Progressive QTc prolongation and reduced heart rate variability in dementia with Lewy bodies compared to Alzheimer's disease.

INTRODUCTION: Autonomic dysfunction (AuD) is a significant clinical challenge in patients with Dementia with Lewy Bodies (DLB). Manifestations of AuD such as orthostatic hypotension (OH) is associated with falls and decreased quality of life. Cardiac autonomic denervation is an early phenomenon in DLB and a potential contributor to OH. This retrospective study was undertaken to explore whether routine ECG tracings could be used to identify signs of autonomic dysfunction in DLB. METHODS: 18 patients with DLB and 18 age-matched patients with Alzheimer's disease (AD) were included. ECGs and clinical data were analyzed retrospectively for heart rate variability (HRV) and QTc interval prolongation. RESULTS: During an average of 10 years observation time (first to last ECG recording), the QTc interval increased in the DLB group, but not in the AD group. HRV was significantly lower at end of follow-up in the DLB group than in the AD group. DLB patients with OH had greater QTc prolongation. CONCLUSION: Longitudinal ECG analysis indicates that signs of AuD in DLB are reflected on routine ECG tracings. If confirmed in larger cohorts, this could influence risk stratification and help direct preventive measures.

Exploring the prevalence of undetected bradyarrhythmia in dementia with Lewy bodies.

PURPOSE: To explore the prevalence of undetected bradyarrhythmia in a cohort of people with dementia with Lewy bodies. METHODS: Thirty participants diagnosed with dementia with Lewy bodies were enrolled from three memory clinics in southern Sweden between May 2021 and November 2022. None had a history of high-grade atrioventricular block or sick sinus syndrome. Each participant underwent orthostatic testing, cardiac [123I]metaiodobenzylguanidine scintigraphy and 24-h ambulatory electrocardiographic monitoring. Concluding bradyarrhythmia diagnosis was obtained until the end of December 2022. RESULTS: Thirteen participants (46.4%) had bradycardia at rest during orthostatic testing and four had an average heart rate < 60 beats per minute during ambulatory electrocardiographic monitoring. Three participants (10.7%) received a diagnosis of sick sinus syndrome, of whom two received pacemaker implants to manage associated symptoms. None received a diagnosis of second- or third-degree atrioventricular block. CONCLUSION: This report showed a high prevalence of sick sinus syndrome in a clinical cohort of people with dementia with Lewy bodies. Further research on the causes and consequences of sick sinus syndrome in dementia with Lewy bodies is thus warranted.

Sudden cardiac death in synucleinopathies.

The purpose of this study was to investigate the cause of death in subjects with α-synucleinopathies (ASs) and the confirmed presence of cardiac α-synuclein (α-syn), compared to non-AS disorders in a neuropathologically confirmed cohort. In total, 78 neuropathologically confirmed AS cases positive for cardiac α-syn were included in the study. Individuals with other neurocognitive diseases, having no α-syn in the brainstem or above, nor in cardiac nerves, served as controls (n = 53). Data regarding the cause of death, cardiac α-syn, pathological cardiac findings, and cardio- and cerebrovascular disease were assembled from autopsy reports and medical records. In the AS group, there was a significantly higher prevalence of sudden cardiac death ([SCD]; n = 40, 51.3%) compared to the control group (n = 12, 22.6%, p < 0.001). No statistically significant differences between the groups were reported regarding other cardiac conditions on autopsy or regarding cardio- and cerebrovascular disease from the medical records. The most prevalent cause of death in the AS group was SCD, which differed significantly from the control group. This suggests that α-syn deposits in cardiac nerves may cause lethal alterations in cardiac function, warranting further research.

On the regional distribution of cerebral microvascular 'raspberries' and their association with cerebral atherosclerosis and acute circulatory failure.

Introduction: In this follow-up study, cerebral microvascular formations termed 'raspberries' were quantified according to cerebral atherosclerosis (C-ASCL) and acute circulatory failure (ACF). We also examined the regional distribution of raspberries throughout the brain. Materials and methods: The study population consisted of adult individuals who had undergone a diagnostic neuropathological autopsy. Groups were formed to examine the association between raspberries, C-ASCL and ACF (control group, C-ASCL group, C-ASCL+ACF group [n = 47 per group] and a combined C-ASCL-tot group [n = 94]). To examine the regional distribution, additional groups were formed based on previously known raspberry densities of the frontal cortex (high-, medium- and low-density group [n = 6 per group]). Raspberries were quantified on scanned haematoxylin-eosin-stained sections. Results: Cortical raspberry density did not differ at a statistically significant level between the control group, the C-ASCL group and the C-ASCL+ACF group (P = 0.10) but did so between the control group and the C-ASCL-tot group (P = 0.033). The total raspberry density of the high-, medium- and low-density groups differed at a statistically significant level (P = 0.005), which remained in group-to-group comparisons of the high- and medium-density groups (P = 0.015) and the high- and low-density groups (P = 0.002). Raspberries were rare in cerebral white matter and in the cerebellum. Conclusion: An association between raspberry density and C-ASCL is supported but is weaker than previously indicated. An association with ACF is not indicated. The raspberry density of the frontal cortex provides an approximation of the brain's total raspberry density.

Locus Coeruleus Degeneration Differs Between Frontotemporal Lobar Degeneration Subtypes.

BACKGROUND: There are few studies on the locus coeruleus (LC) in frontotemporal lobar degeneration (FTLD) and the potential differences in the LC related to the underlying proteinopathy. OBJECTIVE: The aim of this study was to investigate the LC in FTLD subgroups. METHODS: Neuropathological cases diagnosed with FTLD were included. The subgroups consisted of FTLD with tau, transactive response DNA-binding protein 43 (TDP) and fused in sarcoma (FUS). Micro- and macroscopical degeneration of the LC were assessed with respect to the number of neurons and the degree of depigmentation. A group of cognitively healthy subjects and a group with vascular cognitive impairment (VCI) served as comparison groups. RESULTS: A total of 85 FTLD cases were included, of which 44 had FTLD-TDP, 38 had FTLD-tau, and three had FTLD-FUS. The groups were compared with 25 VCI cases and 41 cognitively healthy control cases (N = 151 for the entire study). All FTLD groups had a statistically higher microscopical degeneration of the LC compared to the controls, but the FTLD-tau group had greater micro- and macroscopical degeneration than the FTLD-TDP group. Age correlated positively with the LC score in the FTLD-tau group, but not in the FTLD-TDP group. CONCLUSION: A greater microscopical degeneration of the LC was observed in all FTLD cases compared to healthy controls and those with VCI. The LC degeneration was more severe in FTLD-tau than in FTLD-TDP. The macroscopically differential degeneration of the LC in FTLD subgroups may facilitate differential diagnostics, potentially with imaging.

Cardiac Alpha-Synuclein Is Present in Alpha-Synucleinopathies.

BACKGROUND: Alpha-synucleinopathies (AS) are characterized by pathologic aggregations of alpha-synuclein (α-syn) in the central nervous system, and comprise dementia with Lewy bodies, Parkinson's disease, and multiple system atrophy. Previous studies on AS have reported findings of α-syn pathology in the peripheral nervous system of multiple organs, including the heart. OBJECTIVE: The aim of this study was to further investigate and confirm the presence of cardiac α-syn in AS compared to other major neurocognitive disorders in a neuropathologically confirmed cohort. METHODS: All deceased patients with performed autopsy and with neuropathologically confirmed AS at the Clinical Department of Pathology in Lund 2010-May 2021 were evaluated for inclusion. Cases with insufficiently sampled cardiac tissue or only limited neuropathological investigation were excluded. An age-matched group of individuals with other neurodegenerative diseases, having no α-syn in the CNS, served as controls. In total, 68 AS and 32 control cases were included in the study. Immunohistochemistry for detection of cardiac α-syn aggregates was performed. RESULTS: The AS group had a significantly higher prevalence of cardiac α-syn pathology (p≤0.001) than the control group, 82% and 0%, respectively. CONCLUSION: This study confirms the association between AS and the presence of cardiac α-syn in a neuropathologically confirmed cohort. This motivates further research on potential pathophysiological effects on cardiac function in AS patients.

Are cortical microvascular raspberries caused by cerebral hypoperfusion? An exploratory pathological study.

Introduction: This retrospective study investigated a cortical microvascular formation, termed a 'raspberry' due to its appearance under a bright-field microscope. We examined whether there is support for the hypothesis that raspberry formation is an angiogenic process induced by cerebral hypoperfusion. Materials and Methods: Raspberries were manually quantified in haematoxylin and eosin-stained cortical sections from the anterior frontal lobe of deceased individuals who had undergone a diagnostic neuropathological examination at the Department of Pathology, Lund, Sweden, during April 2019-January 2021. Subjects represented consecutively received cases during this 22-month period. The raspberry density was compared between subjects according to variables collected from medical records and autopsy reports: age, sex, hypertension, diabetes mellitus, atrial fibrillation, orthostatic hypotension, chronic heart failure, acute circulatory failure, aortic atherosclerosis, atherosclerosis of the basal cerebral arteries (referred to as 'cerebral atherosclerosis'), cerebral small vessel disease, cerebral amyloid angiopathy, cerebral infarction, and ischaemic white matter disease. Results: 62 subjects were included. The mean age was 71.9 years (range 46-97 years). 21 subjects (33.9%) were female. Independent-samples t-test showed a higher raspberry density in subjects with cerebral atherosclerosis (p = 0.029; 95% CI 0.7, 11.6 raspberries/cm²). The higher raspberry density in subjects with cerebral atherosclerosis remained in multiple linear regression (p = 0.003; 95% CI 2.3, 11.1 raspberries/cm²). Conclusion: This exploratory study indicates that cortical raspberries could be associated with cerebral atherosclerosis. The remaining results were inconclusive but motivate further examination of variables such as acute circulatory failure.

Cardiovascular Disease, Diabetes Mellitus, and Hypertension in Lewy Body Disease: A Comparison with Other Dementia Disorders.

BACKGROUND: Research concerning the potential roles of cardiovascular disease (CaVD) and diabetes mellitus (DM) as risk factors for Lewy body disease (LBD) is limited. These disorders are, however, established risk factors for vascular dementia (VaD) and have been proposed as risk factors for Alzheimer's disease (AD). OBJECTIVE: The aim of this study was to investigate the prevalence of CaVD and DM in LBD and compare the results with previous findings in cases with AD, VaD, and mixed AD-VaD (MD). METHODS: Autopsy reports at the Clinical Department of Pathology in Lund from 2001-2018 were analyzed. All cases with a complete neuropathological diagnosis of LBD were selected, not distinguishing between subjects with clinical Parkinson disease dementia and dementia with Lewy bodies, on the condition of a clinical diagnosis of dementia. Clinical data were retrieved through the patients' medical records and the Swedish National Diabetes Register (NDR) and compared with those of the AD, VaD, and MD cases. RESULTS: In LBD, there was less CaVD, significantly less DM (p = 0.002) and likewise significantly less hypertension (p < 0.001) than in VaD. The results of the LBD group were consistent with the results of the AD group. CONCLUSION: Our findings of a low prevalence of CaVD and CaVD risk factors in LBD and in AD argue against the association between these risk factors and their contribution to the development of neurodegenerative diseases.

Hippocampus and basal ganglia as potential sentinel sites for ischemic pathology after resuscitated cardiac arrest.

AIMS OF THE STUDY: Neurological impairment after resuscitated cardiac arrest (CA) remains a significant unmet medical need. Brain ischemia associated with CA and subsequent reperfusion is evident as two fundamentally different types of damage on neuropathological examination: frank necrosis (involving all cell types) and selective eosinophilic neuronal death (SEND). These types of damage are not only dissimilar in micromorphology, but also differently detectable with clinical brain imaging methods. In a previous study, SEND was reported in most patients surviving the initial CA. This study was undertaken to further characterize and map SEND in an expanded dataset. METHODS: A cohort of 46 cases was included from an observational study on targeted temperature management (TTM) of resuscitated CA. Six brain and brain stem regions and 21 subregions were examined, and SEND severity was tested for correlation with time to ROSC. Representativity of all regions vis-à-vis global SEND was assessed, to investigate whether any particular region could be used as a "sentinel site" for overall damage. RESULTS: The thalamus, the CA4 subregion of the hippocampus and the Purkinje cell layer of the cerebellum were the most severely affected subregions. Involvement of the hippocampus, cerebellum, cortex or basal ganglia indicated presence of SEND in other regions. There was a significant correlation between time to ROSC and SEND. CONCLUSION: There are regional differences in SEND distribution. Cases free of SEND in the hippocampus or basal ganglia are unlikely to have significant SEND in other regions, suggesting that these regions could be used as "sentinel sites" for global SEND in future studies.

A systematic review and meta-analysis of the fully formed wisdom tooth as a radiological marker of adulthood.

Assessment of third molar development on dental radiograms is one of the most commonly used methods of forensic age estimation. Despite widespread use and numerous studies, there is a paucity of aggregated data on how well a fully mature third molar identifies adulthood (> 18 years), the most important threshold in a medicolegal context. Therefore, a systematic review and meta-analysis was conducted. A total of 1229 studies were screened, and 82 studies were assessed for inclusion. Twenty-four studies, with a pooled cohort of 19,690 individuals, presented true positive (TP), true negative (TN), false positive (FP), and false negative (FN) outcomes, enabling meta-analysis. The outcomes were based on using the third molar in the fully mature stage as a diagnostic test to indicate age 18 years or above. The false positive rate (fall-out/1-specificity) was 3.1% (95% CI 2.1-4.6%), and the true positive rate (recall/sensitivity) was 51% (95% CI 44-58%). Diagnostic accuracy was 71%. These findings, while reassuring in terms of the low false positive rate, highlight the need for complementary age estimation methods to avoid a significant number of false negatives.

Atherosclerosis, Hypertension, and Diabetes in Alzheimer's Disease, Vascular Dementia, and Mixed Dementia: Prevalence and Presentation.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent cause of dementia with vascular dementia (VaD) being second alongside with mixed AD and VaD, according to some. For some time, it has been proposed that cardiovascular disease (CaVD), hypertension, and diabetes mellitus (DM), which are known risk factors for VaD, also are associated with and contribute to the development of AD. OBJECTIVE: The aim of this study was to investigate the prevalence of these proposed general risk factors, and to document presence of CaVD as evidenced from clinical records or from autopsy findings, further to correlate these with the diagnoses AD, VaD and mixed AD-VaD (MD), respectively. METHODS: Autopsy reports at the Clinical Department of Pathology in Lund from 1992-2017 were analyzed. All cases with a complete autopsy report and a neuropathologically diagnosed dementia disorder (AD, VaD, or MD) were selected on the condition of a clinical diagnosis of dementia. Clinical data were retrieved through medical records and the Swedish National Diabetes Register (NDR). A total of 268 subjects were included. RESULTS: In AD, there was less CaVD as significantly less organ/tissue findings (p < 0.05), significantly less hypertension (p < 0.001), and likewise significantly less DM (p = 0.0014) than in VaD, with the MD group results being set between these two in all aspects studied. CONCLUSION: AD and VaD exhibit such different profiles of organ and vascular damage as well as of hypertension and DM that they clearly point toward different pathogenic origin with low likelihood of shared risk factors.

A methodological study of locus coeruleus degeneration in dementing disorders.

BACKGROUND: Degeneration of the locus coeruleus (LC) of the brain stem is a recognized phenomenon in Alzheimer's disease (AD), in dementia with Lewy bodies (DLB), and in Parkinson's disease with dementia (PDD). Prior studies have suggested that LC degeneration can be used to differentiate various dementing disorders histologically, but the paucity of methodological data may hamper systematic research on this nucleus. PURPOSE: The purpose of this study was to evaluate various approaches to quantifying LC degeneration in dementing disorders, and to inform future decisions regarding the most appropriate method for diagnostics and research. METHODS: 105 LCs from brains of demented individuals with AD, DLB/PDD, vascular dementia (VaD), mixed dementia (AD+VaD), or frontotemporal lobar degeneration (FTLD) were examined, and the extent of LC degeneration was assessed using macroscopic evaluation, cell counting, and two degeneration scales. Scores were compared across diagnostic categories; diagnostic utility and intra- and interobserver reliability were assessed. RESULTS: AD and DLB/PDD were associated with greater LC damage using either assessment method, significantly different from VaD and FTLD. Macroscopic appearance was informative, but cell counting was more sensitive and specific. The degeneration scales did not add significant diagnostic value over cell counting and were associated with greater observer variability. CONCLUSIONS: The LC degenerates in certain dementia subtypes, especially in AD and DLB/PDD. Macroscopic assessment of the LC postmortem can be used to differentiate between disorders associated with degeneration (AD, DLB/PDD) or sparing (VaD) of the LC, but counting LC cells in a representative pontine section is the most appropriate method by which to assess LC degeneration.

Initiation of biphasic insulin aspart 30/70 in subjects with type 2 diabetes mellitus in a largely primary care-based setting in Sweden.

AIMS: Despite a wealth of clinical trial data supporting use of the premixed insulin analogue, biphasic insulin aspart 30 (BIAsp 30) in the treatment of type 2 diabetes mellitus (T2DM), there is limited documentation of its use in primary care-based clinical practice. METHODS: An observational study investigating the safety and efficacy of BIAsp 30 in routine clinical practice was conducted. Patients were followed up 3 and 6 months after initiating insulin treatment. Safety and efficacy measures were documented. RESULTS: During the course of the study, 1154 patients were included (age range 20-95 years), of whom 89% completed the 6-month follow-up period. Mean HbA(1c) at baseline was 8.8% (73mmol/mol), and had improved to 7.2% (55mmol/mol) after 6 months of treatment. The rate of total hypoglycaemia at completion of the study was 4.1 events per patient year. Major hypoglycaemic events were rare (two in total). CONCLUSIONS: BIAsp 30 was initiated safely and effectively in insulin-naïve patients with T2DM. The safety and efficacy profile observed in clinical trials was confirmed in this largely primary care-based setting in Sweden.

Evaluation of the long-term cost-effectiveness of insulin detemir compared with neutral protamine hagedorn insulin in patients with type 1 diabetes using a basal-bolus regimen in Sweden.

AIMS: To evaluate the long-term clinical and economic outcomes associated with insulin detemir and neutral protamine hagedorn (NPH) insulin in combination with mealtime insulin aspart in patients with type 1 diabetes in Sweden, based on data from a two-year, multi-national, open-label, randomized, controlled trial. METHODS: Insulin detemir was associated with significant improvements in glycaemic control after 24 months (HbA1c 7.36% versus 7.58%, mean difference -0.22%, p = 0.022) and major hypoglycaemic events (69% risk reduction, p = 0.001) versus NPH. Patients treated with detemir gained less weight (1.7 versus 2.7 kg, P = 0.024). Based on these findings, a published and validated computer model (IMS CORE Diabetes Model) was used to estimate life-expectancy, quality-adjusted life expectancy and both direct medical costs and indirect costs. RESULTS: Basal-bolus therapy with insulin detemir was projected to improve life expectancy by 0.14 years (15.02 ± 0.19 versus 14.88 ± 0.18 years) and quality-adjusted life expectancy by 0.53 quality-adjusted life years (QALYs) versus NPH (8.35 ± 0.11 versus 7.82 ± 0.10 QALYs). Improvements in QALYs were driven by avoided or delayed diabetes-related complications and fewer hypoglycaemic events. Direct medical costs over patient lifetimes were SEK 26,144 higher in the insulin detemir arm (SEK 995,025 ± 19,580 versus 968,881 ± 19,769), leading to an incremental cost-effectiveness ratio of SEK 49,757 per QALY gained. Capturing indirect costs led to insulin detemir being cost saving over patient lifetimes, by SEK 80,113, compared to NPH (SEK 2,959,909 ± 64,727 versus 3,040,022 ± 62,317). CONCLUSIONS: Compared with NPH, insulin detemir is likely to be cost-effective from a healthcare payer perspective and dominant from a societal perspective in patients with type 1 diabetes in Sweden.

Cerebral amyloid angiopathy and cortical microinfarcts as putative substrates of vascular dementia.

BACKGROUND AND PURPOSE: Vascular dementia (VaD) has occasionally been associated with cerebral amyloid angiopathy (CAA), but the prevalence and significance of this counterintuitive relationship are poorly known. Therefore, we investigated the presence and characteristics of CAA in brains of VaD cases. METHODS: We examined temporal and parietal regions of the cerebral cortex of 26 consecutive VaD cases from the Lund Longitudinal Dementia Study. We carried out immunohistochemistry and routine stainings, determined Apolipoprotein E (ApoE) genotypes, and obtained clinical characteristics on the studied group for retrospective analysis. RESULTS: CAA was marked in eight out of 26 cases, and correlated strongly with the presence of cortical microinfarcts, both in the temporal lobe and in the parietal lobe. Based on comparisons with eight age-matched VaD cases without CAA, the clinical records suggested that VaD cases with CAA as a group exhibited less pronounced neurological symptoms. A clear contribution of the ApoE genotype could not be identified. CONCLUSIONS: Based on a combination of the clinical and pathological data, we suggest that microinfarcts in the cerebral cortex associated with severe CAA may be the primary pathological substrate in a significant proportion of VaD cases. Future studies should be undertaken to confirm or dismiss the hypothesis that these cases exhibit a different symptom profile than VaD cases without CAA.

Differential deposition of amyloid beta peptides in cerebral amyloid angiopathy associated with Alzheimer's disease and vascular dementia.

Cerebral amyloid angiopathy (CAA) caused by deposition of amyloid beta (Abeta) peptides in the cerebrovasculature, involves degeneration of normal vascular components and increases the risk of infarction and cerebral hemorrhage. Accumulating evidence suggests that sporadic CAA is also a significant contributor to cognitive decline and dementia in the elderly. However, the mechanisms by which CAA arises are poorly understood. While neuronal sources of Abeta peptides are sufficient to cause CAA in transgenic mice overexpressing the amyloid precursor protein, there is reason to believe that in aging man, vascular disease modulates the disease process. To better understand CAA mechanisms in dementia, we assessed the frontal cortex of 62 consecutive cases of Alzheimer's disease (AD), vascular dementia (VaD), and mixed dementia (MD) using immunohistochemistry with antibodies to Abeta, smooth muscle actin and the carboxyl-terminal peptides to detect Abeta(40) and Abeta(42). While vascular Abeta deposition was invariably associated with smooth muscle degeneration as indicated by absence of smooth muscle cell actin reactivity, VaD/MD cases exhibited markedly more vascular Abeta(42) deposits and smooth muscle actin loss compared to AD cases with similar degrees of CAA and Abeta(40) deposition. This suggests that distinct mechanisms are responsible for the differential deposition of Abeta in CAA associated with AD and that associated with ischemic/cerebrovascular disease. It is plausible that experimental studies on the effects of cerebrovascular disease on Abeta production and elimination will yield important clues on the pathogenesis of CAA.

Locus ceruleus degeneration is ubiquitous in Alzheimer's disease: possible implications for diagnosis and treatment.

Degeneration of the locus ceruleus (LC) and decreased cortical levels of norepinephrine are common findings in Alzheimer's disease (AD), but their significance is unknown. Because the noradrenergic system is accessible to pharmacological intervention, the role of LC degeneration and noradrenergic dysfunction in the pathogenesis and clinical manifestations of AD needs clarification. Hypothetically, loss of noradrenergic innervation could cause microvascular dysfunction and manifest as ischemia. The objectives of this study were to develop a scale for assessment of LC degeneration and to determine whether degeneration of the LC correlates quantitatively with either duration of clinical dementia, overall severity of AD pathology or with measures of ischemic non-focal white matter disease (WMD) in AD. This report is a pathological follow-up of a clinical longitudinal dementia study of 66 consecutive cases of AD without admixture of vascular dementia (VaD) from the Lund Longitudinal Dementia Study, neuropathologically diagnosed between 1990 and 1999. Ten cases of VaD were included for comparative purposes. No correlation between degree of LC degeneration and duration of dementia, AD or WMD severity was found. LC degeneration was significantly more severe in the AD group than in the VaD group. Even though LC degeneration was not associated with WMD or the severity of AD pathology in this AD material, we suggest that clinical studies on the consequences of noradrenergic dysfunction are warranted. Treatment augmenting noradrenergic signaling is available and safe. The marked difference in the level of LC degeneration between AD and VaD cases suggests that LC degeneration could be used as a diagnostic marker of AD.