Neurobiology of Aging 24 (2003) 545–552 MR spectroscopy in Alzheimer’s disease: gender differences in probabilistic learning capacity Michael Colla a,b , Gabriele Ende a , Markus Bohrer a , Michael Deuschle a , Golo Kronenberg a,b , Fritz Henn a , Isabella Heuser a,b,∗ a Central Institute of Mental Health, J 5, 68159 Mannheim, Germany b Department of Psychiatry; Free University of Berlin, Eschenallee 3, 14050 Berlin, Germany Received 10 December 2001; received in revised form 21 June 2002; accepted 27 August 2002 Abstract Degenerative alterations of cortical and subcortical regions in Alzheimer disease (AD) can be estimated by the extent of brain metabolite changes as measured by magnetic resonance spectroscopic imaging (MRSI). A neuropsychological assessment may correlate with metabo- lite levels and could evaluate underlying degenerative processes. Probabilistic-related classification learning, which represents one form of procedural learning, is associated with the neostriatum. The present study was aimed at examining the correlation of spectroscopic imaging in subcortical regions with the evaluation of specific neuropsychological findings. Twenty-two patients with Alzheimer’s disease were compared to 15 healthy elderly control subjects. Proton MRSI of the basal ganglia (BG) and thalamus region was performed for detection of N-acetylaspartate (NAA), trimethylamine (TMA) and creatine ((P)Cr). In addition, a probabilistic-related classification learning task (Weather Prediction Task (WT)) was applied. We observed that in patients a high TMA signal in the basal ganglia region was correlated with a poorer performance in the probabilistic learning task (Spearman rank order correlation (SROC) =-0.6, P< 0.009). Although Alzheimer’s patients, as a group, did not differ from controls with regard to probabilistic learning capacity (PLC), male AD patients, as compared to male controls, displayed an impairment in the task performance by 28% (P< 0.03) and showed a 16% elevation in TMA signaling (P< 0.04). The altered metabolite signals and ratios in combination with the cognitive performance might suggest gender-related neuronal degeneration and dysfunction within subcortical regions in AD. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Magnetic resonance spectroscopy; Magnetic resonance imaging; Implicit memory; Probabilistic learning; Alzheimer disease; Basal ganglia; Striatum; N-acetylaspartate; Trimethylamine; Gender-related degeneration 1. Introduction Human memory is not a single entity. Instead it consists of several separate memory systems that depend upon the integrity of specific anatomical brain regions [40]. The de- generation of specific brain regions within the medial tempo- ral lobe memory system and profound declarative memory impairment is a defining feature of AD [1,7,8]. Apart from the declarative memory system [41] procedural memory— which is part of the implicit memory system—is defined as the memory of representations of skills which cannot be consciously recalled and are difficult to verbalize [10]. Prob- abilistic classification learning, which refers to the learn- ing of associations, can be seen as part of the procedural ∗ Corresponding author. Tel.: +49-30-8445-8701/8702; fax: +49-30-8445-8726. E-mail address: isabella.heuser@medizin.fu-berlin.de (I. Heuser). memory system (cognitive skill learning) [22]. In accor- dance with the hypothesis of dissociable “multiple memory systems” [41], previous Alzheimer’s disease studies have demonstrated, that these patients can acquire cognitive im- plicit skills, even if performance on declarative memory tests is poor [11,17,23,34]. In this context, current neuroanatom- ical and functional studies indicate that the basal ganglia (BG) circuits (striatum) [9] are mandatory for the process- ing of information in these specific cognitive, non-motor and probabilistic tasks [21,26,35,38]. MR spectroscopic imaging (MRSI) enables the direct, in vivo and non-invasive assessment of brain metabolites [36] and is therefore a valuable approach to detect early changes in brain tissue integrity. Proton MR spectroscopic imaging measures N-acetylaspartate (NAA), an amino acid thought to be exclusively in neurons in gray matter and in their axonal processes in white matter, but not in glial cells. A reduction in NAA is thought to be a marker for neuronal dysfunction 0197-4580/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII:S0197-4580(02)00189-6