Cordelia Erickson-Davis

Falls and injuries resulting from falls among patients with Parkinson's disease and other parkinsonian syndromes

We sought to ascertain frequency, type, risk factors of falling, and resulting injuries among parkinsonian patients. A survey was mailed to all patients treated at our center between 1/1/2000 and 4/30/2002 (N = 1,417). Information was collected on falls within the past 2 years, related injuries, and use of health care services. A total of 1,131 responses (response rate, 79.8%) were received. After the exclusion of nonparkinsonian disorders, statistics for the remaining group (n = 1,092) and predictive statistics for those diagnosed before 1/1/2000 (n = 1,013) were calculated. Outcomes included falls, fractures, injuries, surgery, and related use of health care services. Explanatory variables included sex, age, age at diagnosis, disease duration, atypical parkinsonism, and dementia. Most patients (55.9%) were men; 12.2% had atypical parkinsonism; 12.5% had dementia; median age was 74.7 years; median disease duration was 7 years; 55.9% had at least one fall in the past 2 years; 65.0% of them sustained an injury; 33.0% sustained a fracture; 75.5% of injuries required health care services; 40.6% of fractures required surgery. Older age, atypical parkinsonism, longer disease duration, and dementia were risk factors for falling; female sex and older age were predictors of fractures. Need for health care services after an injury was higher among older patients. Further prospective studies will be necessary to elucidate the specific prognostic outcomes of injuries due to falls among parkinsonian patients, and the impact of these injuries on disease progression and quality of life.

Increased number of heterotopic Purkinje cells in essential tremor

Objective Recent postmortem studies reveal degenerative changes, including Purkinje cell (PC) loss, in most brains from individuals with essential tremor (ET). Heterotopic PCs (HPCs) (ie, PC bodies displaced into the molecular layer) may be found in neurodegenerative diseases with PC loss. HPCs have been observed in ET but no quantitative case control analysis has been performed. Methods HPCs were counted in 35 ET brains and 32 control brains (including 21 non-diseased controls and 11 diseased controls with progressive supranuclear palsy (PSP)) using a standard 20×25 mm cerebellar cortical section stained with a modified Bielscholwsky method. Results The median number of HPCs per section was three times higher in 35 ET cases (median 3, mean±SD 3.8±3.6, range 0–14) versus 32 controls (median 1, mean±SD 1.6±1.7, range 0–5) (p=0.007). The number of HPCs was similarly low in the 21 non-diseased controls and 12 PSP brains (median 1 in each group) (p=0.04 and p=0.01 compared with ET). In ET, the number of HPCs was inversely related to the number of PCs (Spearmans rho −0.36, p=0.038) (ie, cases with more HPCs had fewer PCs). Conclusion PC heterotopia, which occurs in cerebellar degenerative disorders, is also a feature of ET. These findings further contribute to our understanding of the postmortem changes in this common neurological disease.

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.

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.

Structural Study of Purkinje Cell Axonal Torpedoes in Essential Tremor

Essential tremor (ET) is one of the most common neurological diseases. A basic understanding of its neuropathology is now emerging. Aside from Purkinje cell loss, a prominent finding is an abundance of torpedoes (rounded swellings of Purkinje cell axons). Such swellings often result from the mis-accumulation of cell constituents. Identifying the basic nature of these accumulations is an important step in understanding the underlying disease process. Torpedoes, only recently identified in ET, have not yet been characterized ultrastructurally. Light and electron microscopy were used to characterize the structural constituents of torpedoes in ET. Formalin-fixed cerebellar cortical tissue from four prospectively collected ET brains was sectioned and immunostained with a monoclonal phosphorylated neurofilament antibody (SMI-31, Covance, Emeryville, CA). Using additional sections from three ET brains, torpedoes were assessed using electron microscopy. Immunoreactivity for phosphorylated neurofilament protein revealed clear labeling of torpedoes in each case. Torpedoes were strongly immunoreactive; in many instances, two or more torpedoes were noted in close proximity to one another. On electron microscopy, torpedoes were packed with randomly arranged 10-12nm neurofilaments. Mitochondria and smooth endoplasmic reticulum were abundant as well, particularly at the periphery of the torpedo. We demonstrated that the torpedoes in ET represent the mis-accumulation of disorganized neurofilaments and other organelles. It is not known where in the pathogenic cascade these accumulations occur (i.e., whether these accumulations are the primary event or a secondary/downstream event) and this deserves further study.

Assessing Cognition in Parkinson Disease: Use of the Cognitive Linguistic Quick Test

Objective: To evaluate the Cognitive Linguistic Quick Test (CLQT) as a cognitive screening tool in Parkinson disease (PD). Methods: A total of 93 patients with PD were evaluated with the Mini-Mental State Examination (MMSE) and the CLQT. The CLQT provides separate ratings for 5 cognitive domains. Descriptive statistics, correlations between the tests, and diagnostic value for dementia were analyzed. Results: Cognitive Linguistic Quick Test correlated well with MMSE. Diagnostic values for dementia were similar for the 2 instruments. Unlike the MMSE, the CLQT also provided domain-specific information on cognitive deficits. Cognitive domains were differentially affected between and within the demented and nondemented patient groups with PD: memory was the weakest domain in the demented group and attention in the nondemented. Conclusions: The CLQT is a valuable instrument in assessing cognitive dysfunction in PD. The CLQT is superior to the MMSE as it also provides cognitive domain-specific information.

Ethical Concerns Regarding Commercialization of Deep Brain Stimulation for Obsessive Compulsive Disorder

The United States Food and Drug Administrations recent approval of the commercial use of Deep Brain Stimulation (DBS) as a treatment for Obsessive Compulsive Disorder (OCD) will be discussed within the context of the existing USA regulatory framework. The purpose will be to illustrate the current lack of regulation and oversight of the DBS market, which has resulted in the violation of basic ethical norms. The discussion will focus on: 1) the lack of available evidence on procedural safety and efficacy, 2) the numerous conflicts of interest held by research investigators, and 3) the ambiguity of both aforementioned categories due to an inherent lack of transparency in the research. It is argued that in order to address these issues, ethical analyses of DBS for psychiatric disorders must include the role of the industry forces that have become the primary impetus for this research. As such, DBS for OCD serves as an important case example in studies of neurotechnology and innovative surgery.

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.

Purkinje cell axonal torpedoes are unrelated to advanced aging and likely reflect cerebellar injury

Torpedoes, swellings of the proximal Purkinje cell axon, are thought to represent a cellular response to injury [3]. They may occur in a variety of cerebellar disorders [7]. Most recently, their numbers were noted to be six-times higher in essential tremor (ET) than control brains [4]. Torpedoes are also often viewed as a cumulative phenomenon associated with advanced aging [3,4], yet there are surprisingly few supporting data. We quantified torpedoes in normal human cerebella spanning a considerable age range to assess whether torpedoes are a cumulative phenomenon of aging. These data help place the relative abundance of torpedoes in ET in context. Control brains at the New York Brain Bank, Columbia University Medical Center (CUMC) had been controls in the Alzheimer’s Disease Research Center or non-neurologic patients at CUMC. Each had a complete neuropathologic assessment [4] including Braak AD stage [2] and CERAD [5] for Alzheimer’s tangle and plaque pathologies. As documented [4], a standard 3 × 20 × 25 mm parasagittal tissue block was harvested from each neocerebellum (N = 48) and immersion-fixed in 10% buffered formalin. Paraffin sections (7 μm thick) were stained with Luxol Fast Blue counterstained with Hematoxylin and Eosin (LH&E) [4]. Torpedoes (Figure 1) in one entire LH&E section were counted blinded to age. Purkinje cells in five randomly-selected 100x LH&E stained fields of the standard cerebellar section were counted and the mean reported. In 32 brains, a second set of sections from the same blocks were used as replicate data. Figure 1 Control cerebellar tissue showing a torpedo (arrow). LH&E 400x magnification. Non-parametric tests (Spearman’s r, Mann Whitney test, Kruskal Wallis test) were used. Because of zero values (0 torpedoes), in linear regression analyses, log10(torpedoes +1) was the dependent variable and age, the independent variable. Age at death ranged from 6–93 years. Mean±SD (median, range) number of torpedoes = 1.8±2.1 (1, 0–11)(Table). Table Clinical characteristics/postmortem features (48 controls) Number of torpedoes was correlated with age at death (r = 0.35, p = 0.02, Table), but not when the brains in the youngest age quartile (≤36 years) were excluded (i.e., in brains with age of death ranging from 37–93 years, r = −0.03, p = 0.85). While (mean±SD, median) number of torpedoes was low in brains in the youngest quartile (quartile 1, ≤36 years, 0.5±0.9, 0), it did not differ among brains in the remaining 3 quartiles: quartile 2 (37–63 years) 1.9±1.6, 1.5; quartile 3 (64–80 years) 2.9±3.2, 2; quartile 4 (≥81 years) 2.0±1.4, 1.5 (for comparison of quartiles 2–4, p = 0.88)(Figure 2). Figure 2 Number of torpedoes (Y axis) by age at death quartile (X axis). In a linear regression analysis, log-transformed number of torpedoes was associated with age (beta 0.004, p = 0.01) but not in a fully adjusted model including gender, race, postmortem interval (PMI), brain weight, number of Purkinje cells, CERAD plaque score and Braak stage(beta for age −0.003, p = 0.71). In unadjusted and adjusted models restricted to age quartiles 2–4, beta = −0.001, p = 0.70 and beta = −0.003 and p = 0.69, respectively. The results of replicate analyses on 32 brains were similar to our primary analyses. The number of torpedoes was lowest in the youngest age quartile (0.2±0.4, 0) but was similar in the remaining three age quartiles (quartile 2: 1.8±1.9, 2; quartile 3: 3.2±2.3, 3.5; quartile 4: 2.7±2.4, 2.5)(for comparison of quartiles 2–4, p = 0.82). We examined control brains spanning a wide age range. Torpedoes were rare in the first four decades of life, but thereafter, there was no aging-associated increase. Torpedoes have been commented on as rare incidental findings in normal human control brains, although it has not been demonstrated that they are more abundant as a function of advanced age. One study [3] examined 32 axons in three normal individuals (ages 64, 70, 86). The 86 year old had two torpedoes. In a study of two normal mouse strains (age 8 days - 32 months)[1], <0.1% of Purkinje cells had torpedoes at 6 months; this increased linearly to 13.7% by age 32 months [1]. However, in a study of other normal mice strains, torpedoes were absent, suggesting that torpedoes are not a “simple aging phenomena” [6]. The lack of an association here between these lesions and advanced aging suggests that the abundance of these lesions in ET is a marker of cerebellar injury and not merely representative of accelerated aging.