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Authors: Bittner, Daniel M. | Heinze, Hans-Jochen | Kaufmann, Jörn

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease (AD), levels of N-acetylaspartate (NAA) is diminished and choline (Cho) and myo-inositol (mI) are increased. In cerebrospinal fluid (CSF), tau and phosphoylated tau (p-tau181P ) is increased and amyloid-β(1-42) (Aβ42 ) decreased. Objectives: 1) To compare metabolites of different 1 H-MRS voxels and assess its utility to differentiate AD from controls and to examine the relationship to cognition and to CSF markers. Methods: 17 healthy controls and 19 AD subjects were studied using 1 H-MRS. In the AD cases, additional CSF analysis was obtained. Results: Relative to controls, AD subjects had reduced NAA/Creatine (Cr) levels in …hippocampus (42.3% to 26.0%, p < 0.001), posterior cingulate gyrus (10.4% to 0.2%, p = 0.04), and parietal lobe (14.9% to 3.8%, p = 0.002). Further differences of Cho/Cr and mI/Cr in the hippocampus (Cho/Cr: p = 0.04; mI/Cr: p = 0.015) and posterior cingulate (Cho/Cr: p = 0.001; mI/Cr: p = 0.001) were observed. NAA/Cr of the hippocampus yielded the highest sensitivity (94.1%) and specificity (92.3%) to differentiate AD from controls. NAA/Cr was associated with general cognition (hippocampus: R = 0.68, p < 0.001; parietal lobe: R = 0.57, p = 0.001; posterior cingulate: R = 0.50, p = 0.003). Higher hippocampal NAA/Cr was related to higher CSF Aβ42 , while lower parietal NAA/Cr was associated with a higher CSF total tau (t-tau) and p-tau181P . Posterior cingulate mI/Cr was related to CSF t-tau and NAA/mI. Conclusion: 1 H-MRS is an appropriate measure in AD. Measurement at different regions presumably reflects different pathological changes. Show more

Keywords: Aβ42, Alzheimer's disease, cerebrospinal fluid, hTau, MR spectroscopy, pTau

DOI: 10.3233/JAD-120778

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 155-163, 2013

Authors: Körtvélyessy, Peter | Gukasjan, Angela | Sweeney-Reed, Catherine M. | Heinze, Hans-Jochen | Thurner, Lorenz | Bittner, Daniel M.

Article Type: Research Article

Abstract: Background: Analysis of cerebrospinal fluid (CSF) has improved over the last few years; thus specific markers for different diseases have emerged, e.g., amyloid-β (Aβ) for Alzheimer’s disease (AD) and progranulin for frontotemporal dementia (FTD). Objective: Evaluation of correlation between biomarkers in CSF and cognitive performance in populations with AD and FTD. Methods: 27 patients with AD and 16 with FTD were included. CSF tau, P-tau181P , Aβ42 , and progranulin (PGRN) were measured and a standardized neuropsychological test battery applied. Olfactory testing was additionally included where available. Results: For all patients across both groups, an association between PGRN and categoric …(p  = 0.016) and letter fluency (p  = 0.029), naming (p  = 0.003), and overall cognition (Mini-Mental State Examination: p  = 0.04) was observed. Aβ42 was strongly associated with memory function (learning: p  = 0.001; recall: p  = 0.002). A correlation between Aβ42 and memory performance was moreover found for each group separately, while PGRN also showed a correlation with recognition memory (p  = 0.04) in AD. Furthermore, an association between reduced PGRN and olfactory dysfunction was revealed (p  = 0.01). Conclusions: CSF-levels of PGRN and Aβ42 levels express deficits in cognition differentially, with PGRN being predominantly associated with frontal and Aβ42 with temporal dysfunction. This mirrors the cerebral occurrence of these proteins. These associations appear to be consistent across both disease groups. The relationship between PGRN and olfaction further underpins the association between PRGN and frontal dysfunction. Show more

Keywords: Alzheimer’s disease, amyloid-beta, cerebrospinal fluid, cognitive neuropsychology in dementia, frontotemporal dementia, progranulin

DOI: 10.3233/JAD-150069

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 375-380, 2015

Authors: Bittner, Daniel M. | Wieseler, Isabel | Wilhelm, Helmut | Riepe, Matthias W. | Müller, Notger G.

Article Type: Research Article

Abstract: It was investigated whether alterations of the pupil's light reflex might reflect Alzheimer's disease (AD) pathology. Changes in the pupil's system might be expected due to AD pathology present in the oculomotor system of the Edinger-Westphal nucleus, and a cholinergic deficit caused by degeneration of the nucleus basalis Meynert. A rather new method of repetitive light stimulation was applied assessing variations in pupil size, latency, and amplitude over time. We analyzed 44 healthy controls, 42 subjects with mild cognitive impairment (MCI), and 66 AD patients. AD and MCI showed a less pronounced pupil size decrease and amplitude increase over time …than controls. A higher MMSE was associated with a higher increase of relative amplitude and greater decrease of latency in AD and MCI, and absolute amplitude increase in AD alone. Pupil size increase correlated with cerebrospinal fluid markers in AD. Summarized pupil light reflex is not stable under repetitive stimulation, but changes systematically and less pronounced in AD and MCI. Thus repetitive stimulation of the pupil's response potentially indicates AD pathology. Show more

Keywords: Alzheimer's disease, amyloid-β 1-42, cerebrospinal fluid, mild cognitive impairment, parasympathetic system, pupil light reflex, repetitive stimulation, sympathetic inhibition, tau

DOI: 10.3233/JAD-140969

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1469-1477, 2014

Authors: Kleinschmidt, Martin | Schoenfeld, Robby | Göttlich, Claudia | Bittner, Daniel | Metzner, Jürgen Erich | Leplow, Bernd | Demuth, Hans-Ulrich

Article Type: Research Article

Abstract: Background: Current treatment in Alzheimer’s disease (AD) is initiated at a stage where the brain already has irreversible structural deteriorations. Therefore, the concept of treatment prior to obvious cognitive deficits has become widely accepted, and simple biochemical tests to discriminate normal aging from prodromal or demented stages are now common practice. Objective: The objective of the study was the differentiation of controls, mild cognitive impairment (MCI) and AD patients by novel blood-based assays in combination with neuropsychological tests. Methods: In a cross-sectional study, 143 subjects aged 18 to 85 years were recruited. All participants were classified by a comprehensive neuropsychological …assessment. Blood samples were analyzed for several amyloid-β (Aβ) species, pro-inflammatory markers, anti-Aβ autoantibodies, and ApoE allele status, respectively. Results: Plasma Aβ1-42 was significantly decreased in MCI and AD compared to age-matched controls, whereas Aβ1-40 did not differ, but increases with age in healthy controls. The Aβ1-42 to Aβ1-40 ratio was stepwise decreased from age-matched controls via MCI to AD, and shows a clear correlation with memory scores. Reduced Aβ1-42 and Aβ1-42 to Aβ1-40 ratio have strongly correlated with carrying ApoE ɛ 4 allele. Autoantibodies against pyroglutamate-modified Aβ, but only a certain subclass, were significantly decreased in AD compared to MCI and age-matched controls, whereas autoantibodies against the unmodified N-terminus of Aβ did not differ. Conclusion: Comprehensive sample preparation and assay standardization enable reliable usage of plasma Aβ for diagnosis of MCI and AD. Anti-pGlu-Aβ autoantibodies correlate with cognition, but not with ApoE, supporting the associated plasma Aβ analysis with additional and independent information. Show more

Keywords: Aging, Alzheimer’s disease, amyloid-β, ApoE, autoantibodies, blood, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-143189

Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 111-126, 2016

Authors: Bueche, Celine Zoe | Garz, Cornelia | Stanaszek, Luiza | Niklass, Solveig | Kropf, Siegfried | Bittner, Daniel | Härtig, Wolfgang | Reymann, Klaus G. | Heinze, Hans-Jochen | Carare, Roxana O. | Schreiber, Stefanie

Article Type: Research Article

Abstract: Background: Cerebral small vessel disease (CSVD) in spontaneously hypertensive stroke prone rats (SHRSP) is accompanied by parenchymal amyloid-β (Aβ) deposition in the brain and by hypertensive nephropathy with tubulointerstitial damage. N-acetylcysteine (NAC) promotes blood-brain barrier (BBB) breakdown in SHRSP and may thus accelerate the failure of vascular and perivascular clearance of Aβ. Objective: In this study, we test the hypothesis that treatment with NAC increases the cerebral Aβ load and improves renal damage in the SHRSP model. Methods: A total of 46 SHRSP (ages 18–44 weeks) were treated daily with NAC (12 mg/kg body weight) and 74 no-treated age-matched SHRSP …served as controls. The prevalence of parenchymal Aβ load, IgG positive small vessels, and small perivascular bleeds was assessed in different brain regions. Tubulointerstitial kidney damage was assessed through a) the presence of erythrocytes in peritubular capillaries and b) tubular protein cylinders. Results: SHRSP treated with NAC had an age-dependent increase of BBB breakdown (assessed by the presence of IgG positive small vessels) and small perivascular bleeds, mainly in the cortex. NAC significantly increased the Aβ plaque load in the cortex while the number of parenchymal amyloid deposits in the remaining brain areas including basal ganglia, hippocampus, thalamus, and corpus callosum were unchanged. There were no significant treatment effects on tubulointerstitial kidney damage. Conclusion: The impact of NAC on cerebral cortical plaque load increase may result from the vascular pathology of SHRSP that accompanies BBB breakdown, leading to the failure of amyloid clearance mechanisms. It remains to be seen whether in humans chronic NAC intake may increase amyloid load in the aging human brain and dementia. Show more

Keywords: Amyloid-β, cerebral small vessel disease, hypertensive nephropathy, N-acetylcysteine rats, spontaneously hypertensive stroke prone rats (SHRSP)

DOI: 10.3233/JAD-132615

Citation: Journal of Alzheimer's Disease, vol. 42, no. s3, pp. S305-S313, 2014

Authors: Ritter, Kerstin | Lange, Catharina | Weygandt, Martin | Mäurer, Anja | Roberts, Anna | Estrella, Melanie | Suppa, Per | Spies, Lothar | Prasad, Vikas | Steffen, Ingo | Apostolova, Ivayla | Bittner, Daniel | Gövercin, Mehmet | Brenner, Winfried | Mende, Christine | Peters, Oliver | Seybold, Joachim | Fiebach, Jochen B. | Steinhagen-Thiessen, Elisabeth | Hampel, Harald | Haynes, John-Dylan | Buchert, Ralph

Article Type: Research Article

Abstract: Background: The cause of cognitive impairment in acutely hospitalized geriatric patients is often unclear. The diagnostic process is challenging but important in order to treat potentially life-threatening etiologies or identify underlying neurodegenerative disease. Objective: To evaluate the add-on diagnostic value of structural and metabolic neuroimaging in newly manifested cognitive impairment in elderly geriatric inpatients. Methods: Eighty-one inpatients (55 females, 81.6±5.5 y) without history of cognitive complaints prior to hospitalization were recruited in 10 acute geriatrics clinics. Primary inclusion criterion was a clinical hypothesis of Alzheimer’s disease (AD), cerebrovascular disease (CVD), or mixed AD+CVD etiology (MD), which remained uncertain after standard …diagnostic workup. Additional procedures performed after enrollment included detailed neuropsychological testing and structural MRI and FDG-PET of the brain. An interdisciplinary expert team established the most probable etiologic diagnosis (non-neurodegenerative, AD, CVD, or MD) integrating all available data. Automatic multimodal classification based on Random Undersampling Boosting was used for rater-independent assessment of the complementary contribution of the additional diagnostic procedures to the etiologic diagnosis. Results: Automatic 4-class classification based on all diagnostic routine standard procedures combined reproduced the etiologic expert diagnosis in 31% of the patients (p  = 0.100, chance level 25%). Highest accuracy by a single modality was achieved by MRI or FDG-PET (both 45%, p ≤0.001). Integration of all modalities resulted in 76% accuracy (p ≤0.001). Conclusion: These results indicate substantial improvement of diagnostic accuracy in uncertain de novo cognitive impairment in acutely hospitalized geriatric patients with the integration of structural MRI and brain FDG-PET into the diagnostic process. Show more

Keywords: Cognitive impairment, geriatric inpatients, magnetic resonance imaging, multimodal classification, positron emission tomography

DOI: 10.3233/JAD-160380

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1319-1331, 2016