In vivo parahippocampal white matter pathology as a biomarker of disease progression to Alzheimer's disease.

Noninvasive diagnostic tests for Alzheimer's disease (AD) are limited. Postmortem diagnosis is based on density and distribution of neurofibrillary tangles (NFTs) and amyloid-rich neuritic plaques. In preclinical stages of AD, the cells of origin for the perforant pathway within the entorhinal cortex are among the first to display NFTs, indicating its compromise in early stages of AD. We used diffusion tensor imaging (DTI) to assess the integrity of the parahippocampal white matter in mild cognitive impairment (MCI) and AD, as a first step in developing a noninvasive tool for early diagnosis. Subjects with AD (N = 9), MCI (N = 8), or no cognitive impairment (NCI; N = 20) underwent DTI-MRI. Fractional anisotropy (FA) and mean (MD) and radial (RD) diffusivity measured from the parahippocampal white matter in AD and NCI subjects differed greatly. Discriminant analysis in the MCI cases assigned statistical membership of 38% of MCI subjects to the AD group. Preliminary data 1 year later showed that all MCI cases assigned to the AD group either met the diagnostic criteria for probable AD or showed significant cognitive decline. Voxelwise analysis in the parahippocampal white matter revealed a progressive change in the DTI patterns in MCI and AD subjects: whereas converted MCI cases showed structural changes restricted to the anterior portions of this region, in AD the pathology was generalized along the entire anterior-posterior axis. The use of DTI for in vivo assessment of the parahippocampal white matter may be useful for identifying individuals with MCI at highest risk for conversion to AD and for assessing disease progression.

The limbic lobe and its output channels: implications for emotional functions and adaptive behavior.

Current dissatisfaction with the limbic system concept reflects a desire to move beyond the limbic system in efforts to explain key facets of emotional functions and motivational behavior. This review promotes an anatomical viewpoint, which originated as a result of histotechnical advances. These improvements paved the way for anatomical discoveries, which in turn led to the concepts of the ventral striatopallidal system and extended amygdala. These two systems, together with the basal nucleus of Meynert and the septum-diagonal band system, serve as output channels for an expanded version of the classic limbic lobe of Broca, which contains all non-isocortical parts of the cortical mantle together with the large laterobasal-cortical amygdaloid complex. Thus defined, the limbic lobe contains all of the major cortical (e.g. orbitofrontal, cingulate and insular cortices in addition to the hippocampal formation) and cortical-like (laterobasal-cortical amygdala) structures known to be especially important for emotional and motivational functions. In their role as output channels for the limbic lobe, the basal forebrain functional-anatomical systems contribute to the establishment of a number of cortico-subcortical circuits, which provide an important part of the anatomical substrate for the elaboration of emotional functions and adaptive behavior.

A new anatomical framework for neuropsychiatric disorders and drug abuse.

Histotechnological breakthroughs in the late 1960s paved the way for anatomical discoveries that led to the concepts of the ventral striatal-pallidal system and the extended amygdala. These two macro-anatomical systems, together with the basal nucleus of Meynert, represent the main components of the new anatomy of the basal forebrain. The concept of the ventral striatal-pallidal system provided the first indication of the existence of parallel cortical-striatal-pallidal-thalamic-cortical circuits, which in turn led to the theory of segregated cortical-subcortical reentrant circuits as a conceptual framework for the study of neuropsychiatric disorders. The multifarious symptoms of neuropsychiatric disorders, however, cannot be understood unless the extended amygdala, the basal nucleus of Meynert, and the septal-diagonal band system are also included in such deliberations. All of these systems serve as output channels for activities in the greater limbic lobe, which usually is critically involved in neuropsychiatric disorders. Within the context of the new anatomy of the basal forebrain, structures such as the accumbens, the olfactory tubercle, and the amygdala have lost legitimacy as independent functional-anatomical units at the same time as the major components of the last uncharted territory of the human brain, the substantia innominata, have been identified.

The legacy of the silver methods and the new anatomy of the basal forebrain: implications for neuropsychiatry and drug abuse.

The first part of the paper highlights the remarkable legacy of the silver methods, with special emphasis on the travails and opportunities offered by the various Nauta methods and their modifications. When the tracer methods based on axoplasmic flow were introduced in the early 1970s, they were exploited on a backdrop of a basic anatomical framework, which had already been established through the tracing of the major CNS pathways by the aid of the silver methods, especially the widely used Nauta-Gygax methods and their modifications. Some of the silver methods that were developed in the late 1960s for the staining of degenerating boutons (e.g. the Fink-Heimer method and de Olmos cupric silver method) provided the necessary technical improvements that eventually led to a new and more productive way to look at the basal forebrain functional/anatomical organization; if it was not for the silver methods, we would in all likelihood still be promoting the nebulous notion of the substantia innominata rather than the concepts of the ventral striatopallidal system and the extended amygdala. The discovery and elaboration of these two macroanatomical systems symbolize what might deservedly be called the "new anatomy" of the basal forebrain. Following a review of the critical experiments which led to the development of the new anatomy of the basal forebrain, its topography in the human is reviewed in drawings of an abbreviated series of coronal sections. The discovery of the ventral striatopallidal system and its thalamic projection to the mediodorsal thalamus rather than to the ventral anterior-ventral lateral thalamic complex ushered in the idea of parallel cortico-subcortical reentrant circuits, which to a large extent has replaced the limbic system as a theoretical framework for neuropsychiatric disorders. The extended amygdala, which appears as a large ring formation around the internal capsule, is still controversial in some quarters, although it is slowly but surely making its way into the general neuroscience literature, especially in the field of addictive disorders. The ventral striatopallidal system and the extended amygdala are interwoven in a complex fashion with the basal nucleus of Meynert within the basal forebrain. Together, these three systems represent important output channels for so-called "limbic" forebrain regions, especially orbitomedial prefrontal cortex and medial temporal lobe structures, which are increasingly implicated in major neuropsychiatric disorders.

NMDA-antagonist MK-801-induced neuronal degeneration in Wistar rat brain detected by the Amino-Cupric-Silver method.

The neurotoxic effect following a single intraperitoneal injection of MK-801 (10 mg/kg) in adult female Wistar rats at different survival times was studied with the 1994 version of de Olmos' Amino-Cupric-Silver (A-Cu-Ag) technique for detection of neural degeneration. In addition to the well documented somatodendritic degeneration observable in cortical olfactory structures, dentate gyrus, retrosplenial and sensory cortices, we detected this type of neuronal degeneration also in the main olfactory bulb, motor and anterior cingulate cortices, thalamus and cerebellum. Terminal degeneration, not reported by previous authors, was detected in cortical olfactory structures, hippocampal formation, sensory, infralimbic, prelimbic, agranular insular, ectorhinal, perirhinal and lateral orbital cortices. These results demonstrate that the A-Cu-Ag procedure is more efficient than other silver methods for detecting the degeneration induced by MK-801. In fact, the use of the A-Cu-Ag method has made it possible to infer the connectional relations between the damaged cell bodies and corresponding terminal degeneration. Our results also indicate that the A-Cu-Ag technique may be a suitable method for the staining of neurons undergoing apoptotic-like degeneration. The probable degenerative mechanism of MK-801 in the main olfactory system is discussed.