We describe the phenomenon of crossed cerebellar diaschisis (CCD) in four subjects diagnosed with Alzheimer's disease (AD) according to the National Institute on Aging -Alzheimer Association (NIA-AA) criteria, in combination with 18F-FDG PET and 11C-PiB PET imaging. 18F-FDG PET showed a pattern of cerebral metabolism with relative decrease most prominent in the frontal-parietal cortex of the left hemisphere and crossed hypometabolism of the right cerebellum. 11C-PiB PET showed symmetrical amyloid accumulation, but a lower relative tracer delivery (a surrogate of relative cerebral blood flow) in the left hemisphere. CCD is the phenomenon of unilateral cerebellar hypometabolism as a remote effect of supratentorial dysfunction of the brain in the contralateral hemisphere. The mechanism implies the involvement of the cortico-ponto-cerebellar fibers. The pathophysiology is thought to have a functional or reversible basis but can also reflect in secondary morphologic change. CCD is a well-recognized phenomenon, since the development of new imaging techniques, although scarcely described in neurodegenerative dementias. To our knowledge this is the first report describing CCD in AD subjects with documentation of both 18F-FDG PET and 11C-PiB PET imaging. CCD in our subjects was explained on a functional basis due to neurodegenerative pathology in the left hemisphere. There was no structural lesion and the symmetric amyloid accumulation did not correspond with the unilateral metabolic impairment. This suggests that CCD might be caused by non-amyloid neurodegeneration. The pathophysiological mechanism, clinical relevance and therapeutic implications of CCD and the role of the cerebellum in AD need further investigation.
During the past 2 decades the collaboration across disciplines and the methodologic and conceptual advances of contemporary neuroscience have brought about a substantial modification of the traditional view of the cerebellum as a mere coordinator of autonomic and somatic motor functions. Growing insights in the neuroanatomy of the cerebellum and its interconnections, evidence from functional neuroimaging and neurophysiological research, and advancements in clinical and experimental neuropsychology have established the view that the cerebellum participates in a much wider range of functions than conventionally accepted. This increase of insight has brought to the fore that the cerebellum modulates cognitive functioning of at least those parts of the brain to which it is reciprocally connected. This article reviews the recently acknowledged role of the cerebellum in cognition and addresses in more detail experimental and clinical data disclosing the modulatory role of the cerebellum in various non-motor language processes such as lexical retrieval, syntax, and language dynamics. In agreement with the findings indicating a topographical organization of the cerebellar structures involved in language pathology we advance the concept of a "lateralized linguistic cerebellum." In our view crossed cerebral diaschisis processes, reflecting a functional depression of supratentorial language areas due to reduced input via cerebellocortical pathways, might represent the relevant pathomechanism for linguistic deficits associated with cerebellar pathology.
The Morris water maze (MWM) was described 20 years ago as a device to investigate spatial learning and memory in laboratory rats. In the meanwhile, it has become one of the most frequently used laboratory tools in behavioral neuroscience. Many methodological variations of the MWM task have been and are being used by research groups in many different applications. However, researchers have become increasingly aware that MWM performance is influenced by factors such as apparatus or training procedure as well as by the characteristics of the experimental animals (sex, species/strain, age, nutritional state, exposure to stress or infection). Lesions in distinct brain regions like hippocampus, striatum, basal forebrain, cerebellum and cerebral cortex were shown to impair MWM performance, but disconnecting rather than destroying brain regions relevant for spatial learning may impair MWM performance as well. Spatial learning in general and MWM performance in particular appear to depend upon the coordinated action of different brain regions and neurotransmitter systems constituting a functionally integrated neural network. Finally, the MWM task has often been used in the validation of rodent models for neurocognitive disorders and the evaluation of possible neurocognitive treatments. Through its many applications, MWM testing gained a position at the very core of contemporary neuroscience research.
The functional role of the cerebellum is traditionally defined as a mere coordinator of automatic and somatic motor functions. This view determined most of the clinical and experimental investigations of the functions of the cerebellum and overshadowed many attempts to expand its role to non-motor functions. However, during the past decades the collaboration across contemporary neuroscience disciplines has brought about a substantial modification of traditional thinking about the cerebellum. Converging evidence from different neuroscientific angles established the view that the human cerebellum participates in a much wider range of functions than conventionally accepted. Studies have brought to the fore that the cerebellum also modulates neurocognitive functions of at least these parts of the brain to which it is reciprocally connected. In less than two decades, the concept of 'cerebellar neurocognition' evolved from a mere afterthought to an exciting new multifaced area of contemporary neuroscientific investigations. Within this area, one of the major avenues of current research is the role of the cerebellum in non-motor language processing. This paper reviews the recently acknowledged role of the cerebellum in neurocognition and linguistic processes.
Arylsulfatase A (ASA)-deficient (-/-) mice and ASA(+/+) controls were constructed as a transgenic model for the lysosomal storage disease, metachromatic leukodystrophy (MLD). One-year-old ASA(-/-) mice showed impaired rotarod performance and altered walking pattern characterized by a shorter pace, later evolving into more severe ataxia with tremor in 2-year-old mice. Examination of cerebellar histology showed that 2-year-old ASA(-/-) mice have lost most of the calbindin immunoreactivity from their Purkinje cell dendrites and show simplified dendritic architecture. Additionally, ASA-deficient mice lost a substantial proportion of their Purkinje cells. Recordings of unitary potentials and stimulation of climbing fibers on cerebellar slices from 2-year-old mice indicated that, although the main cerebellar synapses seem to be present and functioning physiologically, the climbing fibers of ASA-deficient mice may have enhanced effects on Purkinje cell activity. It is concluded that ambulatory dysfunctions in ASA(-/-) mice might be explained by an imbalance in the consequences of climbing fiber signals upon Purkinje cell activity due to selective neurodegeneration within the cerebellum.
In longitudinal brain studies of dementia of the Alzheimer type (DAT), the cerebellum is often used as a reference region for single photon emission computed tomography (SPECT) quantification, which assumes no significant regional influence of physiological fluctuations or pathology. With the use of absolute quantification in DAT patients, reproducibility of cerebellar uptake of technetium-99m-d,l-hexamethylpropyleneamine oxime (HMPAO) was tested and compared with the mean absolute cerebellar tracer uptake value in DAT patients and healthy control subjects. In 13 DAT patients SPECT studies were repeated within 2 weeks to assess reproducibility of cerebellar regional brain uptake (rBU). With calibrated point sources as scaling factors, cerebellar activity was expressed as rBU of HMPAO per cm3 brain tissue in percent of the injected lipophilic dose of 740 MBq (20 mCi). Also, mean cerebellar rBU in patients suffering from DAT was calculated and compared with a previously established database obtained in healthy volunteers. Repeated SPECT studies within a 2-week interval in clinically stable patients resulted in a mean rBU increase of 6.8 +/- 10.3% in the second SPECT study as compared with the first. A similar shift was previously reported in healthy volunteers. Mean cortical cerebellar rBU values in DAT patients and in the healthy reference population concurred, after cumulative corrections for body surface and for a mean brain volume of 1350 ml (obtained in healthy control subjects), showing respective mean values of 53.9 +/- 7.4 and of 52.0 +/- 7.3 x 10(-6) of the injected lipophilic dose 740 MBq (20 mCi) of HMPAO per cm3 of brain tissue. A unidirectional shift in mean absolute cerebellar uptake values occurs between repeat SPECT examinations in DAT patients similar to previous findings in a group of healthy volunteers. The origin of this phenomenon remains elusive but deserves further study with regard to SPECT (semi)quantification in DAT patients. Most interestingly, the presented findings suggest that with the use of HMPAO SPECT in DAT patients the cerebellum remains scintigraphically uninvolved.
L1 is a neural cell adhesion molecule mainly involved in axon guidance and neuronal migration during brain development. Mutations in the human L1 gene give rise to a complex clinical picture, with mental retardation, neurologic abnormalities and a variable degree of hydrocephalus. Recently, a transgenic mouse model with a targeted null mutation in the L1 gene was generated. These knockout (KO) mice show hypoplasia of the corticospinal tract. Here we have performed further studies of these KO mice including magnetic resonance imaging of the brain, neuropathological analysis and behavioral testing. The ventricular system was shown to be abnormal with dilatation of the lateral ventricles and the 4th ventricle, and an altered shape of the Sylvius aqueduct. Additionally, the cerebellar vermis of the KO mice is hypoplastic. Their exploratory behavior is characterized by stereotype peripheral circling reminiscent of that of rodents with induced cerebellar lesions.
A 73-year-old right-handed man with ischemic infarction in the vascular territory of the right arteria cerebellaris superior is described. In the acute phase he presented with cerebellar and brainstem symptoms, followed within a few days by a paresis of the right arm and unexpected language disturbances of aphasic origin. The core features of the aphasic syndrome corresponded to a diagnosis of Luria's dynamic aphasia, complicated by expressive and receptive agrammatism. During one year follow-up the ataxia and paretic symptoms disappeared but the slightly ameliorated aphasic syndrome and the sensory disturbances in the left hemicorpus persisted. In the absence of any neuroradiological evidence for a structural lesion in the left frontal language areas, the hypothetical causative role of the right cerebellar lesion on the contralateral prefrontal aphasic symptomatology is advocated and supported by positive 99mTc-hexamethylpropyleneamine oxime single-photon emission-computed tomography findings, revealing a focal hypoperfusion in the clinically suspected areas. In our case, this phenomenon of so-called 'crossed cerebello-cerebral diaschisis', reflecting the distant functional impact of the right cerebellum on the contralateral prefrontal cortical areas, is for the first time associated with an aphasiologic substrate. The co-occurrence of a right cerebellar lesion and an aphasic syndrome forms the first clinical illustration of the pathophysiological hypothesis of a deactivation of prefrontal left hemisphere language functions due to the loss of excitatory impulses through cerebello-ponto-thalamo-cortical pathways.
The sparse-fur (spf) mouse, with an X-linked hepatic ornithine transcarbamylase (OTC, E.C.126.96.36.199) deficiency, exhibits significantly lower levels of arginine in the brain as compared to normal controls. In the present study, the effect of a sustained lower metabolic arginine was studied by measuring the levels of several arginine-related guanidino compounds in brain. The concentrations of gamma-guanidinobutyric acid (gamma-GBA), N-alpha-acetylarginine (N-alpha-AA), argininic acid (Arg-A), guanidinoacetic acid (GAA), and creatine were significantly lower in spf mice as compared to controls. Since arginine is the precursor for nitric oxide, we also measured the activity of nitric oxide synthase which was significantly reduced in cerebellum, striatum, hippocampus and cerebral cortex of spf mice. The changes seen in cerebral guanidino compound and nitric oxide metabolism of spf mice could be due to a sustained deficiency of arginine, caused by a metabolic block in the area cycle.