ABSTRACT
BACKGROUND: Hearing loss in older adults is associated with increased dementia risk. Underlying mechanisms that connect hearing loss with dementia remain largely unclear. METHODS: We studied the association of hearing loss and biomarkers for dementia risk in two age groups with normal cognition: 65 participants from the European Medical Information Framework (EMIF)-Alzheimer's disease (AD) 90+ study (oldest-old; mean age 92.7 years, 56.9% female) and 60 participants from the EMIF-AD PreclinAD study (younger-old; mean age 74.4, 43.3% female). Hearing function was tested by the 'digits-in-noise test' and cognition by repeated neuropsychological evaluation. Regressions and generalised estimating equations were used to test the association of hearing function and PET-derived amyloid burden, and linear mixed models were used to test the association of hearing function and cognitive decline. In the oldest-old group, mediation analyses were performed to study whether cognitive decline is mediated through regional brain atrophy. RESULTS: In oldest-old individuals, hearing function was not associated with amyloid pathology (p=0.7), whereas in the younger-old individuals hearing loss was associated with higher amyloid burden (p=0.0034). In oldest-old individuals, poorer hearing was associated with a steeper decline in memory, global cognition and language, and in the younger-old with steeper decline in language only. The hippocampus and nucleus accumbens mediated the effects of hearing loss on memory and global cognition in the oldest-old individuals. CONCLUSIONS: Hearing loss was associated with amyloid binding in younger-old individuals only, and with cognitive decline in both age groups. These results suggest that mechanisms linking hearing loss with risk for dementia depends on age.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Hearing Loss , Humans , Female , Aged , Aged, 80 and over , Male , Alzheimer Disease/pathology , Cognitive Dysfunction/pathology , Cognition , Neuropsychological Tests , Hearing Loss/complications , Hearing Loss/epidemiology , Amyloid beta-Peptides/metabolismABSTRACT
Alzheimer's disease is characterized by regional reductions in cerebral blood flow (CBF). Although the gold standard for measuring CBF is [15O]H2O PET, proxies of relative CBF, derived from the early distribution phase of amyloid and tau tracers, have gained attention. The present study assessed precision of [15O]H2O derived relative and absolute CBF, and compared precision of these measures with that of (relative) CBF proxies. Dynamic [15O]H2O, [18F]florbetapir and [18F]flortaucipir PET test-retest (TrT) datasets with eleven, nine and fourteen subjects, respectively, were included. Analyses were performed using an arterial input model and/or a simplified reference tissue model, depending on the data available. Relative CBF values (i.e. K1/K1' and/or R1) were obtained using cerebellar cortex as reference tissue and TrT repeatability (i.e. precision) was calculated and compared between tracers, parameters and clinical groups. Relative CBF had significantly better TrT repeatability than absolute CBF derived from [15O]H2O (r = -0.53), while best TrT repeatability was observed for [18F]florbetapir and [18F]flortaucipir R1 (r = -0.23, r = -0.33). Furthermore, only R1 showed, better TrT repeatability for cognitively normal individuals. High precision of CBF proxies could be due to a compensatory effect of the extraction fraction, although changes in extraction fraction could also bias these proxies, but not the gold standard.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/metabolism , Positron-Emission Tomography , Aniline Compounds , Cerebrovascular Circulation/physiology , Brain/metabolismABSTRACT
INTRODUCTION: Synapse dysfunction is emerging as an early pathological event in frontotemporal dementia (FTD), however biomarkers are lacking. We aimed to investigate the value of cerebrospinal fluid (CSF) neuronal pentraxins (NPTXs), a family of proteins involved in homeostatic synapse plasticity, as novel biomarkers in genetic FTD. METHODS: We included 106 presymptomatic and 54 symptomatic carriers of a pathogenic mutation in GRN, C9orf72 or MAPT, and 70 healthy non-carriers participating in the Genetic Frontotemporal dementia Initiative (GENFI), all of whom had at least one CSF sample. We measured CSF concentrations of NPTX2 using an in-house ELISA, and NPTX1 and NPTX receptor (NPTXR) by Western blot. We correlated NPTX2 with corresponding clinical and neuroimaging datasets as well as with CSF neurofilament light chain (NfL) using linear regression analyses. RESULTS: Symptomatic mutation carriers had lower NPTX2 concentrations (median 643 pg/mL, IQR (301-872)) than presymptomatic carriers (1003 pg/mL (624-1358), p<0.001) and non-carriers (990 pg/mL (597-1373), p<0.001) (corrected for age). Similar results were found for NPTX1 and NPTXR. Among mutation carriers, NPTX2 concentration correlated with several clinical disease severity measures, NfL and grey matter volume of the frontal, temporal and parietal lobes, insula and whole brain. NPTX2 predicted subsequent decline in phonemic verbal fluency and Clinical Dementia Rating scale plus FTD modules. In longitudinal CSF samples, available in 13 subjects, NPTX2 decreased around symptom onset and in the symptomatic stage. DISCUSSION: We conclude that NPTX2 is a promising synapse-derived disease progression biomarker in genetic FTD.
Subject(s)
C-Reactive Protein/cerebrospinal fluid , Frontotemporal Dementia/diagnosis , Nerve Tissue Proteins/cerebrospinal fluid , Adult , Aged , Biomarkers/cerebrospinal fluid , Disease Progression , Female , Frontotemporal Dementia/cerebrospinal fluid , Frontotemporal Dementia/genetics , Heterozygote , Humans , Male , Middle Aged , Neurofilament Proteins/cerebrospinal fluidABSTRACT
Behavioural variant frontotemporal dementia (bvFTD) is characterized by behavioural and social cognitive disturbances, while various psychiatric and neurodegenerative disorders may have similar clinical symptoms. Since neurodegenerative disorders are eventually progressive, whereas primary psychiatric disorders are not, this study aimed to investigate whether the change in clinical symptoms over time differed between groups and which biomarkers predicted rate of decline. Disease trajectories (median follow-upâ¯=â¯3 years) of frontal and stereotyped behaviour, general and frontal cognitive functioning, and social cognition were examined in bvFTD (nâ¯=â¯34), other neurodegenerative (nâ¯=â¯28) and primary psychiatric disorders (nâ¯=â¯43), all presenting with late-onset frontal lobe syndrome (45-75 years), using linear mixed models. To gain more insight in underlying pathological processes driving disease progression, we studied the association of baseline cerebrospinal fluid (CSF) (neurofilament light (NfL) and YKL-40 levels, phosphotau181 to total tau ratio) and neuroimaging markers with disease trajectories. Frontal behavioural symptoms (e.g., disinhibition, apathy) worsened over time in bvFTD, whereas they improved in psychiatric disorders and remained stable in other neurodegenerative disorders. General and frontal cognitive decline was observed in bvFTD and other neurodegenerative disorders, but not in psychiatric disorders. None of the groups showed change in stereotypy and social cognition. For all diagnostic groups, higher CSF NfL levels were associated with faster frontal cognitive decline. A modest association was observed between caudate volume and stereotyped behaviour. Tracking frontal behavioural symptoms and cognition has potential to distinguish bvFTD from other disorders. CSF NfL levels seem to be associated with decline in frontal cognitive functioning.
Subject(s)
Apathy/physiology , Cognition Disorders/etiology , Frontotemporal Dementia/complications , Mental Disorders/complications , Neurodegenerative Diseases/complications , Stereotyped Behavior/physiology , Aged , Cognition Disorders/cerebrospinal fluid , Cognition Disorders/diagnostic imaging , Disease Progression , Female , Frontotemporal Dementia/cerebrospinal fluid , Frontotemporal Dementia/diagnostic imaging , Humans , Image Processing, Computer-Assisted , Longitudinal Studies , Magnetic Resonance Imaging , Male , Mental Disorders/cerebrospinal fluid , Mental Disorders/diagnostic imaging , Middle Aged , Neurodegenerative Diseases/cerebrospinal fluid , Neurodegenerative Diseases/diagnostic imaging , Neuropsychological Tests , Psychiatric Status Rating ScalesABSTRACT
BACKGROUND: Dementia is generally characterized by cognitive impairment that can be accompanied by psychotic symptoms; for example, visual hallucinations are a core feature of dementia with Lewy bodies, and delusions are often seen in Alzheimer's disease. However, for behavioral variant of frontotemporal dementia (bvFTD), studies on the broad spectrum of psychotic symptoms are still lacking. The aim of this study was to systematically and prospectively subtype the wide spectrum of psychotic symptoms in probable and definite bvFTD. METHODS: In this study, a commonly used and validated clinical scale that quantifies the broad spectrum of psychotic symptoms (Positive and Negative Symptom Scale) was used in patients with probable and definite bvFTD (n=22) and with a primary psychiatric disorder (n=35) in a late-onset frontal lobe cohort. Median symptom duration was 2.8 years, and the patients were prospectively followed for 2 years. RESULTS: In total, 22.7% of bvFTD patients suffered from delusions, hallucinatory behavior, and suspiciousness, although the majority of the patients exhibited negative psychotic symptoms such as social and emotional withdrawal and blunted affect (95.5%) and formal thought disorders (81.8%). "Difficulty in abstract thinking" and "stereotypical thinking" (formal thought disorders) differentiated bvFTD from psychiatric disorders. The combined predictors difficulty in abstract thinking, stereotypical thinking, "anxiety", "guilt feelings," and "tension" explained 75.4% of variance in the diagnosis of bvFTD versus psychiatric diagnoses (P<0.001). CONCLUSION: Delusions, hallucinatory behavior, and suspiciousness were present in one-fifth of bvFTD patients, whereas negative psychotic symptoms such as social and emotional withdrawal, blunted affect, and formal thought disorders were more frequently present. This suggests that negative psychotic symptoms and formal thought disorders have an important role in the psychiatric misdiagnosis in bvFTD; misdiagnosis in bvFTD might be reduced by systematically exploring the broad spectrum of psychiatric symptoms.
ABSTRACT
OBJECTIVES: Although bipolar disorder has been understood classically as a cyclic disease with full recovery between mood episodes, in the last decade, evidence has accumulated supporting progressive features. The clinical picture of advanced or end-stage bipolar disorder is heterogeneous with possible deficits in cognition and behavior, as illustrated by our case series. CASES: From our neuropsychiatric outpatient clinic, we describe four cases with bipolar disorder gradually developing a clinical syndrome, including apathy, disinhibition, loss of empathy, stereotypical behavior, and compulsiveness, fulfilling the criteria for possible behavioral variant frontotemporal dementia. All cases were diagnosed with bipolar 1 disorder at least 10 years before the onset of the current symptoms, which were not due to recent mood episodes or switches of medication. In all cases, 3-7 years of follow-up yielded no progression. Repeated neuroimaging was within normal limits. Cerebrospinal fluid biomarker studies were not supportive of underlying neurodegenerative pathology. C9orf72 mutation status was negative in all cases. CONCLUSION: Symptoms fitting the criteria for possible behavioral variant frontotemporal dementia may be present in end-stage of bipolar disorder. An alternative neurodegenerative nature seems unlikely based on repeated normal neuroimaging and the absence of clinical progression. Functional involvement of the frontal-subcortical networks might play a role.
ABSTRACT
Some patients with early-onset Alzheimer's disease (AD) present with a distinct phenotype. Typically, the first and most salient characteristic of AD is episodic memory impairment. A few patients, however, present with focal cortical, non-memory symptoms, such as difficulties with language, visuospatial, or executive functions. These presentations are associated with specific patterns of atrophy and frequently with a young age at onset. Age is not, however, the only determinant of phenotype; underlying factors, especially genetic factors, seem also to affect phenotype and predispose patients to younger or older age at onset. Importantly, patients with atypical early-onset disease seldom carry the APOE É4 allele, which is the most important risk factor for lowering the age of onset in patients with AD. Additionally, theAPOE É4 genotype seems to predispose patients to vulnerability in the medial temporal areas, which leads to memory loss. Conversely, patients negative for the APOE É4 allele and with early-onset AD are more likely to be predisposed to vulnerability of cerebral networks beyond the medial temporal lobes. Other factors are probably involved in determining the pattern of atrophy, but these are currently unknown.