Atrophy (PCA) is a rare dementia syndrome, typically caused by an atypical variant of Alzheimer’s disease, and is characterized by progressive visuospatial decline. Cholinesterase inhibitors (AChEIs), used in typical Alzheimer’s disease, are sometimes prescribed for PCA, but evidence supporting their efficacy in this population remains limited. Objective: To summarize current clinical evidence on pharmacological treatments for PCA. Methods: A systematic review was conducted according to PRISMA guidelines. Searches were performed in PubMed, EMBASE, Scopus, and Web of Science for studies published between January 2010 and May 2025. Keywords included “posterior cortical atrophy,” “pharmacological treatment,” and related terms. Studies were excluded if they addressed other causes of cognitive decline, focused solely on non-pharmacological approaches, were case reports, preclinical studies, or lacked full-text access. Results: Only one study met inclusion criteria: a randomized, double-blind, placebo-controlled trial (Ridha et al., 2018) involving 18 PCA patients treated with donepezil. MMSE scores improved significantly at six weeks (difference of 2.5 points; p<0.05), but not at 12 weeks. No improvements were observed in visuospatial tests. Adverse effects were frequent, especially gastrointestinal symptoms (72%) and vivid dreams (44%). Discussion: The study highlighted recruitment challenges and a high rate of side effects, which may have affected blinding. The small sample limits the generalizability of findings. No other neuropsychological outcomes improved. Conclusion: Evidence on pharmacological treatment for PCA is scarce. High-quality clinical trials are needed to guide therapeutic strategies.
2025-09-02 | Longitudinal impact of cholinesterase inhibitors on cholinergic white matter integrity in mild cognitive impairment: A diffusion MRI study.
Early degeneration of the cholinergic nucleus basalis of Meynert contributes to cognitive decline in Alzheimer's disease (AD). Microstructural damage in downstream cholinergic tracts-the cingulum bundle (CGC), entorhinal cortex (EC), and uncinate fasciculus (UNC)-often precedes volumetric atrophy. While cholinesterase inhibitors (ChEIs) can preserve cortical and hippocampal volume, their influence on white-matter integrity is unclear. To determine whether ChEIs slow microstructural decline in four cholinergic tracts (CGC, EC, UNC, posterior thalamic radiation [PTR]) in mild cognitive impairment (MCI), and whether baseline cognitive status modulates this effect. Diffusion-tensor imaging from the Alzheimer's Disease Neuroimaging Initiative was analyzed in 46 MCI participants receiving donepezil or rivastigmine and 62 untreated MCI controls, each scanned serially over two years. Fractional anisotropy (FA) and mean diffusivity (MD) indexed tract integrity. Linear mixed-effects models tested time × medication × baseline cognition (ADAS-Cog13) interactions, adjusting for age, sex, APOE ε4, and white-matter hyperintensity burden. Across groups, CGC showed progressive degeneration (FA↓, MD↑; p < 0.001). Significant three-way interactions emerged for MD in bilateral CGC, FA in right EC, and MD in left PTR (all p < 0.01). ChEI users with milder baseline impairment (lower ADAS-Cog13) exhibited attenuated FA loss and MD increase, indicating slower microstructural decline; those with greater initial impairment derived minimal benefit. No medication effect was detected in UNC. ChEIs confer tract-specific, stage-dependent protection of cholinergic white matter, particularly in early MCI. The findings underscore the value of initiating ChEI therapy before substantial cognitive deterioration and highlight the need for stage-tailored interventions aimed at preserving white-matter integrity in prodromal AD.
2025-08-20 | Successful Treatment of Posterior Cortical Atrophy: Case Report
Background/Objectives: Posterior cortical atrophy, also referred to as Benson’s syndrome, is a presentation of Alzheimer’s disease that occurs in 5-15% of Alzheimer’s patients. Visual processing is the predominant affected modality in posterior cortical atrophy, and symptoms such as prosopagnosia, simultanagnosia, alexia, optic ataxia, and visual hallucinations may occur, as well as blurred vision and visual distortions. Posterior cortical atrophy is considered to be a disease without known cause or effective treatment. Methods: We report here a patient with posterior cortical atrophy who responded to a personalized, precision medicine protocol. Results: The patient had improved MRI volumetrics, symptoms, and cognitive testing. She regained the ability to read, use her computer, and undertake computer-based brain training, among other cognitive improvements. She has now sustained her improvement for over one year, and continues to regain her independence and confidence. Conclusions: These results argue for additional laboratory testing in the evaluation of patients with posterior cortical atrophy, and support the possibility of utilizing a similar approach in a proof-of-concept trial.
2025-02-04 | Statin is associated with higher cortical thickness in early Alzheimer's disease.
The brain is the most cholesterol-rich organ, essential for myelination and neuronal function. Statins, widely used to lower cholesterol, cross the blood-brain barrier and may impact brain cholesterol synthesis. Despite their widespread use, the effects of statins on cortical regions relevant to Alzheimer's disease (AD) are not well understood. This study aimed to compare cortical thickness between statin-exposed and statin-unexposed older adults and evaluate the potential neuroprotective effects of statins. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The sample included 193 healthy controls (HC), 485 individuals with mild cognitive impairment (MCI), and 169 individuals with Alzheimer's disease (AD). Participants were categorized as statin users if they had used statins for at least two years. MRI data were processed using FreeSurfer software to estimate cortical thickness in 64 regions of interest. ANCOVA models assessed the association between statin use and cortical thickness at baseline, and linear mixed models evaluated longitudinal changes. Statin use was associated with increased cortical thickness in multiple brain regions across HC, MCI, and AD participants. In HC, statin users had greater thickness in the right lateral occipital, left middle temporal, and left parahippocampal regions. MCI participants exhibited additional increases in the right cuneus, right posterior cingulate, and left superior temporal cortex. In AD, statin users had higher thickness in the right cuneus and right superior parietal lobule. Longitudinal analysis revealed no statin-related differences in cortical thickness changes among HC and AD groups, but in MCI, statins slowed cortical thinning in the left medial orbitofrontal cortex. Statin use is associated with greater cortical thickness in older adults, particularly in those with MCI. These findings suggest that statins may have neuroprotective effects, potentially mitigating neurodegenerative changes in early cognitive decline. Further research with larger cohorts and longer follow-up periods is needed to confirm these findings and understand the mechanisms involved.
2024-04-15 | Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease
Importance Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P &lt; .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P &lt; .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P &lt; .001). Hippocampal MRI volume (Spearman ρ = −0.45; P &lt; .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P &lt; .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.
antibodies
2026-08-05 | Eligibility for Anti-Amyloid Therapies in Patients With Biomarker-Confirmed Atypical Alzheimer Disease Phenotypes.
Clinical trials of anti-amyloid therapies (AATs) for Alzheimer disease (AD) primarily enrolled patients with mildly symptomatic, amnestic predominant presentations. The applicability of eligibility criteria to atypical AD phenotypes, including posterior cortical atrophy (PCA), logopenic variant primary progressive aphasia (lvPPA), dysexecutive AD (dAD), and corticobasal syndrome because of AD (CBS-AD), is unknown. We conducted a retrospective eligibility analysis of patients with atypical AD evaluated at Mayo Clinic. Theoretical eligibility for AAT was assessed at initial clinical evaluation by applying inclusion and exclusion criteria from landmark clinical trials (Study to Confirm Safety and Efficacy of Lecanemab in Participants With Early Alzheimer's Disease [CLARITY-AD] and the Study of LY3002813 (Donanemab) in Participants With Early Symptomatic Alzheimer's Disease [TRAILBLAZER-ALZ2]) and appropriate use criteria for lecanemab and donanemab. Eligibility percentages and reasons for exclusion were compared across phenotypes. The cohort included 184 patients (61.4% female) with biomarker-confirmed atypical AD: PCA (n = 98, 53.3%), lvPPA (n = 42, 22.8%), dAD (n = 37, 20.1%), and CBS-AD (n = 7, 3.8%). Age at onset (p = 0.039) and presentation (p < 0.001) differed, with patients with lvPPA oldest (median age at onset, presentation: 63.1, 66.9 years) and patients with dAD youngest (onset, presentation: 55.1, 57.3). Functional impairment differed by phenotype (p = 0.005), with lvPPA more often diagnosed at the mild cognitive impairment/very mild stage (Clinical Dementia Rating [CDR] 0.5; 71.4%), whereas PCA and dAD more frequently presented with mild dementia, although time from symptom onset to diagnosis did not differ (p = 0.634). Mini-Mental State Examination (MMSE) scores differed (p = 0.036), with lower scores in PCA and lvPPA (median 21 and 21, respectively) compared with CBS-AD (median 27). Depending on the eligibility framework applied, 70%-85% of patients would not meet treatment criteria. Bedside cognitive thresholds were the primary drivers of ineligibility (50%-67% of exclusions), despite most patients having early symptomatic disease (global CDR 0.5-1; 82%). Imaging-based exclusions (22%-27%) and severity thresholds (moderate or severe dementia, 19%-23%) were also frequent. Reasons for ineligibility were similar across phenotypes. Most patients with atypical AD would not meet eligibility criteria for AAT, typically because of MMSE-based exclusion rather than measures of cognitive function. Eligibility rates are broadly similar across atypical phenotypes. These findings highlight the need for phenotype-sensitive staging and patient selection for treatment in atypical AD.
2025-06-25 | Posterior cortical atrophy in the age of anti-amyloid treatments: An 11-year retrospective study of eligible patients from the Leenaards Memory Center.
At the era of the anti-amyloid treatments (AAT), it is striking to note posterior cortical atrophy (PCA) cases, the most predictive phenotype of Alzheimer's disease neuropathology, have not been explicitly included or excluded from clinical trials. In a retrospective analysis of the Leenaards Memory Center registry, we identified 41 PCA cases and, applying the recent appropriate use recommendations for lecanemab, estimate high (20%) eligibility rate, that doubles in pure PCA phenotypes with biomarker work-up available (40%). This high proportion of PCA patients eligible for AAT should prompt a timely exploration to assess inclusion/exclusion criteria for these novel therapies.
2024-12-01 | Increased cerebral blood flow after lecanemab infusions: MR‐ASL utility in monitoring Alzheimer disease treatment response
Abstract Background Since lecanemab, an anti‐amyloid monoclonal antibody targeting Aβ protofibrils, only modestly impacts cognition (27% slower cognitive decline over 18 months), tracking the effects on the brain in the early months is a clinical challenge. Serial noncontrast MRI scans are required by the FDA, to assess for the occurrence of amyloid‐related imaging abnormalities (ARIA). Arterial spin‐labeling MR (ASL‐MR) is a 4‐minute non‐contrast easily‐added sequence. Patterns of abnormal cerebral blood flow (CBF) on ASL‐MR can correlate with neurodegenerative markers including FDG‐PET. Method Here we show CBF maps of two patients at baseline, and after receiving 4 infusions of lecanemab. Our figure is representative of six other patients in whom we have noted similar changes on therapy, and who will also be presented. Result Figure 1 shows CBF maps of a man in his early seventies with mild cognitive impairment, due to AD. He had a family history of AD, and was diagnosed with a positive 18F‐florbetaben PET and prescribed donepezil, with mild symptom improvement. His CSF markers were borderline (Abeta42 575 pg/mL, t‐tau 289 pg/mL, p‐tau 51 pg/mL, ATI 0.99.). Figure 2 shows CBF maps of a woman in her fifties, with a history of Crohn’s disease, not currently requiring immunosuppression. She was diagnosed with posterior cortical atrophy due to AD, with a positive 18F‐florbetaben PET and CSF compatible with AD (abeta42 366 pg/mL, t‐tau 486 pg/mL, p‐tau 72 pg/mL, ATI 0.45). She remained employed until a mild COVID infection, at which point her preexisting cognitive symptoms worsened (presumed longCOVID‐related worsening). Both patients carried the ApoE e3/e3 genotype. In both cases, baseline low temporoparietal CBF increased at the scheduled MRI post‐4 th infusion. Conclusion These cases show that CBF increases on lecanemab from baseline to after the 4th infusion. Preclinical investigations have demonstrated that it can protect neurons from Aβ‐induced apoptosis, leading to neuronal viability and improved brain perfusion. CBF increases may also reflect increased synaptic activity after amyloid clearance and/or vascular changes, such as clearance of fibrinogen/amyloid clotting complexes. CBF has potential as a noninvasive and time‐efficient marker of medication effect and perhaps efficacy over time.
2013-09-19 | Cross-sectional and longitudinal analysis of the relationship between Aβ deposition, cortical thickness, and memory in cognitively unimpaired individuals and in Alzheimer disease.
β-amyloid (Aβ) deposition is one of the hallmarks of Alzheimer disease. Aβ deposition accelerates gray matter atrophy at early stages of the disease even before objective cognitive impairment is manifested. Identification of at-risk individuals at the presymptomatic stage has become a major research interest because it will allow early therapeutic interventions before irreversible synaptic and neuronal loss occur. We aimed to further characterize the cross-sectional and longitudinal relationship between Aβ deposition, gray matter atrophy, and cognitive impairment. To investigate the topographical relationship of Aβ deposition, gray matter atrophy, and memory impairment in asymptomatic individuals with Alzheimer disease pathology as assessed by Pittsburgh compound B positron emission tomography (PiB-PET). Regional analysis was performed on the cortical surface to relate cortical thickness to PiB retention and episodic memory. The Australian Imaging, Biomarkers, and Lifestyle Study of Aging, Austin Hospital, Melbourne, Australia. Ninety-three healthy elderly control subjects (NCs) and 40 patients with Alzheimer disease from the Australian Imaging, Biomarkers, and Lifestyle Study of Aging cohort. Participants underwent neuropsychological evaluation as well as magnetic resonance imaging and PiB-PET scans. Fifty-four NCs underwent repeated scans and neuropsychological evaluation 18 and 36 months later. Correlations between cortical thickness, PiB retention, and episodic memory. RESULTS There was a significant reduction in cortical thickness in the precuneus and hippocampus associated with episodic memory impairment in the NC PiB-positive (NC+) group when compared with the NC- group. Cortical thickness was also correlated negatively with neocortical PiB in the NC+ group. Longitudinal analysis showed a faster rate of gray matter (GM) atrophy in the temporal lobe and the hippocampi of the NC+ group. Over time, GM atrophy became more extensive in the NC+ group, especially in the temporal lobe. In asymptomatic individuals, Aβ deposition is associated with GM atrophy and memory impairment. The earliest signs of GM atrophy were detected in the hippocampus and the posterior cingulate and precuneus regions, and with disease progression, atrophy became more extensive in the temporal lobes. These findings support the notion that Aβ deposition is not a benign process and that interventions with anti-Aβ therapy at these early stages have a higher chance to be effective.
proteins
2025-03-30 | Bromelain improved cognitive & mood behaviors, oxido-inflammatory indices and cholinergic transmission in scopolamine-induced neurotoxicity in male wistar rats.
Alzheimer's disease (AD) is associated with pathophysiological and psychological disturbances including cognitive decline, depression, anxiety and motor imbalance. Conventional drugs for managing AD do not address associated non-neurocognitive co-morbidities, hence the need to investigate alternative therapies especially from plants. The neuroprotective benefits of bromelain have been identified, but its impacts on scopolamine-induced neurotoxicity is yet to be elucidated. Twenty-Five male rats were separated randomly into 5 groups: Control (normal saline; 1ml/kg); Scopolamine (i.p; 1mg/kg); Bromelain (50mg/kg); Scopolamine + Bromelain; Scopolamine + Donepezil (reference drug, 1mg/kg). Neurobehavioral paradigms (novel object recognition, elevated plus maze, forced swimming and open field tests were assessed, followed by biochemical (MDA, SOD, AChE, NO, Total protein & IL-1b) assay in the PFC. Data were analyzed using one-way ANOVA (Tukey's posthoc.). Values with p<0.05 were considered significant. Scopolamine reduced memory index (P<0.01) (cognitive function), ambulatory & rearing activities (P<0.05) (motor behavior), open arm duration (P<0.001) (anxiety-like behavior) & increased immobility time (P<0.05) (depressive-like behavior). Exposure to scopolamine also led to significant reduction in the prefrontal cortical levels of SOD (P<0.05) while increasing MDA (P<0.05), acetylcholinesterase (P<0.01) and IL-1β (P<0.05). However, levels of NO and total protein were not significantly altered. In contrast, intervention with bromelain or donepezil significantly reversed most of the behavioral and biochemical alterations induced by scopolamine. Bromelain compared favorably with donepezil in improving memory decline and other non-cognitive dysfunctions associated with scopolamine exposure. This could have resulted from modulation of oxidative stress, inflammation and cholinergic transmission. Key words: Bromelain; Scopolamine; Oxidative stress; Neurotoxicity; Neuro-inflammation; Behavior.
2019-02-07 | Roles of Semaphorins in Neurodegenerative Diseases
Semaphorins are secreted and transmembrane proteins that bind plexin/ neuropilin or integrin receptors, providing paracrine axonal guidance signals and ultimately leading to a functional and developed neuronal network.Following semaphorin's initial discovery, their relevance in the central nervous system (CNS) soon intrigued researchers about the possible links between semaphorins, their receptors and signaling mechanisms and different neurodegenerative diseases.Here, we explore the current knowledge of semaphorin's function and signaling in Alzheimer's disease (AD), Parkinson's disease (PD), Charcot-Marie-Tooth disease (CMT), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP).We focus on the effects of the most known semaphorin subclasses 3A and 4D, yet extending our discussion to other semaphorins that have been found involved in specific neuropathologies and the potential effect of semaphorins modulating the immune system in disorders with inflammatory components.Molecular, cellular, and genetic evidences are reviewed, highlighting the relevance of semaphorins on each disease etiology, pathophysiology, and progression.The newly discovered semaphorin functions in neurological disorders even suggest alternative therapies that may be highly valuable in diseases that have no current cure.
2017-01-10 | Promotion of Cortical Neurogenesis from the Neural Stem Cells in the Adult Mouse Subcallosal Zone.
Neurogenesis occurs spontaneously in the subventricular zone (SVZ) of the lateral ventricle in adult rodent brain, but it has long been debated whether there is sufficient adult neurogenesis in human SVZ. Subcallosal zone (SCZ), a posterior continuum of SVZ closely associated with posterior regions of cortical white matter, has also been reported to contain adult neural stem cells (aNSCs) in both rodents and humans. However, little is known whether SCZ-derived aNSC (SCZ-aNSCs) can produce cortical neurons following brain injury. We found that SCZ-aNSCs exhibited limited neuronal differentiation potential in culture and after transplantation in mice. Neuroblasts derived from SCZ initially migrated toward injured cortex regions following brain injury, but later exhibited apoptosis. Overexpression of anti-apoptotic bcl-xL in the SCZ by retroviral infection rescued neuroblasts from cell death in the injured cortex, but neuronal maturation was still limited, resulting in atrophy. In combination with Bcl-xL, infusion of brain-derived neurotropic factor rescued atrophy, and importantly, a subset of such SCZ-aNSCs differentiated and attained morphological and physiological characteristics of mature, excitatory neurons. These results suggest that the combination of anti-apoptotic and neurotrophic factors might enable the use of aNSCs derived from the SCZ in cortical neurogenesis for neural replacement therapy.
gene therapies
2026-04-13 | Posterior Cortical Atrophy Presenting with Psychotic Delirium
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2026-01-31 | Alzheimer's Disease Continuum: Evaluating the Relationship between Fluid Biomarkers and Patients' Phenotype and Profile.
The measurement of fluid biomarkers such as phosphorylated tau at threonine 181 (pTAU181), amyloid-β 40 (Aβ40), and Aβ42 is a routine medical examination that contributes to achieving an accurate diagnosis within the Alzheimer's disease (AD) clinical continuum. The aim of this study is to compare the concentration of these biomarkers in CSF and plasma and determine their relationship with the patients' clinical variant and profile. Patients were diagnosed following the NIA-AA criteria. Plasma and CSF were obtained from healthy controls (HC), mild cognitive impairment (MCI non-AD), MCI displaying positive AD markers (MCI-AD), and AD patients. Biomarker levels were assessed using the LUMIPULSE® G600II instrument (Fujirebio, Japan). Data showed a significant increase in pTAU181 concentration, specifically in the progression from MCI non-AD to AD conditions. The opposite trend was observed for Aβ42 and Aβ42/Aβ40. Furthermore, these biomarker trends appeared to change consistently with variations in the MMSE score, highlighting the relevance of plasma in detecting changes in patients' cognitive function. Considering the clinical variant, atypical patients displayed the highest pTAU181 and lowest Aβ42 levels, consistent with their lower MMSE scores. Lastly, the posterior cortical atrophy (PCA) profile showed higher pTAU181 and lower Aβ42 levels when compared to other profiles. Nevertheless, these last results are to be cautiously interpreted given the limited number of samples included in the analysis. Hence, further analyses on larger cohorts are needed to better define the role of these biomarkers in distinguishing between patients' clinical variants.
2025-12-01 | Unravelling Posterior Cortical Atrophy: Clinico‐Imaging Insights from a Tertiary Care Cohort in India
BACKGROUND: Posterior Cortical Atrophy (PCA), first described by Benson et al., is a progressive neurodegenerative disorder affecting visual and posterior cognitive functions, while sparing memory and language in early stages. Although Alzheimer's Disease (AD) pathology underlies most cases, alternative etiologies like Dementia with Lewy Bodies (DLB), Corticobasal Degeneration (CBD), and Prion disease have also been reported. This study examines the clinical, etiological, and imaging profiles of PCA patients evaluated at a tertiary care center in India, using Crutch et al. 2017 consensus criteria. METHOD: Eight PCA patients diagnosed at a tertiary hospital in India between 2021 and 2024 were included in this prospective case series. Demographic data, neuropsychological profiles, imaging findings, and biomarker studies were analyzed. Patients were assessed for visual and posterior cognitive impairments. RESULT: PCA predominantly presented as early-onset cognitive decline in the 5th to 6th decade, with equal gender distribution. All patients exhibited initial visuospatial, visuoperceptual, or praxis impairments. Based on Crutch et al.'s classification, 6 patients (75%) were categorized as Pure PCA, and 2 (25%) as PCA Plus, including PCA-CBS and PCA-AD/DLB mixed. Phenotypically, 3 patients were dorsal variant, 3 ventral, and 2 biparietal. CSF AD biomarkers were positive in 2 Pure PCA patients and 1 PCA-AD/DLB patient. MRI revealed posterior cortical atrophy in all cases. FDG-PET showed parieto-temporo-occipital hypometabolism, with frontal involvement in dorsal/ventral subtypes, while biparietal subtypes showed occipital sparing. Tau-PET in selected cases demonstrated increased uptake in affected regions, matching FDG-PET findings. CONCLUSION: PCA remains underrecognized due to its atypical presentation and early onset. This series highlights the clinical and imaging heterogeneity of PCA in Indian subjects. Advanced imaging, like FDG/Tau-PET, can aid in distinguishing phenotypes. Greater research is needed to explore phenotypic variations, identify biomarkers, and develop targeted therapies.
2025-11-12 | A Cerebral Origin for Retinal Degeneration in the Visual Form of Alzheimer's Disease?
Alzheimer's disease (AD) manifests commonly as an amnestic syndrome (tAD), but also as a rarer focal type, such as posterior cortical atrophy (PCA-AD), which primarily impairs visuospatial functions. In addition to the brain atrophy, retinal degeneration has been demonstrated, associated with the accumulation of Ab and Tau protein in this tissue, which shares a common origin with the brain. Additionally, retrograde trans-synaptic degeneration from the brain could affect the retina. We hypothesized that such dying-back phenomenon would be more important in PCA-AD than in tAD and that this would be reflected on specific optical coherence tomography (OCT) measures. Twenty-nine AD patients were categorized into 15 typical and 14 PCA forms. Complaints and symptoms were evaluated using a specific screening battery developed to detect PCA (Q-ACP questionnaire, neuropsychological parietal and non-parietal scales). Neuroimaging was performed to determine brain atrophy and its lateralization. OCT imaging allowed measuring the volumes of the macular ganglion cell layer (GCL) and the retinal nerve fibre layer (RNFL) of the optic nerve. While the global RNFL thickness and GCL volume were not statistically different, PCA-AD patients showed more thinning than tAD in the inferior temporal (IT) sector in both eyes. Moreover, the amount of thinning in this sector was correlated with the score on the Q-ACP questionnaire and on the neuropsychological parietal scales. We propose that the thinning in the IT sector reflects the retrograde damage to the magnocellular pathway, which constitutes a major feed of the dorsal visual stream primarily damaged in PCA.
2025-09-26 | A – 112 Comorbid Multiple Sclerosis and Posterior Cortical Atrophy in a Young Woman
Abstract Objective Multiple sclerosis (MS) is associated with slowed processing speed and executive dysfunction with some variability on visuoconstruction measures. We present a case wherein the nature and extent of cognitive impairments exceeded typical findings for MS, suggesting a second, comorbid neurodegenerative process in a younger individual. Method A 43-year-old, right-handed, Latine woman with a GED diagnosed with MS (relapsing-remitting course) was evaluated for progressive cognitive concerns over seven years. Neurological exam revealed a right visual-field deficit. Brain MRI was consistent with MS but also showed disproportionate posterior regional atrophy that was atypical based on location of lesions and disease duration. She reported marked difficulty with visuospatially mediated tasks, not limited to those given her visual field deficit. Results Using a cut-off of < 1.5 SD, she demonstrated impairments in learning and memory, visuospatial reasoning, and visual attention, not attributable to her known visual field deficit. Performance on all measures of visually-mediated speed and attention was below the 2nd percentile and contrasted with preserved auditory attention. Learning was discrepant across measures with greater encoding of verbal information than non-verbal. Performance on tasks of auditory attention, working memory, and executive functioning were within expectations. Conclusion Given striking impairments on tasks requiring attention to or processing of visual information, we believe the patient demonstrated cognitive performance consistent with posterior cortical atrophy in addition to MS. This case study highlights the importance of consideration of low base rate, comorbid conditions with an appreciation for the cumulative burden of neurodegenerative processes that may alter age of onset and clinical course.
small molecules
2026-02-06 | Pharmacological interventions in patients with posterior cortical atrophy: a systematic review
Background: Posterior Cortical Atrophy (PCA) is a rare dementia syndrome, typically caused by an atypical variant of Alzheimer’s disease, and is characterized by progressive visuospatial decline. Cholinesterase inhibitors (AChEIs), used in typical Alzheimer’s disease, are sometimes prescribed for PCA, but evidence supporting their efficacy in this population remains limited. Objective: To summarize current clinical evidence on pharmacological treatments for PCA. Methods: A systematic review was conducted according to PRISMA guidelines. Searches were performed in PubMed, EMBASE, Scopus, and Web of Science for studies published between January 2010 and May 2025. Keywords included “posterior cortical atrophy,” “pharmacological treatment,” and related terms. Studies were excluded if they addressed other causes of cognitive decline, focused solely on non-pharmacological approaches, were case reports, preclinical studies, or lacked full-text access. Results: Only one study met inclusion criteria: a randomized, double-blind, placebo-controlled trial (Ridha et al., 2018) involving 18 PCA patients treated with donepezil. MMSE scores improved significantly at six weeks (difference of 2.5 points; p<0.05), but not at 12 weeks. No improvements were observed in visuospatial tests. Adverse effects were frequent, especially gastrointestinal symptoms (72%) and vivid dreams (44%). Discussion: The study highlighted recruitment challenges and a high rate of side effects, which may have affected blinding. The small sample limits the generalizability of findings. No other neuropsychological outcomes improved. Conclusion: Evidence on pharmacological treatment for PCA is scarce. High-quality clinical trials are needed to guide therapeutic strategies.
2025-09-02 | Longitudinal impact of cholinesterase inhibitors on cholinergic white matter integrity in mild cognitive impairment: A diffusion MRI study.
Early degeneration of the cholinergic nucleus basalis of Meynert contributes to cognitive decline in Alzheimer's disease (AD). Microstructural damage in downstream cholinergic tracts-the cingulum bundle (CGC), entorhinal cortex (EC), and uncinate fasciculus (UNC)-often precedes volumetric atrophy. While cholinesterase inhibitors (ChEIs) can preserve cortical and hippocampal volume, their influence on white-matter integrity is unclear. To determine whether ChEIs slow microstructural decline in four cholinergic tracts (CGC, EC, UNC, posterior thalamic radiation [PTR]) in mild cognitive impairment (MCI), and whether baseline cognitive status modulates this effect. Diffusion-tensor imaging from the Alzheimer's Disease Neuroimaging Initiative was analyzed in 46 MCI participants receiving donepezil or rivastigmine and 62 untreated MCI controls, each scanned serially over two years. Fractional anisotropy (FA) and mean diffusivity (MD) indexed tract integrity. Linear mixed-effects models tested time × medication × baseline cognition (ADAS-Cog13) interactions, adjusting for age, sex, APOE ε4, and white-matter hyperintensity burden. Across groups, CGC showed progressive degeneration (FA↓, MD↑; p < 0.001). Significant three-way interactions emerged for MD in bilateral CGC, FA in right EC, and MD in left PTR (all p < 0.01). ChEI users with milder baseline impairment (lower ADAS-Cog13) exhibited attenuated FA loss and MD increase, indicating slower microstructural decline; those with greater initial impairment derived minimal benefit. No medication effect was detected in UNC. ChEIs confer tract-specific, stage-dependent protection of cholinergic white matter, particularly in early MCI. The findings underscore the value of initiating ChEI therapy before substantial cognitive deterioration and highlight the need for stage-tailored interventions aimed at preserving white-matter integrity in prodromal AD.
2025-08-20 | Successful Treatment of Posterior Cortical Atrophy: Case Report
Background/Objectives: Posterior cortical atrophy, also referred to as Benson’s syndrome, is a presentation of Alzheimer’s disease that occurs in 5-15% of Alzheimer’s patients. Visual processing is the predominant affected modality in posterior cortical atrophy, and symptoms such as prosopagnosia, simultanagnosia, alexia, optic ataxia, and visual hallucinations may occur, as well as blurred vision and visual distortions. Posterior cortical atrophy is considered to be a disease without known cause or effective treatment. Methods: We report here a patient with posterior cortical atrophy who responded to a personalized, precision medicine protocol. Results: The patient had improved MRI volumetrics, symptoms, and cognitive testing. She regained the ability to read, use her computer, and undertake computer-based brain training, among other cognitive improvements. She has now sustained her improvement for over one year, and continues to regain her independence and confidence. Conclusions: These results argue for additional laboratory testing in the evaluation of patients with posterior cortical atrophy, and support the possibility of utilizing a similar approach in a proof-of-concept trial.
2025-02-04 | Statin is associated with higher cortical thickness in early Alzheimer's disease.
The brain is the most cholesterol-rich organ, essential for myelination and neuronal function. Statins, widely used to lower cholesterol, cross the blood-brain barrier and may impact brain cholesterol synthesis. Despite their widespread use, the effects of statins on cortical regions relevant to Alzheimer's disease (AD) are not well understood. This study aimed to compare cortical thickness between statin-exposed and statin-unexposed older adults and evaluate the potential neuroprotective effects of statins. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The sample included 193 healthy controls (HC), 485 individuals with mild cognitive impairment (MCI), and 169 individuals with Alzheimer's disease (AD). Participants were categorized as statin users if they had used statins for at least two years. MRI data were processed using FreeSurfer software to estimate cortical thickness in 64 regions of interest. ANCOVA models assessed the association between statin use and cortical thickness at baseline, and linear mixed models evaluated longitudinal changes. Statin use was associated with increased cortical thickness in multiple brain regions across HC, MCI, and AD participants. In HC, statin users had greater thickness in the right lateral occipital, left middle temporal, and left parahippocampal regions. MCI participants exhibited additional increases in the right cuneus, right posterior cingulate, and left superior temporal cortex. In AD, statin users had higher thickness in the right cuneus and right superior parietal lobule. Longitudinal analysis revealed no statin-related differences in cortical thickness changes among HC and AD groups, but in MCI, statins slowed cortical thinning in the left medial orbitofrontal cortex. Statin use is associated with greater cortical thickness in older adults, particularly in those with MCI. These findings suggest that statins may have neuroprotective effects, potentially mitigating neurodegenerative changes in early cognitive decline. Further research with larger cohorts and longer follow-up periods is needed to confirm these findings and understand the mechanisms involved.
2024-04-15 | Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease
Importance Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P &lt; .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P &lt; .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P &lt; .001). Hippocampal MRI volume (Spearman ρ = −0.45; P &lt; .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P &lt; .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.
antibodies
2026-08-05 | Eligibility for Anti-Amyloid Therapies in Patients With Biomarker-Confirmed Atypical Alzheimer Disease Phenotypes.
Clinical trials of anti-amyloid therapies (AATs) for Alzheimer disease (AD) primarily enrolled patients with mildly symptomatic, amnestic predominant presentations. The applicability of eligibility criteria to atypical AD phenotypes, including posterior cortical atrophy (PCA), logopenic variant primary progressive aphasia (lvPPA), dysexecutive AD (dAD), and corticobasal syndrome because of AD (CBS-AD), is unknown. We conducted a retrospective eligibility analysis of patients with atypical AD evaluated at Mayo Clinic. Theoretical eligibility for AAT was assessed at initial clinical evaluation by applying inclusion and exclusion criteria from landmark clinical trials (Study to Confirm Safety and Efficacy of Lecanemab in Participants With Early Alzheimer's Disease [CLARITY-AD] and the Study of LY3002813 (Donanemab) in Participants With Early Symptomatic Alzheimer's Disease [TRAILBLAZER-ALZ2]) and appropriate use criteria for lecanemab and donanemab. Eligibility percentages and reasons for exclusion were compared across phenotypes. The cohort included 184 patients (61.4% female) with biomarker-confirmed atypical AD: PCA (n = 98, 53.3%), lvPPA (n = 42, 22.8%), dAD (n = 37, 20.1%), and CBS-AD (n = 7, 3.8%). Age at onset (p = 0.039) and presentation (p < 0.001) differed, with patients with lvPPA oldest (median age at onset, presentation: 63.1, 66.9 years) and patients with dAD youngest (onset, presentation: 55.1, 57.3). Functional impairment differed by phenotype (p = 0.005), with lvPPA more often diagnosed at the mild cognitive impairment/very mild stage (Clinical Dementia Rating [CDR] 0.5; 71.4%), whereas PCA and dAD more frequently presented with mild dementia, although time from symptom onset to diagnosis did not differ (p = 0.634). Mini-Mental State Examination (MMSE) scores differed (p = 0.036), with lower scores in PCA and lvPPA (median 21 and 21, respectively) compared with CBS-AD (median 27). Depending on the eligibility framework applied, 70%-85% of patients would not meet treatment criteria. Bedside cognitive thresholds were the primary drivers of ineligibility (50%-67% of exclusions), despite most patients having early symptomatic disease (global CDR 0.5-1; 82%). Imaging-based exclusions (22%-27%) and severity thresholds (moderate or severe dementia, 19%-23%) were also frequent. Reasons for ineligibility were similar across phenotypes. Most patients with atypical AD would not meet eligibility criteria for AAT, typically because of MMSE-based exclusion rather than measures of cognitive function. Eligibility rates are broadly similar across atypical phenotypes. These findings highlight the need for phenotype-sensitive staging and patient selection for treatment in atypical AD.
2025-06-25 | Posterior cortical atrophy in the age of anti-amyloid treatments: An 11-year retrospective study of eligible patients from the Leenaards Memory Center.
At the era of the anti-amyloid treatments (AAT), it is striking to note posterior cortical atrophy (PCA) cases, the most predictive phenotype of Alzheimer's disease neuropathology, have not been explicitly included or excluded from clinical trials. In a retrospective analysis of the Leenaards Memory Center registry, we identified 41 PCA cases and, applying the recent appropriate use recommendations for lecanemab, estimate high (20%) eligibility rate, that doubles in pure PCA phenotypes with biomarker work-up available (40%). This high proportion of PCA patients eligible for AAT should prompt a timely exploration to assess inclusion/exclusion criteria for these novel therapies.
2024-12-01 | Increased cerebral blood flow after lecanemab infusions: MR‐ASL utility in monitoring Alzheimer disease treatment response
Abstract Background Since lecanemab, an anti‐amyloid monoclonal antibody targeting Aβ protofibrils, only modestly impacts cognition (27% slower cognitive decline over 18 months), tracking the effects on the brain in the early months is a clinical challenge. Serial noncontrast MRI scans are required by the FDA, to assess for the occurrence of amyloid‐related imaging abnormalities (ARIA). Arterial spin‐labeling MR (ASL‐MR) is a 4‐minute non‐contrast easily‐added sequence. Patterns of abnormal cerebral blood flow (CBF) on ASL‐MR can correlate with neurodegenerative markers including FDG‐PET. Method Here we show CBF maps of two patients at baseline, and after receiving 4 infusions of lecanemab. Our figure is representative of six other patients in whom we have noted similar changes on therapy, and who will also be presented. Result Figure 1 shows CBF maps of a man in his early seventies with mild cognitive impairment, due to AD. He had a family history of AD, and was diagnosed with a positive 18F‐florbetaben PET and prescribed donepezil, with mild symptom improvement. His CSF markers were borderline (Abeta42 575 pg/mL, t‐tau 289 pg/mL, p‐tau 51 pg/mL, ATI 0.99.). Figure 2 shows CBF maps of a woman in her fifties, with a history of Crohn’s disease, not currently requiring immunosuppression. She was diagnosed with posterior cortical atrophy due to AD, with a positive 18F‐florbetaben PET and CSF compatible with AD (abeta42 366 pg/mL, t‐tau 486 pg/mL, p‐tau 72 pg/mL, ATI 0.45). She remained employed until a mild COVID infection, at which point her preexisting cognitive symptoms worsened (presumed longCOVID‐related worsening). Both patients carried the ApoE e3/e3 genotype. In both cases, baseline low temporoparietal CBF increased at the scheduled MRI post‐4 th infusion. Conclusion These cases show that CBF increases on lecanemab from baseline to after the 4th infusion. Preclinical investigations have demonstrated that it can protect neurons from Aβ‐induced apoptosis, leading to neuronal viability and improved brain perfusion. CBF increases may also reflect increased synaptic activity after amyloid clearance and/or vascular changes, such as clearance of fibrinogen/amyloid clotting complexes. CBF has potential as a noninvasive and time‐efficient marker of medication effect and perhaps efficacy over time.
2013-09-19 | Cross-sectional and longitudinal analysis of the relationship between Aβ deposition, cortical thickness, and memory in cognitively unimpaired individuals and in Alzheimer disease.
β-amyloid (Aβ) deposition is one of the hallmarks of Alzheimer disease. Aβ deposition accelerates gray matter atrophy at early stages of the disease even before objective cognitive impairment is manifested. Identification of at-risk individuals at the presymptomatic stage has become a major research interest because it will allow early therapeutic interventions before irreversible synaptic and neuronal loss occur. We aimed to further characterize the cross-sectional and longitudinal relationship between Aβ deposition, gray matter atrophy, and cognitive impairment. To investigate the topographical relationship of Aβ deposition, gray matter atrophy, and memory impairment in asymptomatic individuals with Alzheimer disease pathology as assessed by Pittsburgh compound B positron emission tomography (PiB-PET). Regional analysis was performed on the cortical surface to relate cortical thickness to PiB retention and episodic memory. The Australian Imaging, Biomarkers, and Lifestyle Study of Aging, Austin Hospital, Melbourne, Australia. Ninety-three healthy elderly control subjects (NCs) and 40 patients with Alzheimer disease from the Australian Imaging, Biomarkers, and Lifestyle Study of Aging cohort. Participants underwent neuropsychological evaluation as well as magnetic resonance imaging and PiB-PET scans. Fifty-four NCs underwent repeated scans and neuropsychological evaluation 18 and 36 months later. Correlations between cortical thickness, PiB retention, and episodic memory. RESULTS There was a significant reduction in cortical thickness in the precuneus and hippocampus associated with episodic memory impairment in the NC PiB-positive (NC+) group when compared with the NC- group. Cortical thickness was also correlated negatively with neocortical PiB in the NC+ group. Longitudinal analysis showed a faster rate of gray matter (GM) atrophy in the temporal lobe and the hippocampi of the NC+ group. Over time, GM atrophy became more extensive in the NC+ group, especially in the temporal lobe. In asymptomatic individuals, Aβ deposition is associated with GM atrophy and memory impairment. The earliest signs of GM atrophy were detected in the hippocampus and the posterior cingulate and precuneus regions, and with disease progression, atrophy became more extensive in the temporal lobes. These findings support the notion that Aβ deposition is not a benign process and that interventions with anti-Aβ therapy at these early stages have a higher chance to be effective.
proteins
2025-03-30 | Bromelain improved cognitive & mood behaviors, oxido-inflammatory indices and cholinergic transmission in scopolamine-induced neurotoxicity in male wistar rats.
Alzheimer's disease (AD) is associated with pathophysiological and psychological disturbances including cognitive decline, depression, anxiety and motor imbalance. Conventional drugs for managing AD do not address associated non-neurocognitive co-morbidities, hence the need to investigate alternative therapies especially from plants. The neuroprotective benefits of bromelain have been identified, but its impacts on scopolamine-induced neurotoxicity is yet to be elucidated. Twenty-Five male rats were separated randomly into 5 groups: Control (normal saline; 1ml/kg); Scopolamine (i.p; 1mg/kg); Bromelain (50mg/kg); Scopolamine + Bromelain; Scopolamine + Donepezil (reference drug, 1mg/kg). Neurobehavioral paradigms (novel object recognition, elevated plus maze, forced swimming and open field tests were assessed, followed by biochemical (MDA, SOD, AChE, NO, Total protein & IL-1b) assay in the PFC. Data were analyzed using one-way ANOVA (Tukey's posthoc.). Values with p<0.05 were considered significant. Scopolamine reduced memory index (P<0.01) (cognitive function), ambulatory & rearing activities (P<0.05) (motor behavior), open arm duration (P<0.001) (anxiety-like behavior) & increased immobility time (P<0.05) (depressive-like behavior). Exposure to scopolamine also led to significant reduction in the prefrontal cortical levels of SOD (P<0.05) while increasing MDA (P<0.05), acetylcholinesterase (P<0.01) and IL-1β (P<0.05). However, levels of NO and total protein were not significantly altered. In contrast, intervention with bromelain or donepezil significantly reversed most of the behavioral and biochemical alterations induced by scopolamine. Bromelain compared favorably with donepezil in improving memory decline and other non-cognitive dysfunctions associated with scopolamine exposure. This could have resulted from modulation of oxidative stress, inflammation and cholinergic transmission. Key words: Bromelain; Scopolamine; Oxidative stress; Neurotoxicity; Neuro-inflammation; Behavior.
2019-02-07 | Roles of Semaphorins in Neurodegenerative Diseases
Semaphorins are secreted and transmembrane proteins that bind plexin/ neuropilin or integrin receptors, providing paracrine axonal guidance signals and ultimately leading to a functional and developed neuronal network.Following semaphorin's initial discovery, their relevance in the central nervous system (CNS) soon intrigued researchers about the possible links between semaphorins, their receptors and signaling mechanisms and different neurodegenerative diseases.Here, we explore the current knowledge of semaphorin's function and signaling in Alzheimer's disease (AD), Parkinson's disease (PD), Charcot-Marie-Tooth disease (CMT), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP).We focus on the effects of the most known semaphorin subclasses 3A and 4D, yet extending our discussion to other semaphorins that have been found involved in specific neuropathologies and the potential effect of semaphorins modulating the immune system in disorders with inflammatory components.Molecular, cellular, and genetic evidences are reviewed, highlighting the relevance of semaphorins on each disease etiology, pathophysiology, and progression.The newly discovered semaphorin functions in neurological disorders even suggest alternative therapies that may be highly valuable in diseases that have no current cure.
2017-01-10 | Promotion of Cortical Neurogenesis from the Neural Stem Cells in the Adult Mouse Subcallosal Zone.
Neurogenesis occurs spontaneously in the subventricular zone (SVZ) of the lateral ventricle in adult rodent brain, but it has long been debated whether there is sufficient adult neurogenesis in human SVZ. Subcallosal zone (SCZ), a posterior continuum of SVZ closely associated with posterior regions of cortical white matter, has also been reported to contain adult neural stem cells (aNSCs) in both rodents and humans. However, little is known whether SCZ-derived aNSC (SCZ-aNSCs) can produce cortical neurons following brain injury. We found that SCZ-aNSCs exhibited limited neuronal differentiation potential in culture and after transplantation in mice. Neuroblasts derived from SCZ initially migrated toward injured cortex regions following brain injury, but later exhibited apoptosis. Overexpression of anti-apoptotic bcl-xL in the SCZ by retroviral infection rescued neuroblasts from cell death in the injured cortex, but neuronal maturation was still limited, resulting in atrophy. In combination with Bcl-xL, infusion of brain-derived neurotropic factor rescued atrophy, and importantly, a subset of such SCZ-aNSCs differentiated and attained morphological and physiological characteristics of mature, excitatory neurons. These results suggest that the combination of anti-apoptotic and neurotrophic factors might enable the use of aNSCs derived from the SCZ in cortical neurogenesis for neural replacement therapy.
gene therapies
2026-04-13 | Posterior Cortical Atrophy Presenting with Psychotic Delirium
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2026-01-31 | Alzheimer's Disease Continuum: Evaluating the Relationship between Fluid Biomarkers and Patients' Phenotype and Profile.
The measurement of fluid biomarkers such as phosphorylated tau at threonine 181 (pTAU181), amyloid-β 40 (Aβ40), and Aβ42 is a routine medical examination that contributes to achieving an accurate diagnosis within the Alzheimer's disease (AD) clinical continuum. The aim of this study is to compare the concentration of these biomarkers in CSF and plasma and determine their relationship with the patients' clinical variant and profile. Patients were diagnosed following the NIA-AA criteria. Plasma and CSF were obtained from healthy controls (HC), mild cognitive impairment (MCI non-AD), MCI displaying positive AD markers (MCI-AD), and AD patients. Biomarker levels were assessed using the LUMIPULSE® G600II instrument (Fujirebio, Japan). Data showed a significant increase in pTAU181 concentration, specifically in the progression from MCI non-AD to AD conditions. The opposite trend was observed for Aβ42 and Aβ42/Aβ40. Furthermore, these biomarker trends appeared to change consistently with variations in the MMSE score, highlighting the relevance of plasma in detecting changes in patients' cognitive function. Considering the clinical variant, atypical patients displayed the highest pTAU181 and lowest Aβ42 levels, consistent with their lower MMSE scores. Lastly, the posterior cortical atrophy (PCA) profile showed higher pTAU181 and lower Aβ42 levels when compared to other profiles. Nevertheless, these last results are to be cautiously interpreted given the limited number of samples included in the analysis. Hence, further analyses on larger cohorts are needed to better define the role of these biomarkers in distinguishing between patients' clinical variants.
2025-12-01 | Unravelling Posterior Cortical Atrophy: Clinico‐Imaging Insights from a Tertiary Care Cohort in India
BACKGROUND: Posterior Cortical Atrophy (PCA), first described by Benson et al., is a progressive neurodegenerative disorder affecting visual and posterior cognitive functions, while sparing memory and language in early stages. Although Alzheimer's Disease (AD) pathology underlies most cases, alternative etiologies like Dementia with Lewy Bodies (DLB), Corticobasal Degeneration (CBD), and Prion disease have also been reported. This study examines the clinical, etiological, and imaging profiles of PCA patients evaluated at a tertiary care center in India, using Crutch et al. 2017 consensus criteria. METHOD: Eight PCA patients diagnosed at a tertiary hospital in India between 2021 and 2024 were included in this prospective case series. Demographic data, neuropsychological profiles, imaging findings, and biomarker studies were analyzed. Patients were assessed for visual and posterior cognitive impairments. RESULT: PCA predominantly presented as early-onset cognitive decline in the 5th to 6th decade, with equal gender distribution. All patients exhibited initial visuospatial, visuoperceptual, or praxis impairments. Based on Crutch et al.'s classification, 6 patients (75%) were categorized as Pure PCA, and 2 (25%) as PCA Plus, including PCA-CBS and PCA-AD/DLB mixed. Phenotypically, 3 patients were dorsal variant, 3 ventral, and 2 biparietal. CSF AD biomarkers were positive in 2 Pure PCA patients and 1 PCA-AD/DLB patient. MRI revealed posterior cortical atrophy in all cases. FDG-PET showed parieto-temporo-occipital hypometabolism, with frontal involvement in dorsal/ventral subtypes, while biparietal subtypes showed occipital sparing. Tau-PET in selected cases demonstrated increased uptake in affected regions, matching FDG-PET findings. CONCLUSION: PCA remains underrecognized due to its atypical presentation and early onset. This series highlights the clinical and imaging heterogeneity of PCA in Indian subjects. Advanced imaging, like FDG/Tau-PET, can aid in distinguishing phenotypes. Greater research is needed to explore phenotypic variations, identify biomarkers, and develop targeted therapies.
2025-11-12 | A Cerebral Origin for Retinal Degeneration in the Visual Form of Alzheimer's Disease?
Alzheimer's disease (AD) manifests commonly as an amnestic syndrome (tAD), but also as a rarer focal type, such as posterior cortical atrophy (PCA-AD), which primarily impairs visuospatial functions. In addition to the brain atrophy, retinal degeneration has been demonstrated, associated with the accumulation of Ab and Tau protein in this tissue, which shares a common origin with the brain. Additionally, retrograde trans-synaptic degeneration from the brain could affect the retina. We hypothesized that such dying-back phenomenon would be more important in PCA-AD than in tAD and that this would be reflected on specific optical coherence tomography (OCT) measures. Twenty-nine AD patients were categorized into 15 typical and 14 PCA forms. Complaints and symptoms were evaluated using a specific screening battery developed to detect PCA (Q-ACP questionnaire, neuropsychological parietal and non-parietal scales). Neuroimaging was performed to determine brain atrophy and its lateralization. OCT imaging allowed measuring the volumes of the macular ganglion cell layer (GCL) and the retinal nerve fibre layer (RNFL) of the optic nerve. While the global RNFL thickness and GCL volume were not statistically different, PCA-AD patients showed more thinning than tAD in the inferior temporal (IT) sector in both eyes. Moreover, the amount of thinning in this sector was correlated with the score on the Q-ACP questionnaire and on the neuropsychological parietal scales. We propose that the thinning in the IT sector reflects the retrograde damage to the magnocellular pathway, which constitutes a major feed of the dorsal visual stream primarily damaged in PCA.
2025-09-26 | A – 112 Comorbid Multiple Sclerosis and Posterior Cortical Atrophy in a Young Woman
Abstract Objective Multiple sclerosis (MS) is associated with slowed processing speed and executive dysfunction with some variability on visuoconstruction measures. We present a case wherein the nature and extent of cognitive impairments exceeded typical findings for MS, suggesting a second, comorbid neurodegenerative process in a younger individual. Method A 43-year-old, right-handed, Latine woman with a GED diagnosed with MS (relapsing-remitting course) was evaluated for progressive cognitive concerns over seven years. Neurological exam revealed a right visual-field deficit. Brain MRI was consistent with MS but also showed disproportionate posterior regional atrophy that was atypical based on location of lesions and disease duration. She reported marked difficulty with visuospatially mediated tasks, not limited to those given her visual field deficit. Results Using a cut-off of < 1.5 SD, she demonstrated impairments in learning and memory, visuospatial reasoning, and visual attention, not attributable to her known visual field deficit. Performance on all measures of visually-mediated speed and attention was below the 2nd percentile and contrasted with preserved auditory attention. Learning was discrepant across measures with greater encoding of verbal information than non-verbal. Performance on tasks of auditory attention, working memory, and executive functioning were within expectations. Conclusion Given striking impairments on tasks requiring attention to or processing of visual information, we believe the patient demonstrated cognitive performance consistent with posterior cortical atrophy in addition to MS. This case study highlights the importance of consideration of low base rate, comorbid conditions with an appreciation for the cumulative burden of neurodegenerative processes that may alter age of onset and clinical course.
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