Arlene Lawton

Torpedoes in Parkinson's disease, Alzheimer's disease, essential tremor, and control brains†‡

Purkinje cell axonal swellings (“torpedoes”), described in several cerebellar disorders as well as essential tremor (ET), have not been quantified in common neurodegenerative conditions. The aim of this study was to quantify torpedoes Parkinsons disease (PD) and Alzheimers disease (AD) compared with ET and control brains. Brains included 40 ET cases (34 cerebellar ET, 6 Lewy body variant of ET) and age‐matched comparison brains (21 AD, 14 PD/diffuse Lewy body disease, 25 controls). Torpedoes were counted in 20 × 25 mm cerebellar cortical sections stained with Luxol Fast Blue/Hematoxylin and Eosin. The median number of torpedoes in cerebellar ET (12) was 12× higher than that of controls (1) and nearly 2.5× higher than in AD (5) or PD/DLBD (5) (all P ≤ 0.005). Furthermore, in a logistic regression model that adjusted for age and Alzheimers‐type changes, each torpedo more than doubled the odds of having cerebellar ET (Odds ratiocerebellar ET vs. control = 2.57, P = 0.006), indicating that the association between increased torpedoes and cerebellar ET was independent of these Alzheimers‐type changes. Although torpedoes are increased in AD and PD, as well as cerebellar ET, the magnitude of increase in cerebellar ET is greater, and cannot be accounted for by concomitant AD or PD pathology.

Rest tremor in advanced essential tremor: a post-mortem study of nine cases

Background Rest tremor may occur in as many as 30% of essential tremor (ET) patients. It is not clear whether this tremor is a sentinel marker for brainstem Lewy body pathology. Here we report the clinical and post-mortem findings of nine ET cases with upper-extremity rest tremor in the absence of other parkinsonian features. Methods All brains had a complete neuropathological assessment. Tissue sections from the brainstem and basal ganglia were immunostained with α-synuclein antibody. Results All cases had longstanding ET (median duration=42 years) with moderate to severe arm tremor. Rest tremor involved both arms in seven (77.8%) cases and one arm in two cases. The rest tremor score was correlated with the total action tremor score (r=0.69, p=0.04). The number of torpedoes was elevated, and Purkinje cells, reduced. Post-mortem changes in the substantia nigra pars compacta (SNc), caudate, putamen and globus pallidum were minimal, and neither Lewy bodies nor Lewy neurites were evident. Conclusions In nine ET brains with upper-extremity rest tremor, neither Lewy body-containing neurons nor Lewy neurites were found on α-synuclein immunostained sections, and other pathological changes in the basal ganglia were minimal. These data support the notion that isolated rest tremor in longstanding ET is not the expression of underlying Lewy body pathology in the SNc.

Older Onset Essential Tremor: More Rapid Progression and More Degenerative Pathology

There are few data on rate of progression in essential tremor (ET). To quantify the rate of tremor progression in a cross‐sectional sample of 348 ET cases in an epidemiological study; characterize the relationship between age of tremor onset and rate of tremor progression in that sample; and characterize the relationship between age of tremor onset, rate of tremor progression, and severity of underlying brain changes in 9 cases from a brain repository. Rate of tremor progression was defined as tremor severity ÷ duration. The degeneration index = number of torpedoes per section ÷ Purkinje cell linear density. In the epidemiological study, older age of tremor onset was associated with faster rate of tremor progression (P < 0.001). In the brain repository, older age of tremor onset was associated with higher degeneration index (P = 0.037), and higher degeneration index was associated with faster rate of tremor progression (P = 0.018). In a large clinical sample, older age of onset was associated with more rapid tremor progression. In a brain bank, older age of onset was associated with more degenerative pathology in the cerebellum. As in several neurodegenerative disorders, in older onset cases, it is possible that the disease advances more rapidly.

The Role of Routine Laboratory Studies and Neuroimaging in the Diagnosis of Dementia: A Clinicopathological Study

OBJECTIVE: To determine the neuropathological diagnoses of longitudinally followed patients with potentially reversible causes of dementia and to examine the results of the “dementia work‐up,” especially neuroimaging, by comparison with the pathological diagnosis.

Soluble amyloid beta levels are elevated in the white matter of Alzheimer’s patients, independent of cortical plaque severity

Alzheimer’s disease (AD) is the most common neurodegenerative disease and the leading cause of dementia. In addition to grey matter pathology, white matter changes are now recognized as an important pathological feature in the emergence of the disease. Despite growing recognition of the importance of white matter abnormalities in the pathogenesis of AD, the causes of white matter degeneration are still unknown. While multiple studies propose Wallerian-like degeneration as the source of white matter change, others suggest that primary white matter pathology may be due, at least in part, to other mechanisms, including local effects of toxic Aβ peptides. In the current study, we investigated levels of soluble amyloid-beta (Aβ) in white matter of AD patients (n=12) compared with controls (n=10). Fresh frozen white matter samples were obtained from anterior (Brodmann area 9) and posterior (Brodmann area 1, 2 and 3) areas of post-mortem AD and control brains. ELISA was used to examine levels of soluble Aβ -42 and Aβ -40. Total cortical neuritic plaque severity rating was derived from individual ratings in the following areas of cortex: mid-frontal, superior temporal, pre-central, inferior parietal, hippocampus (CA1), subiculum, entorhinal cortex, transentorhinal cortex, inferior temporal, amygdala and basal forebrain. Compared with controls, AD samples had higher white matter levels of both soluble Aβ -42 and Aβ -40. While no regional white matter differences were found in Aβ -40, Aβ -42 levels were higher in anterior regions than in posterior regions across both groups. After statistically controlling for total cortical neuritic plaque severity, differences in both soluble Aβ -42 and Aβ -40 between the groups remained, suggesting that white matter Aβ peptides accumulate independent of overall grey matter fibrillar amyloid pathology and are not simply a reflection of overall amyloid burden. These results shed light on one potential mechanism through which white matter degeneration may occur in AD. Given that white matter degeneration may be an early marker of disease, preceding grey matter atrophy, understanding the mechanisms and risk factors that may lead to white matter loss could help to identify those at high risk and to intervene earlier in the pathogenic process.

Essential tremor with ubiquitinated Purkinje cell intranuclear inclusions

Despite intensive efforts to collect essential tremor (ET) brains, the number of postmortem examinations remains limited, and the range of pathological changes associated with ET has not been fully catalogued [3]. We report an ET patient who had a pattern of pathological change not previously reported in ET or another neurological disease. The patient had childhood-onset, familial, kinetic arm tremor that progressively worsened during adulthood. She experienced difficulty eating and writing and developed head tremor. The clinical diagnosis was ET (see Supplementary online materials). She died at age 79 of myocardial infarction. The brain was removed and placed on ice 6 h after death. At the New York Brain Bank, Columbia University, external examination (J.P.G.V.) revealed mild (1+) frontal and parietal atrophy and two small, bilateral striatal infarcts. As described [3], blocks were taken from standardized brain regions and embedded in paraffin; 7-μm-thick sections were stained with Luxol fast blue counter-stained with hematoxylin–eosin (LH&E). Additional sections from selected blocks were stained with modified Bielschowsky silver stain or antibodies directed against alpha-synuclein, beta-amyloid, hyperphosphorylated tau (AT8), glial fibrillary acidic protein (GFAP), ubiquitin, 1C2, and TDP-43. Torpedoes in one entire 20 × 25 mm LH&E-stained parasagittal cerebellar cortical section and another entire Bielschowsky-stained section were counted [3]. Bergmann cells were assessed (GFAP-immunostained section). In the cerebellum, there were abundant torpedoes [18 (LH&E) and 29 (Bielschowsky)] (Fig. 1a) and segmental loss of Purkinje cells (PCs) with Bergmann gliosis (Fig. 1b, c). The dentate nucleus was normal. Throughout the section, PCs contained one or two prominent ubiquitinated, nuclear inclusions that could clearly be distinguished from the nucleoli (Fig. 1d, e). These inclusions, observed in approximately 3% of PCs, were not observed in astrocytes, oligodendrocytes, or neurons aside from PCs. Ubiquitinated inclusions were not observed on sections of the medulla, pons, superior frontal cortex, hippocampal formation, entorhinal region, caudate, putamen, nucleus accumbens, or globus pallidum. In the substantia nigra, rare neurons contained Marinesco bodies. 1C2 immunoreactivity in the PC cytoplasm indicated the formation of polyglutamine aggregates (Fig. 1f). TDP-43 immunoreactivity was normal. Fig. 1 a Torpedo (green arrow) associated with a PC (blue arrow) (Bielschowsky, 200× magnification). b Bergmann gliosis (GFAP, 400× magnification). c PC (green arrow) with adjacent segmental loss of PCs and Bergmann gliosis (green circle) (LH&E, ... On LH&E- and alpha-synuclein-immunostained sections, no Lewy bodies or Lewy neurites were evident in the dorsal vagal nucleus, inferior olivary nucleus, locus ceruleus or substantia nigra. Argyrophilic neuronal tangles or AT8-labeled neurons and threads were present throughout the cerebral cortex, with the involvement greatest in the entorhinal cortex, parahippocampal and occipitotemporal gyri, and temporal pole. Up to 20 neuritic plaques/100× microscopic field were found in the motor cortex. In the hippocampal formation, up to 5 neuritic plaques/100× microscopic field were found in the Sommer sector and subiculum. The Braak and Braak [1] Alzheimers disease (AD) stage was VI. Postmortem testing of frozen brain tissue was negative for fragile X tremor ataxia syndrome (FXTAS) and spinocerebellar ataxia (SCA) 1, 2, 3 and 6. In recent postmortem studies, two subtypes of ET seem to have emerged [3]. The majority of ET brains have degenerative changes, including PC loss [3], in the cerebellum (i.e., “cerebellar ET”). A smaller number of brains have Lewy bodies in the brainstem with relatively normal cerebella (i.e., “Lewy body variant of ET”) [3]. We now report what seems to be a third pattern of change, namely, PCs with ubiquitinated nuclear inclusions with cerebellar pathology. The pattern of changes observed in this ET brain is likely to be rare, as it occurred in only 1 in 46 ET brains prospectively collected at our brain bank to date. Nevertheless, the current case is important for several reasons. First, it again demonstrates the pathological heterogeneity of ET and, by implication, suggests that ET is either a family of diseases or a syndrome. Second, it is of particular interest that the nuclear inclusions in this case were confined to the cerebellum. As in cerebellar ET, the main form of ET, the localization of pathological changes is in the cerebellum and postmortem changes are not observed in other brain regions. This serves to further confirm the importance of the cerebellum as the anatomical localization of the pathological changes in most cases of ET. Finally, as with the other two subtypes of ET (cerebellar ET and Lewy body variant of ET), the changes are of a degenerative nature, thereby, further reinforcing the notion of this disease as neurodegenerative. The observation of ubiquitinated protein inclusions is one of the hallmarks of neurodegeneration. Ubiquitinated intranuclear inclusions are found in a variety of neurode-generative diseases including FXTAS, SCAs, and Huntingtons disease; however, in these disorders inclusions are rare or not found in the PCs, but present in widespread brain regions, and accompanied by marked additional changes on postmortem [2]. Our patient did not have FXTAS as the inclusions were limited to the PCs and genetic testing was negative. Furthermore, an ET-like phenotype is very rare in that disorder. Against a diagnosis of SCA is the clinical presentation (kinetic tremor rather than intention tremor, absence of other cerebellar signs), negative genetic test results, and postmortem findings (e.g., absence of: pontine atrophy or neuronal loss in inferior olivary nucleus or more complete loss of PCs). Our patient developed AD in the final year of life. AD patients do not have ubiquitinated intranuclear inclusions in the PCs or elsewhere, the exception being the Marinesco bodies within the scattered neurons of the substantia nigra pars compacta. In summary, this ET patient had a pattern of pathological change that has not been reported previously. This case further reinforces the notion that ET is likely to be a family of degenerative diseases whose pathology is usually centered in the cerebellum.

Essential tremor with ubiquitinated intranuclear inclusions and cerebellar degeneration.

Background: Essential tremor (ET), a progressive, age-associated disease, is one of the most common neurological disorders. Yet until recently, there had been few postmortem examinations so that the full range of pathological changes associated with this disease has not been catalogued. Objectives: We report a patient with ET who had a pattern of pathological change which to our knowledge has not previously been reported in ET or another neurological disease. Methods: Clinical-pathological case report. Results: The patient had adult-onset, non-familial, kinetic arm tremor that gradually worsened. Voice and head tremors were also present. The clinical diagnosis was ET. She died at age 102. On postmortem examination, there was severe segmental loss of Purkinje cells, Bergmann gliosis and numerous torpedoes in the cerebellum. The other outstanding change was the presence of neurons in the cerebral cortex and hippocampus that contained an ubiquitinated, nuclear inclusion. These inclusions were not detected in Luxol fast blue/hematoxylin and eosin-stained sections. Conclusions: This ET patient had a pattern of pathological change that has not been reported previously. This case further reinforces the view that ET is likely to be a heterogeneous family of degenerative diseases whose underlying pathological anatomy involves the cerebellum.