Axonal injury and membrane alterations in Alzheimer's disease suggested by in vivo proton magnetic resonance spectroscopic imaging

We used spin-echo magnetic resonance imaging and prton magnetic resonance spectroscopic imaging in 8 patients with probable Alzheimer's disease and in 10 age-matched elderly control subjects to assess the effects of Alzheimer's disease on the brain. On magnetic resonance images the patients showed signficant ventricular enlargements relative to the control subjects. We measured the distribution and relative signal intensities of N-acetylaspartate (a putative neuronal marker), of choline residues representing lipid metabolities, and of creatine-containing metabolites in a large section of the centrum semiovale containing white and mesial gray matter. Throughout the white matter of the patients with Alzheimer's disease compared to elderly control subjects, N-acetylaspartate was decreased relative to choline (N-acetylaspartate–choline ration) and creatine-containing metabolities (N-acetylaspartate–creatine ratio) with no changes in the choline-creatine ratio. The N-acetylaspartate–choline ratio was lower and choline-creatine higher in the mesial gray matter of AD patients relative to elderly controls. The posterior section of the centrum semiovale in the patients showed increased choline-creatine and choline–N-acetylaspartate ratios with the N-acetylaspartate–creatine ratio unchanged between the patients and control subjects. These spectroscopic findings give suggestive evidence of diffuse axonal injury and membrane alterations in gray and white matter of the centrum semiovale in patients with Alzheimer's disease.     

MR spectroscopy and diffusion tensor imaging of the brain in congenital muscular dystrophy with merosin deficiency: metabolite level decreases, fractional anisotropy decreases, and apparent diffusion coefficient increases in the white matter

Brain magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) in one patient with merosin-deficient congenital muscular dystrophy (MDCMD) revealed significant metabolite (choline, creatine, N-acetyl aspartate) level reductions, fractional anisotropy (FA) reduction and increased apparent diffusion coefficient (ADC) in the white matter (p<0.01, all). In the gray matter, the MRS properties did not differ significantly from those in controls. The ADC and FA, however, differed significantly as in the white matter, although the differences were less pronounced. This is the first quantitative MR study of the brain in a patient with MDCMD, which revealed that the concentrations of all MRS measured metabolites were decreased only in the white matter. This observation, combined with the DTI observed ADC increases and FA decrease, indicated a presence of vasogenic edema in the white matter.     

多发性硬化患者智能改变与头颅磁共振成像测量及弥散张量成像研究

目的　研究多发性硬化 (MS)患者认知功能障碍的发生情况及认知改变的病理解剖基础。方法　对 70例MS患者进行韦氏智力量表测查及头颅MRI检查 ,对其中 5 0例患者的头颅MRI成像进行了定量测量 ;7例患者进行了弥散张量成像 (DTI)扫描。结果　智能测试发现MS组全量表智商低于正常 (<90分 )者为 4 0 % (2 8/ 70 ) ,与正常组比较差异有非常显著意义 (P <0 0 1)。智能测试与MRI测量中的两侧尾状核比率相关性最显著 ,其次为胼胝体指数。DTI显示病灶周围看似正常组织、看似正常白质及灰质较对照组相应部位脑组织的表观扩散系数增高 ,各向异性值减低。结论　MS患者中存在认知障碍。病灶的范围及其严重程度 ,包括看似正常白质中的微小病灶的数量和严重程度决定认知障碍的程度。灰质功能障碍也与认知改变有关。     

MR spectroscopy in 18q syndrome suggesting other than hypomyelination

We reported a 5-year-old boy with 18q^- syndrome who showed typical magnetic resonance imaging (MRI) findings of high signal intensity on T2-weighted imaging, and a slightly high but lower than normal signal on T1-weighted imaging of the white matter. MR spectroscopy (MRS) revealed increased concentrations of creatine, myoinositol and choline with a normal N-acetylaspartate one. The cerebral white matter lesions observed on MRI in patients with 18q^- syndrome have been considered to reflect hypomyelination due to a decrease in myelin basic protein so far, however, MRS suggested reactive astrocytic gliosis and accelerated myelin turnover, which are compatible with recent pathological reports of 18q^- syndrome.     

Late effects of high‐dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: Converging results from multimodal magnetic resonance imaging

The neural substrate underlying cognitive impairments after chemotherapy is largely unknown. Here, we investigated very late (>9 years) effects of adjuvant high‐dose chemotherapy on brain white and gray matter in primary breast cancer survivors (n = 17) with multimodal magnetic resonance imaging (MRI). A group of breast cancer survivors who did not receive chemotherapy was scanned for comparison (n = 15). Neuropsychological tests demonstrated cognitive impairments in the chemotherapy group. Diffusion tensor imaging (DTI) with tract‐based spatial statistics showed that chemotherapy was associated with focal changes in DTI values indicative for reduced white matter integrity. Single voxel proton MR spectroscopy (1H‐MRS) in the left centrum semiovale (white matter) showed a reduction of N‐acetylasparate/creatine indicative of axonal injury. Voxel‐based morphometry demonstrated a reduction of gray matter volume that overlapped with fMRI hypoactivation (as reported in a previous publication) in posterior parietal areas and colocalized with DTI abnormalities. Also, DTI correlated with 1H‐MRS only in the chemotherapy group. These results converge to suggest that high‐dose adjuvant chemotherapy for breast cancer is associated with long‐term injury to white matter, presumably reflecting a combination of axonal degeneration and demyelination, and damage to gray matter with associated functional deficits. Hormonal treatment with tamoxifen may also have contributed to the observed effects, although results from other studies indicate that it is unlikely that tamoxifen is solely or largely responsible. Using this multimodality approach we provide for the first time insight into the neural substrate underlying cognitive impairments following systemic administration of cytotoxic agents many years after treatment. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

MRI mean diffusivity detects widespread brain degeneration in multiple sclerosis

We investigated the magnetic resonance imaging (MRI) findings of 32 multiple sclerosis (MS) patients using voxel-based morphometry (VBM) and voxel-based analysis of white matter fluid-attenuated inversion recovery image (FLAIR) high-intensity lesions and diffusion tensor imaging (DTI). Compared with 18 healthy controls, MS patients showed gray matter volume reduction in the thalamus, hypothalamus, caudate, limbic lobe, and frontal lobe. A marked volume reduction of white matter was evident along the ventriculus lateralis and corpus callosum. FLAIR high-intensity lesions were observed beside the ventriculus lateralis. DTI revealed reduced fractional anisotropy areas similar to those of the FLAIR high-intensity lesions. Changes in the volume of increased mean diffusivity (MD) were the most widespread and extended to normal-appearing white matter (p<0.001). Multiple regression analysis revealed that MD values were significantly correlated with both disease duration (r=0.381, p=0.032) and expanded disability status scale scores (EDSS) (r=0.393, p=0.026). This study demonstrated that combined voxel-based analysis for volumetry, FLAIR high-intensity lesions, and DTI could reveal widespread brain abnormalities in MS patients. Furthermore, DTI, especially MD, showed far more widespread brain degeneration than other MRI parameters, and was significantly correlated with both severity and disease duration.     

Diffusion tensor imaging of lesions and normal-appearing white matter in multiple sclerosis.

OBJECTIVE: To determine whether diffusion tensor imaging (DTI) can detect structural changes in normal-appearing white matter, and to distinguish between plaques of different pathologic severity, in patients with MS. BACKGROUND: Conventional MRI detects lesions sensitively in MS but has limited pathologic specificity. The diffusion of water molecules in brain tissue, most fully expressed mathematically by a tensor quantity, reflects its intrinsic microstructure. It is now possible to estimate the diffusion tensor noninvasively in the human brain using MR DTI. This method is unique in providing precise and rotationally invariant measurements of the amount and directional bias (anisotropy) of diffusion in white matter tracts relating to tissue integrity and orientation. METHODS: DTI was performed in six patients with MS and in six age-matched control subjects. Diffusion was characterized in normal-appearing white matter in both groups, and in lesions of different pathologic subtypes (inflammatory, noninflammatory, T1 hypointense, and T1 isointense). RESULTS: DTI identified significantly altered water diffusion properties in the normal-appearing white matter of patients compared with control subjects (p < 0.001), and distinguished between lesion types. The highest diffusion was seen in destructive (T1 hypointense) lesions, whereas the greatest change in anisotropy was found in inflammatory (gadolinium-enhancing) lesions. CONCLUSIONS: DTI detects diffuse abnormalities in the normal-appearing white matter of MS patients, and the findings in lesions appear to relate to pathologic severity. Its use in serial studies and in larger clinical cohorts may increase our understanding of pathogenetic mechanisms of reversible and persistent disability.     

Early silent microstructural degeneration and atrophy of the thalamocortical network in multiple sclerosis

Recent studies on patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS) demonstrated thalamic atrophy. Here we addressed the following question: Is early thalamic atrophy in patients with CIS and relapsing‐remitting MS (RRMS) mainly a direct consequence of white matter (WM) lesions—as frequently claimed—or is the atrophy stronger correlated to “silent” (nonlesional) microstructural thalamic alterations? One‐hundred and ten patients with RRMS, 12 with CIS, and 30 healthy controls were admitted to 3 T magnetic resonance imaging. Fractional anisotropy (FA) was computed from diffusion tensor imaging (DTI) to assess thalamic and WM microstructure. The relative thalamic volume (RTV) and thalamic FA were significantly reduced in patients with CIS and RRMS relative to healthy controls. Both measures were also correlated. The age, gender, WM lesion load, thalamic FA, and gray matter volume‐corrected RTV were reduced even in the absence of thalamic and extensive white matter lesions—also in patients with short disease duration (≤24 months). A voxel‐based correlation analysis revealed that the RTV reduction had a significant effect on local WM FA—in areas next to the thalamus and basal ganglia. These WM alterations could not be explained by WM lesions, which had a differing spatial distribution. Early thalamic atrophy is mainly driven by silent microstructural thalamic alterations. Lesions do not disclose the early damage of thalamocortical circuits, which seem to be much more affected in CIS and RRMS than expected. Thalamocortical damage can be detected by DTI in normal appearing brain tissue. Hum Brain Mapp 37:1866–1879, 2016. © 2016 Wiley Periodicals, Inc .     

Preferential spinal central gray matter involvement in neuromyelitis optica

Objective To delineate the MRI features that distinguish neuromyelitis optica (NMO) from multiple sclerosis (MS). Methods We compared the distribution of the spinal cord lesions by analyzing 1) lesion area, 2) lesion density (by superimposing the lesions onto the standard sections of the cervical and thoracic cord with appropriate transparencies using computer software), and 3) T1-hypointensity in axial sections of MRI in NMO and MS. Results In NMO, 60–70% of the cervical and thoracic cord MRI lesions occupied more than half of the cord area and mainly involved the central gray matter in the acute stage. In the chronic stage, half or more of the lesions were localized at the central gray matter region. The lesion superimposition analysis also revealed much higher densities in the central gray matter region than in the peripheral white matter regions. Two patients with NMO had T1-hypointense lesions in the central region. In contrast, over 80% of the lesions in MS were localized in the lateral and posterior white matter regions of the cord in the chronic as well as acute stage. Lesion densities were much higher in the lateral and posterior white matter regions than in the central gray matter region. None of the lesions in MS were T1-hypointense. Conclusions These MRI findings strongly suggest a preferential involvement in the spinal central gray matter in NMO which is distinct from MS.     

The contribution of <Superscript>1</Superscript>H-magnetic resonance spectroscopy in defining the pathophysiology of multiple sclerosis

Proton magnetic resonance spectroscopy (¹H-MRS) is considered a suitable investigation technique for obtaining in vivo information on pathological changes in multiple sclerosis (MS) brain. The main betabolites identified are choline-containing compounds, creatine, N-acetylaspartate (NAA), lactate, mobile lipids, myo-inositol, glutamate and glutamine. Proton spectra may be acquired from localized volumes of interest on single MS lesions or from the entire brain by ¹H-MRS imaging.An increase of choline and lipids (markers of demyelination) and the presence of lactate (marker of acute inflammatory reaction) have been demonstrated in active Gd-enhancing MS plaques. A reduction of NAA (marker of neuronal or axonal damage) has been found in inactive MS lesions. The recent evidence of an early NAA decrease in active plaques and in normal appearing white matter suggests that axonal damage is an early event in the evolution of demyelinating lesions. The correlation between NAA decrease and clinical disability conforms that axonal damage has important functional consequences, and indicates that the prevention of irreversible axonal loss might be a major target for the design and the timing of therapeutical strategies.     

Localized proton magnetic resonance spectroscopy of a cerebellar tumor in a two-year-old child

Noninvasive localized proton magnetic resonance spectroscopy (MRS) was used for differential diagnosis of a focal brain lesion in a 2.5-year-old girl. The clinical signs were a mild head tilt and neck pain. Magnetic resonance imaging (MRI) revealed a lesion in the right hemisphere of the cerebellum, but its nature remained obscure. In this lesion quantitative determinations of cerebral metabolites by fully relaxed, short-echo-time proton MRS revealed markedly lowered N-acetylaspartate (NAA) and pronounced elevations of choline-containing compounds (Cho) and myo-inositol (Ins), whereas metabolite concentrations in cortical gray matter and white matter were within normal ranges. The metabolite pattern of the lesion indicated loss of vital neuroaxonal tissue (low NAA) and enhanced glial proliferation (high Cho and Ins), which, together with the MRI morphology, suggested a brain tumor. The diagnosis was established by neurosurgical exploration and total extirpation of the tumor. Histology confirmed an astrocytoma (WHO II). After 2 weeks' recovery the child was discharged with no neurological signs.     

Biochemical alterations in multiple sclerosis lesions and normal-appearing white matter detected by in vivo 31P and 1H spectroscopic imaging

The goals of the current study were threefold: first, to confirm previous single volume proton (¹H) magnetic resonance spectroscopy results of reduced N-acetyl aspartate (NAA, a putative marker of neurons) in multiple sclerosis (MS) white matter lesions using multiple volume ¹H magnetic resonance spectroscopic imaging (MRSI); second, to measure the phospholipid metabolites phosphomonoesters and phosphodiesters in such lesions using phosphorus (³¹P) MRSI; and third, to test the hypothesis that biochemical changes occur in the normal-appearing (on spin echo T2-weighted magnetic resonance images) white matter in patients with MS. Thirteen subjects with clinically definite MS were studied with both ¹H and ³¹P MRSI, and 19 controls were studied with either ¹H MRSI, ³¹P MRSI, or both. MS lesion, MS normal-appearing white matter, and region-matched control spectra from the centrum semiovale were analyzed. The major findings of this study were that in both white matter lesions and normal-appearing white matter in patients with MS, the metabolite ratio NAA/creatine and the total ³¹P peak integrals were significantly reduced compared with controls. In addition, in MS lesions NAA/choline and phosphodiesters/total ³¹P were significantly reduced compared with controls, and in MS normal-appearing white matter there was a trend for NAA/choline to be reduced compared with controls. In normal-appearing white matter in patients with MS, total creatine and phosphocreatine were significantly increased compared to controls, as detected with both ¹H (total creatine peak integrals) and ³¹P (phosphocreatine/total ³¹P) MRSI techniques. These results suggest reduced neuronal density and altered phospholipid metabolites in white matter lesions in patients with MS. Furthermore, the results suggest the presence of biochemical abnormalities not detected by standard spin echo magnetic resonance imaging in normal-appearing white matter in MS.     

Water diffusion is elevated in widespread regions of normal-appearing white matter in multiple sclerosis and correlates with diffusion in focal lesions.

Pathological changes in the normal-appearing white matter in multiple sclerosis are well recognised, but their relationship to pathology in focal lesions is not well understood. Magnetic resonance diffusion imaging is sensitive to abnormalities in the integrity, size and geometry of water spaces in brain tissue. This study investigated the anatomical distribution of normal-appearing white matter diffusion abnormalities and their relationship to diffusion in focal lesions in multiple sclerosis (MS). The average apparent diffusion coefficient (ADCav) was measured by three-axis echoplanar diffusion imaging in normal-appearing white matter regions and lesions throughout the brain in 40 patients, and in white matter in 14 matched controls. The correlation between the ADCav in normal-appearing white matter and lesions was determined. In controls and patients, diffusion was highest in the corpus callosum. Patients had a higher mean ADCav than controls in widespread regions including the corpus callosum, cerebellar, temporal and occipital normal-appearing white matter. Mean normal-appearing white matter ADCav correlated strongly with mean lesion ADCav (r = 0.67, P < 0.001). This study demonstrates that water diffusion is elevated in widespread areas of normal-appearing white matter in MS, and is correlated with diffusion in lesions. These findings suggest that the pathogenetic mechanisms causing tissue damage in lesions and normal-appearing white matter are at least partly linked.     

The blood-brain barrier in cortical multiple sclerosis lesions

The blood-brain barrier (BBB) is composed mainly of specialized endothelial cells characterized by the presence of intercellular tight junctions. Additionally, perivascular cells, astrocytes, and surrounding basement membranes determine BBB integrity. BBB disruption is an early phenomenon in the formation of new white matter multiple sclerosis (MS) lesions; however, knowledge of the extent of BBB changes in gray matter MS lesions is lacking. Here, we studied several markers for BBB integrity in well-characterized brain tissue of patients with MS. Plasma protein leakage was enhanced in white matter lesions compared with that in normal-appearing white matter, whereas plasma protein leakage was absent in gray matter lesions. White matter lesions showed irregular basement membranes and parenchymal depositions of collagen type IV, whereas purely gray matter lesions lacked basement membrane alterations. Similarly, we observed no evidence for astrogliosis and tight junction changes in cortical MS lesions. Although BBB dysfunction is a common feature of white matter MS lesions, cortical MS lesions lack markers for BBB disruption or astrogliosis. Our data may indicate that BBB breakdown is not a critical event in the formation of gray matter MS lesions.     

Proton magnetic resonance spectroscopy of the brain in dementia

Proton magnetic resonance spectroscopy (MRS) allows accurate and noninvasive biochemical assay of living tissues. In vivo measurements provided by MRS have greatly enhanced our understanding of the pathophysiology of dementia. Increases in choline and myo-inositol (markers of membrane turnover) have been demonstrated in several studies on patients with Alzheimer's disease (AD), suggesting the presence of a significant cellular membrane (and glial) pathology in this disorder. Large decreases in brain N-acetylaspartate (NAA) (a marker of neuroaxonal integrity) are commonly seen in AD as well as in other forms of dementia in cerebral gray and white matter, indicating the presence of significant axonal damage. Since greater NAA decreases have been demonstrated in brains of patients with clinically more severe disease, NAA could provide an index relevant to patients' clinical status. Brain metabolic changes can be independent of abnormalities detected by conventional magnetic resonance imaging (MRI), since proton MRS may show a normal metabolic pattern in patients with mild neurological impairment and severe MRI abnormalities. However, quantitative measurements of regional brain volumes can be useful in the diagnosis of dementia. Thus, proton MRS, alone or combined with new quantitative magnetic resonance techniques, can provide sensitive indices able to monitor disease progresson or effects of drug therapy.     

MRI quantification of gray and white matter damage in patients with early–onset multiple sclerosis

Background and objective Contrary to what happens in adult–onset multiple sclerosis (MS), in a previous preliminary magnetic resonance imaging (MRI) study we showed only subtle normal–appearing brain tissue changes in patients with earlyonset MS. Our objective was to evaluate the presence and extent of tissue damage in the brain normalappearing white matter (NAWM) and gray matter (GM) from a larger population of patients with earlyonset MS. Methods Using diffusion tensor (DT) and magnetization transfer (MT) MRI, we obtained DT and MT ratio (MTR) maps of the NAWM and GM from 23 patients with early–onset MS and 16 sex– and age–matched healthy volunteers. Results Compared with healthy volunteers, patients with early–onset MS had significantly increased average MD (p = 0.02) and FA peak height (p = 0.007) and decreased average FA (p <0.0001) of the NAWM.Brain dual–echo lesion load was significantly correlated with average FA (r = –0.48, p = 0.02) and with FA peak height (r = 0.45, p = 0.03) of the NAWM. No MTR and diffusion changes were detected in the GM. Conclusions This study confirms the paucity of the ‘occult’ brain tissue damage in patients with earlyonset MS. It also suggests that in these patients GM is spared by the disease process and that NAWM changes are likely to be secondary to Wallerian degeneration of fibers passing through macroscopic lesions.     

Weekly follow up of acute lesions in three early multiple sclerosis patients using MR spectroscopy and diffusion

Object

Pathophysiological mechanisms underlying multiple sclerosis (MS) lesion formation, including inflammation, demyelination/remyelination and axonal damage, and their temporal evolution are still not clearly understood. To this end, three acute white matter lesions were monitored using a weekly multimodal magnetic resonance (MR) protocol.

Proton magnetic resonance spectroscopy of systemic lupus erythematosus involving the central nervous system

We examined 13 patients with neurological manifestations of systemic lupus erythematosus (SLE) based on previous and/or current neurological or psychotic episodes by magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) together with psychiatric and cognitive assessment. MRI was abnormal in 7 patients, showing high signal lesions in the white matter and/or cerebral atrophy. Proton MRS centred on white matter lesions in 5 patients showed a reduction in theN-acetyl aspartate creatine ratio compared with normal appearing white matter in the SLE group and in 10 healthy controls. This pattern of abnormality does not allow differentiation of SLE lesions from the chronic plaques occurring in multiple sclerosis. There was a very high incidence of current psychiatric morbidity in the SLE group, namely in 12 of the 13 patients. There was no correlation between the presence of current psychiatric involvement and/or cognitive dysfunction and abnormalities detected with MRI or MRS.     

<Superscript>1</Superscript>H MR spectroscopy of gray and white matter in carbon monoxide poisoning

Carbon monoxide (CO) intoxication leads to acute and chronic neurological deficits, but little is known about the specific noxious mechanisms. ¹H magnetic resonance spectroscopy (MRS) may allow insight into the pathophysiology of CO poisoning by monitoring neurochemical disturbances, yet only limited information is available to date on the use of this protocol in determining the neurological effects of CO poisoning. To further examine the short-term and long-term effects of CO on the central nervous system, we have studied seven patients with CO poisoning assessed by gray and white matter MRS, magnetic resonance imaging (MRI) and neuropsychological testing. Five patients suffered from acute high-dose CO intoxication and were in coma for 1–6 days. In these patients, MRI revealed hyperintensities of the white matter and globus pallidus and also showed increased choline (Cho) and decreased N-acetyl aspartate (NAA) ratios to creatine (Cr), predominantly in the white matter. Lactate peaks were detected in two patients during the early phase of high-dose CO poisoning. Two patients with chronic low-dose CO exposure and without loss of consciousness had normal MRI and MRS scans. On follow-up. five of our seven patients had long-lasting intellectual impairment, including one individual with low-dose CO exposure. The MRS results showed persisting biochemical alterations despite the MRI scan showing normalization of morphological changes. In conclusion, the MRS was normal in patients suffering from chronic low-dose CO exposure; in contrast, patients with high-dose exposure showed abnormal gray and white matter levels of NAA/Cr, Cho/Cr and lactate, as detected by ¹H MRS, suggesting disturbances of neuronal function, membrane metabolism and anaerobic energy metabolism, respectively. Early increases in Cho/Cr and decreases of NAA/Cr may be related to a poor long-term outcome, but confirmation by future studies is needed.     

A study of the mechanisms of normal-appearing white matter damage in multiple sclerosis using diffusion tensor imaging

Diffusion tensor imaging (DTI) investigates brain tissue microstructure in vivo. In multiple sclerosis (MS) Wallerian degeneration of axons traversing focal lesions is a potential mechanism of damage in normal-appearing white matter. In vivo evidence for this hypothesis is limited. The present study investigated the relationship between DTI-derived indices in the normal-appearing corpus callosum (CC) and the lesion loads (LLs) in connected cerebral regions. DTI was performed in 39 MS patients and in 21 age-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) were estimated in the genu, body and splenium of CC. Patients showed lower FA and higher MD in the CC than controls and both correlated with the total LL (r = −0.56 and r = 0.54, p < 0.0001). The LL of individual cerebral lobes correlated with both FA and MD in the corresponding callosal regions, with the body showing the strongest correlations with frontal and parietal LL (p < 0.0001). The strong correlations between DTI indices in the CC and the extent of lesions in connected brain regions support the hypothesis that Wallerian degeneration of axons transected by remote, but connected focal lesions, is an important pathogenic mechanism of damage in MS. Received: 16 July 2002, Received in revised form: 8 October 2002, Accepted: 14 October 2002 Correspondence to Prof. A. J. Thompson