Hearing loss in older adults is suspected to play a role in social isolation, depression, disability, lower quality of life, and risk of dementia. Such suspected associations still need to be ...consolidated with additional research. With a particularly long follow-up, this study assessed the relationship between hearing status and four major adverse health events: death, dementia, depression, and disability.
Prospective community-based study of 3,777 participants aged ≥65 followed up for 25 years. At baseline, 1,289 reported hearing problems and 2,290 reported no trouble. The risk of occurrence of the negative outcomes, including death, dementia, depressive symptoms, disability in activities of daily living (ADL), and instrumental ADL (IADL), was assessed with Cox proportional hazards models.
Adjusting for numerous confounders, an increased risk of disability and dementia was found for participants reporting hearing problems. An increased risk of depression was found in men reporting hearing problems. In additional exploratory analyses, such associations were not found in those participants using hearing aids. Mortality was not associated with self-reported hearing loss.
Our study confirms the strong link between hearing status and the risk of disability, dementia, and depression. These results highlight the importance of assessing the consequences of treating hearing loss in elders in further studies.
Hyperorality is a distinctive feature of the behavioral variant of frontotemporal dementia (bvFTD), but little is known about its significance in early-stage disease. This study examined the ...cognitive and psychiatric symptom profiles associated with hyperorality, using data from subjects with early-stage bvFTD enrolled in Alzheimer's Disease Research Centers. We found that hyperorality was not associated with cognitive performance, but was associated with psychosis, elation, and disinhibition. Hyperorality may share neurobiology with a subset of early psychiatric symptoms, a finding which could help identify targets for future treatment.
Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders
. The ...pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins
. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes
. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.
Background: To evaluate the value of total tau (tau) and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) in the differential diagnosis of dementia, more specifically: dementia with Lewy ...Bodies (DLB), frontotemporal lobar degeneration (FTLD), vascular dementia (VaD), and Creutzfeldt-Jacob disease (CJD). Methods: A systematic literature search was performed to identify studies on tau and p-tau in DLB, FTLD, VaD and CJD. Tau concentrations were compared to healthy controls and to subjects with Alzheimer's disease (AD) using random effect meta-analysis. Outcome measures were Cohen's delta, sensitivity and specificity. Results: Compared to controls, tau concentrations are moderately elevated in DLB, FTLD and VaD, while p-tau concentrations are only slightly elevated in DLB and not elevated in FTLD and VaD. Compared to AD, lower tau concentrations differentiated DLB with a sensitivity of 73% and a specificity of 90%, FTLD with sensitivity and specificity of 74%, and VaD with a sensitivity of 73% and a specificity of 86%. Relative to AD, lower p-tau values differentiated FTLD with a sensitivity of 79% and specificity of 83%, and VaD with a sensitivity of 88% and a specificity of 78%. CJD is characterized by extremely elevated tau concentrations with a sensitivity of 91% and a specificity of 98% vs. AD. Conclusions: CSF tau concentrations in DLB, FTLD and VaD are intermediate between controls and AD patients. Overlap with both controls and AD patients results in insufficient diagnostic accuracy, and the development of more specific biomarkers for these disorders is needed. CJD is characterized by extremely increased tau values, resulting in a sensitivity and specificity that exceeds 90%.
White matter hyperintensities (WMH) are often seen on MRI brain scans in frontotemporal dementia (FTD) due to progranulin (GRN) mutations, but their pathological correlates are unknown. We examined ...the histological changes underlying WMH in a patient with GRN mutation associated behavioral variant FTD. In vivo and cadaveric MRI showed progressive, asymmetric frontotemporal and parietal atrophy, and asymmetrical WMH predominantly affecting frontal mid-zones. We first performed segmentation and localization analyses of WMH present on cadaveric MRI FLAIR images, then selected five different brain regions directly matched to differing severities of WMH for histological analysis. We used immunohistochemistry to assess vascular pathology, degree of spongiosis, neuronal and axonal loss, TDP-43, demyelination and astrogliosis, and microglial burden and morphology. Brain regions with significant WMH displayed severe cortical and white matter pathology, and prominent white matter microglial activation and microglial dystrophy, but only mild axonal loss and minimal vascular pathology. Our study suggests that WMH in GRN mutation carriers are not secondary to vascular pathology. Whilst cortical pathology induced axonal degeneration could contribute to white matter damage, individuals with GRN mutations could develop selective white matter vulnerability and myelin loss due to chronic, regional microglial dysfunction arising from GRN haploinsufficiency.
Frontotemporal dementia (FTD) is a neurodegenerative brain disorder primarily affecting the frontal and/or temporal lobes. Three main subtypes have been recognized: behavioural-variant FTD (bvFTD), ...semantic dementia (SD), and progressive nonfluent aphasia (PNFA), each of which has a distinct clinical and cognitive profile. Although the role of the cerebellum in cognition is increasingly accepted, knowledge of cerebellar changes across neuroimaging modalities and their contribution to behavioural and cognitive changes in FTD syndromes is currently scant. We conducted an anatomical/activation likelihood estimation (ALE) meta-analysis in 53 neuroimaging studies (structural MRI: 42; positron emission tomography: 6; functional MRI: 4; single-photon emission computed tomography: 1) to identify the patterns of cerebellar changes and their relations to profiles of behavioural and cognitive deficits in FTD syndromes. Overall, widespread bilateral cerebellar changes were found in FTD and notably the patterns were subtype specific. In bvFTD, ALE peaks were identified in the bilateral Crus, left lobule VI, right lobules VIIb and VIIIb. In SD, focal cerebellar changes were located in the left Crus I and lobule VI. A separate ALE meta-analysis on PNFA studies was not performed due to the limited number of studies available. In addition, the ALE analysis indicated that bilateral Crus I and Crus II were associated with behavioural disruption and cognitive dysfunction. This ALE meta-analysis provides the quantification of the location and extent of cerebellar changes across the main FTD syndromes, which in turn provides evidence of cerebellar contributions to behavioural and cognitive changes in FTD. These results bring new insights into the mechanisms mediating FTD symptomatology.
Background and purpose
Data on epilepsy in dementia, particularly on its risk factors, are scarce. Confounding comorbidities and the rising incidence of epilepsy in older age have hampered studies in ...this field. The occurrence and risk factors for epilepsy in the Swedish Dementia Registry (SveDem), a large cohort of patients with dementia, have been examined.
Methods
Information on epilepsy and seizure‐related diagnoses, comorbidities and survival were extracted for all individuals in SveDem (n = 81 192) and three randomly selected age‐ and gender‐matched controls from the population register, excluding all with a dementia diagnosis (n = 223 933). The risk of epilepsy following dementia diagnosis was estimated with Kaplan–Meier curves, and Cox proportional hazard modelling was used to identify risk factors and adjust for comorbidities.
Results
A diagnosis of epilepsy was found more frequently amongst dementia patients 4.0%, 95% confidence interval (CI) 3.8–4.1 than controls (1.9%, 95% CI 1.9–2.0). The risk of incident epilepsy after dementia was 2.1% (95% CI 1.9–2.3) at 5 years and 4.0% (95%CI 3.4–4.6) at 10 years, compared to 0.8% (95% CI 0.8–0.8) and 1.6% (95% CI 1.4–1.8) respectively for controls. The risk was greatest for early‐onset Alzheimer's disease. In multivariate analysis, dementia was associated with a hazard ratio of 2.52 (95% CI 2.31–2.74) for epilepsy. Young age, male sex, stroke, brain trauma, brain tumour and low Mini‐Mental State Examination score significantly increased the risk.
Conclusions
Dementia, particularly young‐onset Alzheimer's disease, increases the risk of subsequent epilepsy. Further studies are needed to determine optimal management and the impact of epilepsy on prognosis.
IMPORTANCE: Trends in type 2 diabetes show an increase in prevalence along with younger age of onset. While vascular complications of early-onset type 2 diabetes are known, the associations with ...dementia remains unclear. OBJECTIVE: To determine whether younger age at diabetes onset is more strongly associated with incidence of dementia. DESIGN, SETTING, AND PARTICIPANTS: Population-based study in the UK, the Whitehall II prospective cohort study, established in 1985-1988, with clinical examinations in 1991-1993, 1997-1999, 2002-2004, 2007-2009, 2012-2013, and 2015-2016, and linkage to electronic health records until March 2019. The date of final follow-up was March 31, 2019. EXPOSURES: Type 2 diabetes, defined as a fasting blood glucose level greater than or equal to 126 mg/dL at clinical examination, physician-diagnosed type 2 diabetes, use of diabetes medication, or hospital record of diabetes between 1985 and 2019. MAIN OUTCOMES AND MEASURES: Incident dementia ascertained through linkage to electronic health records. RESULTS: Among 10 095 participants (67.3% men; aged 35-55 years in 1985-1988), a total of 1710 cases of diabetes and 639 cases of dementia were recorded over a median follow-up of 31.7 years. Dementia rates per 1000 person-years were 8.9 in participants without diabetes at age 70 years, and rates were 10.0 per 1000 person-years for participants with diabetes onset up to 5 years earlier, 13.0 for 6 to 10 years earlier, and 18.3 for more than 10 years earlier. In multivariable-adjusted analyses, compared with participants without diabetes at age 70, the hazard ratio (HR) of dementia in participants with diabetes onset more than 10 years earlier was 2.12 (95% CI, 1.50-3.00), 1.49 (95% CI, 0.95-2.32) for diabetes onset 6 to 10 years earlier, and 1.11 (95% CI, 0.70-1.76) for diabetes onset 5 years earlier or less; linear trend test (P < .001) indicated a graded association between age at onset of type 2 diabetes and dementia. At age 70, every 5-year younger age at onset of type 2 diabetes was significantly associated with an HR of dementia of 1.24 (95% CI, 1.06-1.46) in analyses adjusted for sociodemographic factors, health behaviors, and health-related measures. CONCLUSIONS AND RELEVANCE: In this longitudinal cohort study with a median follow-up of 31.7 years, younger age at onset of diabetes was significantly associated with higher risk of subsequent dementia.
Vascular insults can initiate a cascade of molecular events leading to neurodegeneration, cognitive impairment, and dementia. Here, we review the cellular and molecular mechanisms in cerebral blood ...vessels and the pathophysiological events leading to cerebral blood flow dysregulation and disruption of the neurovascular unit and the blood–brain barrier, which all may contribute to the onset and progression of dementia and Alzheimer's disease (AD). Particularly, we examine the link between neurovascular dysfunction and neurodegeneration including the effects of AD genetic risk factors on cerebrovascular functions and clearance of Alzheimer's amyloid-β peptide toxin, and the impact of vascular risk factors, environment, and lifestyle on cerebral blood vessels, which in turn may affect synaptic, neuronal, and cognitive functions. Finally, we examine potential experimental treatments for dementia and AD based on the neurovascular model, and discuss some critical questions to be addressed by future studies. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock
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•Cerebrovascular damage may initiate molecular events leading to neurodegeneration.•Major genetic risk factors for AD are linked to brain vascular dysfunction.•Vascular risk factors increase incidence of sporadic AD.•Midlife lifestyle changes may protect the neurovasculature and prevent AD.•Vasculoprotective therapies may delay the onset and progression of AD.
It is essential to determine the specificity of AV-1451 PET for tau in brain imaging by using pathological comparisons. We performed autoradiography in autopsy-confirmed Alzheimer disease and other ...neurodegenerative disorders to evaluate the specificity of AV-1451 binding for tau aggregates.
Tissue samples were selected that had a variety of dementia-related neuropathologies including Alzheimer disease, primary age-related tauopathy, tangle predominant dementia, non-Alzheimer disease tauopathies, frontotemporal dementia, parkinsonism, Lewy body disease and multiple system atrophy (n = 38). Brain tissue sections were stained for tau, TAR DNA-binding protein-43, and α-synuclein and compared to AV-1451 autoradiography on adjacent sections.
AV-1451 preferentially localized to neurofibrillary tangles, with less binding to areas enriched in neuritic pathology and less mature tau. The strength of AV-1451 binding with respect to tau isoforms in various neurodegenerative disorders was: 3R + 4R tau (e.g., AD) > 3R tau (e.g., Pick disease) or 4R tau. Only minimal binding of AV-1451 to TAR DNA-binding protein-43 positive regions was detected. No binding of AV-1451 to α-synuclein was detected. "Off-target" binding was seen in vessels, iron-associated regions, substantia nigra, calcifications in the choroid plexus, and leptomeningeal melanin.
Reduced AV-1451 binding in neuritic pathology compared to neurofibrillary tangles suggests that the maturity of tau pathology may affect AV-1451 binding and suggests complexity in AV-1451 binding. Poor association of AV-1451 with tauopathies that have preferential accumulation of either 4R tau or 3R tau suggests limited clinical utility in detecting these pathologies. In contrast, for disorders associated with 3R + 4R tau, such as Alzheimer disease, AV-1451 binds tau avidly but does not completely reflect the early stage tau progression suggested by Braak neurofibrillary tangle staging. AV-1451 binding to TAR DNA-binding protein-43 or TAR DNA-binding protein-43 positive regions can be weakly positive. Clinical use of AV-1451 will require a familiarity with distinct types of "off-target" binding.
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