D is a chronic, nonlinearly progressive, multifactorial neurodegenerative disease that affects mu... more D is a chronic, nonlinearly progressive, multifactorial neurodegenerative disease that affects multiple domains of an affected individual's life during advanced stage of progression, such as cognition, behavior, functional abilities and social interactions. AD is the most common cause of dementia, accounting for around 60-80% of cases 1. In 2019, over 50 million people were living with dementia worldwide, and the number is expected to rise to 152 million by 2050, largely driven by the projected increases in low-income and middle-income countries 2. With population growth and aging, AD is becoming one of the most burdensome and costly diseases facing global society today 3. Historically, the diagnosis and treatment of AD focused on clinical symptoms. In the past three decades, in vivo biomarker studies identified core pathophysiological alterations-including amyloid and tau-that characterize and underly AD across its decades-long preclinical and prodromal phases. Such evidence has transformed the disease concept from clinically defined to biologically defined (Box 1) 4,5. This transformation opened the gate to biomarkerguided, molecular pathway-based targeted therapies 6,7. To date, a new wave of pharmacological compounds targeting AD pathophysiological hallmarks have reached late-stage clinical development with one agent recently approved by the US Food and Drug Administration (FDA) for clinical use in treating AD 8-12 .
The reconceptualization of Alzheimer's disease (AD) as a clinical and biological construct has fa... more The reconceptualization of Alzheimer's disease (AD) as a clinical and biological construct has facilitated the development of biomarker-guided, pathway-based targeted therapies, many of which have reached late-stage development with the near-term potential to enter global clinical practice. These medical advances mark an unprecedented paradigm shift and requires an optimized global framework for clinical care pathways for AD. In this Perspective, we describe the blueprint for transitioning from the current, clinical symptom-focused and inherently late-stage diagnosis and management of AD to the next-generation pathway that incorporates biomarker-guided and digitally facilitated decision-making algorithms for risk stratification, early detection, timely diagnosis, and preventative or therapeutic interventions. We address critical and high-priority challenges, propose evidence-based strategic solutions, and emphasize that the perspectives of affected individuals and care partners need to be considered and integrated. NATuRe AGING | www.nature.com/nataging PersPective NATure AgINg Box 1 | The conceptual transformation of Alzheimer's disease from a clinical-pathological and primarily symptom-based entity to a clinical-biological construct • In 1984, diagnostic criteria for AD were first defined by the US NINCDS-ADRDA 137 . • Definitive AD: diagnosis requires autopsy. • Probable AD: Clinical entity; discordance between clinical diagnosis and AD-type neuropathology at postmortem showed approximately 30% mismatch . • Atypical phenotypes show different patterns of progression . • In 2007, the IWG defined AD as a clinical-biological entity. • AD defined by specific clinical phenotypes and in vivo fluid and neuroimaging biomarkers. • Definition broadened and included the pre-dementia stages 141 . • By 2016, the IWG expanded the natural history for AD recommending classifications of the preclinical/presymptomatic stages and atypical presentations . • In 2010, the NIA-AA working groups formulated three research diagnostic criteria based on cognitive changes and pathophysiological evidence using biomarkers. These included the dementia phase of AD, the symptomatic pre-dementia phase (MCI) of AD, and the asymptomatic, preclinical phase of AD . • In 2016, the AT(N) research framework was developed (Table 1) 147 . • ' A' = Aβ biomarker (amyloid PET or CSF Aβ 42 or Aβ 42/40 ratio) • 'T' = tau pathology biomarker (CSF p-tau or tau PET) • 'N' = neurodegeneration or neuronal injury (CSF total tau, 18 F-FDG-PET, or structural MRI) • ATX(N): 'X' = additional novel pathophysiological markers 9 . 2010 IWG Research Clinical and research evolution of the diagnostic criteria for Alzheimer's disease. This timeline highlights key milestones in the development and updates to the diagnostic criteria for AD, the biological and clinical requirements that accompany their use, and their applicability in research and clinical settings. ADRDA,
We report the case of a 68-year-old depressive patient who developed severe thrombocytopenia duri... more We report the case of a 68-year-old depressive patient who developed severe thrombocytopenia during hospitalization. EDTA-associated thrombocytopenia and psychodrug-induced thrombocytopenia are illustrated as potential causes of low platelet counts, particularly in regard to psychiatric patients. thromhocytopenia / psychodrug-induced thrombocytopenia / EDTA-associated pseudothrombocytopenia
Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer... more Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer's disease (AD). We asked to what extent the core biomarker candidates cerebro-spinal fluid (CSF) bamyloid 1-42 (Ab 1-42) and CSF tau protein concentrations predict conversion from MCI to AD. We studied 52 patients with MCI, 93 AD patients, and 10 healthy controls (HC). The MCI group was composed of 29 patients who had converted to AD during follow-up, and of 23 patients who showed no cognitive decline. CSF Ab 1-42 and tau protein levels were assessed at baseline in all subjects, using enzyme-linked immunosorbent assays. For assessment of sensitivity and specificity, we used independently established reference values for CSF Ab 1-42 and CSF tau. The levels of CSF tau were increased, whereas levels of Ab 1-42 were decreased in MCI subjects. Ab 1-42 predicted AD in converted MCI with a sensitivity of 59% and a specificity of 100% compared to HC. Tau yielded a greater sensitivity of 83% and a specificity of 90%. In a multiple Cox regression analysis within the MCI group, low baseline levels of Ab 1-42 , but not other predictor variables (tau protein, gender, age, apolipoprotein E e4 carrier status, Mini Mental Status Examination score, observation time, antidementia therapy), correlated with conversion status (Po0.05). Our findings support the notion that CSF tau and Ab 1-42 may be useful biomarkers in the early identification of AD in MCI subjects.
Procalcitonin is elevated in the cerebrospinal fluid of patients with dementia and acute neuroinflammation
Journal of Neuroimmunology, 2007
Procalcitonin (PCT) is an established marker for severe systemic bacterial infection and sepsis i... more Procalcitonin (PCT) is an established marker for severe systemic bacterial infection and sepsis in blood. Here we measured PCT by immunoassay in CSF and matched serum/plasma samples of controls and patients with different primary dementia disorders and acute neuroinflammation. PCT in CSF was significantly increased in patients with probable Alzheimer's disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and acute neuroinflammation (encephalitis, meningitis) compared to non-demented controls. In contrast, PCT levels in matched plasma samples were normal in dementia groups, but elevated in meningitis/encephalitis. Our results indicate a central production of PCT and suggest PCT as a valuable marker candidate for the monitoring of dementia and acute neuroinflammation.
European Archives of Psychiatry and Clinical Neuroscience, 2012
Increased degradation of tryptophan (TRP) through the kynurenine (KYN) pathway (KP) is known to b... more Increased degradation of tryptophan (TRP) through the kynurenine (KYN) pathway (KP) is known to be involved in the molecular mechanisms resulting in the neuropathogenesis of Alzheimer's disease (AD). Activation of the KP leads to the production of neurotoxic metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) by immune cells and neuroprotective derivates kynurenic acid (KYNA) and picolinic acid (PIC) by astrocytes and neurons. We therefore investigated whether an imbalance between neurotoxic and neuroprotective kynurenine metabolites could be detected in patients with AD. We measured serum levels of TRP, KYNA, 3-HK, PIC and QUIN in 20 patients with AD and for comparison in 20 patients with major depression, and 19 subjectively cognitive impaired subjects. Serum levels of 3-HK were markedly increased in AD patients compared to the comparison groups (p \ .0001). Serum levels of the other KP metabolites were not significantly different between groups. Our data indicate an increased production of the neurotoxic KP metabolite 3-HK in AD. In contrast to its downstream metabolites QUIN and PIC, 3-HK can cross the blood-brain barrier via an active transport process. Our data therefore indicate an enhanced availability of 3-HK in the brain of AD patients, which may be related to the previously reported higher production of QUIN in AD brains.
Recent advances in understanding the molecular mechanisms underlying various paths toward the pat... more Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that ''treatments'' need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light
Background: Severe neurofibrillary degeneration and loss of basal forebrain (BF) cholinergic neur... more Background: Severe neurofibrillary degeneration and loss of basal forebrain (BF) cholinergic neurons is a major pathological hallmark of Alzheimer's disease (AD). Post mortem autopsy studies suggest a regional specificity of neuronal degeneration within the subnuclei of the
While we may not be able to find a cure for Alzheimer's disease (AD) in the near future, seve... more While we may not be able to find a cure for Alzheimer's disease (AD) in the near future, several drugs presently in trials have shown promise as possible modifiers of disease progression. However, we may not be able to demonstrate efficacy due to issues of recruitment, retention, site-to-site variability, and other methodological issues. It is thus incumbent on the scientific community to find solutions to these problems, particularly as the field moves toward preventing illness or treating the disease in its prodromal stages, where these methodological issues will become even more critical. We need to better understand why participants agree or refuse to enter drug trials, and why both primary care physicians and Alzheimer's specialists agree or refuse to involve their patients. We also need to quantify the impact of requiring imaging studies, extensive questionnaires, cognitive testing, and lumbar punctures on recruitment and retention. With these concerns in mind, an inte...
In the earliest clinical stages of Alzheimer's Disease (AD), when symptoms are mild, clinical... more In the earliest clinical stages of Alzheimer's Disease (AD), when symptoms are mild, clinical diagnosis will still be difficult. AD related molecular mechanisms precede symptoms. Biological markers can serve as early diagnostic indicators, as markers of preclinical pathological change, e.g. underlying mechanisms of action (MoA). Hypothesis based candidates are derived from structural and functional neuroimaging as well as from cerebrospinal fluid (CSF) and plasma. Unbiased exploratory approaches e.g. proteome analysis or rater independent fully automated imaging post-processing methods yield novel candidates. Recent progress in the validation of core feasible imaging and neurochemical biomarkers for functions such as early detection, classification, progression and prediction of AD is summarized. Single core feasible biomarkers can already be used to enrich populations at risk for AD and may be further enhanced using distinct combinations. Some biomarkers are currently in the pr...
[German-speaking memory clinics: state of the art and practical recommendations]
Zeitschrift für Gerontologie und Geriatrie, 2003
The 7th annual meeting of the memory clinics of Germany, Switzerland and Austria in March 2002 in... more The 7th annual meeting of the memory clinics of Germany, Switzerland and Austria in March 2002 in Göttingen, Germany was an optimal opportunity to make an inventory about the state of the art in diagnostic and therapy of dementia and mild cognitive impairment in German-speaking memory clinics. Several problems were discussed including difficulties in 1) diagnosis of patients with aphasia or foreign patients, 2) handling of demented patients without a caregiver, 3) psychological support for patients, who have been diagnosed in a very early stage, 4) misunderstandings between general practitioners, neurologists and psychiatrists in private practice on the one hand and the memory clinics on the other hand, 5) recommendations for prevention of dementia, 6) recommendations concerning dementia and car driving and 7) questions of genetic counselling. The following paper is a summary of the results of a workshop in Göttingen and gives practical recommendations based on the experiences of th...
[Practical application of the CERAD test battery as a neuropsychological dementia screening test]
Der Nervenarzt, 2001
The CERAD neuropsychological test battery is becoming the standard measure for screening cognitiv... more The CERAD neuropsychological test battery is becoming the standard measure for screening cognitive deficits associated with dementia. The seven subtests of the CERAD battery (Mini-Mental State Examination or MMSE, verbal fluency, Modified Boston Naming Test or MBNT, construction ability, learning of word lists, recall, and recognition), a short test of crystallized intelligence (vocabulary test or WST), and a simple test of visuo-motor tracking (number relation test-G or ZVT-G) were applied to 30 healthy control subjects, 49 depressed patients, and 98 mildly to severely demented patients. All subtests of the CERAD battery separated controls from mildly demented patients. Overall, depressed patients scored between controls and mildly demented patients. Score differences between depressed patients and mildly demented patients were significant for MMSE, learning and recall of the word list, verbal fluency, and MBNT. This paper contains a profile sheet for the CERAD battery developed ac...
[Your help is needed! Autopsy brings new knowledge regarding Alzheimer dementia]
MMW Fortschritte der Medizin, Jan 28, 2000
Diagnosis upon autopsy of patients suffering from Alzheimer's disease (AD) and other dementin... more Diagnosis upon autopsy of patients suffering from Alzheimer's disease (AD) and other dementing disorders is required to confirm or reject the clinical diagnosis. Autopsy studies are crucial to validate diagnostic criteria as well as to gain new insights in AD epidemiology, genetics, pathophysiology and therapy. The current decrease of autopsy rates leads to a lack of research which is essential to improve diagnosis and therapy of AD. Only the cooperation between physicians in memory-clinics, general practitioners and neuropathologists can prevent this unfortunate development. Brain-Net, the German brain bank, is a unique approach to provide organisational support for such a concerted action.
[Old myths hinder therapy. Memory disorders are not an expression of "normal" aging]
MMW Fortschritte der Medizin, Jan 22, 2000
Considering the variability of the collateral sulcus in the segmentation of parahippocampal cortex structures from MR images
Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics... more Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD.
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Papers by Harald Hampel