Dementia with Lewy Bodies Drug Therapies in Clinical Trials: Systematic Review up to 2022.

INTRODUCTION: Reviews of randomized clinical trials (RCTs) in dementia with Lewy bodies (DLB) are essential for informing ongoing research efforts of symptomatic therapies and potentially disease-modifying therapies (DMTs). METHODS: We performed a systematic review of all clinical trials conducted until September 27, 2022, by examining 3 international registries: ClinicalTrials.gov, the European Union Drug Regulating Authorities Clinical Trials Database, and the International Clinical Trials Registry Platform, to identify drugs in trials in DLB. RESULTS: We found 25 agents in 40 trials assessing symptomatic treatments and DMTs for DLB: 7 phase 3, 31 phase 2, and 2 phase 1 trials. We found an active pipeline for drug development in DLB, with most ongoing clinical trials in phase 2. We identified a recent trend towards including participants at the prodromal stages, although more than half of active clinical trials will enroll mild to moderate dementia patients. Additionally, repurposed agents are frequently tested, representing 65% of clinical trials. CONCLUSION: Current challenges in DLB clinical trials include the need for disease-specific outcome measures and biomarkers, and improving representation of global and diverse populations.

Characterization of Depressive Symptoms in Dementia and Examination of Possible Risk Factors.

Background: Depression in individuals with Alzheimer's disease (AD) is common, distressing, difficult to treat, and inadequately understood. It occurs more frequently in AD than in older adults without dementia. The reasons why some patients develop depression during AD and others do not remain obscure. Objective: We aimed to characterize depression in AD and to identify risk factors. Methods: We used data from three large dementia focused cohorts: ADNI (n = 665 with AD, 669 normal cognition), NACC (n = 698 with AD, 711 normal cognition), and BDR (n = 757 with AD). Depression ratings were available using the GDS and NPI and in addition for BDR the Cornell. A cut-off of≥8 was used for the GDS and the Cornell Scale for Depression in Dementia,≥6 for the NPI depression sub-scale, and≥2 for the NPI-Q depression sub-scale. We used logistic regression to examine potential risk factors and random effects meta-analysis and an interaction term to look for interactions between each risk factor and the presence of cognitive impairment. Results: In individual studies there was no evidence of a difference in risk factors for depressive symptoms in AD. In the meta-analysis the only risk factor which increased the risk of depressive symptoms in AD was previous depression, but information on this was only available from one study (OR 7.78 95% CI 4.03-15.03). Conclusion: Risk factors for depression in AD appear to differ to those for depression per se supporting suggestions of a different pathological process, although a past history of depression was the strongest individual risk factor.

Persistent depressive symptoms are associated with frontal regional atrophy in patients with Alzheimer's disease.

BACKGROUND: Depression in individuals with Alzheimer's disease (AD) is common, difficult to treat and inadequately understood. Previous studies have identified possible differences in regional brain atrophy in individuals with AD and depression, but the results have been inconsistent and some studies had less robust definitions of depression. We aimed to examine regional brain atrophy in two large dementia focused cohorts. METHODS: We used data from Alzheimer's disease neuroimaging initiative (ADNI) and the National Alzheimer's Co-ordinating Center (NACC), for those with data from at least one MRI scan. Depression ratings were available using the Geriatric Depression Scale (GDS) and Neuropsychiatric Inventory (NPI). Intermittent depressive symptoms were defined as one episode above threshold (≥8 on GDS, ≥6 on NPI depression subscale and ≥2 on the Neuropsychiatric Inventory version Q depression sub-scale) and persistent as ≥2 episodes. Derived regional volumetric data was available from ADNI and the NACC. RESULTS: Data was available from 698 individuals with AD in NACC and from 666 individuals in ADNI. We found no evidence of between group differences in regional brain volume at baseline, or of differential atrophy in NACC. In ADNI we found evidence of increased brain atrophy in several frontal brain areas. LIMITATIONS: Because this study was limited to those with MRI data, the numbers in some analyses were low. MRI parcellation differed between studies making direct comparison difficult. For some individuals only the NPI was used to rate depression. CONCLUSIONS: We have found mixed evidence of increased regional atrophy in depression in AD, mainly in frontal brain regions. We found no evidence to support a vascular basis for depression in AD.

Efficacy results of pimavanserin from a multi-center, open-label extension study in Parkinson's disease psychosis patients.

INTRODUCTION: Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved for hallucinations and delusions associated with Parkinson's disease psychosis (PDP). We present durability of response with pimavanserin in patients with PDP for an additional 4 weeks of treatment. METHODS: This was an open-label extension (OLE) study in patients previously completing one of three double-blind, placebo-controlled (Core) studies. All patients received pimavanserin 34 mg once daily. Efficacy assessments included the Scale for the Assessment of Positive Symptoms (SAPS) PD and H + D scales, Clinical Global Impression (CGI) Improvement and Severity scales and Caregiver Burden Scale (CBS), through 4 weeks in the OLE. Safety assessments were conducted at each visit. RESULTS: Of 459 patients, 424 (92.4%) had a Week 4 efficacy assessment. At Week 4 (10 weeks total treatment), SAPS-PD mean (standard deviation) change from OLE baseline was -1.8 (5.5) and for SAPS-H + D was -2.1 (6.2) with pimavanserin 34 mg. Patients receiving placebo during the Core studies had greater improvements (SAPS-PD -2.9 [5.6]; SAPS-H + D -3.5 [6.3]) during the OLE. For participants treated with pimavanserin 8.5 or 17 mg during the Core studies, further improvement was observed during the OLE with pimavanserin 34 mg. The mean change from Core Study baseline for SAPS-PD score was similar among prior pimavanserin 34 mg and prior placebo-treated participants (-7.1 vs. -7.0). The CGI-I response rate (score of 1 or 2) at Week 4 was 51.4%. Adverse events were reported by 215 (46.8%) patients during the first 4 weeks of OLE. The most common AEs were fall (5.9%), hallucination (3.7%), urinary tract infection (2.8%), insomnia (2.4%), and peripheral edema (2.2%) CONCLUSIONS: Patients previously on pimavanserin 34 mg during three blinded core studies had durability of efficacy during the subsequent 4 week OLE SAPS-PD assessment. Patients previously on blinded placebo improved after 4 weeks of OL pimavanserin treatment. These results in over 400 patients from 14 countries support the efficacy of pimavanserin for treating PDP.

Patterns of Mitochondrial TSPO Binding in Cerebral Small Vessel Disease: An in vivo PET Study With Neuropathological Comparison.

Small vessel disease (SVD) is associated with cognitive impairment in older age and be implicated in vascular dementia. Post-mortem studies show proliferation of activated microglia in the affected white matter. However, the role of inflammation in SVD pathogenesis is incompletely understood and better biomarkers are needed. We hypothesized that expression of the 18 kDa translocator protein (TSPO), a marker of microglial activation, would be higher in SVD. Positron emission tomography (PET) was performed with the second-generation TSPO ligand [11C]PBR28 in 11 participants with SVD. TSPO binding was evaluated by a two-tissue compartment model, with and without a vascular binding component, in white matter hyperintensities (WMH) and normal-appearing white matter (NAWM). In post-mortem tissue, in a separate cohort of individuals with SVD, immunohistochemistry was performed for TSPO and a pan-microglial marker Iba1. Kinetic modeling showed reduced tracer volume and blood volume fraction in WMH compared with NAWM, but a significant increase in vascular binding. Vascular [11C]PBR28 binding was also increased compared with normal-appearing white matter of healthy participants free of SVD. Immunohistochemistry showed a diffuse increase in microglial staining (with Iba1) in sampled tissue in SVD compared with control samples, but with only a subset of microglia staining positively for TSPO. Intense TSPO staining was observed in the vicinity of damaged small blood vessels, which included perivascular macrophages. The results suggest an altered phenotype of activated microglia, with reduced TSPO expression, in the areas of greatest white matter ischemia in SVD, with implications for the interpretation of TSPO PET studies in older individuals or those with vascular risk factors.

Evaluation of the efficacy of pimavanserin in the treatment of agitation and aggression in patients with Alzheimer's disease psychosis: A post hoc analysis.

OBJECTIVES: Patients with Alzheimer's disease psychosis (ADP) commonly experience concomitant agitation and aggression. We investigated whether a reduction in ADP following pimavanserin treatment conferred a reduction in associated agitation and aggression. METHODS: ACP-103-019 was a 12-week, randomized, double-blind, placebo-controlled study that evaluated the efficacy of pimavanserin (34 mg) in reducing psychotic symptoms in patients with ADP. The primary endpoint was change from baseline in Neuropsychiatric Inventory-Nursing Home Version-Psychosis Score (NPI-NH-PS) at week six. A post hoc analysis examined whether there was a greater reduction in agitation and aggression (NPI-NH domain C [agitation/aggression] and Cohen-Mansfield Agitation Inventory-Short Form [CMAI-SF]) in pimavanserin-treated patients who experienced a reduction of hallucinations and delusions (psychosis responders defined as ≥50% reduction from baseline in NPI-NH-PS, week six) when compared with those who did not (nonresponders). RESULTS: Pimavanserin-treated patients with ≥50% response in psychotic symptoms (n = 44) showed a greater improvement in agitation and aggression symptoms on the NPI-NH domain C (week six, least squares mean [LSM] difference = -3.64, t = -4.69, P < .0001) and the CMAI-SF (week six, LSM difference = -3.71, t = -2.01, P = .0483) than nonresponders (n = 32). Differences between psychosis responders and nonresponders were also observed in patients with more severe agitation and aggression at baseline on the NPI-NH domain C (responders, n = 26; nonresponders, n = 13; week six, LSM difference = -3.03, t = -2.44, P = .019). CONCLUSIONS: Patients with ADP, who show improvement in psychotic symptoms after pimavanserin treatment, also experience an improvement in concomitant agitation and aggression.

Long-term evaluation of open-label pimavanserin safety and tolerability in Parkinson's disease psychosis.

INTRODUCTION: Pimavanserin is a selective 5-HT2A inverse agonist/antagonist approved for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Results from short-term, placebo-controlled studies demonstrated a positive benefit/risk profile. This multi-year, open-label study assessed long-term safety and tolerability of pimavanserin. METHODS: This was an open-label extension (OLE) study in patients previously completing a double-blind, placebo-controlled study or a previous OLE study. Safety was evaluated from adverse events (AEs), clinical laboratory results, motor symptoms, electrocardiograms (ECG), and mortality. Durability of response was assessed from the Clinical Global Impression-Severity (CGI-S) scale and Caregiver Burden Scale (CBS). RESULTS: Of 459 participants treated in this OLE study (average age 71.2 years), the median duration of treatment was 454 days. Over the entire study period (approximately 11 years), ≥1 AE occurred in 392 (85.4%) patients; the majority were of mild to moderate intensity, with fall (32.0%), urinary tract infection (19.0%), and hallucination (13.7%) most common. Serious AEs occurred in 188 (41.0%) patients, and an AE leading to study termination or dose discontinuation occurred in 133 (29.0%) patients. Sixty-one patients died, 59 (12.9%) during treatment or within 30 days after the last dose of study drug; the observed mortality rate was 6.45 per 100 patient-years of exposure. Mean scores for the CGI-S scale and CBS generally remained stable for up to 192 weeks (>3.5 years). CONCLUSIONS: Long-term treatment with pimavanserin 34 mg once daily demonstrated a favorable benefit/risk profile with no unexpected safety concerns. Mortality rates suggested no increased risk following long-term treatment.

Temporal Relationship Between Depressive Symptoms and Cognition in Mid and Late Life: A Longitudinal Cohort Study.

OBJECTIVES: To examine the bidirectional temporal relationship between depressive symptoms and cognition in relation to risk, reaction, and prodrome. DESIGN: Cross-lag analysis of longitudinal data collected online at baseline and 12-month follow-up. SETTING AND PARTICIPANTS: A United Kingdom population cohort of 11,855 participants aged 50 years and over. MEASURES: Patient Health Questionnaire-9 (depressive symptoms), cognitive measures: Paired Associate Learning, Verbal Reasoning, Spatial Working Memory, and Digit Span. RESULTS: Depressive symptoms predicted a decline in paired associates learning [ß = -.020, P = .013, (95% confidence interval [CI], ‒.036, -.004)] and verbal reasoning [ß = -.014, P = .016, (95% CI ‒.025, -.003)] but not vice versa. Depressive symptoms predicted [ß = -.043, P < .001, (95% CI ‒.060, -.026); ß = -.029, P < .001, (95% CI ‒.043, -.015)] and were predicted by [ß = -.030, P = < .001, (95% CI ‒.047, -.014); ß = -.025, P = .003, (95% CI ‒.041, -.009)], a decline in spatial working memory and verbal digit span, respectively. CONCLUSIONS AND IMPLICATIONS: Depressive symptoms may be either a risk factor or prodrome for cognitive decline. In addition, a decline in attention predicts depressive symptoms. Clinical implications and implications for further research are discussed.

A role for APP in Wnt signalling links synapse loss with ß-amyloid production.

In Alzheimer's disease (AD), the canonical Wnt inhibitor Dickkopf-1 (Dkk1) is induced by ß-amyloid (Aß) and shifts the balance from canonical towards non-canonical Wnt signalling. Canonical (Wnt-ß-catenin) signalling promotes synapse stability, while non-canonical (Wnt-PCP) signalling favours synapse retraction; thus Aß-driven synapse loss is mediated by Dkk1. Here we show that the Amyloid Precursor Protein (APP) co-activates both arms of Wnt signalling through physical interactions with Wnt co-receptors LRP6 and Vangl2, to bi-directionally modulate synapse stability. Furthermore, activation of non-canonical Wnt signalling enhances Aß production, while activation of canonical signalling suppresses Aß production. Together, these findings identify a pathogenic-positive feedback loop in which Aß induces Dkk1 expression, thereby activating non-canonical Wnt signalling to promote synapse loss and drive further Aß production. The Swedish familial AD variant of APP (APPSwe) more readily co-activates non-canonical, at the expense of canonical Wnt activity, indicating that its pathogenicity likely involves direct effects on synapses, in addition to increased Aß production. Finally, we report that pharmacological inhibition of the Aß-Dkk1-Aß positive feedback loop with the drug fasudil can restore the balance between Wnt pathways, prevent dendritic spine withdrawal in vitro, and reduce Aß load in vivo in mice with advanced amyloid pathology. These results clarify a relationship between Aß accumulation and synapse loss and provide direction for the development of potential disease-modifying treatments.

Ras-ERK-ETS inhibition alleviates neuronal mitochondrial dysfunction by reprogramming mitochondrial retrograde signaling.

Mitochondrial dysfunction activates the mitochondrial retrograde signaling pathway, resulting in large scale changes in gene expression. Mitochondrial retrograde signaling in neurons is poorly understood and whether retrograde signaling contributes to cellular dysfunction or is protective is unknown. We show that inhibition of Ras-ERK-ETS signaling partially reverses the retrograde transcriptional response to alleviate neuronal mitochondrial dysfunction. We have developed a novel genetic screen to identify genes that modify mitochondrial dysfunction in Drosophila. Knock-down of one of the genes identified in this screen, the Ras-ERK-ETS pathway transcription factor Aop, alleviates the damaging effects of mitochondrial dysfunction in the nervous system. Inhibition of Ras-ERK-ETS signaling also restores function in Drosophila models of human diseases associated with mitochondrial dysfunction. Importantly, Ras-ERK-ETS pathway inhibition partially reverses the mitochondrial retrograde transcriptional response. Therefore, mitochondrial retrograde signaling likely contributes to neuronal dysfunction through mis-regulation of gene expression.

Mitochondrial Translocase of the Outer Membrane Alterations May Underlie Dysfunctional Oxidative Phosphorylation in Alzheimer's Disease.

BACKGROUND: The translocase of the outer membrane (TOM) is a vital mitochondrial transport system facilitating the importation of nuclear encoded proteins into the organelle. While mitochondrial dysfunction, including perturbation of oxidative phosphorylation (OXPHOS) complex, is evident in Alzheimer's disease (AD), it remains unclear whether the observed OXPHOS deficits may be associated with TOM alterations. OBJECTIVES: To correlate TOM subunits with OXPHOS complex proteins in AD. METHODS: Postmortem neocortex (BA40) from AD and age-matched controls were processed to obtain mitochondrial enriched homogenates for the measurement of Tom20, Tom22, Tom40, and Tom70 as well as components of OXPHOS complex I-V by immunoblotting. RESULTS: Tom20 and Tom70 immunoreactivities were significantly reduced in AD, as were components of OXPHOS complex I and III. Both Tom20 and Tom70 positively correlated with complex III and V, while Tom20 also correlated withcomplex IV. CONCLUSION: Reductions in certain TOM subunits and their correlations with specific OXPHOS complex proteins suggest that an impaired mitochondrial transportation system may contribute to previously observed oxidative phosphorylation deficits in AD. Follow-up studies are needed to corroborate the present correlative study.

Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium.

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Increased Transforming Growth Factor ß2 in the Neocortex of Alzheimer's Disease and Dementia with Lewy Bodies is Correlated with Disease Severity and Soluble Aß42 Load.

BACKGROUND: Of the three transforming growth factor (TGF)-ß isoforms known, TGFß1 deficits have been widely reported in Alzheimer's disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGFß2, which has been shown to mediate amyloid-ß (Aß)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden. OBJECTIVE: To measure neocortical TGFß2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), known to manifest relatively high and low Aß plaque burden, respectively. METHODS: Postmortem samples from temporal cortex (BA21) were measured for TGFß2 using a Luminex-based platform, and correlated with scores for neuritic plaques, neurofibrillary tangles, α-synuclein pathology, dementia severity (as measured by annual decline of Mini-Mental State Examination scores) as well as soluble and total fractions of brain Aß42. RESULTS: TGFß2 was significantly increased in AD and DLB, but not in PDD. TGFß2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble Aß42 concentration, but not with neuritic plaque scores, total Aß42, or monomeric α-synuclein immunoreactivity. CONCLUSIONS: TGFß2 is increased in the temporal cortex of AD and DLB, and its correlations with neuropathological and clinical markers of disease severity as well as with soluble Aß42 load suggest a potential pathogenic role in mediating the neurotoxicity of non-fibrillar Aß. Our study also indicates the potential utility of targeting TGFß2 in pharmacotherapeutic approaches to AD and DLB.

Muscarinic M1 Receptor Coupling to G-protein is Intact in Parkinson's Disease Dementia.

BACKGROUND: Postsynaptic cholinergic deficits, including reduced cortical muscarinic M1 receptor coupling to G-proteins, are neurochemical findings postulated to underlie the limited efficacy of presynaptically-targeted cholinergic replacement therapies in Alzheimer's disease (AD). While the loss of M1-G-protein coupling has been associated with ß-amyloid (Aß) burden in AD, the status of M1 coupling to G-proteins in Parkinson's disease-related or mixed dementias is unclear. OBJECTIVE: To test the hypothesis that M1 receptor uncoupling is correlated with Aß burden, we aimed to study muscarinic M1 neurochemical parameters in neurodegenerative dementias characterized by low and high Aß loads. METHODS: M1 receptors, M1 coupling to G-proteins as well as Aß were measured in postmortem frontal cortex of a cohort of longitudinally assessed patients with Parkinson's Disease Dementia (PDD, low Aß load) and AD with significant subcortical cerebrovascular disease (AD + CVD, high Aß load). RESULTS: We found unchanged levels of M1 receptors in both dementia groups, while M1 coupling was reduced only in AD + CVD (p < 0.01). Furthermore, Aß concentration was significantly increased only in AD + CVD, and correlated negatively with M1-G-protein coupling in the dementia groups. CONCLUSIONS: Our study suggests that loss of M1 coupling to G-proteins may be a neurochemical feature of neurodegenerative dementias with high cortical Aß burden, and that cholinergic replacement therapies may be more efficacious for PDD due to low Aß burden.

Increased phosphorylation of collapsin response mediator protein-2 at Thr514 correlates with ß-amyloid burden and synaptic deficits in Lewy body dementias.

Collapsin response mediator protein-2 (CRMP2) regulates axonal growth cone extension, and increased CRMP2 phosphorylation may lead to axonal degeneration. Axonal and synaptic pathology is an important feature of Lewy body dementias (LBD), but the state of CRMP2 phosphorylation (pCRMP2) as well as its correlations with markers of neurodegeneration have not been studied in these dementias. Hence, we measured CRMP2 phosphorylation at Thr509, Thr514 and Ser522, as well as markers of ß-amyloid (Aß), tau-phosphorylation, α-synuclein and synaptic function in the postmortem neocortex of a longitudinally assessed cohort of LBD patients characterized by low (Parkinson's disease dementia, PDD) and high (dementia with Lewy bodies, DLB) burden of Alzheimer type pathology. We found specific increases of pCRMP2 at Thr514 in DLB, but not PDD. The increased CRMP2 phosphorylation correlated with fibrillogenic Aß as well as with losses of markers for axon regeneration (ß-III-tubulin) and synaptic integrity (synaptophysin) in LBD. In contrast, pCRMP2 alterations did not correlate with tau-phosphorylation or α-synuclein, and also appear unrelated to immunoreactivities of putative upstream kinases glycogen synthase kinase 3ß and cyclin-dependent kinase 5, as well as to protein phosphatase 2A. In conclusion, increased pCRMP2 may underlie the axonal pathology of DLB, and may be a novel therapeutic target. However, antecedent signaling events as well as the nature of pCRMP2 association with Aß and other neuropathologic markers require further study.

Dementia in Parkinson's disease is associated with enhanced mitochondrial complex I deficiency.

BACKGROUND: Dementia is a common feature of Parkinson's disease (PD), but the neuropathological changes associated with the development of Parkinson's disease dementia (PDD) are only partially understood. Mitochondrial dysfunction is a hallmark of PD but has not been studied in PDD. METHODS: Molecular and biochemical approaches were used to study mitochondrial activity and quantity in postmortem prefrontal cortex tissue. Tissues from pathologically confirmed PD and PDD patients and from age-matched controls were used to analyze the activity of mitochondrial enzyme complex nicotinamide adenine dinucleotide:ubiquinone oxidoreductase, or complex I (the first enzyme in the mitochondrial respiratory chain), mitochondrial DNA levels, and the expression of mitochondrial proteins. RESULTS: Complex I activity was significantly decreased (27% reduction; analysis of variance with Tukey's post hoc test; P < 0.05) in PDD patients, and mitochondrial DNA levels were also significantly decreased (18% reduction; Kruskal-Wallis analysis of variance with Dunn's multiple comparison test; P < 0.05) in PDD patients compared with controls, but neither was significantly reduced in PD patients. Overall, mitochondrial biogenesis was unaffected in PD or PDD, because the expression of mitochondrial proteins in patients was similar to that in controls. CONCLUSIONS: Patients with PDD have a deficiency in mitochondrial complex I activity and reduced mitochondrial DNA levels in the prefrontal cortex without a change in mitochondrial protein quantity. Therefore, mitochondrial complex I deficiency and reduced mitochondrial DNA in the prefrontal cortex may be a hallmark of dementia in patients with PD.

Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia.

Alpha-synuclein (α-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), but are also frequently present in Alzheimer's disease (AD). Much remains unknown about the role of α-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key 'SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor' (SNARE) proteins as a consequence of alterations in the aggregation state of α-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p <  0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric α-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α-syn.

Stage-specific changes in neurogenic and glial markers in Alzheimer's disease.

BACKGROUND: Reports of altered endogenous neurogenesis in people with Alzheimer's disease (AD) and transgenic AD models have suggested that endogenous neurogenesis may be an important treatment target, but there is considerable discrepancy among studies. We examined endogenous neurogenesis and glia changes across the range of pathologic severity of AD in people with and without dementia to address this key question. METHODS: Endogenous neurogenesis and glia in the subventricular zone and dentate gyrus neurogenic niches were evaluated using single and double immunohistochemistry and a validated antibody selection for stage-specific and type-specific markers in autopsy tissue from a representative cohort of 28 participants in the Medical Research Council Cognitive Function and Ageing Study. Immunopositive cells were measured blinded to diagnosis using bright-field and fluorescent microscopy. RESULTS: The number of newly generated neurons significantly declined only in the dentate gyrus of patients with severe tau pathology. No other changes in other neurogenic markers were observed in either of the neurogenic niches. Alterations in astrocytes and microglia were also observed in the dentate gyrus across the different stages of tau pathology. No change in any of the markers was observed in individuals who died with dementia compared with individuals who did not die with dementia. CONCLUSIONS: Alterations in endogenous neurogenesis appeared to be confined to a reduction in the generation of new neurons in the dentate gyrus of patients with AD and severe neurofibrillary tangle pathology and were accompanied by changes in the glia load. These data suggest that intervention enhancing endogenous neurogenesis may be a potential therapeutic target in AD.

Dynamin protein in stroke and vascular dementia.

Damage to sub-cortical white matter is a key substrate of vascular dementia (VaD) leading to deficits in executive function and cognitive processing speed. Dynamin1 is a 100 kDa protein, accounting for 0.4% of the total brain protein, and has a central role in many intracellular processes such as synaptic vesicle trafficking and recycling. In this study, we examined the status of Dynamin1 in the white matter from frontal cortex area. In order to measure the levels of Dynamin1, we isolated cortical white matter from a total of 34 post-mortem brains derived from controls (N=11), mixed Alzheimer's disease (AD) and VaD (N=8), VaD (N=7), and stroke no dementia (SND, N=8) subjects. A commercial ELISA kit was then used to determine the level of Dynamin1. In comparison to controls, Dynamin1 was elevated in patients SND (+400%) and reduced in patients with mixed VaD (-50%). Furthermore, levels of Dynamin1 were significantly associated with preserved cognition as indicated by the MMSE and CAMCOG and upregulation of vesicular glutamate transporter 1. This work indicates that Dynamin1 is associated with both preserved cognition and regenerative responses in older people with cerebrovascular disease and may represent a novel treatment target.

Decreased immunoreactivities of neocortical AMPA receptor subunits correlate with motor disability in Lewy body dementias.

Dementia with Lewy bodies and Parkinson's disease dementia are different clinical phenotypes of Lewy body dementias differentiated by the temporal relationship between parkinsonism and dementia onset. At present, it is unclear whether the glutamatergic system is affected in these disorders. In this study, we measured α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA subunits in the postmortem neocortex of a cohort of prospectively studied Lewy body dementia cases, as well as age-matched controls by immunoblotting. We found losses of GluA2/3/4 immunoreactivities in Lewy body dementias which correlated with higher pre-death Hoehn and Yahr scores and with longer Parkinson's disease duration before dementia onset, but not with dementia severity, cortical Lewy body burden, or amyloid plaque and neurofibrillary tangle burden. Our study suggests that GluA2/3/4 losses may be a neurochemical marker of motor disability in Lewy body dementias.